new seriesnew series offical publication of: hong kong college of paediatricians hong kong...

New Series

Offical Publication of:Hong Kong College of PaediatriciansHong Kong Paediatric Society

HK J Paediatr (New Series) Vol 26. No. 1 January 2021

ISSN 2309-5393 (online)ISSN 1013-9923 (print)

Indexed in EMBASE/Excerpta Medica,Science Citation Index Expanded (SCIE) and ScopusFull text online at www.hkjpaed.org

EditorialBringing Systems Medicine to Paediatrics 1Cheung

Original ArticlesDiagnostic Value of Procalcitonin and C-Reactive 3Protein Level for Predicting Appendiceal Perforationin ChildrenFeng, Lai, Lou, Liu

The Diagnostic Value of Serum Amyloid A inEarly-Onset Neonatal Sepsis in Premature Infants 8Dorum, Özkan, Çakir, Köksal, Gözal, Çelebi,Hacimustafo lu

The Impact of Paediatric Neuromuscular Disorders 14on Parents' Health-Related Quality of Life andFamily FunctioningHo, Liang, Ip, Zhi, Wong, Chan

Does Subclinical Hypothyroidism Affect Lipid and 21Epicardial Fat Tissue Thickness in Children?Unal, Akin, Yildirim, Türe, Balik, Ta ,P i r in ç ç i o lu, Haspolat

Case ReportsMultilocus Inherited Neoplasia Alleles Syndrome:Case Report of Two Cases 27Ho, Lo, Luk

A New Case - Heterozygote PACS1 Mutation in 31a Patient with Schuurs-Hoeijmakers Syndromeand a Left Duplex Kidney: Case ReportDilber, Arslan Acar, Cebi, Cansu

Safety and Effectiveness of Herbal Medicine 34Administered from the Early Neonatal Period inTwo Neonates with Congenital Cystic LymphaticMalformationsHashimoto

Restless Leg Syndrome in a Child and an Adolescent 38with Excellent Responses to Iron ReplacementTherapyHoo, Lau, Ko

Contemporary Practice in PaediatricsManagement of Atopic Dermatitis in Children: 422020 Review by the Guidelines DevelopmentPanel of Hong Kong College of PaediatriciansLeung, Cheng, Chan, Chow, Chow, Hon, Ho,Lam, Luk, Ng, Sugunan

Clinical QuizWhat is the Diagnosis? 58Cheng, Lo, Luk

MCQs 59

Announcement 61

HONG KONG JOURNAL OF PAEDIATRICS

Medcom Limited

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HK J Paediatr (new series) 2021;26:1-2

Hong Kong Journal of Paediatrics (New Series)

An Official Publication ofHong Kong College of Paediatricians &Hong Kong Paediatric Societyc/o Hong Kong College of Paediatricians, Room 801,Hong Kong Academy of Medicine Jockey Club Building,99 Wong Chuk Hang Road, Aberdeen,Hong Kong.

Editorial Board

Chief EditorCHEUNG Yiu Fai

Associate EditorsHON Kam Lun IP Patrick

Honorary SecretaryFUNG Cheuk Wing

MembersBUT Wan Man CHAN Chi Fung CHAO Sih Yin FUNG Po Gee KWAN Yat Wah KWONG Ling LAM Hung San LEE Mun Yau LEE So Lun LEUNG SY LIU Sze Wai LO Fai Man LUK Chi Kong WONG Hiu Lei YEUNG Wai Lan

Honorary Advisors to the EditorialBoardAndrew BUSH, United KingdomDon M. ROBERTON, AustraliaDavid K. STEVENSON, USAGUI Yong-Hao, China

Business ManagerTSOI Nai Shun

PublisherHong Kong Journal of Paediatrics is publishedby Medcom Ltd, Flat E8, 10/F, Ka Ming Court,688-690 Castle Peak Road, Kowloon, Hong KongSAR. Tel: (852) 2578 3833, Fax: (852) 2578 3929,Email: [email protected]

Indexed in EMBASE/Excerpta Medica, ScienceCitation Index Expanded (SCIE) and Scopus

Website: www.hkjpaed.org

ISSN 2309-5393 (online)ISSN 1013-9923 (print)

Editorial

"On ne voit bien qu'avec le coeur, l'essentiel est invisible pour les yeux",wrote Antoine de Saint-Exupéry in Le Petit Prince. It is with your heart that youfeel essentials that are invisible to your eyes. Eyes of reductionists focus onpreconceived matters of consequence. Sir William Osler said, "The good physiciantreats the disease, the great physician treats the patient who has the disease."Diagnosis precedes treatment. Are we then just diagnosing disease, or shouldwe be trying to understand and diagnose perturbation of the patient's healthmilieu that results in the disease?

In this issue of the Journal, two articles explored the value of serum biomarkersin diagnosing and predicting occurrence of childhood illnesses. Feng et alevaluated the value of procalcitonin and C-reactive protein as predictors ofappendiceal perforation in children with acute appenditis.1 They found thatprocalcitonin has the highest sensitivity and specificity in predicting occurrenceof this complication in 201 children with a mean age of 7.6 years, as compared withthe use of C-reactive protein. In another study, Dorum et al evaluated the diagnosticvalue of serum amyloid A in early-onset neonatal sepsis in preterm infants born24 to 36 weeks of gestation.2 They found that serum levels of amyloid A, ascompared to C-reactive protein and procalcitonin levels on admission, at 24 hours,and at 48 hours, have the greatest area under the curve by receiving operatingcurve analysis for diagnosing early-onset neonatal sepsis. The aforementionedstudies explored the use of circulating biomarkers known to be associated withthe body inflammatory response for diagnostic purposes. Blood delivers oxygenand nutrient to different organs, removes waste from body tissues, and carries inthe circulation information on how the body reacts to different diseasedconditions. Hence, circulating biomarkers of inflammation, albeit non-specific forthe underlying disease condition or unrevealing of the underlying pathogenesis,have been commonly used to aid the diagnosis of infective and inflammatoryconditions in children.

Novel approaches that utilise cutting edge technologies are increasingly usedto identify new biomarkers, which may be involved in the pathogenesis, inpaediatric conditions. As an example, recent studies in patients with Kawasakidisease aimed to analyse the serum proteome to identify candidate proteinmarkers that may help in diagnosing and understanding the pathogenesis ofKawasaki disease. Kimura et al used mass spectrometry-based proteomicsanalysis and identified differential expression of about 1800 proteins duringthe acute and recovery phases of the illness.3 Of these, three proteins werefound to be higher during the acute phase of the illness and may facilitate diagnosisof Kawasaki disease. Lech et al performed more extensive molecular profilingwith mass spectrometry-based shotgun proteomics, transcriptomics, andglycomics in paediatric and adult patients with Kawasaki disease.4 Theseinvestigators found that complex patterns of biomarkers of inflammation andcell trafficking can persist long after the acute phase of Kawasaki disease. Thesestudies represent endeavours of the paediatric community to study disease

Bringing Systems Medicineto Paediatrics

2 Bringing Systems Medicine to Paediatrics

conditions using the multi-omics approach to understandperturbations and to unveil more specific and noveldiagnostic markers in childhood conditions from theperspective of the whole body system.

A fundamental concept of systems medicine is to viewthe human body as a network of networks.5-7 Each level ofbiological complexity, from genome to phenome, from cellsto organ, and from molecules to individuals, can beconceptualised and modeled as networks with specificcomponents and interactions among these variousnetworks.5 This holistic perspective of a network ofnetworks is in sharp contrast with the reductionistic view ofa handful of pathways to explain causal pathophysiologicalrelationships between the aetiologic factors and diseaseoccurrence. From the perspective of systems medicine, it isperhaps not difficult to understand the disagreement amongdifferent studies of usefulness of biomarkers in diagnosingspecific conditions and the difficulties of translating thebiomarker assay for clinical use. In essence, the non-linearphysiological responses to internal health milieu and externalstimuli renders interpretation of the biological andpathophysiological variations of circulating biomarkersdifficult. It is intuitive, therefore, to design studies that takeinto account of the complexity and variability of humanphysiology, which would entail the collection and analysesof multi-dimensional datasets. The pioneering wellness studyof 108 individuals using personal, dense, dynamic data (pD3)clouds has clearly demonstrated the feasibility of building adataset that can be mined for novel biological and medicaldiscoveries.8 In this project, personal data including wholegenome sequences, proteomes, metabolomes, gutmicrobiomes, and clinical laboratory results were collectedover a nine-month period. Importantly, integration of thedata generated 3470 statistically significant cross-sectionalcorrelations. The correlation network had revealedcommunities of related analytes associated with physiologyand disease and that the connectivity further enabledidentification of known and candidate biomarkers.

Generation of pD3 clouds of children in health and

disease is yet to be materialised. Nonetheless, largeamounts of paediatric data that provide information onprenatal well-being, postnatal growth, neurodevelopmentalmilestones, childhood illnesses, hospitalisations, use ofmedications, vaccination, and lifestyle-related informationare continuously collected, albeit residing in differentdatabase. How to harness the power of these healthinformation, how to systemically collect the multi-omicsdataset, and how to generate bioinformatics and big dataplatforms for their integrated analysis are challenges thatneed to be solved to bring system medicines to paediatrics.

YF CHEUNG

Chief Editor

References

1. Feng S, Lai XH, Lou Y, Liu W. Diagnostic value of procalcitoninand C-reactive protein level for predicting appendiceal perforationin children. HK J Paediatr (new series) 2021;26:3-7.

2. Dorum BA, Özkan H , Çakir SÇ, et al. The diagnostic value ofserum amyloid A in early-onset neonatal sepsis in premature infants.HK J Paediatr (new series) 2021;26:8-13.

3. Kimura Y, Yanagimachi M, Ino Y, et al. Identification of candidatediagnostic serum biomarkers for Kawasaki disease usingproteomic analysis. Sci Rep 2017;7:43732.

4. Lech M, Guess J, Duffner J, et al. Circulating markers ofinflammation persist in children and adults with giant aneurysmsafter Kawasaki disease. Circ Genom Precis Med 2019;12:e002433.

5. Trachana K, Bargaje R, Glusman G, Price ND, Huang S, HoodLE. Taking systems medicine to heart. Circ Res 2018;122:1276-89.

6. Comte B, Baumbach J, Benis A, et al. Network and systemsmedicine: position paper of the European Collaboration onScience and Technology Action on Open Multiscale SystemsMedicine. Netw Syst Med 2020;3:67-90.

7. Gustafsson M, Nestor CE, Zhang H, et al. Modules, networksand systems medicine for understanding disease and aidingdiagnosis. Genome Med 2014;6:82.

8. Price ND, Magis AT, Earls JC, et al. A wellness study of 108individuals using personal, dense, dynamic data clouds. NatBiotechnol 2017;35:747-56.


Diagnostic Value of Procalcitonin and C-Reactive Protein Levelfor Predicting Appendiceal Perforation in Children

S FENG, XH LAI, Y LOU, W LIU

Abstract Background: Acute appendicitis is one of the most common abdominal pain in children. Perforatedappendicitis can result in a variety of potentially serious complications. The aim of this study was toevaluate the value of procalcitonin (PCT) and C-reactive protein (CRP) as predictors of appendicealperforation in children. Materials and methods: We identified 201 children (75 female; 126 male, meanage, 7.6 years) with histologically confirmed acute appendicitis after appendectomy between January2015 and January 2018. Preoperative laboratory data such as CRP, white blood cell (WBC), PCT andpart of postoperative histologic results were analysed retrospectively. We also performed a multivariatelogistic regression model to determine patient's age and laboratory tests associated with perforatedappendicitis. Results: Mean plasma PCT level of all patients was 1.98 ng/mL (5.73 SD; range, 0.02-64.77 ng/mL; median, 0.18 ng/mL). Children with appendiceal perforation had a mean PCT level of 6.26ng/mL (9.39 SD; range, 0.2-64.77 ng/mL; median, 3.10 ng/mL), which was significantly higher thanthose with nonperforated children (P=0.001). Mean CRP values were 60.24 mg/L (55.02 SD, range,1.0-260 mg/L; median, 44.0 mg/L) in all patients, whereas they were significantly higher in perforatedgroup (mean, 114.53 mg/L, 53.88 SD, range, 30-260 mg/L) compared with non-perforated children(P=0.001). Multivariate logistic analysis revealed that both PCT and CRP were associated withperforation (P=0.001). Area under the receiver operating characteristic curve of PCT for discriminatingacute perforated appendicitis from non-perforated groups was larger than that of WBC and CRP.Conclusions: Both PCT and CRP are useful markers, and PCT is better than CRP for the diagnosis ofperforated appendicitis in children.

Key words Appendiceal perforation; Children; C-reactive protein; Diagnosis; Procalcitonin

Department of Pediatric Surgery, Hangzhou Children'sHospital, Hangzhou 310015, China

S FENG MDY LOU MDW LIU MD

School of Biology & Food Science, Shangqiu NormalUniversity, Shangqiu, Henan Province, China

XH LAI MD, PhD

Correspondence to: Dr W LIUEmail: [email protected]

Received October 29, 2018

Original Article

Introduction

Acute appendicitis is one of the most commonabdominal pain in children.1 The diagnosis of acuteappendicitis in children is a challenge as many childrenwith acute appendicitis do not have typical clinicalmanifestation.2,3 Furthermore, younger children, especiallyinfants, usually cannot describe pain and many of them justhave some nonspecific signs such as irritability, anorexia andlethargy.4 The initial misdiagnosis rate in children is veryhigh, ranging from 28% to 57% for older children andnearly 100% for those two years or younger.5 The delay

Diagnostic Value of PCT and CRP in Appendiceal Perforation4

in the diagnosis of an acute appendicitis can result inincreased risk of perforation. The rate of perforatedappendicitis varies from 5% to 75% and can even reach100% for those who are less than one year of age.6

Perforated appendicitis can result in a variety of potentiallyserious complications such as bacterial peritonitis, smallbowel obstruction, and abdominal abscess formation. Thisleads to a longer hospital stay and higher mortality rate.7

Therefore, it is very important for pediatric surgeons toimprove preoperative diagnosis rate of perforatedappendicitis accurately. Several previous studies haveevaluated C-reactive protein (CRP), procalcitonin (PCT),and white blood count (WBC) for predicting the severityof acute appendicitis.8,9 In this study we performed aretrospective chart review of 201 children withhistologically confirmed acute appendicitis in whombiochemical markers were routinely tested before surgery.We expected to evaluate the role of CPR, PCT, and WBCin predicting an appendix perforation.

Materials and Methods

All children under 15 years old admitted betweenJanuary 2015 and January 2018 were screened in the study.Patients were included in the study if they hada p p e n d e c t o m i e s ( l a p a r o s c o p i c o r o p e n ) a n dhistopathological findings consistent with acuteappendicitis. However, patients were deemed ineligible ifthey had appendiceal abscess or under antibiotherapy in thestudy. The initial diagnosis was based on the patient'ssymptoms and abdominal examination and it was confirmedby pathological report after surgery in all of them. Thepreliminary diagnosis of appendiceal perforation was madeby the surgeon on the basis of macroscopy appearance andall cases that were identified as having a macroscopicperforation were sent for pathological confirmation. Aftera retrospective chart review, 201 consecutive patients wereenrolled in the study. Routine preoperative C-reactiveprotein, procalcitonin, and white blood count for patients

undergoing appendectomy were collected and analysised.The normal range of procalcitonin levels is between 0 and0.46 ng/ml. Normal value of WBC and CRP were definedas 4.0/nL to 12.0/nL and less than 8.0 mg/L, respectively.

Statistical Analysis

SPSS Version 20.0 was applied for statistical analysis.Mean values and SD were calculated for WBC, CRP, andPCT levels. The data distribution was assessed by theKolmogorov-Smirnov test. For normal distributed data,Student's t test was used to compare the perforated andnon-perforated groups. For non-normal data distribution,the Kruskal-Wallis test was used instead. A multivariatelogistic regression analysis was performed to identifyvariables that were associated with perforated appendicitis.The independent variables of interest were age, PCT, WBC,and CRP. In addition, calculation of sensitivity, specificity,negative predictive value, and positive predictive value ofPCT, WBC, and CRP as predictors for appendicealperforation was included in data analysis. Statisticalsignificance was set at the 5% level (2-sided).

Results

A total of 201 children (75 female; 126 male; medianage, 7.6±3.0 SD year; range, 2-15 years) with histologicallyconfirmed acute appendicitis were included in the study.The mean values of PCT, WBC, and CRP for these patientsare listed in Table 1. The mean PCT level of all patients inthe present study was 1.98 ng/mL (5.73 SD; range, 0.02-64.77 ng/mL; median, 0.18 ng/mL). The mean PCT levelfor patients in perforated children was 6.26 ng/mL(9.39SD; range, 0.2-64.77 ng/mL; median, 3.10 ng/mL), whichwas significantly higher when compared with the non-perforated ones (P=0.001). Of the potential relevantvariables (age, WBC, CRP, and PCT), logistic regressionanalysis indicated CRP and PCT had independent

Table 1 Details of laboratory values in perforated and non-perforated children in the present study

Group CRP (mg/L) WBC (x109) PCT (ng/ml)

Perforated children (58) 114.53±53.88 15.61± 6.20 6.26±9.39

Non-perforated children (143) 38.22±37.50 14.55±5.71 0.25±0.59

P value 0.001 0.354 0.001

CPR=C-reactive protein, WBC=white blood count, PCT=procalcitonin

Feng et al 5

association with increasing perforation rates (P=0.001;Table 2).

Receiver operating characteristic curve (ROC) analysisfor PCT, WBC, and CRP shown that PCT had the largestarea under receiver operating characteristic curve (0.97)compared with WBC (0.54) and CRP (0.89) (Figure 1).The optimal ratio of sensitivity (0.93) and specificity(0.93) was calculated when the PCT level was greater than0.49 ng/mL regarding perforated appendiceal (Table 3). Acutoff for PCT of greater than 0.46 ng/mL had 93%sensitivity and a negative predictive value of 93% forappendiceal perforation. Specificity of PCT for thepreoperative diagnosis of appendiceal perforation was thehighest (0.92) and PCT still had an acceptable sensitivityfor predicting appendiceal perforation compared withWBC and CRP. Details of sensitivity, specificity andpredictive values are listed in Table 4.

The mean value of WBC was 14.8/nL (5.8 SD; range,3.3-38.8/nL) whereas patients in perforated group had amean of 15.6/nL (6.2 SD; range, 4.7-38.8/nL) with no

Figure 1 Receiver operating characteristic curve analysis for PCT, WBC, and CRP showed

PCT had the largest area under receiver operating characteristic curve (0.97) compared with

WBC (0.54) and CRP (0.89).

Table 2 Multivariate analysis of age and laboratory tests inrelation to perforated appendix rates

Factor OR (95%CI) p

Age 0.99 (0.81-1.21) 0.92

CRP 1.02 (1.01-1.04) 0.001

PCT 3.20 (1.75-5.85) 0.001

WBC 0.95 (0.86-1.04) 0.27


Table 3 The highest sum of sensitivity and specificity for WBC,CRP and PCT

Laboratory value Sensitivity Specificity Serum level

WBC 0.44 0.71 15.38

CRP 0.89 0.75 55.0

PCT 0.93 0.93 0.49


Diagnostic Value of PCT and CRP in Appendiceal Perforation6

statistical difference compared with patients in the non-perforated group (P=0.354). Mean CRP values were60.24 mg/L (55.02 SD, range, 1.0-260 mg/L; median,44.0 mg/L) in all patients, whereas they were significantlyhigher in perforated group (mean, 114.53 mg/L, 53.88 SD,range, 30-260 mg/L) compared with non-perforatedchildren (P=0.001) (Table 1). ROC analysis shown thatthe highest sum of sensitivity and specificity for CRP was55.0 mg/L. A cutoff for CRP of greater than 8 mg/L had100% sensitivity and 25% specificity for appendicealperforation. The specificity were lower in predictingappendiceal perforation compared with PCT (Table 4).

Discussion

Acute appendicitis is a common cause of acute abdomenand requires surgical treatment, while delayed diagnosiscan lead to perforation. The reported overall perforatedrate of appendicitis is 18.3% and 34.0%, but this risesremarkably in children or older patients. Appendicealperforation is associated with plenty of postoperativecomplications and higher mortality compared toappendicitis without perforation.7 Appendectomy forperforated appendicitis is still a topic of debate becauseof the presence of severe inflammation and seriousadherence of the surrounding structures. Emergencysurgery is strongly recommended for non-perforatedappendicitis while nonsurgical treatment may have a lowercomplication rate for perforated appendicitis.10 Therefore,accurate preoperative diagnosis of a perforated appendicitisbecomes very important. Physical examination such asdiffuse peritonitis and board-like rigidity of the abdomenare helpful for the preoperative diagnosis of perforation,but the definitive diagnosis of perforated appendicitis stillrequires surgery and histological diagnosis. Althoughlaboratory testing such as WBC and CRP are useful makersfor diagnosing the appendicitis, their sensitively andspecificity in predicting appendiceal perforation are notwell studied.

Procalcitonin is constitutively secreted by the K cellsof the lungs and the C cells of the thyroid gland, and PCTlevel always increases with severity of infection inchildren.11,12 Unlike CRP and some other biomarkers, thePCT level does not raise with viral infection or sterileinflammation in patients.13 Therefore, PCT can be used asan important marker of bacterial infection, such as sepsis,wound infection and acute appendicitis. Several studieshave shown PCT was an excellent marker of severe bacterialinfection. For example, the level of plasma PCT issignificantly higher in the infection of renal parenchymathan lower urinary tract infection.14 Besides, because ofits high sensitivity and specificity, PCT has even beenapplied to predict the surgical wound infection after heartsurgery.15 Although PCT has a lower diagnostic value fordiagnosing acute appendicitis compared with other markerssuch as CRP or WBC,16-18 several studies have suggestedthat PCT was a useful marker for predicting complicatedappendicitis.18,19 Yu et al conducted a systematic review onthe diagnostic accuracy of PCT, CRP, and WBC from sevenstudies, which shown that PCT had the highest diagnosticvalue for complicated appendicitis.18 In a research madeby Kafetzis et al,19 PCT level >0.5 ng/ml was found to havea predictive value for the diagnosis of appendicealperforation or gangrene with a sensitivity of 73.4% and aspecificity of 94.6% in children. Our results were basicallyconsistent with those in that report.

In the present study, we assessed the diagnostic accuracyof PCT, WBC, and CRP for predicting appendicealperforation in children. Our study revealed that thepreoperative laboratory CRP and PCT parameters areuseful for predicting appendiceal perforation in thepediatric patients. The highest sum of sensitivity andspecificity for PCT was 0.49 ng/mL and a cutoff for PCTof greater than 0.46 ng/mL had 93% sensitivity and 92%specificity for appendiceal perforation. Using a cutoff forPCT of greater than 0.5 ng/mL, the results of the studymade by Kafetzis et al were basically consistent with uswith a sensitivity of 73.4% and a specificity of 94.6%.19

Logistic regression analysis results shown both CRP and

Table 4 Sensitivity, specificity, positive predictive value, and negative predictive value for WBC, CRP, and PCT

Laboratory value Sensitivity Specificity Positive predictive value Negative predictive value

WBC>12/nL 0.69 0.35 0.51 0.53

CRP>8 mg/L 1.00 0.25 0.57 1.00

PCT>0.46 ng/mL 0.93 0.92 0.92 0.93

WBC=white blood count, CPR=C-reactive protein, PCT=procalcitonin

Feng et al 7

PCT are significant markers of a perforated appendicitis.However, the highest sum of sensitivity and specificityfor CRP was significant higher than the normal value(55.0 vs 8.0 mg/L).

Our work had several limitations. Fistly, this study is aretrospective study, and surgeons were not blind to thelaboratory values before surgery. Secondly, it is hard toget the complete blood test results for each patient, whichreduced the number of patients available for our study.Thirdly, We did not analyse the histological results of thenon-perforated group and the definition of the stages ofappendicitis varies in the literature.20,21 Lastly, our studyhad difficulty in identifying the relationship between theblood tests and the subsequent complications such asperitonitis, abscesses, and/or intestinal obstruction.

Our study investigated the diagnostic accuracy of PCT,WBC, and CRP as promising predictive markers forappendiceal perforation in a group of 201 children. Weobserved that patients with appendiceal perforation havesignificantly higher PCT and CRP levels than patientswithout perforation. In addition, specificity and positivepredictive value of PCT were considerably higher comparedwith WBC or CRP. Although logistic regression analysisshown CRP were also associated with perforation withconsiderable sensitivity and specificity, the highest sumof sensitivity and specificity for it was significant higherthan the normal value compared with PCT. Therefore, ourstudy indicated that PCT was an independent predictor ofappendiceal perforation and it had the largest area underreceiver operating characteristic curve compared withWBC and CRP in predicting appendiceal perforation.

Compliance with Ethical Standards

The authors report no conflicts of interest in thiswork.

This article does not contain any studies with humanparticipants or animals performed by any of the authors.

References

1. Williams RF, Blakely ML, Fischer PE, et al. Diagnosing rupturedappendicitis preoperatively in pediatric patients. J Am Coll Surg2009;208:819-25.

2. Sivit CJ, Siegel MJ, Applegate KE, Newman KD. When appendicitisis suspected in children. Radiographics 2001;21:247-62.

3. Sivit CJ, Newman KD, Boenning DA, et al. Appendicitis: usefulnessof US in diagnosis in a pediatric population. Radiology 1992;185:549-52.

4. Kulik DM, Uleryk EM, Maguire JL. Does this child have

appendicitis? A systematic review of clinical prediction rules forchildren with acute abdominal pain. J Clin Epidemiol 2013;66:95-104.

5. Singh M, Kadian YS, Rattan KN, Jangra B. Complicated appendicitis:analysis of risk factors in children. Afr J Paediatr Surg 2014;11:109-13.

6. Aprahamian CJ, Barnhart DC, Bledsoe SE, Vaid Y, Harmon CM.Failure in the nonoperative management of pediatric rupturedappendicitis: predictors and consequences. J Pediatr Surg 2007;42:934-8.

7. Blomqvist PG, Andersson RE, Granath F, Lambe MP, EkbomAR. Mortality after appendectomy in sweden, 1987-1996. AnnSurg 2001;233:455-60.

8. Gavela T, Cabeza B, Serrano A, Casado-Flores J. C-reactive proteinand procalcitonin are predictors of the severity of acute appendicitisin children. Pediatr Emerg Care 2012;28:416-9.

9. Guraya SY, Al-Tuwaijri T A, Khairy G A, Murshid KR. Validity ofleukocyte count to predict the severity of acute appendicitis. SaudiMed J 2005;26:1945-7.

10. Henry MC, Gollin G, Islam S, et al. Matched analysis ofnonoperative management vs immediate appendectomy forperforated appendicitis. J Pediatr Surg 2007;42:19-23.

11. Brunkhorst FM, Heinz U, Forycki ZF. Kinetics of procalcitoninin iatrogenic sepsis. Intensive Care Med 1998;24:888-9.

12. Becker KL, Nylen ES, White JC, Muller B, Snider RH. Clinicalreview 167: Procalcitonin and the calcitonin gene family of peptidesin inflammation, infection, and sepsis: a journey from calcitoninback to its precursors. The Journal of Clinical Endocrinology &Metabolism, 2004;89:1512-25.

13. Assicot M, Bohuon C, Gendrel D, et al. High serum procalcitoninconcentrations in patients with sepsis and infection. Lancet 1993;341:515-8.

14. Benador N, Siegrist CA, Gendrel D, et al. Procalcitonin is a markerof severity of renal lesions in pyelonephritis. Pediatrics 1998;102:1422-5.

15. Jebali M A, Hausfater P, Abbes Z, et al. Assessment of the accuracyof procalcitonin to diagnose postoperative infection after cardiacsurgery. Anesthesiology 2007;107:232-8.

16. Sand M, Trullen XV, Bechara FG, Pala XF, Sand D, Landgrafe G,Mann B. A prospective bicenter study investigating the diagnosticvalue of procalcitonin in patients with acute appendicitis. Eur SurgRes 2009;43:291-7.

17. Kaya B, Sana B, Eris C, Karabulut K, Bat O, Kutanis R. Thediagnostic value of D-dimer, procalcitonin and CRP in acuteappendicitis. Int J Med Sci 2012;9:909-15.

18. Yu CW, Juan LI, Wu MH, Shen CJ, Wu JY, Lee CC. Systematicreview and meta-analysis of the diagnostic accuracy ofprocalcitonin, C-reactive protein and white blood cell count forsuspected acute appendicitis. Br J Surg 2013;100:322-9.

19. Kafetzis DA, Velissariou IM, Nikolaides P, et al. Procalcitonin as apredictor of severe appendicitis in children. Eur J Clin MicrobiolInfect Dis 2005;24:484-7.

20. Roberts JK, Behravesh M, Dmitrewski J. Macroscopic findingsat appendicectomy are unreliable: implications for laparoscopy andmalignant conditions of the appendix. Int J Surg Pathol 2008;16:386-90.

21. Hussain A, Mahmood H, Singhal T, Balakrishnan S, El-HasaniS. What is positive appendicitis? A new answer to an oldquestion. Clinical, macroscopical and microscopical findingsin 200 consecutive appendectomies. Singapore Med J 2009;50:1145-9.


The Diagnostic Value of Serum Amyloid A in Early-OnsetNeonatal Sepsis in Premature Infants

BA DORUM, H ÖZKAN, SÇ ÇAKIR, N KöKSAL, Z GöZAL, S ÇELEBI, M HACIMUSTAFO LU

Abstract Purpose: In this study, the aim was to determine the distinct effectiveness of serum amyloid A in the earlystage of early-onset neonatal sepsis in premature infants. Methods: Preterm newborns hospitalised between2014 and 2017 for suspected early-onset neonatal sepsis were included in this prospective study. Patientswere evaluated according to clinical and laboratory findings at admission and at the 24th and 48th hoursafter admission. The serum amyloid A values of the patients with sepsis and a control group were compared,and the blood cultures were evaluated. Results: A total of 319 premature newborns were included in thestudy: 150 in the sepsis group and 169 in the control group. Their birth weight ranged between 590 g and3000g and the gestational age was 24-36 weeks. The serum amyloid A values at admission weresignificantly higher in the cases diagnosed with sepsis compared to the control group. Conclusion:Serum amyloid A is a reliable diagnostic marker for the early onset of neonatal sepsis, and it has a highersensitivity at symptom onset or in the first hours after birth in premature infants.

Key words Early-onset neonatal sepsis; Premature; Serum amyloid A

Department of Pediatrics, Division of Neonatology, MedicalFaculty of Bursa Uludag University, Gorukle 16059, Nilufer,Bursa, Turkey

BA DORUM MDH ÖZKAN Associate ProfessorSÇ ÇAKIR MDN KöKSAL Professor

Department of Pediatrics, Medical Faculty of Bursa UludagUniversity, Gorukle 16059, Nilufer, Bursa, Turkey

Z GöZAL MD

Department of Pediatrics, Division of Infectious Disease,Medical Faculty of Bursa Uludag University, Gorukle 16059,Nilufer, Bursa, Turkey

S ÇELEBI ProfessorM HACIMUSTAFO LU Professor

Correspondence to: Dr BA DORUM

Email: [email protected]

Received July 25, 2019

Original Article

Introduction

Despite the advances in prenatal health care, neonatalsepsis remains one of the biggest causes of neonatal deaths.1

Suspected neonatal sepsis is amongst the diagnoses thatneonatal specialists consider the most because of a lack ofspecific signs and symptoms and the absence of a precisemarker to distinguish from non-infectious settings withthe same manifestations.2 Symptoms that are miscible withsepsis are frequently encountered, especially in prematureinfants.

Early diagnosis and early antibiotherapy are of criticalimportance to reduce mortality and morbidity related toneonatal sepsis. Therefore, antibiotic therapy should bestarted immediately in any newborn presenting with thesigns of sepsis. It takes time to obtain the results of theblood culture, which is the gold standard in diagnosis.3

However, the blood culture may be negative, despite ageneralised bacterial infection, or false positive due to

Dorum et al 9

contamination.3 Besides, there is evidence thatunnecessarily prolonged antibiotic use in prematurenewborns is associated with an increased risk of late-onsetneonatal sepsis and necrotising enterocolitis and increasedmortality.4

For this reason, numerous laboratory parameters,including white blood cell count (WBC), the ratio ofimmature neutrophil count to total neutrophil count,platelet count (PLT), C-reactive protein (CRP), serumamyloid A (SAA), procalcitonin (PCT) and differentcytokines, are used for the early diagnosis of neonatalsepsis.5-8 Amongst these, CRP and PCT are widely used.The sensitivity of CRP is low in the early period of early-onset sepsis and is remarkably increased after 10-12 hours.8

PCT can physiologically increase immediately after birth,which limits its usage in diagnosing early-onset sepsis.9

SAA defines a family of polymorphic apolipoproteinsreleased mainly from the hepatocytes.10 Its release isregulated by proinflammatory cytokines.11 It increasestenfold in infectious and non-infectious conditions12 andcan also be used as an acute phase reactant in the diagnosisof neonatal sepsis.12 Several studies reported that SAAincreases in the earlier phases of inflammation and hasmore superior diagnostic value compared to CRP.13 Furtherstudies are needed to determine and strengthen the role ofSAA in the diagnosis and monitoring of neonatal sepsis.

The current study aimed to identify the role of SAA inthe early diagnosing of early-onset neonatal sepsis (EOS)in premature newborns. Moreover, it aimed to determinethe cut-off value for SAA in predicting early-onset neonatalsepsis with high specificity and sensitivity.

Methods

This study was carried out prospectively in a tertiaryhospital's neonatal intensive care unit. Preterm newbornswho were hospitalised between 2014 and 2017 forsuspected early-onset neonatal sepsis were included in thestudy. The study was approved by the ethics committee ofour university (201813/21). EOS was defined as sepsisoccurring in the first 72 hours of life. Newborns with acongenital anomaly, chromosomal anomaly, history ofhypoxic birth and suspected necrotising enterocolitis, andinfants whose parents did not give consent were excluded.The gestational age, birth weight, route of delivery, Apgarscores and prenatal demographics of the participants, aswell as the history of the early rupture of the membranesand chorioamnionitis, were retrieved from the electronic

patient files. The WBC, absolute neutrophil count(ANC), PLT, CRP, PCT and SAA values studied at threedifferent time points – at admission and at the 24th and48th hours of admission – were recorded. The resultsof the overall blood cultures taken in the first 72 hourswere evaluated.

Patients were evaluated by the European MedicinesAgency (EMA) neonatal sepsis criteria at the 24th and 48thhours of admission.14 The patients were divided into twogroups according to the results of two evaluations: thesepsis group (Group 1) and the control group (Group 2).Antibiotic treatment was discontinued in patients who werere-evaluated at the 48th hour of hospitalisation, and theywere excluded from the sepsis group according to the EMAcriteria.14 The patients in the sepsis group were evaluatedin two groups: proven sepsis (group 1a) and clinical sepsis(group 1b), according to their culture results.

The newborns with a history of premature rupture ofmembranes (PROM) and chorioamnionitis were managedin accordance with the AAP guidelines.2 Accordingly,antibiotic therapy was started after the blood culture wastaken from all the newborns with chorioamnionitis andfrom the premature newborns with PROM. The decisionfor the maintenance of treatment was made based on theresults of both the acute phase reactants and the clinicalevaluations performed at admission and at the 24th and48th hours of admission as the routine procedure of ourclinic.

All CRP, PCT and SAA levels are studied in samelaboratory using the ELISA method; CRP >9 mg/L, PCT >0.5 µg/L are considered positive according to ourlaboratory.

In each group, the demographic characteristics of thepatients, the prenatal risk factors and the maternal andneonatal characteristics were evaluated. The laboratoryfindings were compared between each of the three groupsas well as between the overall sepsis cases (Group 1 andGroup 2) and non-sepsis cases. In the early-onset neonatalsepsis cases, the cut-off values were calculated for CRP,PCT and SAA on different days. The sensitivity andspecificity of the cut-off values given by our laboratoryfor CRP and PCT were evaluated for the patients.

SPSS software (V.23) was used for the comparisons. Thedemographic data were evaluated by a student t-test andchi-square test. The laboratory data of the groups wereevaluated using the Mann Whitney U test. P<0.05 wasconsidered significant. The MedCalc (V.13) programmewas used to evaluate the cut-off values and to analyse thereceiver operating characteristic (ROC).

Serum Amyloid A in Early-onset Neonatal Sepsis10

Results

There were a total of 420 premature babies admitted toour NICU over a period of four years for early-onsetneonatal sepsis suspicion. Of these newborns, 101 wereexcluded since they met at least one of the exclusioncriteria, or their parents did not give consent. Finally, 319newborns with birth weights between 590 g and 3000 gand gestational ages between 24 and 36 weeks wereincluded in the study – 150 in Group 1 and 169 in Group 2.

No difference was determined between the demographiccharacteristics of the newborns in both of the two groups(Table 1).

At admission, the most common clinical signs in thesuspected sepsis cases were respiratory distress, feedingintolerance and non-specific signs that were mentioned inthe EMA neonatal sepsis criteria (Table 2).

Both of the two groups were not different in terms ofPCT values at admission. The CRP and SAA values atadmission were significantly higher in the cases diagnosedwith sepsis compared to the control group. The CRP, PCTand SAA at the 24- and 48- hour samples were significantlyhigher in the sepsis cases (Table 3). No significantdifference was determined between the proven sepsis(n: 40) and clinical sepsis (n: 110) groups in terms of theCRP, PCT and SAA values obtained from any sample.

The cut-off values and ROC analysis for the sepsisprediction of SAA, PCT and CRP in predicting sepsis, andthe area under the ROC curve, sensitivity and specificityfor these values are demonstrated in Table 4.

The breakdown list of bacterial species causing EOSwas shown in Table 5.

No difference was determined between the three groupsin terms of the WBC, ANC and platelet count at any time.

Discussion

Infections in the neonatal period, which is the mostsensitive period of life, cause substantial side effects. Whileearly-onset sepsis does not manifest itself with significantclinical symptoms in the first hours, it is associated withhigh mortality rates unless treated.15,16 Therefore, it isimportant to start appropriate antibiotherapy in newbornswith any sepsis-related suspected clinical symptom or whoare at high risk for early-onset sepsis.15 However, aclinicians' concern may result in many newborns receivingunnecessary antibiotherapy. In the present study, linkingthe symptoms to non-sepsis etiologies during monitoring,antibiotherapy was discontinued in 53% of the newbornswith suspected early-onset sepsis. Likewise, Murphy et alreported that sepsis was excluded and antibiotherapy wasdiscontinued in the early period in nearly 50% of thepatients.17

Although numerous acute phase reactants and scoringsystems are being used, there is yet no single laboratorytest that will rapidly and reliably detect the infection innewborns with suspected sepsis.8 The current studydemonstrated that SAA provides significant informationconcerning the diagnosis of early-onset sepsis from thefirst hours of birth.

SAA is mainly secreted from the liver in response toinflammation.12 Arnon et al demonstrated that SAA issuperior to CRP as a marker of early-onset sepsis.11

Cetinkaya et al found that SAA is an accurate and reliablemarker for the diagnosis and monitoring of neonatal sepsisand is beneficial for the rapid diagnosis of neonatal sepsis,particularly in the beginning of an infection. They statedthat it can be safely and accurately used together withother sepsis markers, such as CRP and PCT, as well as for

Table 1 Birth and clinical characteristics of infants included in the study

Group 1 (n: 150) Group 2 (n: 169) p

Gestational age (week), mean±SD 31.19±3.0 31.55±3.28

Birth weight (g), mean±SD 1620±639 1594±594

Admission time (hour), mean±SD 3.15±2.2 2.55±1.9

Apgar min 5, med (min-max) 8 (7-10) 8 (7-10)>0.05

Cesarean delivery, % 51.5 49.7

PROM, % 9.1 15.7

Choriamnionitis, % 3 2.6

Multiparity, % 32.4 29.4

PROM; premature rupture of membrane

Dorum et al 11

the diagnosis and monitoring of neonatal sepsis in pretermnewborns.10 After this and the similar studies, a meta-analysis performed in 2013 reported that SAA is a valuablemarker of neonatal sepsis, and it has proper diagnosticaccuracy.12 Moreover, the literature reports that SAA notonly has high accuracy in the early detection of neonatalsepsis, but it also shows the inverse relationship withmortality.8 In the current study, SAA studied in the early

Table 3 CRP, PCT, and SAA values of the infants included in the study

Group 1 (n: 150) Group 2 (n: 169) p

CRP (mg/L), median (min-max)

Admission 5.5 (3.3-96) 4.5 (3.3-15) 0.02

24th hour 25.5 (3.3-126) 3.6 (3.3-28) <0.001

48th hour 25 (9-197) 3.3 (3.3-20) <0.001

PCT (µg/L), median (min-max)

Admission 0.29 (0.05-79) 0.31 (0.05-55) 0.65

24th hour 7.9 (1.55-327) 3.9 (0.05-56) <0.001

48th hour 5.38 (2.05-200) 1.67 (0.05-36) <0.001

SAA (mg/L), median (min-max)

Admission 13.62 (4.5-84) 3.55 (3.3-30) <0.001

24th hour 22.05 (7.3-185) 3.83 (3.3-31) <0.001

48th hour 23.10 (8.1-207) 5.22 (3.3-25) <0.001CRP: C-reactive protein; PCT: procalcitonin; SAA: serum amyloid A

Table 4 Cut-off values and ROC analysis for sepsis prediction for CRP, PCT, and SAA

Variable Cut-off AUC P Sensivity 95% CI Specifity 95% CI

CRP (mg/L)Admission >3 0.593 <0.001 72 66.1 - 77.9 42 36.1 - 49.4

>9 35 30.8 - 40.3 94 91.8 - 98.9

24th hour >4 0.716 <0.001 53 47.2 - 60.4 83 77.7 - 88.0>9 75 69.2 - 81.9 91 88.4 - 93.7

48th hour >4 0.794 <0.001 76 70.6 - 81.3 76 70.3 - 81.5

>9 82 76.6 - 89.2 89 85.2 - 91.7

PCT (µg/L)

Admission >3.25 0.542 0.12 17 12.7 - 23.0 91 87.3 - 95.0

>0.5 35 29.0 - 41.9 68 62.2 - 74.9

24th hour >7 0.626 <0.001 46 40.1 - 53.6 75 68.5 - 80.7

>0.5 82 77.1 - 87.5 28 22.8 - 35.5

48th hour >1.7 0.636 <0.001 62 56.4 - 68.8 60 54.4 - 67.2

>0.5 82 76.8 - 86.7 31 25.4 - 37.7

SAA (mg/L)

Admission >9.5 0.706 <0.001 63 56.2 - 68.8 80 73.4 - 84.8

24th hour >10 0.779 <0.001 63 55.7 - 68.6 88 82.9 - 92.0

48th hour >11 0.875 <0.001 80 74.3 - 84.5 85 80.2 - 89.6

CRP: C-reactive protein; PCT: procalcitonin; SAA: serum amyloid A: ROC: receiver operating characteristic; AUC: area under the ROC curve; CI: confidenceinterval

Table 2 Clinical findings in suspected sepsis cases

Clinical signs N: 319

Respiratory instability, n (%) 280 (88)

Gastrointestinal signs, n (%) 203 (64)

Non-specific signs*, n (%) 166 (52)

Temperature instability, n (%) 102 (32)

* Irritability, lethargy and, hypotonia

Serum Amyloid A in Early-onset Neonatal Sepsis12

period for the diagnosis of early-onset sepsis was higherin the sepsis cases compared to the control group. Therewas no difference between the SAA values of the clinicaland proven sepsis cases.

Different studies have reported different values for thecut-off value of SAA.18 These differences have beenattributed to the differences in the methods used and inthe patients' ages.12 In the current study, the cut-off valueof SAA for early-onset sepsis was 9.5 mg/L for the samplesobtained at admission, 10 mg/L for the samples obtainedat the 24th hour and 11 mg/L for the samples obtained atthe 48th hour of admission.

Mithal et al determined significantly higher CRP andSAA values in the umbilical cords of the cases with provensepsis compared to the control group.19 However, theydetermined no elevation in the suspected sepsis cases butsimilar PCT values between the three groups.19 In thecurrent study, both the proven and clinical sepsis caseshad significantly higher SAA and CRP values compared tothe non-sepsis cases at admission. However, the PCT valuesat admission showed no difference between the sepsis andnon-sepsis cases.

The white blood cell count and absolute neutrophil counthave been widely used for years as screening tests forneonatal infections. However, they have very low diagnosticvalues in early-onset neonatal sepsis. In the first 72 hours,the neutrophil count is influenced by the gestational age,route of delivery and gender.20 Murphy et al stated that

normal WBC values do not exclude EOS.17 Similarly, theliterature reported no significant difference between theWBC and PLT counts of the cases with and withoutsepsis.6,10 Furthermore, in the current study, no significantdifference was determined between the early-onset sepsiscases and non-sepsis cases in terms of white blood cellcount and neutrophil count studied consecutively in thefirst three days. The ratio of the immature neutrophil countto total neutrophil count (I/T ratio) is considered to be amore sensitive marker.17 In the current study, the I/T ratiowas not evaluated.

Although thrombocytopenia can accompany neonatalinfections, it is within the normal limits in the majority ofinfected newborns. The thrombocyte count has a weaksensitivity in diagnosing early-onset sepsis, monitoringresponse to treatment and in estimating the efficacy.8,21

Moreover, in the current study, the number ofthrombocytopenic patients and the mean thrombocytecount were similar between the cases with and withoutsepsis. Likewise, studies investigating early-onset and late-onset sepsis cases determined no significant differencein terms of the thrombocyte count and the number ofthrombocytopenia cases compared to the non-sepsiscases.6,10

In the current study, there was no significant differencebetween the acute phase reactants of the proven and clinicalsepsis cases. Likewise, the literature determined similaracute phase reactant values between the sepsis cases withand without growth in the blood culture.10

The limitations of this study were the low number ofcases of proven sepsis and the large distribution of birthweights and gestational ages of the babies.

In conclusion, the present study revealed that SAA is areliable diagnostic marker for EOS, and it has highersensitivity at symptom onset or in the first hours after birth.Based on the results of the current study, taking 10 mg/Las the cut-off value for SAA appears to be reasonable.

Declaration of Interest

The authors have no conflicts of interest to disclose.

Acknowledgement

None

Table 5 The breakdown list of bacterial species causing early-onset neonatal sepsis

Staphylococcus epidermidis 7

Group B streptococcus 5

Escherichia coli 5

Enterococcus spp. 5

Enterobacter spp. 4

Klebsiella spp. 3

Staphylococcus aureus 3

Candida spp. 2

Moraxella osloensis 1

Staphylococcus haemolyticus 2

Burkholderia cepacia 1

Ralstonia picketti 1

Cronobacter sakasakii 1

Dorum et al 13

References

1. Satar M, Arisoy AE, Celik IH. Turkish Neonatal Society guidelineon neonatal infections-diagnosis and treatment. Turk Pediatri Ars2018;53:S88-100.

2. Polin RA, Committee on Fetus and Newborn. Management ofneonates with suspected or proven early-onset bacterial sepsis.Pediatrics 2012;129:1006-15.

3. Bedford Russell AR, Kumar R. Early onset neonatal sepsis:diagnostic dilemmas and practical management. Arch Dis ChildFetal Neonatal Ed 2015;100:350-4.

4. Puopolo KM, Mukhopadhyay S, Hansen NI, et al. Identificationof Extremely Premature Infants at Low Risk for Early-OnsetSepsis. Pediatrics 2017;140:e20170925.

5. Seliem W, Sultan AM. Presepsin as a predictor of early onsetneonatal sepsis in the umbilical cord blood of premature infantswith premature rupture of membranes. Pediatr Int 2018;60:428-32.

6. Can E, Hamilcikan S, Cen C. The Value of Neutrophil toLymphocyte Ratio and Platelet to Lymphocyte Ratio for DetectingEarly-onset Neonatal Sepsis. J Pediatr Hematol Oncol 2018;40:e229-32.

7. Rashwan NI, Hassan MH, Mohey El-Deen ZM, Ahmed AE. Validityof biomarkers in screening for neonatal sepsis – A single center –hospital based study. Pediatr Neonatol 2019;60:149-55.

8. Chauhan N, Tiwari S, Jain U. Potential biomarkers for effectivescreening of neonatal sepsis infections: An overview. MicrobPathog 2017;107:234-42.

9. Bell SG. Procalcitonin and Neonatal Sepsis: Is This the BiomarkerWe Are Looking For? Neonatal Netw 2017;36:380-4.

10. Cetinkaya M, Ozkan H, Köksal N, Celebi S, Hacimustafaoglu M.Comparison of serum amyloid A concentrations with those of C-reactive protein and procalcitonin in diagnosis and follow-up of

neonatal sepsis in premature infants. J Perinatol 2009;29:225-31.11. Arnon S, Litmanovitz I, Regev RH, Bauer S, Shainkin-Kestenbaum

R, Dolfin T. Serum amyloid A: An early and accurate marker ofneonatal early-onset sepsis. J Perinatol 2007;27:297-302.

12. Yuan H, Huang J, Lv B, et al. Diagnosis value of the serum amyloidA test in neonatal sepsis: A meta-analysis. Biomed Res Int 2013:520294.

13. Gilfillan M, Bhandari V. Biomarkers for the diagnosis of neonatalsepsis and necrotizing entercolitis: Clinical practice guidelines. EarlyHum Dev 2017;105:25-33.

14. European Medicines Agency. Report on the Expert Meeting onNeonatal and Pediatric Sepsis. London. December 2010 ReportNo: EMA/477725/2010. Available from https://www.ema.europa.eu/en/documents/report/report-expert-meeting-neonatal-paediatric-sepsis_en.pdf

15. Simonsen KA, Anderson-Berry AL, Delair SF, Dele Davies H.Early-onset neonatal sepsis. Clin Microbiol Rev 2014;27:21-47.

16. Memar MY, Alizadeh N, Varshochi M, Kafil HS. Immunologicbiomarkers for diagnostic of early-onset neonatal sepsis. J MaternNeonatal Med 2017;32:143-53.

17. Murphy K, Weiner J. Use of leukocyte counts in evaluation ofearly-onset neonatal sepsis. Pediatr Infect Dis J 2012;31:16-9.

18. Delanghe JR, Speeckaert MM. Translational research andbiomarkers in neonatal sepsis. Clin Chim Acta 2015;451:46-64.

19. Mithal LB, Palac HL, Yogev R, Ernst LM, Mestan KK. Cord bloodacute phase reactants predict early onset neonatal sepsis in preterminfants. PLoS One 2017;12:e0168677.

20. Schmutz N, Henry E, Jopling J, Christensen RD. Expected rangesfor blood neutrophil concentrations of neonates: The Manroe andMouzinho charts revisited. J Perinatol 2008;28:275-81.

21. Manzoni P, Mostert M, Galletto P, et al. Is thrombocytopeniasuggestive of organism-specific response in neonatal sepsis? PediatrInt 2009;51:206-10.


The Impact of Paediatric Neuromuscular Disorderson Parents' Health-Related Quality of Life and

Family Functioning

MHT HO, R LIANG, YT IP, H ZHI, WHS WONG, SHS CHAN

Abstract Aims: This study aimed to evaluate the impact of hereditary neuromuscular disorders on parent's health-related quality of life and family functioning, and to study the correlation of parental stress on familyimpact. Methods: This retrospective cross-sectional study analysed responses from 80 parents of 80children with different neuromuscular disorders on two self-reported questionnaires: the Chinese versionof PedsQL™ Family Impact Module and the Parental Stress Scale. Results: We found the Parental StressScore exhibited a moderate negative correlation with the PedsQL™ Family Impact Module total score(Pearson correlation coefficient: -0.55). Among different neuromuscular disorders, spinal muscular atrophyhad the worst negative family impact. Additionally, a non-walking status had moderate negative effectson family impact (T-test effect size: 0.71). Conclusion: Neuromuscular disorders cause a significantnegative family impact. Evaluation of parental stress, parental health-related quality of life and familyfunctioning should be part of the standard of care for affected families.

Key words Neuromuscular disorders; Quality of life research

Department of Paediatrics and Adolescent Medicine, Li KaShing Faculty of Medicine, The University of Hong Kong,102 Pokfulam Road, Pokfulam, Hong Kong SAR, China

MHT HO MBBS (HK)R LIANG BSc, MPhil(HK)WHS WONG PhDSHS CHAN MMedSc(HK), FHKAM(Paed), FHKCPaed

Department of Clinical Psychology, The Duchess of KentChildren's Hospital at Sandy Bay, 12 Sandy Bay Road,Pokfulam, Hong Kong SAR, China

YT IP MSocSc(Clin.Psy.), MPhil(HK), RCP(HKPS)

Biostatistics and Clinical Research Methodology Unit, Li KaShing Faculty of Medicine, The University of Hong Kong,102 Pokfulam Road, Pokfulam, Hong Kong SAR, China

H ZHI BA (Economics), BS (Probability and Statistics),PhD

Correspondence to: Dr SHS CHAN


Received May 14, 2019

Original Article

Introduction

Hereditary neuromuscular disorders (NMDs) are aheterogeneous group of conditions cause by underlyinggenetic mutation(s) leading to diseases arising fromdifferent parts of the lower motor neuron units. Thesediseases differ regarding age of onset, disease progressionand life expectancy and commonly cause orthopaedic,respiratory, cardiovascular, nutritional and gastrointestinalcomplications. A child with an NMD presents a complexchallenge to the whole family. Parents of chronically illchildren frequently report physical, emotional andcognitive problems.1 Conversely, the family's wellbeingaffects the care received by the ill child.2 Therefore, theimportance of assessing the impact of chronic illness onparents or families has become evident. Parents withchildren having chronic illnesses often have significantstress affecting multiple aspects of their life.3

The family impact of an NMD can be evaluated byconsidering the effects of the disease on individual

Ho et al 15

members (e.g., the parental HRQOL) and the overall family(e.g., family functioning). The parental HRQOL is a multi-dimensional construct used to evaluate parents' perceptionsof the effects of their children's disease on the different lifedomains related to physical, mental and social wellbeing.4

Family functioning refers to a family's ability to accomplishtasks important to wellbeing, adapt to changingcircumstances or balance the needs of individuals withthose of the entire family.5 Up to date, very few reportshave documented the family impacts of NMDs, or comparedthe family impacts of different paediatric NMDs.

The Family Impact Module (FIM) of the PaediatricQuality of Life Inventory (PedsQL™ 4.0) (PedsQL™ © 1998JW Varni, Ph.D. All rights reserved) is a validated parent-report questionnaire developed by Varni et al6 and cross-culturally adapted into Chinese by Chen et al.7 The Chineseversion comprises nine domains-Physical functioning,Emotional functioning, Social functioning, Cognitivefunctioning, Communication, Worry, Daily activities,Family relationships and Finance. The first 4 subscalesmeasures parent self-reported HRQOL functioning, and theDaily activities and Family relationships subscales measureparent-reported family functioning and is commonly usedto assess family impact. By contrast, other availableinstruments are generally brief and one-dimensional.8

The Chinese version of the Parental Stress Scale (PSS),a validated self-report scale developed by Cheung,9 wasadapted from the Parental Stress Scale developed by Berryand Jones.10 This scale measures the level of stressexperienced by parents and considers both positive (e.g.,emot ional benef i t s , se l f -enr ichment , personaldevelopment) and negative components of parenthood(e.g., demands on resources, opportunity costs,restrictions). This one-page questionnaire is half the lengthof the PedsQL™ FIM and is commonly used in Hong Kongto screen and identify parents experiencing stress and tofacilitate early referrals to clinical psychology services.However, it remains uncertain whether the PSS scorecorrelates with a poor parental HRQOL or poor familyfunctioning. Therefore, this study aimed to systemicallyevaluate the parental HRQOL and family functioning in thefamilies of paediatric patients with NMD and to examinethe correlations of these measures with parental stress.

Methods

Study DesignAt our hospital, all families of children with hereditary

NMDs attend paediatric neuromuscular disorder clinicsand complete the Chinese versions of the PSS andPedsQL™ FIM upon diagnostic confirmation. Thisretrospective study evaluated the parents' responses to bothques t ionnai res dur ing fo l low-up v is i t s a t ourneuromuscular disorder clinics during the period of 4thJuly 2016 to 15th March 2018. Data on the age, sex,diagnosis, comorbidities, ambulation status (walker/non-walker), ventilation support (does/does not require) andfeeding status (requires/does not require assistance) of eachpaediatric NMD patient were systematically collected fromthe electronic patient health record system at the sametime as the questionnaire completion.

The patients' diagnoses were classified into one of fourgroups. Group 1 comprised patients with deterioratingmuscle diseases, mainly Duchenne muscular dystrophy andcongenital muscular dystrophy. Group 2 comprisedpatients with types 1 to type 3 5q spinal muscular atrophy(SMA), representing deteriorating motor neuron diseases.Group 3 comprised patients with stable neuromusculardiseases including congenital myopathy and congenitalmyasthenic syndrome. All patients with congenitalmyasthenic syndrome received oral medical therapy thatresulted in clinical motor improvement. Group 4comprised patients with hereditary stable peripheral nervediseases with minimal or mainly distal weakness.

The parent who served as the main caregiver was invitedto complete the questionnaires. If the questionnaires werecompleted during multiple visits, only the results from thefirst set were collected and documented. The total score,parental HRQOL summary score, family functioningsummary score and each dimensional score in the PedsQL™Family Impact Module were computed according to theguideline provided by the developer. The total PSS scorewas also computed.

MeasuresThe primary study outcomes were the parental HRQOL

and level of family functioning, measured by the PedsQL™FIM. The secondary outcome was the correlation betweenPedsQL™ FIM and PSS.

The PedsQL™ FIM comprised 37 items across 9domains. The Finance domain was not included in theanalysis since this domain was only introduced in theChinese version of the questionnaire and was not part ofthe validated original questionnaire developed by Varni etal. The parental HRQOL summary score was calculated asthe average of the physical, emotional, social and cognitivefunctioning scores. The family functioning summary score

Paed NMD on Parental HRQOL & Family Functioning16

was calculated as the average of the daily activities andfamily relationships scores.8 All scores ranged from 0 to100, with higher scores indicative of better functioning.The total PedsQL™ FIM scores were compared with thoseof children with other neurological conditions. These wereobtained from published studies that used the PedsQL™FIM to assess paediatric neurological diseases incomparable sample sizes. The selected data forcomparison were extracted from a study of acquired braininjury by de Kloet et al.11

The PSS comprised 17 items scored on a 6-point scale;higher scores indicate greater stress. Previous dataindicated that a cut-off point of 52/53 could be used todemarcate parent groups exhibiting satisfactory adjustmentvs maladjustment. This scale had demonstrated satisfactorylevels of internal reliability and test-retest reliability.9,10

Statistical AnalysisDescriptive statistics were calculated for the

demographic features. Means and standard deviations (SD)of the PedsQL™ FIM and PSS scores were calculated forthe total study sample and subgroups stratified bydiagnosis and ambulation status. A t-test was used tocompare data sets.

To compare the PedsQL™ FIM scale and total scores ofpatients with different diagnoses, the data was log10transformed before analysis since the distribution of thedata was not normal. A one-way analysis of variance(ANOVA) and post-hoc Tukey Kramer analysis wereconducted.

A Pearson product-moment correlation analysis wasused to determine the linear correlation between the PSSscore and PedsQL™ FIM scale and summary scores. Allstatistical analyses were conducted using SPSS Statistics20 (IBM, Armonk, NY, USA). Statistical significance wasdefined as p-value of <0.05.

EthicsThis study was approved by the relevant Institutional

Review Board.

Results

Eighty parent reported PedsQL™ FIM and PSSquestionnaires were collected from 21 fathers and 59mothers. Most of the affected NMD children weremedically stable and ambulatory (81% walkers, 94% notrequiring ventilation support, 99% on full oral feeding).

The distribution of the patient demographics and age rangesof patients in the four disease groups are shown in Table 1.

The means and standard deviations of the PedsQL™ FIMscores of the four NMD groups are presented in Table 2.Among the eight inventory domains, the domain on 'Worry'received the worst scale score. The Cronbach's alphacoefficients for the total and all scale scores ranged from0.86 to 0.98. No floor or ceiling effect was observed (floor/ceiling percentages: 0.0-18.7%). Furthermore, when thePedsQL™ FIM scores were compared among the 4 differentgroups of NMDs, parents in Group 2 (deteriorating motorneuron diseases) reported the lowest total and scale scoresacross all items. Parents in Group 4 (hereditary peripheralneuropathies) yielded the highest total and scale scores. Aone-way ANOVA revealed significant differences amongthe mean PedsQL™ FIM total, parental HRQOL and familyfunctioning scores of different disease groups (all p<0.01).A post-hoc analysis revealed that Group 2 accounted forthe greatest differences in the mean scores when comparedwith the other groups. The results of the ANOVA and post-hoc analysis are shown in Table 3. Additionally, thePedsQL™ FIM scores were compared according toambulation status. A non-walking status was found to havemoderate negative effects on the overall family impact,parent HRQOL and family functioning scores (T-test effectsize: 0.71-0.83) (Table 4). Moreover, the PedsQL™ FIMtotal score in our NMD cohort was worse than that of thepatients with acquired brain injuries,11 as demonstrated inTable 5.

The Cronbach's alpha coefficient for the PSS was 0.89,indicating high internal consistency. The PSS scoreexhibited a moderate negative correlation with thePedsQL™ FIM total score (Figure 1) (Pearson correlationcoefficient: -0.55). Specifically, parents with a higher levelof stress reported a significantly lower HRQOL and poorerfamily functioning. When a cut-off of 52/53 was used tocategorise parents into low- and high-stress groups, 36.63%of parents were in the high stress group. The correspondingmean PedsQL™ FIM total scores were 75.92 (SD = 12.83)and 62.16 (SD = 15.38), respectively. This difference wassignificant and had a large effect size of 0.98.

Discussion

This study conducted a multi-dimensional investigationof the family impact of NMDs. In this cohort, the affectedNMD patients were mostly medically stable andambulatory. The parents reported a poor parental HRQOL

Ho et al 17

Table 1 Patient demographics

Demographic factors Number Percentage

Age (years) 0-4 18 22.5 5-8 26 32.5 9-12 15 18.9 13-18 21 26.2

Sex Male 60 75.0 Female 20 25.0

Ambulation status Walker 65 81.3 Non-walker† 15 18.8

Ventilation status No ventilation support needed 75 93.8 Ventilation support needed‡ 5 6.2

Feeding status Oral feeding 79 98.8 Tube feeding 1 1.2

Diagnosis Mean age (years) Age range (years) Deteriorating muscles diseases § 26 32.5 8.7 3.6-16.5 Deteriorating motor neuron diseases 12 15.0 6.0 1.2-17.6 Stable neuromuscular diseases 34 42.5 9.2 0.9-17.2 Stable peripheral nerve diseases 8 10 12.0 5.4-17.8

†Bedridden = 1, Wheelchair user = 14‡Nocturnal non-invasive ventilation = 5§Congenital muscular dystrophy (unclassified) = 3, Duchenne muscular dystrophy = 17, Emery-Dreifuss muscular dystrophy = 1, Infantile facioscapulohumeral

muscular dystrophy = 1, Megaconial congenital muscular dystrophy = 1, Muscular dystrophy (unclassified) = 2, Ulrich congenital muscular dystrophy= 1

Table 2 PedsQL™ FIM scores

NMD Group 1 NMD Group 2 NMD Group 3 NMD Group 4 TotalMean S.D. Mean S.D. Mean S.D. Mean S.D. Mean S.D.

Total score 71.9 13.42 58.19 16.8 68.57 15.76 81.44 6.31 69.55 15.58

Parent HRQOL summary score 69.66 16.02 49.79 23.62 63.81 19.77 76.59 12.32 64.80 20.27

Physical functioning 72.84 14.98 59.72 17.5 73.02 14.76 83.62 10.59 65.42 20.10

Emotional functioning 72.89 16.12 58.67 24.51 68.59 18.28 81.33 19.55 62.37 24.50

Social functioning 75.19 14.87 60.83 20.6 71.37 19.36 85.83 12.39 65.81 23.33

Cognitive functioning 77.78 16.49 60.33 17.77 70.82 18.52 80 12.65 65.77 23.02

Family functioning summary score 65.22 17.80 44.47 19.02 62.34 22.17 76.39 16.26 62.06 22.18

Daily activity 68.72 16.41 50 19.72 66.86 22.95 83.81 10.61 58.44 26.71

Family relation 74 16.24 59.67 21.19 71.41 17.33 80 19.94 65.00 24.10

Communication 73.46 18.56 58.89 20.52 66.67 21.08 89.52 14.19 62.23 26.24

Worry 57.38 17.04 54.67 16.52 57.88 19.55 72.57 16.76 48.27 23.56

PedsQL™: Paediatric Quality of Life Inventory, FIM: Family Impact Module, HRQOL: health-related quality of life, S.D.: standard deviation, NMD:

neuromuscular disorder


and a low level of family functioning significantly worsethan those reported in acquired brain injury. Our findingssuggested that rare hereditary NMD diseases with complexmedical needs, have significant negative family impactsand the family needs should not be neglected.

This study found that out of the eight domains of thePedsQL™ FIM, parents reported the worst scores in the'Worry' domain, which included worries about others'reactions to their child's condition. Previous studies

revealed that some parents of children with disabilitiesavoided their relatives and friends since their child's andfamily's needs were often not understood by others.14 AsNMDs are rare diseases, they are often poorly understoodby the general public. Therefore, parents might beparticularly worried about others' reactions to theiraffected child. The Worry domain also addressed worrieson the efficacy and safety of the child's treatment, as wellas the child's future. The current findings may correlate

Table 3 One-way ANOVA table of (log-transformed) total score, parental HRQOL summary score and functioning summary score

Score NMD NMD NMD NMD Tukey Post Hoc Test - p-valueGroup 1 Group 2 Group 3 Group 4 Multiple comparisons^#

Total score* 1.86 ±0.78 1.75±0.14 1.82±0.11 1.91±0.04 Group 1, Group 2: 0.11 (0.02-0.20) 0.012(n=26) (n=12) (n=34) (n=7) Group 2, Group 3: 0.08 (0.01-0.17) 0.101

Group 2, Group 4: 0.17 (0.04-0.29) 0.005

Parental HRQOL 1.83±0.11 1.64±0.259 1.78±0.15 1.88±0.08 Group 1, Group 2: 0.19 (0.05-0.34) 0.004Summary score* (n=26) (n=12) (n=34) (n=7) Group 2, Group 3: 0.15 (0.006-0.28) 0.037

Group 2, Group 4: 0.24 (0.05-0.44) 0.009

Family 1.80±0.13 1.60±0.24 1.76±0.19 1.88±0.10 Group 1, Group 2: 0.20 (0.04-0.36) 0.010Functioning (n=25) (n=12) (n=34) (n=7) Group 2, Group 3: 0.16 (0.01-0.32) 0.036Summary score* Group 2, Group 4: 0.28 (0.06-0.50) 0.007

*Score are expressed in Mean ± SD; # Statistically significant result (p<0.05) were shown

^ Multiple comparisons are expressed in Mean Difference (95% CI)

NMD: neuromuscular disorder, HRQOL: health-related quality of life

Table 4 Independent T test comparing ambulation status with scale scores and total scores for PedsQL™ FIM impact for NMD sample

Walker Non-walkerMean S.D. Mean S.D. Difference Effect Size

PedsQL™ FIM total score 71.57 14.79 60.93 15.92 10.64* 0.71

Parental HRQOL summary score 67.47 18.91 53.42 22.57 14.05* 0.72

Family functioning summary score 65.43 20.60 47.92 23.70 17.51* 0.83

*Statistically significant result (p<0.01) were shown

PedsQL™: Paediatric Quality of Life Inventory, FIM: Family Impact Module, NMD: neuromuscular disorder, S.D.: standard deviation,

HRQOL: health-related quality of life

Table 5 Independent T test comparison of PedsQL™ FIM total scores of this NMD cohort and acquired brain injury cohort11

NMD (N=80) Acquired Brain Injury (N=108)Mean S.D. Mean S.D. Difference Hedges' g effect size

Total score 70.55 15.58 80.4 17.9 -9.85* -0.58

*Statistically significant result (p<0.05) was shown

PedsQL™: Paediatric Quality of Life Inventory, FIM: Family Impact Module, NMD: neuromuscular disorder, S.D.: standard deviation

Ho et al 19

with the fact that treatments for some NMDs remain underresearch and there are still lack of cures or disease-modifying treatments for many NMDs at the current stage.Furthermore, NMDs have variable prognoses, and theuncertain treatment outcomes might increase parents'concerns about their child's future.

The lack of the availability of effective treatment thatresulted in a negative family impact at the time of thisstudy, was especially evident in the deteriorating motorneuron disease group 2 comprised of patients with 5q SMA.SMAs are mainly treated via supportive interventionsduring the study period from July 2016 to March 2018.The first US Food and Drug Administration (FDA)-approved drug treatment for SMA, named nusinersen, wasavailable in the United States since December 2016.During the study period, Spinraza was not available to thepatients with SMAs in Hong Kong. Parents were anxiousabout the deteriorating course of the disease withoutaccessibility to the available treatment, and these concernsmay have contributed to the poorer parental HRQOL andlevel of family functioning in this group. On the otherhand, the PedsQL™ FIM scores from the deterioratingmuscles diseases (the group with muscular dystrophies)and the stable neuromuscular diseases groups (the groupwith congenital myopathy and congenital myasthenicsyndrome) were comparable. The PedsQL™ FIM scores ofthe peripheral neuropathy group were highest. This suggeststhe inaccessibility of available treatment might have asignificant negative family impact in addition to the rate ofdisease progression. For DMD, the currently available

steroid treatments help to maintain the motor function anddelay motor deterioration; so, the negative family impactwas not as significant as that for SMA. In Hong Kong,nusinersen was eventually made available to patients withSMA type I in May 2018 and to patients with later onsetSMA in 2019. A follow-up study of the HRQOL and familyfunctioning of those families with children receiving thetreatment would be valuable to evaluate the proposedimpact of treatment on parental HRQOL and family impact.

Our findings also revealed lower parental HRQOL andfamily functioning scores in the group of non-walkers whencompared to those remained ambulant. This finding wasconsistent with previous reports of a negative correlationof parents' QOL with children's functional independence.In Bray P et al study, parents had greatest emotionaldisturbance of their child's DMD during the time of loss ofambulation.12 In Liang R et al study, the overall familyfunctioning in those with affected DMD boy was found toworsen as the child increased in age with advancing diseasestage.13 These results suggest the need for a reassessmentof family impact as the child's ambulation deteriorates ordevelops additional medical complications. Ourobservation that the PedsQL™ FIM scores of the peripheralneuropathy group 4 were highest again added support tothe above findings, as all the affected children in this groupwere ambulant with minimal or only distal weakness, anddid not required other medical support having a stabledisease course.

We further examined the correlations of the PedsQL™FIM with PSS scores. Notably, we demonstrated that a PSScut-off point of 52/53 could be used effectively to identifyparents with poor HRQOL and low level of familyfunctioning with significant difference in mean PedsQL™FIM total scores between high stress and low stress groupsbeing demonstrated. While the shorter PSS could be usedas a brief screening tool to identify high-risk parents, italso helps to identify families with significant negativefamily impact and impair functioning that needs earlysupport.

This study had several limitations. First, comparisonsof our findings with other neurological diseases wereperformed using data extracted from previous report, giventhe lack of local PedsQL™ FIM score data for directcomparison. Future research should consider the inclusionof time-matched samples of other disease condition fordirect comparison. Second, the collected parentaldemographic information was limited, and the effects ofsome factors on the family impact such has the familyincome, accommodation, parents' educational level and

Figure 1 Scatter plot of the Paediatric Quality of Life

Inventory (PedsQL™) Family Impact Module (FIM) total score

against the Parental Stress Scale (PSS) score.


health status, could not be assessed. Furthermore, familiesbetween NMD groups were not matched by demographicvariables, as inter-group differences may not be solelyexplained by the difference in diagnosis. Future studieswith larger number of NMD patients with data stratificationby different demographic variables, could be helpful toidentify underlying risk and protective factors for parentalstress and family functioning. Finally, this study includedonly patients attending the outpatient NMD clinics with astable general health and not those with frequent inpatientadmissions with more severe disease complications.Therefore, the results may not be able to reflect the familyimpact of NMDs of the whole spectrum of severity butonly those more stable with higher functional performance.

In conclusion, this is the first multi-dimensional studyon the family impact using PedsQL™ FIM on paediatricNMDs. We found that paediatric onset NMDs can causesignificant negative family impact and affect the familyfunctioning. Evaluation of parental stress, parental health-related quality of life and family functioning should bepart of the standard of care for families with affectedchildren with NMDs. The significantly lower family impactin the group of 5q-SMA may be attributed to both therapid deteriorating disease course and the inaccessibilityof treatment available overseas, at the time of the study.While PSS could be used in the clinic setting to screen forhigh risk families with affected paediatric NMD children,the use of PedsQL™ FIM self- reported questionnaires helpto understand the affected parental HRQOL and the familyimpact better, so to guide the necessary support for thefamily.

Acknowledgements

The authors thank Mapi Research Trust for theirapproval to use PedsQL-2.0-FIM_AU2.0_cmn-CN_Academic-Translation version in our research. Theauthors also take this opportunity to thank all theparticipating families. Without their support and help, thisstudy will not be possible.


The author(s) declared no potential conflicts of interestwith respect to the research, authorship, and/or publicationof this article.

References

1. Haverman L, van Oers HA, Maurice-Stam H, Kuijpers TW,Grootenhuis MA, van Rossum MA. Health related quality of lifeand parental perceptions of child vulnerability among parentsof a child with juvenile idiopathic arthritis: results from a web-based survey. Pediatr Rheumatol Online J 2014;7;12:34.

2. Panepinto JA, Hoffmann RG, Pajewski NM. A psychometricevaluation of the PedsQL Family Impact Module in parents ofchildren with sickle cell disease. Health Qual Life Outcomes 2009;7:32.

3. Cousino MK, Hazen RA. Parenting stress among caregivers ofchildren with chronic illness: A systematic review. J Pediatr Psychol2013;38:809-28.

4. Defenderfer EK, Rybak TM, Davies WH, Berlin KS. Predictingparent health-related quality of life: evaluating conceptualmodels. Qual Life Res 2017;26:1405-15.

5. Epstein NB, Bishop DS, Baldwin LM. McMaster Model of FamilyFunctioning: A view of the normal family. In: Walsh F, ed.Guilford family therapy series. Normal family processes.Guilford Press, New York, 1982;115-41.

6. Varni JW, Sherman SA, Burwinkle TM, Dickinson PE, Dixon P.The PedsQL Family Impact Module: preliminary reliability andvalidity. Health Qual Life Outcomes 2004;2:55.

7. Chen R, Hao Y, Feng L, Zhang Y, Huang Z. The Chinese versionof the Pediatric Quality of Life Inventory™(PedsQL™ FamilyImpact Module: cross-cultural adaptation and psychometricevaluation. Health Qual Life Outcomes 2011;9:16.

8. Jastrowski Mano KE, Khan KA, Ladwig RJ, Weisman SJ. Theimpact of pediatric chronic pain on parents' health-related qualityof life and family functioning: reliability and validity of thePedsQL 4.0 Family Impact Module. J Pediatr Psychol 2011;36:517-27.

9. Cheung SK. Psychometric properties of the Chinese version ofthe Parental Stress Scale. Psychologia 2000;43:253-61.

10. Berry JO, Jones WH. The parental stress scale: Initial psycho-metric evidence. J Soc Pers Relat 1995;12:463-72.

11. de Kloet AJ, Lambregts SA, Berger MA, van Markus F,Wolterbeek R, Vliet Vlieland TP. Family impact of acquiredbrain injury in children and youth. J Dev Behav Pediatr 2015;36:342-51.

12. Bray P, Bundy AC, Ryan MM, North KN, Burns J. Health statusof boys with Duchenne muscular dystrophy: a parent'sperspective. J Paediatr Child Health 2011;47:557-62.

13. Liang R, Chan SHS, Ho FKW, et al. Health-related quality of life inChinese boys with Duchenne muscular dystrophy and theirfamilies. J Child Health Care 2019;23:495-506.


Does Subclinical Hypothyroidism Affect Lipid andEpicardial Fat Tissue Thickness in Children?

E UNAL, A AKIN, R YILDIRIM, M TÜRE, H BALIK, FF TA , AG PIRINççIO LU, YK HASPOLAT

Abstract Objective: The aim of this study was to measure serum lipid levels and epicardial adipose tissue thicknessin patients determined with subclinical hypothyroidism. Methods: The study included 61 paediatricpatients with a diagnosis of subclinical hypothyroidism and a control group of 61 healthy children. Thethyroid hormone levels, lipid parameters and epicardial adipose tissue thickness were examined in allthe patients. Results: The mean epicardial adipose tissue thickness of the subclinical hypothyroidismpatients was higher than that of the control group but not at a level of statistical significance (4.15±0.91vs 4.06±0.99, p=0.598). The mean high-density lipoprotein cholesterol level of the subclinicalhypothyroidism group was statistically lower than that of the control group (p=0.040). Conclusion: Theresults of this study showed a significant decrease in the high-density lipoprotein cholesterol levels ofchildren with subclinical hypothyroidism. No significant increase was seen in the epicardial adiposetissue thickness of the children with subclinical hypothyroidism. This is the first study to have examinedepicardial adipose tissue thickness in children with subclinical hypothyroidism.

Key words Children; Epicardial adipose tissue; Subclinical hypothyroidism

Department of Pediatric Endocrinology, Dicle UniversityFaculty of Medicine, Diyarbak r, Turkey

E UNAL MDFF TA MDYK Haspolat MD

Department of Pediatric Cardiology, Dicle UniversityFaculty of Medicine, Diyarbak r, Turkey

A AKIN MDM TÜRE MDH BALIK MD

Department of Pediatric Endocrinology, Diyarbak rChildren's Hospital, Diyarbak r, Turkey

R YILDIRIM MD

Department of Pediatrics, Dicle University Faculty ofMedicine, Diyarbak r, Turkey

AG PIRINÇÇIO LU MD

Correspondence to: Dr E UNAL


Received June 26, 2018

Original Article

Introduction

Subcl inical hypothyroidism (SH) is def inedbiochemically as a state when the serum thyroid stimulatinghormone (TSH) concentration is above the upper normalreference limit while serum free thyroxin (fT4) is withinthe normal range. The frequency of SH seen in adults hasbeen reported as 4-20% with a clearly greater risk ofprogressing to hypothyroidism.1 Although there is a limitednumber of epidemiological studies of children andadolescents, the SH prevalence in the paediatric populationhas been reported as <2%.2

Although SH is usually incidentally diagnosed, anassociation between SH and atherosclerotic heart diseasehas been demonstrated. Subclinical hypothyroidismfeatures some of the risk factors that can accelerate thedevelopment of atherosclerosis. Such risk factors includean increased body mass index (BMI), greater visceraladipose t issue, insul in resis tance, a therogenicdyslipidemia, hypercoagulability, and systolic and diastolichypertension.3-5 Moreover, higher TSH levels even in the

Subclinical Hypothyroidism and Epicardial Fat22

normal range are associated with an increased mass ofvisceral adipose tissue, which is an independent risk factorfor the development of coronary heart disease.6,7

Epicardial adipose tissue (EAT) is an important indicatorof intra-abdominal visceral fat accumulation.8 Therefore,it was aimed to investigate the thickness of EAT in patientswith SH.

In recent years, non-invasive methods have started tobe used in the determination of atherosclerosis, whichconstitutes a risk for cardiovascular disease. Epicardialadipose tissue is defined as the visceral adipose tissuebetween the pericardium and the myocardium and it ismeasured with transthoracic echocardiography (TE). Thereare few studies that have evaluated the relationshipbetween EAT thickness and SH. Some of these studies havereported a relationship between EAT thickness and SH9-12

and other studies have reported no relationship.13,14 To thebest of our knowledge, this is the first study to haveevaluated the relationship between EAT thickness and SHin children.

Subjects and Methods

Study PopulationThe study included 61 children diagnosed with SH in

the Paediatric Endocrinology Clinic and a control groupof 61 healthy children with normal thyroid functions (serumTSH, fT4). The children with SH were referred to ourpaediatric endocrinology clinic from the community bytheir paediatricians because of the incidental finding ofelevated TSH concentrations in their routine annual check-up. Subclinical hypothyroidism was diagnosed on the basisof elevated serum TSH levels (TSH, 4.2-20 µIU/L) andserum fT4 levels within the normal range in 2 separatefasting blood samples taken at an interval of 2-6 weeks.The aetiology of patients diagnosed with SH wasinvestigated and only idiopathic patients were includedin the study. Hashimoto's thyroiditis was diagnosed on thebasis of the presence of either antithyroglobulin (anti-Tg)or antithyroid peroxidase (anti-TPOAb) antibodies (orboth) in the serum. Hashimoto's thyroiditis patients wereexcluded from the study. None of the patient or controlgroup subjects had hypertension, liver or kidney functiondisorders, cardiac pathology or chronic disease. Exclusioncriteria for both groups included diabetes mellitus, obesityor a history of medication use. Height was measured usinga Harpenden stadiometer with a sensitivity of 0.1 cm andweight was measured using a scale with a sensitivity of 0.1 kg

(SECA, Hamburg, Germany). The weight of each subjectwas measured with all clothing removed exceptundergarments. Body mass index was calculated bydividing weight (kg) by height squared (m2).

The study protocol was approved by the EthicsCommittee of Dicle University Faculty of Medicine, andwritten informed consent was obtained from all participants,prior to enrollment in the study (date: 16 December 2016,registration number: 21).

Serological ParametersSerum TSH, free triiodothyronine (fT3) and fT4 levels

were measured by electrochemilumines immunoassay(ECLIA) in a Cobos e601 analyser (Roche HITACHIGermany). In the laboratory where the study wasconducted, the normal reference values were 0.27-4.2 µIU/mL for TSH, 3.69-9.85 pmol/L for fT3 and 12-22.8 pmol/Lfor fT4. Fasting blood samples were obtained byvenipuncture in the morning at 8 a.m., after an overnightfast of at least 12 h. Serum concentrations of totalcholesterol (TC), high-density lipoprotein (HDL)cholesterol, and triglycerides (TG) were measured byenzyme assay (Abbott diagnostics C16000 chemistryanalyser, IL, USA). The value of low-density lipoprotein(LDL) cholesterol was calculated using Friedwald'sequation.

Echocardiographic Assessment of Epicardial AdiposeTissue

Before the procedure, all the patients were applied with12-derivation surface electrocardiography (ECG) and 2-dimensional (2D), M-mode and colour Dopplerechocardiography. The patients were then placed in thelateral decubitus position. Using 2D long and short heartaxis views, EAT thickness was evaluated in the rightventricle free wall at the end of the systole (Vivid 3; GEVingmed, Horten, Norvay). A total of 5 measurements weretaken of EAT thickness during 5 cycles of 2D long andshort heart axis views. For each patient an average of thevalues was calculated. Epicardial adipose tissue is seen asan echo-free space anterior to the right ventricular walland the thickness is measured at the point between theepicardial surface of the right ventricle and the parietalpericardium.

Statistical AnalysisData obtained in the study were analysed statistically

using IBM SPSS 21.0 for Windows statistics software.Measured variables were stated as mean±standard deviation

Unal et al 23

(SD), and categorical variables as number (n) andpercentage (%). Conformity to normal distribution of thedata was evaluated. The Student's t-test was applied in thecomparison of 2 selected groups with normal distribution,and in the comparison of 2 groups not showing normaldistribution, the Mann Whitney U-test was used. Chi-squaretest analysis was applied for the comparison of qualitativevariables between groups. To evaluate relationshipsbetween numerical variables, Pearson Correlation analysiswas applied. The hypotheses were two-way and a value ofp<0.05 was accepted as statistically significant.

Results

The 61 patients diagnosed with SH comprised 28 malesand 33 females with a mean age of 8.0±3.3 years. Thecontrol group of 61 healthy euthyroid children comprised28 males and 33 females with a mean age of 8.4±2.4 years.No significant difference was determined between thegroups in respect of age, gender, weight and BMI. Thedemographic characteristics and the thyroid function testresults of the patients are shown in Table 1.

In comparison with the control group, the TSH level inthe SH group was statistically significantly high (p<0.001).Of the total 61 patients, TSH was <10 µIU/mL in 51 patientsand ≥10 µIU/mL in 10 patients. No statistically significantdifference was determined between the groups in respectof total cholesterol, LDL-C and triglyceride levels. TheHDL-C level was statistically significantly lower in theSH patient group than in the control group (p=0.040).

No significant correlation was found in the two groups

of children for mean EAT thickness (p=0.598). There wasalso no significant correlation between TSH and EATthickness (r: 0.052; p=0.689). When the patients wereseparated into two groups as TSH <10 µIU/mL and≥10 µIU/mL, no statistically significant difference wasdetermined in respect of EAT thickness and lipid values.The EAT thickness values and biochemical parameters ofthe SH patient group and the control group are shown inTable 2.

Discussion

The effects of thyroid hormones on the cardiovascularsystem have long been known. Cross-sectional and cohortstudies have concluded that hypothyroidism increasesatherosclerosis. There is a clear relationship in particularof hypothyroidism with increased LDL-cholesterol, highdiastolic blood pressure, a low degree of inflammation andhypercoagulability and this has been shown to contributeto the development of atherosclerotic plaque.15,16 It is notclear whether or not SH increases the risk of cardiovasculardisease. Just as there are studies that have shown norelationship between SH and cardiovascular risk, arelationship between coronary artery disease andatherosclerosis has been reported in a meta-analysis.17-19

In some placebo-controlled studies in adults, it has evenbeen shown that L-thyroxin treatment had positive effectson atherosclerotic changes and cardiovascular risk inpatients with SH.20,21 However, all the above-mentionedstudies have been conducted on adults and there have beenvery few studies that have evaluated the relationship

Table 1 Demographic characteristic of study groups

Variables SH group (n=61) Control group (n=61) p value

Sex (Male/Female) 28/33 38/23 0.069

Age (year)* 8.0±3.37.3 (3.5-15) 8.4±2.48.1 (4.0-13.8) 0.501

Weight (kg) 24.3±10.4 25.1±7.3 0.645

Weight SDS -1.01±1.03 -0.79±1.04 0.38

Height (cm) 120.7±18.2 126.0±13.3 0.072

Height SDS -1.28±1.10 -0.56±1.07 0.01

BMI 16.0±2.1 15.6±1.9 0.283

BMI SDS -0.40±0.95 -0.71±0.98 0.055

Data are given as mean ± SD

*Data are given as mean ± SD (range)

BMI, body mass index; SH, subclinical hypothyroidism SDS, standard deviation score


between SH and cardiac functions in children.22,23 In a studyby Çatli et al22 it was shown that both systolic and diastolicimpairments in the left ventricle led to an increase in theleft ventricle mass index in children with SH. Sert et al23

also showed that there was an increase in left ventriclemass index in SH children.

There are very few studies in literature that haveevaluated the lipid profile of children with SH.22,24-27 In astudy which evaluated both paediatric and adult SH patients,it was reported that no lipid anomaly developed inpaediatric SH patients with TSH <10 µlU/L and in thosewith TSH >10 µlU/L, there was only a decrease in the HDLlevel.24 Çatli et al22 reported no statistically significantdifference between a paediatric SH patient group and acontrol group in respect of TC, TG, HDL and LDL levels.In a study of 49 children diagnosed with SH, Cerbone et al25

determined a statistically significant lower HDL-C levelcompared to the control group. Paoli-Valeri et al26

examined children aged 2-9 years diagnosed with SH andfound that the HDL cholesterol level was significantly lowin these children. Although Unal et al27 found no differencebetween a paediatric SH patient group and a control groupin respect of HDL-C and TG, the total cholesterol and LDL-C levels were seen to be significantly increased. In thecurrent study, the HDL-C level of the SH patients was foundto be significantly low compared to that of the controlgroup and no significant change was observed in the otherlipid parameters. As it was considered that the low HDL-Cin the SH group could have been coincidental, power

analysis was performed in this study. Using the HDL-Cdata in the power analysis, the power of the study wasfound to be 85%. This demonstrated that the low HDL-Cvalues in the SH group were not coincidental.

In recent years, non-invasive methods have started tobe used in the determination of atherosclerosis, whichconstitutes a risk for cardiovascular disease. Epicardialadipose tissue thickness is a new measurement tool in theearly determination of atherosclerosis.28 It is thought thatan increase in EAT causes the development of coronaryatherosclerosis through autocrine and vasocrinemechanisms.29,30 In other studies, EAT thickness has beenshown to have a relationship with coronary artery disease,independent of obesity31 and a positive correlation hasbeen shown between EAT thickness and the severity ofcoronary artery disease.8 Epicardial adipose tissue isvisceral fat tissue stored around the heart, especially onthe right ventricle free wall and the left ventricle apex. It isalso known to be stored around the atriums. Magneticresonance imaging (MRI) is accepted as the gold standardtest for the measurement of visceral body fat and it hasbeen determined that MRI measurement of visceral fattissue and EAT thickness measured with TE have shown agood correlation.8,32

There have been very few studies evaluating therelationship between EAT and SH. In some studiesconducted on adults, EAT thickness has been shown to begreater in SH patients, compared to the control group.10,11

In a study by Korkmaz et al12 the EAT thickness was shown

Table 2 Biochemical characteristics and epicardial adipose tissue thickness of the study groups

Variables SH group (n=61) Control group (n=61) p value

TSH (µIU/mL)* 7.44±2.31 2.52±0.79 0.0006.5 (5-14.5) 2.5 (0.82-4.27)

fT4 (pmol/L) 16.77±1.85 17.12±2.03 0.061

fT3 (pmol/L) 6.86±0.68 6.87±0.66 0.926

Total cholesterol (mmol/L) 158.0±29.6 155.5±21.9 0.603

LDL-C (mmol/L) 87.2±26.8 82.4±16.0 0.234

HDL-C (mmol/L) 53.8±9.9 57.8±11.2 0.040

Triglycrides (mmol/L) 84.0±44.4 73.0±24.5 0.092

EATT (mm) 4.15±0.91 4.06±0.99 0.598

Data are given as mean ± SD

*Data are given as mean ± SD and median (range)

EATT, Epicardial adipose tissue thickness; fT4, free thyroxine; fT3, free triiodothyronine; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density

lipoprotein cholesterol; SH, subclinical hypothyroidism; TSH, thyroid-stimulating hormone

Unal et al 25

to be greater in the SH patients compared to the controlgroup, and the increase was more significant in patientswith TSH ≥10 µIU/mL. In the same study, there wasreported to be a significant correlation between TSH andEAT. In a cross-sectional study of adults, EAT thicknesswas found to be similar in the patient and control groups,but a positive correlation was determined between EATand TSH in the SH group. However, an important drawbackof that study is that all the patients had a TSH value<10 µIU/mL.14 In another study of adults, no differencewas found between the SH and control groups in respectof EAT thickness and there was not determined to be anyrelationship between EAT thickness and TSH. However, thatstudy had the disadvantage of being cross-sectional, thepatient numbers were low and there was no informationabout the duration of the disease.13

To the best of our knowledge, there has been no previousstudy in literature which has evaluated the relationshipbetween SH and EAT thickness in children. In this study,EAT thickness in children with SH was greater than in thecontrol group, but the difference was not statisticallysignificant. In addition, no significant correlation wasfound in the current study between EAT thickness and TSH,total cholesterol, triglyceride, LDL-C and HDL-C. In aprevious study of adult SH patients, EAT thickness wasshown to be greater in those with TSH >10 µlU/mL.14

However, in another study of patients with TSH <10 µIU/mL, no significant difference was determined between thepatient and control groups in respect of EAT thickness andthere was no positive correlation between EAT thicknessand TSH.7 In the current study patient group, only 10patients had TSH ≥10 µIU/mL.

Study Limitations

This study had some limitations. First, it was a cross-sectional study and did not include any long-term follow-up, so the durat ion of exposure to subclinicalhypothyroidism was not clear. The second point TSH>10 µIU/mL was found only 10 of 61 patients in subclinicalhypothyroid group. In previous adult studies, therelationship between SH and EAT thickness has beendetermined especially in patients with TSH ≥10. Therefore,there is a need for further studies including many morepatients with TSH ≥10 µIU/mL to be able to evaluate therelationship between TSH and EAT thickness.

In conclusion, the results of this study demonstratedthat the HDL-C levels of children with SH were significantly

low. Although there is known to be a relationship betweenlow HDL and the risk of cardiovascular disease, there is aneed for further long-term studies of greater numbers ofpatients to be able to better understand the clinicalimportance of low HDL in relation to subclinicalhypothyroidism. In the current study, a significant increasein EAT thickness was not determined in the children withSH. As this study was cross-sectional, it did not includelong-term follow-up, so until these patients are followedup in the long-term, it is not known how SH in paediatricpatients affects EAT thickness. As this is the first study toevaluate EAT thickness in children with SH, there is a needfor further studies to support these findings so that a moredefinitive conclusion can be reached.

Conflicts of Interest

The authors declare no conflict of interests.

References

1. Cooper DS, Biondi B. Subclinical thyroid disease. Lancet 2012;379:1142-54.

2. Wu T, Flowers JW, Tudiver F, Wilson JM, Punyasavatsut N.Subclinical thyroid disorders and cognitive performance amongadolescents in the United States. BMC Pediatr 2006;6:12.

3. Tzotzas T, Krassas GE, Konstantinidis T, Bougoulia M. Changesin lipoprotein(a) levels in overt and subclinical hypothyroidismbefore and during treatment. Thyroid 2000;10:803-8.

4. Caraccio N, Ferrannini E, Monzani F. Lipoprotein profile insubclinical hypothyroidism: response to levothyroxinereplacement, a randomized placebo-controlled study. J ClinEndocrinol Metab 2002;87:1533-8.

5. Natale F, Tedesco MA, Mocerino R, et al. Visceral adiposity andarterial stiffness: echocardiographic epicardial fat thicknessreflects, better than waist circumference, carotid arterial stiffnessin a large population of hypertensives. Eur J Echocardiogr 2009;10:549-55.

6. Hak AE, Pols HA, Visser TJ, Drexhage HA, Hofman A, WittemanJC: Subclinical hypothyroidism is an independent risk factor foratherosclerosis and myocardial infarction in elderly women: theRotterdam Study. Ann Intern Med 2000;132:270-8.

7. Westerink J, van der Graaf Y, Faber DR, Visseren FL; SMARTstudy group: The relation between thyroid-stimulating hormoneand measures of adiposity in patients with manifest vasculardisease. Eur J Clin Invest 2011;41:159-66.

8. Iacobellis G, Assael F, Ribaudo MC, et al. Epicardial fat fromechocardiography: a new method for visceral adipose tissueprediction. Obes Res 2003;11:304-10.

9. Belen E, De irmencio lu A, Zencirci E, et al. The Associationbetween Subclinical Hypothyroidism and Epicardial AdiposeTissue Thickness. Korean Circ J 2015;45:210-5.

10. Unubol M, Eryilmaz U, Guney E, Akgullu C, Kurt Omurlu I.


Epicardial adipose tissue in patients with subclinicalhypothyroidism. Minerva Endocrinol 2014;39:135-40.

11. Asik M, Sahin S, Ozkul F, et al. Evaluation of epicardial fattissue thickness in patients with Hashimoto thyroiditis. ClinEndocrinol (Oxf) 2013;79:571-6.

12. Korkmaz L, Sahin S, Akyuz AR, et al. Epicardial adipose tissueincreased in patients with newly diagnosed subclinicalhypothyroidism. Med Princ Pract 2013;22:42-6.

13. Arpaci D, Toco lu AG, Yilmaz S, et al. Epicardial Adipose TissueThickness in Patients With Subclinical Hypothyroidism and theRelationship Thereof With Visceral Adipose Tissue Thickness.J Clin Med Res 2016;23:215-9.

14. Santos OC, Silva NA, Vaisman M, et al. Evaluation of epicardialfat tissue thickness as a marker of cardiovascular risk in patientswith subclinical hypothyroidism. J Endocrinol Invest 2015;238:421-7.

15. Cappola AR, Ladenson PW. Hypothyroidism and atherosclerosis.J Clin Endocrinol Metab 2003;88:2438-44.

16. Biondi B, Klein I. Hypothyroidism as a risk factor forcardiovascular disease. Endocrine 2004;24:1-13.

17. Cappola AR, Fried LP, Arnold AM, et al. Thyroid status,cardiovascular risk, and mortality in older adults. JAMA 2006;295:1033-41.

18. Rodondi N, Newman AB, Vittinghoff E, et al. Subclinicalhypothyroidism and the risk of heart failure, other cardiovascularevents, and death. Arch Intern Med 2005;165:2460-6.

19. Razvi S, Shakoor A, Vanderpump M, Weaver JU, Pearce SH.The influence of age on the relationship between subclinicalhypothyroidism and ischemic heart disease: a metaanalysis.J Clin Endocrinol Metab 2008;93:2998-3007.

20. Razvi S, Ingoe L, Keeka G, Oates C, McMillan C, Weaver JU. Thebeneficial effect of L-thyroxine on cardiovascular risk factors,endothelial function, and quality of life in subclinicalhypothyroidism: randomized, crossover trial. J Clin EndocrinolMetab 2007;92:1715-23.

21. Monzani F, Caraccio N, Kozakowa M, et al. Effect oflevothyroxine replacement on lipid profile and intima-mediathickness in subclinical hypothyroidism: a double-blind, placebo-

controlled study. J Clin Endocrinol Metab 2004;89:2099-106.22. Çatl G, K r M, An k A, Y lmaz N, Böber E, Abac A. The effect of

L-thyroxine treatment on left ventricular functions in children withsubclinical hypothyroidism. Arch Dis Child 2015;100:130-7.

23. Sert A, Pirgon Ö, Aypar E, Yilmaz H, Odabas D. SubclinicalHypothyroidism as a Risk Factor for the Development ofCardiovascular Disease in Obese Adolescents With NonalcoholicFatty Liver Disease. Pediatr Cardiol 2013;34:1166-74.

24. Marwaha RK, Tandon N, Garg MK, et al. Dyslipidemia insubclinical hypothyroidism in an Indian population. Clin Biochem2011;44:1214-7.

25. Cerbone M, Capalbo D, Wasniewska M, et al. Cardiovascularrisk factors in children with long-standing untreated idiopathicsubclinical hypothyroidism. J Clin Endocrinol Metab 2014;99:2697-703.

26. Paoli-Valeri M, Guzman M, Jimenez-Lopez V, Arias-Ferreira A,Briceno-Fernandez M, Arata-Bellabarba G. Atherogenic lipidprofile in children with subclinical hypothyroidism. An Pediatr2005;62:128-34.

27. Unal E, Ak n A, Y ld r m R, Demir V, Yildiz , Haspolat YK.Association of Subclinical Hypothyroidism with Dyslipidemiaand Increased Carotid Intima-Media Thickness in Children.J Clin Res Pediatr Endocrinol 2016;9:144-9.

28. Jeong JW, Jeong MH, Yun KH, et al. Echocardiographic epicardialfat thickness and coronary artery disease. Circulation Journal.2007;71:536-9.

29. Sacks HS, Fain JN, Memphis TN. Human epicardial adiposetissue: a review. Am Heart J 2007;153:907-17.

30. Iacobellis G. Epicardial adipose tissue in endocrine and metabolicdiseases. Endocrine 2014;46:8-15.

31. Iacobellis G, Lonn E, Lamy A, Singh N, Sharma AM. Epicardialfat thickness and coronary artery disease correlate independentlyof obesity. Int J Cardiol 2011;146:452-4.

32. Iacobellis G, Ribaudo MC, Assael F, et al. Echocardiographicepicardial adipose tissue is related to anthropometric and clinicalparameters of metabolic syndrome: a new indicator ofcardiovascular risk. J Clin Endocrinol Metab 2003;88:5163-8.


Multilocus Inherited Neoplasia Alleles Syndrome:Case Report of Two Cases

Abstract The advancement of genomic testing allows the detection of individuals affected by multilocus inheritedneoplasia alleles syndrome (MINAS), a term that refers to those who harbour two or more dominantcancer predisposing germline variants. Although the phenotypic implication for MINAS is yet to beestablished, it is postulated that it might lead to a more severe or atypical phenotype. Herein we report2 individuals each harbouring 2 pathogenic germline cancer predisposition gene variants. The first patientis a 18-year-old Chinese boy with likely pathogenic variants in NM_003000.2(SDHB):c.137G>A(p.Arg46Gln) and NM_000264.3(PTCH1):c.2380C>T(p.Gln794*). He has a relatively earlier onset ofparaganglioma compared to the mean age of diagnosis in individuals harbouring a pathogenic SDHBmutation. The second patient is a 12-year-old Chinese boy with pathogenic variants identified inNM_000729.3(BRCA1):c.4372C>T(p.Gln1458*) and NM_000314.4(PTEN):c.1003C>T(p.Arg335*).He has clinical features of PTEN hamartoma tumour syndrome including developmental delay andmacrocephaly, but enjoys good health and has no oncological disease to date.

Key words MINAS; Multilocus inherited neoplasia alleles syndrome

9/F, Tower B, Hong Kong Children's Hospital, 1 ShingCheong Road, Kowloon Bay, Kowloon, Hong Kong SAR,China

S HO MBChB(CUHK), FHKAM(Paed)IFM LO MBChB(HK), FHKAM(Paed), FHKCPaedHM LUK MD(HK), FHKAM(Paed), FRCPCH(UK)

Correspondence to: Dr HM LUK


Received August 26, 2019

Case Report

Introduction

The term multilocus inherited neoplasia allelessyndrome (MINAS) was first introduced by Whitworth etal in 2016.1 It is used to describe patients who harbourdominant germline variants in two or more cancerpredisposing genes. Previously believed to be a rarehenomenon, more individuals with MINAS are uncovereddue to the increasing application of next-generation

sequencing that enables simultaneous parallel sequencingof multiple cancer predisposition genes. Although thephenotypic implication for MINAS is yet to be established,it is postulated that it might lead to a more severe or atypicalphenotype. In this case report, we presented 2 patients eachcarrying 2 dominant cancer predisposing genetic variants.

Case Report

Case 1The index patient is an 18-year-old Chinese gentleman

who is the only child of a non-consanguineous Chinesecouple. He first presented to paediatricians for milddevelopmental delay and macrocephaly at 10 months old.Physical examination revealed hypertelorism and frontalbossing (Figure 1). He was subsequently found to haveex te rna l hydrocepha lus requ i r ing endoscop icventriculostomy at 2 years of age. He developed maxillaryand mandibular odontogenic keratocysts with surgicalresection at 13 years of age. He was found to be

S HO, IFM LO, HM LUK

Multilocus Inherited Neoplasia Alleles Syndrome28

hypertensive at 14 years old and subsequent CT scan ofthe abdomen showed a soft tissue enhancing lesion at theright side of the aortic bifurcation at the aortocaval region.Operative histological evaluation confirmed that he wassuffering from para-aortic paraganglioma and complete

Figure 1 Clinical photos of proband taken at 2 years old. There

is macrocephaly, hypertelorism and frontal bossing (a, b). Clinical

photo of proband at 18 years old (c). Clinical photo of mother of

proband. She has similar facial features including macrocephaly,

hypertelorism and frontal bossing (d). She also has bilateral palmer

pits (e).

tumour removal was achieved. He had catch up indevelopment and graduated from a mainstream secondaryschool. There is no otherwise family history ofparaganglioma, pheochromocytoma or hypertension.

He was referred to Clinical Genetic Service at 6 yearsold for developmental delay and macrocephaly. Genetictesting including karyotyping, NSD1 sequencing andFragile X testing were unremarkable. Subsequent clinicalexome sequencing detected likely pathogenic variants inNM_003000.2(SDHB):c.137G>A (p.Arg46Gln) [PS1, PM2,PP5] and NM_000264.3(PTCH1): c.2380C>T(p.Gln794*)[PVS1, PM2].

Family cascade screening showed that the mother alsocarries the same pathogenic variants in both the SDHB andPTCH1 genes. On physical examination, she hasmacrocephaly, frontal bossing and also bilateral palmerpits (Figure 1). She had history of basal cell carcinoma(BCC) over the right cheek and left upper lip and hadexcision at the age of 54. Both affected individuals werereferred to have relevant investigations and regularsurveillance.

Case 2The index patient is a 12-year-old Chinese boy who

presented with developmental delay and macrocephaly at2 years old. Physical examination showed frontal bossingand mildly depressed nasal bridge (Figure 2). With PTENhamartoma tumour syndrome in mind, hereditary cancerpredisposition syndrome panel was offered to the probandafter detailed discussion with the parents. The possibilityof identification of secondary and incidental findings wasalso conveyed to the parents. The hereditary cancerpredisposition syndrome panel revealed two clinicallysignificant pathogenic variants in NM_000729.3(BRCA1):c.4372C>T(p.Gln1458*) [PVS1, PS1, PM2, PP5] and

Figure 2 Clinical photos of proband with macrocephaly, frontal

bossing and mildly depressed nasal bridge.

Ho et al 29

NM_000314.4(PTEN):c.1003C>T(p.Arg335*) [PVS1,PM1, PM2, PP5].

The genetic findings and their implications includingthe risk of developing malignancies and the need of regularsurveillances were explained to the parents. The BRCA1gene pathogenic variant is paternally inherited while thePTEN pathogenic variant is de novo. Currently, both theproband and his father has no known oncological disease.There is no family history of breast or ovarian cancer.

Discussion

SDHB (Succinate dehydrogenase complex iron sulfursubunit B) is an essential component in the mitochondrialrespiratory chain and citric acid cycle. SDHB gene mutationis associated with paragangliomas 4 [MIM115310], anautosomal dominant disorder that predisposes affectedindividuals to developing extra-adrenal sympatheticparagangliomas with an increased risk of metastasis;phaeochromocytoma and other malignancies such as renalcell carcinoma. For individuals harbouring the SDHBmutations, 34% developed malignancy.2 The penetranceof paraganglioma/phaeochromocytoma was estimated tobe 21.8- 57.6% at the age of 60.3 Individuals at risk shouldhave annual biochemical and clinical surveillance forfeatures of paraganglioma and full-body MRI or otherwisecross-sectional imaging biennially.

PTCH1 gene is a tumour suppressor gene which encodesthe protein patched-1, a receptor for sonic hedgehog, andtogether they prevent uncontrolled cell proliferation.PTCH1 gene is associated with basal cell naevus syndrome[MIM109400], also inherited in an autosomal dominantmanner. Basal cell naevus syndrome (BCNS), also knownas Gorlin-Glotz syndrome (GGS), is characterised bymacrocephaly, development of multiple jaw keratocysts,basal cell carcinomas, cardiac and ovarian fibromas. Basalcell carcinomas can occur in early childhood but usuallypresented at the age of 30s. Surveillance for affectedindividuals would include head circumference anddevelopment monitoring, orthopantogram and skinexamination at regular intervals.

In this report, patient 1 has a younger age of diagnosisof paraganglioma when compared to the median age atdiagnosis in SDHB carriers (30 years old).2 Although theSDHB and PTCH1 genes are involved in different cellularpa thways and the mothe r has no t deve lopedparaganglioma yet at the age of 56, a synergistic effectfrom harbouring pathogenic variants in both genes cannot

be excluded. In the proband's mother, she had basal cellcarcinoma during her 50s, which is slightly later comparedto the average age of onset in affected individuals withPTCH1 variant.

For case 2, PTEN hamartoma tumour syndrome (PHTS)is a tumour suppressor gene that produces phosphatase andtensin homolog, a phosphatase protein product involvedin the regulation of cell proliferation via antagonising theP13K/AKT pathway. Affected individuals have anincreased risk of developing benign tumours, harmatomasand also malignancies involving different organs (e.g.breast, thyroid, renal cell, endometrial, colon cancer andmelanoma) and might have developmental delay. Themajority of malignancies occur after the age of 30s, thoughthere is reported case of thyroid cancer occurring as earlyas 7 years of age.4 Individuals harbouring PTEN pathogenicvariant are recommended to have regular surveillanceincluding annual dermatological examination and thyroidultrasound. Women are encouraged to have monthly breastself-examination, annual breast screening and transvaginalultrasound or endometrial biopsy. Regular colonoscopyand renal imaging is also recommended.

BRCA1 is a tumour suppressor gene responsible forDNA break repair or destruction of cells when beyondrepair by its interaction with other cyclin protein and cylin-dependent kinase. Mutation of BRCA1 gene could led toan increased genomic instability and predispose affectedindividuals to oncological diseases. BRCA1-associatedhereditary breast and ovarian cancer syndrome (HBOC) ischaracterised by an increased risk of breast and ovariancancer development. Monthly breast self-examination,annual/semiannual clinical breast examination, annualmammography and breast MRI is advocated for breastcancer screening in affected female individuals. Foraffected males, breast self-examination and annual clinicalbreast examination and annual screening of prostate canceris also recommended.

Although PTEN and BRCA1 appeared functionallydistinct, mutual interaction between these two genes hasbeen proposed as both were involved in the p53 pathway.5

However, there is of note no published study regardingaffected individuals with both mutations having a moresevere/atypical phenotype. A close follow up of ourproband is needed to watch out for evolving oncologicaldiseases.

The term multilocus inherited neoplasia allelessyndrome (MINAS) was first introduced in 2016 byWhitworth et al.1 Previously believed to be a rarephenomenon, more individuals with MINAS are uncovered

Multilocus Inherited Neoplasia Alleles Syndrome30

due to the increasing application of next-generationsequencing that enables simultaneous parallel sequencingof multiple cancer predisposition genes. Out of the 314cancer panels performed in our center, only 1 individualwas identified to have MINAS. Most of the reported casesinvolve affected individuals with a hereditary cancer genemutation that is related to the presenting cancer phenotype;and a second mutation that has no manifestation in theproband and related family members at the time ofreporting. Current reported cases of MINAS mainly involvebreast and colorectal cancer related genes (e.g. BRCA1and BRCA2 mutation) or those genes related toconstitutional mismatch repair syndrome. Ascertainmentbias is difficult to eliminate as certain types of cancer andtheir related genes are more readily recruited for analysis.Affected individuals with a more severe phenotype and astrong family history are also more likely subjected togenetic testing. It is postulated that MINAS involving acertain combination of mutations might produce a moresevere phenotype. However, due to the heterogeneity ofmutation combinations and varying mechanisms ofoncogenes, whether or not MINAS could lead to a moresevere phenotype (e.g. an earlier onset, unusual tumourcharacteristics) remains inconclusive. Existing data giveconflicting information even for the better-known BRCA1and BRCA2 mutation combination.6,7 For the othermutation combinations, only limited case reports andanimal studies are available.

It is believed with the advancement of medicalknowledge and increasing readiness of genetic testing,more individuals with MINAS will be detected. A preciseinterpretation of mutation combinations will be on demandin order to facilitate personalised management and riskestimation. Based on current limited experiences withMINAS, affected individuals with a more severe phenotypeexist but there is not enough evidence to extend to aconclusion. From our data, we can see there is a relativelyearlier onset of paraganglioma in the proband harbouringboth SDHB and PTCH1 variant, but there is no furtherevidence to support an atypical or more severe clinicalphenotype in individuals with MINAS. Prospective followup of these two probands and their families would be ofvalue in order to appreciate the age-dependent penetrance

of the variants. Further functional studies and tumourprofiling might be able to provide further insight into thephenotypic effect of MINAS. Data sharing with continuousupdate is encouraged as it might hopefully help to improveour understanding of MINAS.

Acknowledgement

The authors acknowledge the patients and their familiesfor contributing the clinical data and photographs for thisstudy. Written informed consents for publishing clinicalinformation with photographs were obtained from theparents.

Conflict of Interest

All authors have disclosed no conflicts of interest.

References

1. Whitworth J, Skytte A, Sunde L, et al. Multilocus InheritedNeoplasia Alleles Syndrome: A Case Series and Review. JAMAOncol 2016;2:373-9.

2. Online Mendelian Inheritance in Man, OMIM®. Johns HopkinsUniversity, Baltimore, MD. MIM Number: {115310}: {05/01/2018}:. World Wide Web URL: https://omim.org/

3. Else T, Greenberg S, Fishbein L. Hereditary Paraganglioma-Pheochromocytoma Syndromes. 2008 May 21 [Updated 2018Oct 4]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors.GeneReviews® [Internet]. Seattle (WA): University of Washington,Seattle; 1993-2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1548/

4. Smith JR, Marqusee E, Webb S, et al. Thyroid nodules andcancer in children with PTEN hamartoma tumor syndrome.J Clin Endocrinol Metab 2011;96:34-7.

5. Minami A, Nakanishi A, Ogura Y, Kitagishi Y, Matsuda S.Connection between Tumor Suppressor BRCA1 and PTEN inDamaged DNA Repair. Front Oncol 2014;4:318.

6. Heidemann S, Fischer C, Engel C, et al. Double heterozygosityfor mutations in BRCA1 and BRCA2 in German breast cancerpatients: implications on test strategies and clinical management.Breast Cancer Res Treat 2012;134:1229-39.

7. Leegte B, van der Hout AH, Deffenbaugh AM, et al. Phenotypicexpression of double heterozygosity for BRCA1 and BRCA2germline mutations. J Med Genet 2005;42:e20.


A New Case - Heterozygote PACS1 Mutation in a Patient withSchuurs-Hoeijmakers Syndrome and a Left Duplex Kidney:

Case Report

Abstract PACS1 is a rare form of monogenic disorder characterised by intellectual disability, developmentaldelay, and mild distinctive facial features. The typical facial features include a low hairline on theforehead, eyes that are spaced far apart and slanting downwards, thick eyebrows that may be connectedto each other, long eyelashes, large ears that are set low on the head, and gaps between the teeth.Diagnosis is made through a genetic analysis, particularly by whole exome sequencing. Although renalabnormalities are rarely seen in such patients, we present an atypical case of a 33-month-old girl with aleft duplex kidney.

Key words Down-like face; Duplex kidney; PACS1; Typical facial features

Department of Pediatric Neurology, Karadeniz TechnicalUniversity, Trabzon, Turkey

B DILBER MDE ARSLAN ACAR MDA CANSU Prof.

Department of Genetic, Karadeniz Technical University,Trabzon, Turkey

AH CEBI MD

Correspondence to: Dr B DILBER



Case Report

Introduction

PACS1 gene is found on the long arm of the chromosome11 (11q13.1-13.2). The mutations showing autosomaldominant inheritance in this gene are known to causeSchuurs-Hoeijmakers syndrome. For the first time, Schuurs-Hoeijmakers et al diagnosed PACS1 as a de novo mutationin two boys who had similar findings and no cognation.The findings included similar typical facial appearance,intellectual and motor disability, and cryptorchidism.1 Ade novo c.607C>T (p.R203W) mutation was detected inboth boys and their clinical appearance were highly similar.In 2014, three other patients with similar findings and

PACS1-associated symptoms were described by Gadzickiet al.2

The only known cause of Schuurs-Hoeijmakerssyndrome is the PACS1 mutation. Typical manifestationsof this syndrome include intellectual disability,characteristic facial features such as a mouth with down-turned corners, seizures, and cerebral abnormalities. A denovo c.607C>T (p.R203W) mutation is typically seen inPACS1. Also, Miyake N et al reported a de novo missensePACS1 (c.608G>A (p.R203Q) mutation.3 In the casepresented in this study, a heterozygous missense c.607C>T (p.R203W) mutation was detected in the PACS1 geneand the patient was diagnosed with whole exomesequencing (WES). Additionally, the patient was detectedwith a left duplex kidney, which is a rare occurrence insuch patients.

Case Presentation

A 33-month-old girl with a body weight of 12.8 (10th-25th percentile), height of 90 cm (10th percentile), and ahead circumference of 48 cm (10th percentile) presentedto the paediatric neurology clinic due to speech retardationand atypical facial appearance. Neuromotor developmentof the patient was retarded and it was revealed that she couldhold her head steady at 4 months, sat without support at 18

B DILBER, E ARSLAN ACAR, AH CEBI, A CANSU

Schuurs-Hoeijmakers Syndrome and a Left Duplex Kidney32

months, started to walk at 26 months. Although the patientproduced only four meaningful words, she was friendly andgood-humoured. Her IQ was revealed to be 54 accordingto the Denver Developmental Screening Test (DDST). Shewas the first living child delivered at the third pregnancy ofher mother who was 27 years old during the time of delivery.It was also revealed that the mother had been followed updue to oligohydramnios throughout the gestational periodand her father was a 32-year-old healthy individual. Theparents had no consanguineous relationship. Patient historyrevealed that the patient had been monitored undermechanical ventilation after birth due to neonatal meconiumaspiration syndrome. Moreover, she experienced apnoeicseizures three times in the neonatal period, followed by afocal seizure on her right arm at the age of 3 months. Afterthe age of two, her antiepileptic treatment was discontinuedwhen she had no more seizures. Physical examinationrevealed hypertelorism, mild ptosis, a large mouth,depressed and wide nasal bridge, long philtrum, flateyebrows, eyelids drooping downwards, prominent ears,thin upper lip, overlapping toes in the right foot, and pectusexcavatum (Figure 1). Additionally, a grade 1/6 systolicejection murmur was heard. Other system examinationswere normal and biochemical analyses were unremarkable.No immunodeficiency was found. A patent foramen ovale(PFO) was detected on electrocardiography (ECG). Renalultrasonography (US), which was performed due to thepresence of recurrent urinary tract infections, revealed aleft duplex kidney. Cranial magnetic resonance imaging(MRI) scan was normal and electroencephalography (EEG)was unremarkable. WES revealed a heterozygous de novomissense c.607C>T (p.R203W) mutation in the PACS1gene.

Discussion

Abnormal migration of nerve cells resulting from thereplacement of arginine by tryptophan in the furin-bindingregion is considered to play a role in the etiopathogenesisof PACS1, and similar facial findings are explained byzebrafish research.4 However, the presence of similar facialfeatures in other symptoms including Baraitser-Wintersyndrome, Cornelia de Lange syndrome, Mowat-Wilsonsyndrome, and Kabuki syndrome complicates the diagnosisof PACS1 mutations. This challenge can be eliminated bythe use of WES analysis, which can also detect theabnormalities accompanying these facial features.

The PACS1 mutation detected in our patient wascharacterised by intellectual disability, prominentcraniofacial characteristics (hypertelorism, mild ptosis, alarge mouth, depressed and wide nasal bridge, longphiltrum, flat eyebrows, eyelids drooping downwards,prominent ears, and thin upper lip), psychomotorretardation, mild-to-moderate speech retardation,hypotonia, seizures, structural malformations (heart, brain,eyes, kidneys, and bones), and additional congenitalanomalies (Tables 1 & 2). The WES analysis performed inour patient detected a heterozygous missense c.607C>T(p.R203W) mutation in the PACS1 gene. This mutation wasalso shown to be heterozygous in the DNA sequencinganalysis performed with the Sanger method. Additionally,the parents were also examined and were found to be normal.

Schuurs-Hoeijmakers et al, in their series of 19 casesaged 2-21 years, found typical facial anomalies in allpatients as well as different abnormalities including cardiacabnormalities in 10 patients and renal problems in threepatients.4 Additionally, almost half of the patients

Figure 1 Clinical photo showing hypertelorism, mild ptosis, a large mouth, depressed and wide nasal bridge, long philtrum, flat eyebrows,

eyelids drooping downwards, prominent ears, thin upper lip, overlapping toes in the right foot, and pectus excavatum.

Dilber et al 33

presented with gastrointestinal problems such as severefeeding, swallowing, and reflux problems. Renalabnormality was seen in only three cases and two of themhad right renal duplex anomaly and urethral diverticulum.No vesicourethral reflux was observed.4 In our case,however, had a left duplex kidney and grade IVvesicoureteral reflux. We consider that advanced geneticanalyses are helpful for the establishment of diagnosis inthese patients, as was in our case. Accordingly, WESanalysis appears to be ideal option in the diagnosis of thesepatients.

Conclusion

Whole exome sequencing (WES) appears to be an idealmethod for the diagnosis of patients with moderateintellectual disability, prominent speech retardation, and

Table 1 Typical facial appearance findings of PACS1 mutation

Facial apperance

Arched eyebrows

Hypertelorism with downslanting palpebral fissures

Long eye lashes

Ptosis (in some)

Low set and simple ears

Bulbous nasal tip

Wide mouth with downturned corners

Thin upper lip with an unusual "wavy" profile

Fat philtrum

Diastema of the teeth

Table 2 Major organ involvement for Schuurs-Hoeijmakers syndrome

Growth & Feeding Microcephaly Failure to thrive Oral aversion Reflux G-tube

Neurodevelopmental features Developmental delay/ Language Temper tantrums/intellectual disability development agression

Neurological disorder & Hypotonia Structural brain Dysmorphic facial Autism spectrumBehaviour seizures abnormalities features disorder

Cerebral imaging

Skeletal abnormalities Pectus excavatum Scoliosis Clinodactyly of 5th finger Abnormal skull shape

Congenital malformations ASD/VSD Colobomata Single palmar crease Kidney abnormalityCryptorchidism

non-persistent seizures, particularly of patients withsimilar facial appearance. Patients with PACS1 mutationmay rarely present with renal abnormalities, most of whichare treatable. The use of social media platforms (e.g. PACS1groups) by the parents of children diagnosed with PACS1mutation could be helpful for raising awareness andeliminating concerns among these patients and theirparents. Accordingly, by presenting the current case, weaimed to raise awareness among the parents of childrenwith a PACS1 mutation by emphasizing that a PACS1mutation could be present in syndromic patients withintellectual disability and similar facial appearance andthat there could be additional abnormalities in such patientsthat may require clinical follow-up.

Conflict of Interest

All the authors declare no conflict of interest for thisstudy.

References

1. Schuurs-Hoeijmakers JH, Oh EC, Vissers LE, et al. Recurrent denovo mutations in PACS1 cause defective cranial-neural-crestmigration and define a recognizable intellectual-disability syndrome.Am J Hum Genet 2012;91:1122-7.

2. Gadzicki D, Döcker D, Schubach M, et al. Expanding the phenotypeof recurrent de novo variant in PACS1 causing intellectual disability.Clin Genet 2015;88:300-2.

3. Miyake N, Ozasa S, Mabe H, et al. A novel missense mutationaffecting the same amino acid as the recurrent PACS1 mutation inSchuurs-Hoeijmakers syndrome. Clin Genet 2018;93:929-30.

4. Schuurs-Hoeijmakers JH, Landsverk ML, Foulds N, et al. Clinicaldelineation of the PACS1-related syndrome-Report on 19 patients.Am J Med Genet A 2016;170:670-5.


Safety and Effectiveness of Herbal Medicine Administered fromthe Early Neonatal Period in Two Neonates with Congenital

Cystic Lymphatic Malformations

Abstract There are various treatments of lymphatic malformations. Herbal medicine (TJ-28) is effective for treatinglymphatic malformations. TJ-28 was administered from the early neonatal period to two neonates withlymphatic malformations at birth. In Case 1, a lymphatic malformation on the neck at birth was treatedwith TJ-28 from 5 days old. The lymphatic malformation was greatly reduced, but there was a mildtransient elevation in liver aminotransferases levels, which were unlikely to be related to TJ-28. In Case2, a lymphatic malformation in the femur at birth was treated with TJ-28 from 3 days old. There were noadverse events, but the lymphatic malformation was not reduced until 7 months old. TJ-28 administeredfrom the early neonatal period showed no serious adverse events and it was effective in one of two cases.Therefore, TJ-28 may be a treatment for neonates with lymphatic malformations when surgery orsclerotherapy is difficult.

Key words Herbal medicine; Lymphatic malformation; Neonate; Safety

Department of Pediatrics, Kushiro City General Hospital,1-12, Shunkodai, Kushiro-shi, Hokkaido, 085-0822, Japan

S HASHIMOTO MD

Correspondence to: Dr S HASHIMOTO


Received March 22, 2019

Case Report

Introduction

Treatments of lymphatic malformations (LMs) arevaried, such as surgery, sclerotherapy, and oralmedication.1-3 Recently, the effectiveness of herbalmedicine (Eppikajyutsuto, TJ-28; Tsumura Co., Tokyo,Japan) in treating LMs was reported.4-6 Whether TJ-28 issafe and effective for administration from the early neonatalperiod or for neonates with large congenital LMs at birthis unclear. This report describes two neonates with largeLMs at birth who were safely treated with TJ-28 from theearly neonatal period.

Case Report

Case 1The neonate's mother was 37 years old and had a normal

course of pregnancy. A foetal ultrasound and magneticresonance imaging (MRI) examination showed a mass onthe right neck, which suggested LM, at 39 weeks and 4days of pregnancy. The neonate was delivered at 39 weeksand 5 days of gestation by caesarean section.

The neonate was a boy and his birth weight was 3430 g.The Apgar score was 8 points at 1 minute and 9 points at5 minutes, and his cardiorespiratory dynamics were stable.He had a mass in the right neck, and it was soft, elastic, andundulating. There were no symptoms of the respiratorytract and oesophageal exclusion. He had no external orinternal malformations excluding the mass in the neck.MRI showed a multicystic mass with T1 low intensity andT2 hyperintensity, and this mass was located from the rightsubmandibular to lateral cervical areas (Figures 1A & 1B).The pharynx and airway were retracted and contralaterallydeviated. The cyst was diagnosed as mixed micro- andmacrocystic LM. Informed consent was obtained from the

S HASHIMOTO

Hashimoto 35

patient's parents regarding the fact that the safety andeffectiveness of herbal medicine administered in theneonatal period to treat LMs has not been established, andTJ-28 was administered at a dose of 0.2 g/kg/day from theage of 5 days. The patient was discharged home at the ageof 7 days.

The patient had no symptoms caused by the LM afterdischarge. The LM was not complicated by bleeding,infection, or trauma, and was gradually reduced. At 3months old, apparent swelling of the neck had almostdisappeared. MRI showed that the LM was greatly reducedat 5 months old (Figures 1C & 1D). There was a mildincrease in liver aminotransferase levels at 5 months ofage, and aspartate transaminase was 98 IU/L and alaninetransaminase was 94 IU/L; however, both values weremaximums at that point and normalised spontaneously by9 months of age even though administration continued.Therefore, we assessed that this adverse event was not likelyrelated to TJ-28. TJ-28 treatment did not inducepseudoaldosteronism and sympathetic hyperactivitysymptoms, and there were no other serious adverse events.TJ-28 administration was stopped at 9 months old. At thetime of this report, the patient was 15 months old, and theLM remained, but there was no regrowth. TJ-28 or otheradditional treatments have not been required.

Case 2The neonate's mother was 25 years old. A foetal

ultrasound and MRI examination showed a mass in theright thigh from 20 weeks of pregnancy. There were noother abnormal findings and no pleural or peritonealeffusion. The neonate was delivered at 39 weeks and0 day of gestation by vaginal delivery.

The neonate was a boy and his birth weight was 2725 g.The Apgar score was 8 points at 1 minute and 9 points at5 minutes, and his general condition was stable. He had amass in the right femur, and it was soft, elastic, andundulating. The circumference of the right thigh was19 cm and the ratio of right/left was 1.36. MRI showed amulticystic mass with T1 low intensity and T2hyperintensity, and the mass was located from the rightperineum to frontal and interior of the femur (Figures 1E& 1F). The mass was diagnosed as mixed micro- andmacrocystic LM. Informed consent was obtained from thepatient's parents to use TJ-28, and it was administered at adose of 0.3 g/kg/day from 3 days old. He was dischargedhome at 6 days old.

The LM showed no bleeding or infection, but it has not

been reduced to date (Figures 1G & 1H). At the time ofthis report, the patient was 7 months old, and has beencontinuing TJ-28 administration. There have been noadverse events, including pseudoaldosteronism andsympathomimetic symptoms. The circumference of theright femur was 32 cm and the ratio of right/left was 1.33.

Discussion

Treatment of LMs has remained a challenge dependingon the tumour size, location, and age of onset.1-3 In Japan,the effectiveness of an herbal medicine, TJ-28, has beenreported since 2011.4-6 The use and efficacy of TJ-28 inneonates have not been clarified until our report.Furthermore, treatment of large LMs of the neck in infants,particularly early infancy, tend to be surgery orsclerotherapy because of airway obstruction.2,3 Sometimessurgery or sclerotherapy is difficult. This is because surgeryhas the risk of injury to surrounding normal tissues.Sclerotherapy has little effect on some types of LMs andthere is the possibility of respiratory obstruction accordingto reactive enlargement when it is on the neck. New oraltherapies, including propranolol, sildenafil, and sirolimus,are effective.1 However, there is insufficient evidence forthe effectiveness of these drugs and serious side effectscan occur in a few cases. Caution should be applied foradministering these drugs in neonates. Therefore, thecurrent cases were treated with TJ-28 in consideration ofsafety.

The effect of TJ-28 to LMs is yet to be fully clarified.Mao, which is the main component of TJ-28, suppressespros tag land in E

2 b iosyn thes i s , express ion o f

cyclooxygenase 2 protein, and activation of the inhibitorof the nuclear factor-k B-dependent signalling pathway.4

These actions might not only reduce the mass, but alsoprevent bleeding or infection. In one of our cases, the LMwas greatly reduced. In the other case, the size of the LMdid not decrease, but we continued TJ-28 administrationbecause of the possibility of preventing an increase in thesize of the mass, bleeding and infection. Mao is an Ephedraherb and sometimes induces sympathomimetic symptoms.Attention must be paid to tachycardia and hypertension inolder people who take Mao, particularly those who haveischaemic heart disease. TJ-28 also contains theGlycyrrhizae radix, "Kanzo", so it occasionally inducespseudoaldosteronism. We used TJ-28 while carefullyconsidering the risk of hypertension, tachycardia, oedema,

Lymphatic Malformations and Herbal Medicine36

Figure 1 Magnetic resonance imaging (MRI) scan (T2-weighted image).

A, B (Case 1, at birth): MRI shows a large multicystic mass of the neck (arrow). The pharynx and airway are retracted and contralaterally

deviated (arrow head); C, D (Case 1, at 5 months old): The mass shows a marked reduction (arrow) and the pharynx and airway are not

deviated (arrow head); E, F (Case 2, at birth): MRI shows a large multicystic mass of the thigh (arrow). The cyst is widely spread from the

right perineum to frontal and interior of the femur in subcutaneous tissue; G, H (Case 2, at 5 months old): The mass is not reduced compared

with at birth (arrow).

(A) (B) (C)

(D)(E)

(F)

(G)

(H)

Hashimoto 37

irritability and hypokalaemia. There were no seriousadverse events, including pseudoaldosteronism andsympathomimetic symptoms, in both of our cases duringthe administration of TJ-28. Also, the side effects of TJ-28 have not been reported in paediatric patients with LMs.One of our cases showed a mild transient elevation in liveraminotransferase levels; however, this increase was notlikely related to TJ-28 treatment. TJ-28 use in neonates islikely safe; however, further studies are needed to confirmits safety.

The most important advantage of TJ-28 therapy for LMsis that it is noninvasive compared with surgery orsclerotherapy, so TJ-28 can be administered as anoutpatient treatment. However, the possibility of recurrenceafter administration, and the optimum dose and durationare unknown. Also, TJ-28 sometimes has a poor effectdepending on the location or type.4 TJ-28 treatment is moreeffective for mixed micro- and macrocystic LMs than formacrocystic LMs because TJ-28 prevents the accumulationof lymphatic fluid, and micro- and macrocystic LMs containless lymphatic fluid than macrocystic LMs.4 Additionally,LMs of the head and neck occasionally spontaneouslydecrease under observation alone.7 These factors mayexplain the different effects of TJ-28 in our two cases. Thereare still some problems that must be solved regarding TJ-28 therapy for LMs. However, TJ-28 is easy to use in infants,particularly in neonates, who have problems of safety withother treatments. Therefore, TJ-28 should be attemptedbefore surgery or sclerotherapy from the early neonatalperiod.

In conclusion, TJ-28 treatment from the earlyneonatal period had no serious adverse events. Thistreatment was effective for congenital cystic LMs atbirth in one of our two cases. In the other case, the LMdid not decrease in size, but TJ-28 might have preventedan increase in the size of the mass, bleeding andinfection. TJ-28 may be a treatment option for neonateswith large LMs when there is difficulty with surgery orwith sclerotherapy.


The author declares that there is no conflict of interest.

Declaration of Informed Consent

Informed written consent was obtained in both casesfrom the patients' parents.

Acknowledgment

We thank Ellen Knapp, PhD, and Jane Charbonneau,DVM, from Edanz Group (www.edanzediting.com/ac) forediting a draft of this manuscript.

References

1. Bagrodia N, Defnet AM, Kandel JJ. Management of lymphaticmalformations in children. Curr Opin Pediatr 2015;27:356-63.

2. Boardman SJ, Cochrane LA, Roebuck D, Elliott MJ, Hartley BE.Multimodality treatment of pediatric lymphatic malformations ofthe head and neck using surgery and sclerotherapy. ArchOtolaryngol Head Neck Surg 2010;136:270-6.

3. Ma J, Biao R, Lou F, et al. Diagnosis and surgical treatment ofcervical macrocystic lymphatic malformations in infants. Exp TherMed 2017;14:1293-8.

4. Hashizume N, Yagi M, Egami H, et al. Clinical efficacy of herbalmedicine for pediatric lymphatic malformations: a pilot study.Pediatr Dermatol 2016;33:191-5.

5. Ogawa-Ochiai K, Sekiya N, Kasahara Y, et al. A case of mediastinallymphangioma successfully treated with Kampo medicine.J Altern Complement Med 2011;17:563-5.

6. Shinkai T, Masumoto K, Chiba F, Tanaka N. A large retroperitoneallymphatic malformation successfully treated with traditionalJapanese Kampo medicine in combination with surgery. Surg CaseRep 2017;3:80.

7. Gilony D, Schwartz M, Shpitzer T, Feinmesser R, Kornreich L,Ravehet E. Treatment of lymphatic malformations: a moreconservative approach. J Pediatr Surg 2012;47:1837-42.


Restless Leg Syndrome in a Child and an Adolescent withExcellent Responses to Iron Replacement Therapy

Abstract We report symptomatic Restless Leg Syndrome (RLS) in an adolescent with normal intelligence, and ayoung autistic child who suffered from stroke. Both were found to have low serum ferritin levels. In bothcases, iron replacement therapy resulted in complete remission of symptoms. The findings substantiatethe hypothesis that brain iron deficiency is implicated in the pathophysiology of RLS. Ferritin levelbelow 112 pmol/L (50 ng/ml) serves as a useful threshold to aid diagnosis and treatment in symptomaticyoung children who cannot tell their discomfort.

Key words Iron deficiency; Iron supplementation; Restless leg syndrome; Serum ferritin

Department of Paediatrics and Adolescent Medicine,Caritas Medical Centre, 111 Wing Hong Street, ShamShui Po, Kowloon, Hong Kong SAR, China

CPL HOO MRCPCH, MBChB (CUHK)

WL LAU MRCPCH, DCH (International RCPCH),FHKAM (Paediatrics)

CH KO FHKAM (Paediatrics), FRCP (Glasg)

Correspondence to: Dr CPL HOO



Case Report

Case One

An 18-year-old girl presented with lower back injuryduring volleyball practice. She complained of low backpain, lower limb weakness and numbness. X-ray andMagnetic Resonance Image (MRI) of lumbosacral spinewere unremarkable. After a course of physiotherapy, shestill complained of persistent lower limb numbness despiteimprovement in weakness and pain. She described thefeeling as "a sense of insufficient blood flow" to lowerlimbs and therefore an urge to move in order to relievesuch discomfort. The discomfort was more obvious duringnighttime that made her difficult to initiate sleep.Examination showed decrease in touch sensation over rightlower limb below knee level, but no definite gloves and

s tockings d is t r ibut ion of numbness . No foca lneurological signs were elicited. Complete blood count,liver, renal and thyroid function, muscle enzymes (CKand LDH), fasting glucose, vitamin B12 and folate levelwere normal. Nerve conduction studies (NCV), visualevoked potentials (VEP) and somatosensory evokedpotentials (SSEP) did not reveal any evidence ofneuropathy. However, she was found to have low serumferritin level 18 pmol/L (reference 24-675 pmol/L) andiron saturation 8% (reference 15-50%); notably serumiron, total iron binding capacity (TIBC), haemoglobinlevel and mean corpuscular volume (MCV) were normal.Ferrous sulphate 300 mg twice daily (equivalent toelemental iron 195 mg daily, or 4 mg/kg/day) was given.Ferritin level raised to 51 pmol/L 9 weeks aftersupplementat ion at which t ime she has part ia limprovement in symptoms, while she declined furtherblood taking thereafter. Total 3 months of ironsupplementation was given. Sustained remission withimproved sleep six months after iron therapy was takenoff was noted in subsequent follow-up.

Case Two

A 3-year-old right hemiplegic autistic boy withidiopathic acute ischemic stroke was admitted for neuro-rehabilitation. Mother reported and video-recorded marked

CPL HOO, WL LAU, CH KO

Hoo et al 39

irritability, repetitive non-stereotyped left lower limbmovement at nighttime which disturbed sleep. The childremained fully conscious but was difficult to beconsoled. Family history was negative for RLS.Investigations revealed low serum ferritin 48 pmol/L(reference 53-739 pmol/L); serum iron, TIBC,haemoglobin level and MCV were normal. He wasempirically started on elemental iron 90 mg per day(6.2 mg/kg/day). Two months later the symptomspersisted and rechecked serum ferritin varied from42 to 90 pmol/L. Iron supplement was increased to120 mg per day (8.3 mg/kg/day). Serum ferritin levelsubsequently raised to 132 pmol/L at four months aftertreatment, associated with total resolution of symptoms.He was given six months of iron supplement, and motherreported sustained remission of leg movement withimproved sleep five months after cessation of treatment.

Discussion

RLS is a common, complex while treatable neurologicalcondit ion affecting the central nervous systemsensorimotor network. Paediatric population-based studiesreveal a prevalence ranging from 2-6%, with 25% childrenand 50% adolescents experiencing moderate to severe

symptoms.1 Intriguingly, the condition is not commonlyreported in local literature. Zhang et al conducted a localpopulation-based family study using a single question toscreen for RLS symptoms in 1549 adolescents, revealinga prevalence of 2.8%.2 Prevalence in children was notstudied. A thorough search through the Hospital AuthorityClinical Data Analysis and Reporting System (CDARS)from 1st January 2014 to 31st December 2018 retrievedtwo in-patients with the diagnosis of RLS among 431,322Paediatric admissions, yielding an estimated incidence of4.6 per 100,000 admissions. While the exceptionally lowincidence is likely due to low hospitalisation rate for RLS,this also reflects under-diagnosis of this treatable condition,particularly in young children who cannot tell theirsymptoms.

Table 1 summarises the National Institute of Health(NIH) diagnostic criteria for definite RLS in children andadolescents.3 As illustrated in case one, in most adult andadolescent cases aged 13-18, the diagnosis of RLS isentirely based on clinical history which can be summarisedas the acronym "URGE":• Urge to move legs, usually associated with unpleasant

sensation• Rest induces symptoms• Getting active brings relief• Evening and night make symptoms worse

Table 1 NIH workshop diagnostic criteria for RLS in children and adolescents

Diagnostic criteria for definite RLS in children 2-12 years old:

"Definite 1" RLS

A. All four adult essential criteria are met:

1. An urge to move the legs;

2. The urge to move begins or worsens when sitting or lying down;

3. The urge to move is partially or totally relieved by movement;

4. The urge to move is worse in the evening or night than during the day or only occurs in the evening or night; and

B. The child uses his/her own words to describe leg discomfort.

or

''Definite 2" RLS

A. All four adult essential criteria are met, and

B. 2-3 supportive criteria are met:

1. Sleep disturbance inappropriate for age

2. Biological parent or sibling has definite RLS

3. The child has a sleep study documenting a periodic limb movement index ≥5h of sleep

Diagnostic criteria for definite RLS in adolescents 13-18 years old:

All four adult essential criteria are met.

For all ages: The leg sensations are not solely accounted for as symptoms of another medical or a behavioural disorder

Iron Therapy in Restless Leg Syndrome40

Definitive diagnosis is more difficult in children aged2-12 years, who often have difficulty to describe the legdiscomfort in his/her own words. Diagnosis in the latterrequires supportive criteria including first degree familyhistory, polysomnographic evidence of periodic limbmovement or significant sleep disturbance (Table 1). Asillustrated in case 2 who had limited speech and negativefamily history, definitive diagnosis is challenging for thefamily paediatrician who does not readily have access topolysomnography. Moreover, mimics such as orthopaedicproblems, myalgia, dermatitis, polyneuropathy, cramps orarthritis will need to be excluded.3 RLS may also beoverlooked in children who present as impaired cognitionand daytime functioning secondary to sleep disturbance.Co-morbid conditions such as attention deficit/hyperactive disorder (ADHD) and mood disorders may alsobe the chief complaints shrouding underlying RLS in youngkids.4

Brain iron deficiency has been implicated in thepathophysiology of RLS. Paediatric studies identified lowferritin levels below 112 pmol/L in over 80% of RLScases.5 Iron is a co-factor for tyrosine hydroxylase, animportant enzyme in the synthesis of dopamine. Irondeficiency below 112 pmol/L is hypothesised to disruptdopamine production in norepinephrine and serotoninneurotransmitter systems.4 Physicians should be aware thiscut-off level is higher than the lower-limit-of-normal fordiagnosis of iron deficiency anaemia, as hemoglobinsynthesis is only affected with ferritin level below 22.5-27.0 pmol/L.6 In symptomatic young children withprobable RLS (i.e. first degree family history, together withurge to move legs, rest induces symptoms, getting activebrings relief, but symptoms may not be worse towardevenings), the finding of low ferritin level below 112 pmol/Lis a useful guide to initiate iron replacement. A favorabletherapeutic response, in retrospect, may help confirm thediagnosis in young children. Sleep study may be reservedfor those probable RLS with normal ferritin levels, or non-responders to iron replacement therapy.1

Dye et al evaluated 105 children with RLS and serumferritin below 112 pmol/L.7 Clinical improvement ofperiodic limb movement coincided with serum ferritinincreases. The latest clinical practice guidelines by theInternational Restless Legs Syndrome Study Group(IRLSSG) in 2017 also supports setting a therapeutic targetfor serum ferritin ≥112 pmol/L for oral iron in RLS. Theusual recommended dose is 3-6 mg/kg/day of elementaliron for three months, with repeat serum ferritin levels toassess response and avoid iron overload.7 As illustrated in

case 2, refractory symptoms with suboptimal ferritin levelafter initial iron replacement may warrant augmentationof supplement to attain ultimate therapeutic threshold. Ifferritin levels are very low or levels fail to improve aftertreatment with iron, further evaluation is required toexclude occult blood loss and malabsorption.4,7

Intravenous iron therapy is effective in refractory adultRLS cases with severe iron deficiency or malabsorption.The IRLSSG recommended that intravenous iron is used iffollowing occur: a prior iron treatment of at least 3 monthshas not produced an adequate benefit or was discontinuedbecause of adverse effects and there has been no appreciablerise in serum ferritin levels with 3 months of oral irontreatment.8 Non-pharmacological treatment includesmaintaining good sleep hygiene, avoid medications,nicotine and caffeine that may aggravate RLS symptoms.Pharmacological treatment is used in cases with ongoingsignificant symptoms despite iron supplementation.Dopaminergic agents including ropinirole and pramipexoleare considered first-line agents in adult RLS. Clonidineand gabapentin have also been shown to improve symptomsin children with prominent sleep disturbance.4,7

Conclusion

RLS is a complex but treatable condition; yet it is likelyto be under-diagnosed in local paediatric population.Careful history taking, physical examination and relevantinvestigations are mandatory to detect the conditionand look for comorbid conditions. Ferritin level below112 pmol/L is a useful diagnostic as well as therapeuticthreshold to guide initiation of iron replacement insymptomatic children.


All authors do not have any financial and personalrelationships with other people or organisations that couldinappropriately influence their work.

References

1. Picchietti D, Allen RP, Walters AS, Davidson JE, Myers A, Ferini-Strambi L. Restless legs syndrome: prevalence and impact inchildren and adolescents - the Peds REST study. Pediatrics 2007;120:253-66.

2. Zhang J, Lam SP, Li SX, Li AM, Kong APS, Wing YK. Restless

Hoo et al 41

legs symptoms in adolescents: Epidemiology, heritability, andpubertal effects. Journal of Psychosomatic Research 2014;76:158-64.

3. Allen RP, Picchietti D, Hening WA,Trenkwalder C, Walters AS,Montplaisir J. Restless legs syndrome: diagnostic criteria, specialconsiderations, and epidemiology. A report from the restless legssyndrome diagnosis and epidemiology workshop at the nationalinstitutes of health. Sleep Med 2003;4:101-19.

4. Picchietti MA, Picchietti DL. Advances in pediatric restless legssyndrome: Iron, genetics, diagnosis and treatment. Sleep Med2010;11:643-51.

5. Kotagal S, Silber MH. Childhood-onset restless legs syndrome.

Ann Neurol 2004;56:803-7.6. Khatwa U, Kothare SV. Restless legs syndrome and periodic

limb movements disorder in the pediatric population. Sleepand respiratory neurobiology. Curr Opin Pulm Med 2010;16:559-67.

7. Dye TJ, Jain SV, Simakajornboon N. Outcomes of long-term ironsupplementation in pediatric restless legs syndrome/periodic limbmovement disorder (RLS/PLMD). Sleep Med 2017;32:213-9.

8. Allen RP, Picchietti DL, Auerbach M, et al. Evidence-based andconsensus clinical practice guidelines for the iron treatment ofrestless legs syndrome/Willis-Ekbom disease in adults and childrenan IRLSSG task force report. Sleep Med 2018;41:27-44.


Management of Atopic Dermatitis in Children:2020 Review by the Guidelines Development Panel of

Hong Kong College of Paediatricians

Abstract The Guidelines Development Panel on "Management of Atopic Dermatitis (AD) in Children" has performedthe first updated review on the topic since the publication of the management guidelines by the Hong KongCollege of Paediatricians in 2013. While most of the recommendations of the original guidelines are stillvalid, various management issues are further elaborated based on recent evidences in addition to the latestinternational and regional guidelines. Using validated clinical scores for assessment of severity of AD areadvocated by the European guidelines to guide stepwise management and monitor progress. There are moreevidences to support the proactive approach with use of topical anti-inflammatory agents as long-term treatmentfor the control of chronic recurrent AD. Topical corticosteroids remain first line topical agents for AD, whiletopical calcineurin inhibitors are indicated for sensitive areas and can be used as maintenance treatment. Therole of newer therapeutic agents including topical phosphodiasterase 4 inhibitors, biologics and allergenimmunotherapy for use in paediatric patients are deliberated. Management of itch, tackling issues of steroidphobia and compliance remain challenges in AD management. The concepts of skin barrier dysfunction in ADand targeting the skin for allergy prevention strategies are discussed.

Key words Allergy; Atopic Dermatitis; Child; Guidelines

Department of Paediatrics and Adolescent Medicine, TheUniversity of Hong Kong, Pokfulam, Hong Kong SAR, China

TNH LEUNG MBBS, FRCPCH, FHKAM(Paed)

Department of Paediatrics & Adolescent Medicine, UnitedChristian Hospital, 130 Hip Wo Street, Kwun Tong,Kowloon, Hong Kong SAR, China

JWCH CHENG MBBS, FHKAM(Paed), PGDipClinDerm(QMUL)

YY LAM MBChB, FHKAM(Paed), PGDipClinDerm(QMUL)

DCK LUK MBChB, FRCPCH, FHKAM(Paed)

Department of Paediatrics and Adolescent Medicine,Caritas Medical Centre, 111 Wing Hong Street, ShamShui Po, Kowloon, Hong Kong SAR, China

SCW CHAN MBChB, MSc(Clinical Dermatology)(London), FHKAM(Paed)

Department of Paediatrics, Prince of Wales Hospital,30-32 Ngan Shing Street, Shatin, N.T., Hong Kong SAR,China

CM CHOW MBChB, FHKCPaed, FHKAM(Paed)

TNH LEUNG, JWCH CHENG, SCW CHAN, CM CHOW, PY CHOW,KL HON, KM HO, YY LAM, DCK LUK, SC NG, VK SUGUNAN

Contemporary Practice in Paediatrics

Hong Kong Children's Hospital, 1 Shing Cheong Road,Kowloon Bay, Kowloon, Hong Kong SAR, China

KL HON MBBS, MD, FAAP, FCCM

Social Hygiene Services, Department of Health, 3/F, WestKowloon Health Centre, Cheung Sha Wan Government Offices,303 Cheung Sha Wan Road, Kowloon, Hong Kong SAR, China

KM HO MBBS, FRCP(Glasg, Edin), FHKAM(Medicine)

SC NG MBBS, FHKCP, FHKAM(Medicine)

Private Practice, Hong Kong SAR, China

PY CHOW MBChB(Glasg), FHKCPaed, FHKAM(Paed)VK SUGUNAN MBBS(Qld), MRCP(UK), FHKAM(Paed)

Correspondence to: Dr TNH LEUNG


Received August 27, 2020

Leung et al 43

Introduction

The first set of "Clinical Guidelines on Management ofAtopic Dermatitis (AD) in Children" was endorsed by theHong Kong College of Paediatricians (HKCPaed) inDecember 2012.1 The guidelines highlighted practicalrecommendations with reference to National Institute forHealth and Clinical Excellence (NICE) guidelines"Management of Atopic Eczema in children, from birth to12 years" published in December 2007.2,3 Subsequently,NICE has further produced seven quality statements asstandard of care in September 2013, which are regularlyreviewed.4 International guidelines from other countrieshave also been updated. In 2014, the American Academyof Dermatology (AAD) published a set of guidelines infour sect ions compris ing more comprehensiverecommendations as compared with the Joint Task Forcepractice parameters published in 2012.5-10 The 2018European consensus-based guidelines on management ofatopic dermatitis in adults and children were issued in theJournal of European Academy of Dermatology andVenereology.11,12 Regional guidelines were released by theJapanese Dermatology Association and the JapaneseSociety of Allergology in 2016 and 2017 respectively13,14

and guidelines from the Asia-Pacific Consensus Group forAtopic Dermatitis were available in 2015.15 Theseguidelines have addressed recommendations for childrenin various areas. The HKCPaed Guidelines DevelopmentPanel has reviewed these updated guidelines and togetherother new evidences, the panel agreed that our local practicerecommendations in 2013 are still applicable. Severalmanagement issues are further elaborated in this article:• Clinical scores for severity assessment to guide

management• Proactive approach for maintenance• New therapeutic agents including topical anti-

inflammatory agents , biologics and al lergenimmunotherapy

• Targeting the skin for prevention of AD and otherallergy diseases

Prevalence of AD

Atopic dermatitis (AD) affects children globally withprevalence of up to 20% in some countries and there is atwo-to-threefold increase in industrialised countries in thepast decades.16 In Hong Kong, results of the International

Study on Asthma and Allergy in Childhood (ISAAC) phaseone (1994-95) and phase three (1999-2001) studiesrevealed that the prevalence of children with currenteczema remained similar at 3.8% and 3.9% for 13 to 14years old, and slightly increased from 3.6% to 4.2% for 6 to7 years old.17-20 Another publication in 2007 showed aprevalence of 5.6% in pre-school children.21 There hasbeen a lack of more recent local prevalence data for morethan 10 years. From 2001-2017, a local cross-sectionalsurvey using the ISAAC questionnaire has recruited 2000parents of children 6 to 7 years old, but results are not yetpublished at the time when this article is written.22

Diagnosis of AD

The diagnosis of AD remains clinical and is based onthe widely adopted Hanifin and Rajka clinical criteria.23

The NICE and Japanese guidelines describe diagnosticfeatures specifically for children, and highlighted AD beingan inflammatory, pruritic and chronically relapsing skindisease often occurring in families with other atopicdiseases.6,11,13,14 AD rashes have classical distributions thatvary with age.13 Atopic tendencies can be defined either by(1) a personal or family history of bronchial asthma,allergic rhinitis, allergic conjunctivitis or atopicdermatitis, or (2) an overproduction of immunoglobulin E(IgE).6,13 There is no pathognomonic laboratory biomarkerfor the diagnosis of AD.6 Serum total or allergen-specificIgE levels, and skin prick tests with specific allergens mayhelp the diagnosis of IgE-associated atopic tendencies.11

Raised total IgE levels are seen in up to 80% of patientswith AD and correlate with disease severity,13 whileeosinophilia may be found in some but not all AD patients.Atopy patch testing is useful in diagnosing contactdermatitis that might occur concomitantly in recalcitrantwidespread eczema.11

Use of Clinical Scores to Document DiseaseSeverity and Guide Stepwise Management

SCORAD (SCORing Atopic Dermatitis),24 EASI (EczemaAreas and Severity Index)25 and NESS (Nottingham EczemaSeverity Score)26 are some of the most commonly usedvalidated clinical scores for documenting extent andseverity of lesions.27 These scores are useful to guidemanagement and assess response to treatment.11 CDLQI

Management of Atopic Dermatitis in Children44

(Children's Dermatology Life Quality Index) is a short termsubjective symptom score for monitoring of life impacton various skin conditions including AD.28 ValidatedChinese versions of SCORAD, NESS and CDLQI scoresare available.29,30 PO-SCORAD (Patient-OrientedSCORAD)31 and POEM (Patient-Oriented EczemaMeasure)32 are useful tools for patients to monitor theirown disease activity.

In a systematic review, 15 AD severity scores werefound to be in good correlation. Assessment of itch andsleep disturbance are the two parameters common to mosteczema scores.33 In the latest European guidelines,SCORAD is included to guide management.11 If clinicalscores are not used in practice, the following should beassessed and documented to guide stepwise managementof AD as in Table 13,11,13

• Signs: extent and severity• Symptoms: itch and sleep• Quality of life (QoL): psychological well-being of child

and family

Goals of Management

The goals of AD management in children should aim atdisease control to prevent chronic skin damage usingtherapeutic agents with minimal side effects, and to ensurethe physical and psychological well-being of the childand family.

Basic Management

Basic management for all severities of AD involves(1) skin hydration with emollients; (2) identification andavoidance of triggers; and (3) education and psychologicalsupport.

1. Emollients and Bathing PracticesGenetic defects in filaggrin (FLG), an epidermal protein

responsible for aggregating the cytoskeleton, contributeto skin barrier dysfunction in AD and are linked to

Table 1 Stepwise treatment of atopic dermatitis in children12

Level of severity Physical signs Quality of life (QoL) Treatment

assessment

Severe or persistent Widespread areas of dryness Incessant itch - HospitalisationSCORAD >50 Redness Sleepless nights, disruption - Potent to very potent TCS

Swelling of QoL - Systemic immunosuppressantsLichenification Loss school days (e.g. Cyclosporin A, Azathioprine,Oozing/Scabs Methotrexate)Scratch marks and alteration - Dupilumab if age appropriate

Moderate or recurrent Localised areas of dry skin Frequent itching - Moderate to potent TCSSCORAD = 25-50 Redness +/- excoriation or Sleep disruption - TCI

localised skin thickening Moderately affects QoL - Proactive therapy with TCS or TCI- Wet wrap therapy- Phototherapy for older children

Mild or transient Areas of dry skin Infrequent itching - Mild to moderate potent TCSSCORAD <25 Small areas of redness Some disturbance in sleep - TCI

Minimal impact of QoL - Antiseptics and antimicrobials forsecondary infections

Dry skin only and for Basic management:all severity - Skin hydration, emollients

- Addressing specific triggering factors- Education and psychological support

STEP UP according to severity*

SCORAD: SCORing Atopic Dermatitis

*For each step:

- Add on treatment to previous level as appropriate

- Consider the need for treatment of superimposed infections

- Ensure compliance and review for alternative diagnoses before stepping up

- Referral to dermatological specialist as indicated

Leung et al 45

development of other allergic diseases in later life.34

Maintenance of skin barrier function is the cornerstoneof AD therapy for controlling transepidermal water loss,itch, inflammation and infections. Emollients should beused as basic skin care even when the skin is clear of activelesions.35

1.1 Choice of EmollientsCochrane review in 2017 and recent studies revealed

that regular use of emollients could improve symptoms,decrease flares, and reduce the need for topicalcorticosteroids in AD.36,37 Emollients containing glycerol,urea or glycyrrhetinic acid were reported to be bettercompared to controls (vehicles, placebo or withoutemollients). Newer formulations of emollients containingceramides, cholesterol, fatty acids and new technologiesare developed to enhance delivery of these substances toenhance skin barrier. However, current evidences do notsupport demonstrate any emollient being significantlybetter than another.36,37

Most emollients are found to be safe but adversee f f e c t s h a v e b e e n r e p o r t e d . U r e a - c o n t a i n i n gemoll ients are effect ive but i rr i tat ion has beenreported especially when applied to skin with lesions.Though the risk of 5% urea cream in causing renaldysfunction in infants has not been established, itmight best be avoided for children younger than 2years o ld and a more d i lu ted concent ra t ion i spreferred for toddlers.11,37,38 Emollients containingproteinaceous allergens such as oat-meal, peanut oil,lanolin may cause contact allergy,11,37 while otheremollients containing antiseptic or antibacterialagents l ike benzalkonium chloride may producecontact dermatitis.

Sodium lauryl sulphate (SLS) is a surfactant commonlyfound in bathing substitutes and leave-on emollients suchas emulsifying ointment and aqueous cream. In the pastdecade, studies suggested that SLS might cause skinirritation, dryness and thinning especially in children withAD.39,40 The adverse effects depend on concentration ofSLS, duration of exposure, individual skin condition andage.41 With review of available evidences, authorities inEuropean Countries (EU),41 United Kingdom (UK),42

United States (US)43 and Australia44 have issuedrecommendations concerning the use and proper labellingof SLS in topical emollients. In general, SLS-containingemollients are safe to use as soap substitutes when appliedbriefly and washed off, while their use as leave-onemollients have a potential risk of irritation. Therecommended threshold concentration of SLS in these

products is 1% in US and 1.5% in Australia43,44 andlabelling of products containing any concentration of SLSis needed for EU.41,42 Yet, side effects vary amongindividuals and there has been long history of use by patientswho do not report significant adverse effects. SLS-containing products can be applied upon weighing of risksand benefits while patients should be alerted to the possibleadverse effects. SLS-free emollients shall be prescribedinstead when irritation arises.42 It is worth mentioning thatother than SLS, emollients may contain other surfactants,preservatives or components that can also cause irritation.

"Natural" oils are getting more popular as non-conventional emollients. However, it has been shown thatolive oil can disrupt the skin barrier, increase dryness andworsen AD. Further research is needed for other naturaloils, such as sunflower oil and coconut oil, before anyrecommendations can be made.45

The best emollient is one that is acceptable andaffordable to patient and family. Ideal emollients frompatients' and parents' perspectives include non-fragrant,non-herbal, white or transparent preparations that requireapplications of no more than two to three times per day.46

Oily ointments have higher moisture retaining propertiesbut should be balanced with comfort and tolerability whichmay affect compliance.13 Different emollients may beneeded for different times of the day, seasons and bodyparts depending on patient's preference and enviromentalconditions.

1.2 Quantities of EmollientsAdequate quantities of emollients are estimated

according to the age of patients. Infants require about 125grams per week, small children 250 grams per week, whilelarge children or adults may need around 500 grams perweek.4,11 Emollients should be applied at least twice a dayor more liberally depending on skin conditions.13

1.3 Bathing PracticesBathing daily in lukewarm water thoroughly but gently

for not more than 5-10 minutes is recommended.11,47

Recently, the BATHE study showed no difference insymptom scores with and without addition of bathemollients for AD management in children.48 Bathingfollowed by emollient application (referred to as the"soak and seal" method) is probably more relevant.47

Bathing and showering practices are influenced byculture. Showering can remove sweat and it is preferredto bathing especially during humid summer seasons inHong Kong.13,49 The use of antiseptics is discussed inthe section of management of infections.


2. Identification and Avoidance of Triggers2.1 Common Triggers and Avoidance

Common triggers of AD include mechanical or chemicalirritants, extreme temperatures, tobacco smoke, local andsystemic infections, and specific allergens (Table 2).3,11,13

Heat and sweat are the commonest triggers during the hothumid weather in Hong Kong. General advice include theuse of light breathable clothing and bedding, wiping offsweat properly, ensuring cool and smoke-freeenvironment.50 Clinical studies on specific aeroallergenavoidance against house dust mites have been ambivalent.Climate therapy and relocation to mite-free environmentshave been shown to be beneficial to some AD patients.11

For pet avoidance, studies have demonstrated acorrelation between cat exposure with AD, while dogexposure at early life seems be unrelated to or evenprotective against AD.11 Clothing and cleanser choicesshould be non-irritating,11 but large scale studies arelacking in terms of protective clothing. Psychologicalstress is also a major contributor to itch and ADespecially in late childhood and adult populations.

2.2 Food Allergy and ADFood allergy is a contributing factor in up to one-third

of young children with moderate to severe AD.11,13 Basedon current evidences, food allergy is a trigger rather thana cause of AD. Recent data suggest that AD precedes andcontributes to the development of food allergy.51 It ispostulated that cutaneous exposure of food antigensthrough the inflammed skin in AD in early life give rise tosensitisation.52

Type I IgE-mediated food hypersensitivity skin reactionsare typically non-eczematous urticarial rashes presentingalong with systematic reactions including anaphylaxis,

angioedema, or gut dysmotility symptoms within 2 hours ofexposure and usually resolve within a day.3,11 Eczematousflares triggered by food antigens are Type IV delayed-typehypersensitivity reactions appear at around 6-48 hours afterexposure. A combination of Type I and Type IV reactionsoccurs in approximately 40% of children.11 Diagnosis of foodallergies is made by detailed history taking, allergen tests,food elimination and provocation test as indicated.13 Skinprick tests are used for the diagnosis of type I reactions.Type IV food hypersensitivities may be confirmed by atopypatch tests.11 Other allergy tests with unproven diagnosticvalue provided by community and online suppliers arediscouraged.3 Definitive diagnosis of food allergy isconfirmed by supervised double-blind placebo-controlledfood challenges which is contraindicated in patients withsevere allergic reactions or anaphylaxis.11

For non-breastfed infants younger than six months oldwith moderate to severe AD resistant to standard treatment,the British guidelines recommend empirical trial ofextensively hydrolysed protein or amino acid based milkformulas for six to eight weeks.3 In Hong Kong, parentscommonly practice dietary exclusion of foods, in particularfish, seafood and beef for their children with AD.53

Comprehensive reviews showed that there were insufficientdata to support indiscriminate elimination diets for AD.53,54

3. Education and Psychological SupportPatients and their carers should be empowered to

participate in management of AD according to thepersonalised treatment plan. Misconceptions and fallaciesabout eczema are common and frequently lead to problemsof non-compliance, treatment failure and psychosocialstress.55 Healthcare providers should allow sufficient timeduring consultations to provide education, agree on a planto achieve the goals of management, and address concernson the various aspects of eczema management includingdiagnosis and prognosis, triggering factors, therapeuticoptions and the related side effects. At every clinical visit,compliance and proper application of AD prescriptions haveto be reinforced, use of alternative treatments, and impacton quality of life and psychosocial issues should beexplored.3 Studies have shown that non-compliance totreatment is a major issue in AD management.12

Psychological stress exacerbating the itch-scratch cycle,and intrafamilial psychodynamics can contribute to non-compliance. Education of patients and caregivers throughnurse-led or digital mediated educational programmes,eczema workshops or camps to provide multidisciplinary

Table 2 Common triggers of atopic dermatitis

Triggers of AD Common examples

Irritants Sweat, wool fabrics, soap

Environment Extremes of temperature, dryness, smoke, air

pollutants

Infections Local infections with microbes, systemic

infections (e.g. viral illness)

Psychosocial Stress, anxiety

Allergens Food, animal dander or saliva, house dust mites

(HDM), mould, pollen, fragrances contact

allergens

Leung et al 47

age-related structured group training programmes havebeen recommended as adjuncts to conventional ADtreatment.12,56

Psychosocial issues are often untended to withdepression, anxiety, stress and guilt feelings of patientsand caregivers complicating the management of eczema.Severe complications and tragedy with deaths due tomalnutrition, suicide and homicide related to eczema havebeen reported locally.57-59 Provision of psychosocial andpsychiatric intervention are of paramount importance toallow timely support of individuals and their caregivers3,11

Psychotherapy, counselling, behavioural therapy andrelaxation techniques could help patients and family tobetter cope with disease.9,12,13

Topical Anti-inflammatory Agents for AcuteFlare and Maintenance Treatment

Therapeutic agents used for management of AD dependon severity assessment (Table 1). Most children with ADcan be effectively managed with topical anti-inflammatoryagents. Adjunctive therapies include anti-pruriticmedications for management of itch, antiseptics andantibiotics for management of infections.

Principles of Topical Anti-inflammatory Agents UseTopical corticosteroids (TCS) and topical calcineurin

inhibitors (TCI) are the most commonly used topical anti-inflammatory agents for treatment of acute flares andmaintenance therapy.

Acute flares: Treat with topical anti-inflammatory(usually TCS) with potency appropriate for the severity atthe first sign of active flare and continued at least untilvisible lesions are cleared, then followed by step-wisetapering with either a less potent TCS or less frequentapplication can prevent rebound of AD symptoms. It mustbe stressed that tapering of TCS should not be done tooearly as subclinical inflammation persists.11,14,60

Proactive versus reactive approach for maintenancetherapy: AD is a chronic inflammatory condition withsubclinical inflammation present in skin without visiblelesions.61 The classical reactive approach of using topicalanti-inflammatory agents only during acute flares for shortduration is applicable to mild transient disease (Table 1).The proactive management strategy of AD control hasemerged for prevention of flares in moderate to severeand recurrent disease as supported by recent evidences andinternational guidelines.9,11,14,62 The proactive approach is

the induction of remission of acute eczema with topicalanti-inflammatory agents, followed by maintenancetreatment with low dose TCS or TCI intermittently two tothree times per week to the treated areas, while usingemollients for skin care over all affected and unaffectedareas.11,62-64 Studies have shown the effectiveness inpreventing AD flares and safety of proactive use of TCSfor up to 20 weeks and TCI for up to 52 weeks.3,11,60,62,65

There is no consensus on the exact length of proactivetherapy.

1. Topical Corticosteroids (TCS)TCS remains the mainstay of medical therapy for

AD.11,13,60 Appropriate strength, dosage and correctapplication of topical anti-inflammatory agents are thethree main pillars of effective AD treatment.11 There aredifferent classification systems for TCS potency indifferent countries. In this article, we have used theNiedner's classification (used in UK, Australia and NewZealand) with 4 classes of steroids namely mild, moderate,potent and very potent, instead of using Roman numbers(I, II, III, IV) to avoid confusion with other classificationsystems.66 Common TCS formulations available in HongKong are listed in Table 3.

Dilution of TCS with emollients will not reduce itspotency or side effects.11,60 With the same compound andconcentration, ointments are more potent than creams andlotions. In the same class of potency, newer TCS (e.g.mometasone furoate and fluticasone diproprionate) haveless adverse effects like skin atrophy then old halogenatedTCS (e.g. fluocinolone acetonide), and are therefore moreappropriate for infants and sensitive skin areas.1,5,63 Dosageof TCS can be measured by the fingertip unit (FTU),67 whichapproximates to 0.5 gram of the ointment squeezed from atube with a 5 mm nozzle along the index finger from thetip to the first finger joint. One FTU of ointment applied"even and thin" is adequate to cover skin area equivalent totwo adult hands with fingers together. The maximal amountof FTUs applied can be estimated according to age and bodyparts (Table 4).68

Evidences to support recommendations on how to applyTCS are limited. A Cochrane review protocol on theeffectiveness and safety of different practices in applicationof TCS for people with eczema has been recently submittedin 2019.69 Its generally recommended to apply TCS foronce or twice daily, and more recent studies suggest thatonce daily application of newer TCS may suffice.3,7,70 Atleast 15 minutes should lapse between application ofdifferent topical medications and emollients. Whether a


formulation should be applied first or last depends solelyon patient's preference.3

TCS applied two to three times per week as maintenancetreatment with a monthly amount of 15 g in infants, 30 g inchildren and 90 g in adolescents is generally safe.11

Duration of therapy depends on individual AD severity, siteof application and the choice of TCS formulation.1 NICEguidelines in 2006 recommended TCS to be applied 7 to14 days for acute flares of AD.3 Studies suggest thatproactive intermittent use of low potency TCS (e.g. 1%hydrocortisone cream or ointment) to mid potency TCS(e.g. 0.05% fluticasone diproprionate cream or 0.1%

methylprednisolone aceponate) twice per week for up to20 weeks are considered safe and effective.11,65,71,72

Local adverse effects of TCS like hypertrichosis, skinatrophy, telangiectasis, striae are uncommon and foundmainly after inappropriate usage.60 Hypopigmentation orhyperpigmentation is related to the clearing of the eczemarather than due to side effects of TCS. Use of TCS has to bemore cautious over sensitive areas and skin folds includingface, axilla, neck and napkin area.11,13 Severe side effectsincluding cataracts, hypothalamic-pituitary-adrenal axissuppression and Cushing's disease are rare. Risks of adverseeffects increased with high potency TCS, prolonged use

Table 3 Potency of common topical corticosteroids available in Hong Kong

Potency Generic name Strength Formulation*

Mild Hydrocortisone acetate 0.1%-2.5% L/C/O

Moderate Clobestasone butyrate 0.05% C/ODesonide 0.05% L/C/OFluocinolone acetonide 0.005-0.0125% C/OTriamcinolone acetonide 0.1% C/O

Potent Betamethasone dipropionate 0.025-0.05% L/C/OBetamethasone valerate 0.1% L/C/OFluocinolone acetonide 0.025% C/O/gelFluticasone proprionate 0.05% CMethylprednisolone aceponate 0.1% C/OMometasone furoate 0.1% L/C/O

Very potent Betamethasone dipropionate in propylene glycol 0.05% C/OClobetasol propionate 0.05% L/C/O/SDiflucortolone valerate 0.1% C/O/fatty ointment

L = Liquid which includes lotion# and those label as "scalp application" S= Shampoo

C = Cream

O = Ointment

*For the same drug, in order of potency L<C<O

References: (15, 119)

Table 4 Maximal amount of TCS applied to body parts according to age68

Infants Infants Small child Child Adolescent3-6 months 1-2 year 3-5 years 6-10 years >12 years

Finger-tip unit (FTU)#

Face and Neck 1 1.5 1.5 2 2.5

Trunk (Front) 1 2 3 3.5 7

Trunk (Back + buttock) 1.5 3 3.5 5 7

1 Arm + Hand 1 1.5 2 2.5 3+1

1 Leg + Feet 1.5 2 2 4.5 6+2

# Finger-tip unit (FTU)= 0.5 gram of the ointment squeezed from a tube with 5 mm nozzle along the index finger from the tip to first finger joint of adult hand.

One FTU of ointment applied

Leung et al 49

and occlusion.60 Tachyphylaxis is not proven in TCS.13 Thereis good evidence to support the safety of appropriate TCSuse for paediatric AD.60

Steroid PhobiaSteroid phobia is an important reason for treatment

failure. A systematic review of 16 worldwide studiesincluding two local studies found that the prevalence ofsteroid phobia ranged from 21% to 83.9% in variouscountries. The main concerns are skin thinning and otherskin adverse effects, growth and development problemsand other non-specific long term effects.73 Steroid phobiainfluences acceptability and usage of TCS by patients andcaregivers, which in turn leads to poor AD control.74

In our local population, misconceptions and fallacieson AD are related to mistrust and unrealistic expectationsabout Western Medicine, phobias of anti-inflammatoryagents, and use of complementary and alternative therapies.55

On-going education by healthcare professionals andprovision of updated information to caregivers are oftopmost priority.60

2. Topical Calcineurin Inhibitors (TCI)TCI is indicated for acute and proactive treatment of

AD, especially over sensitive body areas like face, eyelids,intertriginous and anogenital areas. For acute flares, initialuse of TCS to induce remission followed by TCI may beconsidered.7 The age indications for the three availableTCIs have remained unchanged (see below). With theavailability of safety data of the two TCIs, the latestAmerican and European guidelines recommend off-labeluse of 0.03% tacrolimus and 1% pimecrolimus ointmentfor children less than 2 years old if clinically indicated.7,11

TCI Age indication AD severity

1% pimecrolimus cream ≥2 years old Mild-Moderate

0.03% tacrolimus ointment ≥2 years old Moderate-Severe

0.1% tacrolimus ointment ≥16 years old Moderate-Severe

Duration and dosage of TCI for proactive therapydepend on individual AD severity. Studies have shownthat TCI use twice per week up to one year is safe andeffective in reducing AD flares and improving qualityof life.11,12,65,71 Dosage recommendation of 0.03%tacrolimus ointments applied per day for children aged2-5 years (or body weight <20 kg) is ≤1 g; children6-12 years (or 20-50 kg) is ≤2-4 g; while children 13years or older (>50 kg) is ≤5 g.13

Side effects of TCI are mild, tingling or burningsensations that occur within an hour of application, tendto resolve after a few days or with emollient application.TCI has the advantage of increasing skin thickness contrastto the risk of skin atrophy for TCS. Systemic absorptionof TCI is minimal with no increase in infection orcarcinogenic risks. Although the FDA has not withdrawnits black box warning issued in 2006 with concerns oflymphoma risks shown in animal studies, subsequentclinical studies have not shown any increase in risk oflymphoma or other related cancers from TCI use.63,75

However, UV protection for TCI use to reduce the potentialrisk of carcinogenicity is still recommended.11,13 Cliniciansare advised to alert patients and caregivers to the black-box warning before starting treatment.

3. New Topical Anti-inflammatory AgentsCr i saboro l e 2% top i ca l o in tmen t ( t o p i c a l

phosphodiesterase 4 inhibitor) - Efficacy and safety of twicedaily application of Crisaborole topical ointment for up toone year treatment of mild to moderate eczema has beendemonstrated. The drug has been recently approved forpatients 3 months and older and may soon be availablelocally. Other new selective topical phosphodiesterase 4inhibitors are currently under investigation. However, theirefficacy when compared with TCI and TCS is not yetdetermined.11,76

Sodium cromoglycate 4% emulsion - A newformulation of an old drug has been investigated withpositive results for eczema in children and safe for longterm use up to 15 months.76,77 However, this is not availablein Hong Kong.

Other novel topical anti-inflammatory agents underinvestigations including lipoxins and janus kinaseinhibitors (JAKi) e.g. tofacitinib76 require further studiesto prove the efficacy and safety in paediatric population.

Adjunctive Therapy

1. Dry Wrap and Wet Wrap TherapyBandages or cotton clothing can be used for dry or wet

wrapping. Localised wrapping after application ofemollients and TCS is indicated for chronic lichenifiedAD with acute flares.3 The treatment can be maintained for3 to 14 days to control flares effectively and improvepatients' tolerance to corticosteroids.3,11,78 Effects may lastfor one month and can be continued with emollients aloneuntil AD resolves.3,78 Whole body dry or wet wrap therapy


with emollients and TCS should not be the first-line therapyand must be supervised by healthcare professionals.3

Occlusive dressings, dry or wet wrap therapy should notbe used for infected AD and these are not recommendedfor TCI due to uncertainty of systemic absorption.13

2. Anti-pruritic AgentsItch is the most disturbing symptom which affects sleep

and quality of life and the itch-scratch cycle furtheraggravates AD. The pathogenesis of itch in eczema iscontributed by multiple factors including skin barrierdysfunction, abnormal Th2 immune response, various itchmediators and hyperinnervation of skin. Exacerbatingfactors trigger cytokines and mediators release that induceitch through stimulating nerve endings.50 Effectivetreatment of AD with emollients and topical anti-inflammatory medications are the cornerstone for themanagement of itch. Identification and avoidance ofexternal triggers of itch are essential.

2.1 Oral Antihistamines1st and 2nd generation oral H1 antihistamines have long

been used in AD. However, a recent Cochrane meta-analysis of studies in adults and children showed noevidence that oral H1 antihistamines are effective as "add-on" treatment of AD.79 Antihistamines may be consideredfor type I hypersensitivity reactions like urticaria andallergic rhinitis that coexist with AD. First generationantihistamines may be beneficial in AD through its sedativeeffect.11 However, there are also concerns on the adverseeffects on sleep quali ty with long term use ofantihistamines.

2.2 Other Anti-pruritic TherapyThere is insufficient evidence to prove that topical

antihistamines, topical cannabinoid receptor antagonists,topical non-steroidal anti-inflammatory drugs ("NSAIDs")or topical anaesthetics are effective antipruritic therapy.11,13

Provision of adequate education, age-appropriatedistraction techniques such as breathing and relaxationexercises, and activity involvement are adjunctivetreatments for itch relief.80

3. Anti-microbials and Antiseptics for Management ofInfectionsMicrobial dysbiosis by an overgrowth of Staphylococcusaureus has been found to be associated with AD flares.Secondary infections can be due to bacteria such asStaphylococcus aureus and Streptococcus pyogenes,

viruses like herpes simplex and molluscum contagiosumand fungi. Routine skin swab sampling is not recommendedand are only needed when antibiotic resistance or whenorganisms other than S. aureus or methicillin-resistantS. aureus (MRSA) are suspected.3,8 Antibiotic use for non-infected AD skin is not recommended.3,9,12 Topicalantibiotics can be applied alone or combined with TCS onAD skin with localised infections.3 Systemic anti-staphylococcal antibiotics like oral flucloxacillin or firstgeneration cephalosporins could be prescribed as first lineantibiotics when bacterial superinfection is found.12

Upon diagnosis of eczema herpeticum, prompt initiationof antiviral therapy with systemic acyclovir and referral tospecialists or emergency medical service is indicated.3,4,12

Add-on systemic antibiotics may be required in cases withsecondary bacterial infection or when such possibilitycannot be ruled out.3 Treatment of other viral infectionssuch as molluscum contagiosum and Coxsackie infectionis mainly symptomatic.12 Antifungal therapy includingtopical ketoconazole shampoo or systemic itraconazole,fluconazole may be indicated to add on to topical anti-inflammatory agents for head and neck dermatitis orpatients with Malassezia spp. IgE sensitisation.12 Ingeneral, TCS should be continued during antimicrobial usein most conditions provided specific treatment for theinfections are given.12 Topical steroids are notrecommended during the acute illness of eczemacoxsackium but can be reintroduced to treat eczema oncethe child is afebrile.81 TCI should be stopped during acuteinfection.

Diluted bleach bath with 0.005% bleach (i.e. 1:1200 ofhome-used bleach containing 6% sodium hypochlorite)twice per week can be used as an antiseptic for moderateto severe or infected eczema for its benefits in reductionof bacteria and repair of skin barrier.7,11,12,82 Coal tar hasbeen shown to have anti-inflammatory and antisepticeffects. A local randomised control trial (RCT) on addingpine tar for bathing showed significant improvement insymptom scores and decrease in Staphylococcus aureuscolonisation in paediatric subjects with moderate to severeAD compared with vehicle.83 There is no evidence for usingantiseptic bath soaps in non-infected AD patients.84

Phototherapy, Systemic Agents and OtherTherapies

Phototherapy, systemic immunosuppressive agents andbiologics are second line therapeutic options for more

Leung et al 51

severe or recalcitrant AD. Before considering thesetreatment modalities, the patient should be evaluated forpossible alternative diagnoses, treatment compliance,optimisation of management with topical therapy,avoidance of triggers and adequate education. The severityof AD and impact on quality of life has to be balanced withrisks of therapy.85 Referral to specialist care is highlyrecommended should these therapies be considered.Detailed discussions and recommendations on theseadvanced therapies are beyond the scope of this article.

1. PhototherapyExposure to natural or artificial ultraviolet ("UV") light

has been found to be mostly beneficial on AD patients,though some may worsen following UV exposure.Explanations for its benefits vary but include theimmunomodulatory and anti-inflammatory effects of UVand vitamin D.8,11,13 Phototherapy is considered an effectiveand safe second-line therapy with anti-pruritic effects formoderate to severe AD in adults and children. Systematicreview of small studies on narrowband UVB (NB-UVB)and UVA (UVA1) showed that both are effective inimproving clinical scores of AD and safe with minimalside effects.86,87 There is little evidence on differences oncomparative studies.88 In Hong Kong, NB-UVB is morecommonly used. Choice of wavelength and dose shall beindividualised depending on the skin type and tolerance.8

The common side effects of phototherapy includephotodamage, xerosis, erythema, actinic keratosis,sunburns and tenderness.86 There has been limited clinicaldata on the long-term risk of skin cancer associated withUV therapy in children.

Emollients and TCS can be continued until 2 hoursbefore the phototherapy while TCI shall be avoided.63 Theenclosed hot environment and compliance issues havelimited the application of this treatment modality inchildren. Patients need to travel to designated centres withthe equipment to receive treatment 2-3 times per weekfor 6-12 weeks. However, the relatively small size of ourcity could be an acceptable option for older children withmoderate to severe AD who do not respond to the usualtopical treatment.8,11,13 Targeted phototherapy delivers highenergy UV light to the involved areas only. It allowstreatment of localised areas such as the scalp, nose,genitals, etc; it is easy to administer and is better toleratedby children.89 More research is needed to demonstrate itseffectiveness for localised AD in children. Moreover, theuse of daylight phototherapy and home-based phototherapyare currently being explored.

2. Systemic Immunomodulatory TherapyIn a systematic review which include limited paediatric

data, cyclosporin A is recommended as the first-linesys temic immunomodula tory t rea tment , whi leazathioprine and methotrexate could be recommended asalternative options for moderate to severe AD.90

2.1 Short-term Oral GlucocorticoidsSystemic steroids may be considered in adults but should

not be used for AD in children as risks outweighs thebenefits.8,12,13

2.2 Cyclosporine A (Cys A)For severe AD, Cys A can be started at 2.5 mg/kg/dose

twice daily and reduced by 0.5-1.0 mg/kg/day every 2weeks when treatment effect has been achieved. Trials forchildren 2-16 years old revealed similar results withintermittent short-term treatment of 12 weeks or low dosecontinuous treatment for 1 year. Side effects includingnephrotoxicity and hypertension shall be closelymonitored. There is no role of drug trough levels inmonitoring of cyclosporine A treatment.11,13

2.3 AzathioprineAn off-label treatment for children with severe AD

starting at 1-3 mg/kg/day can be considered if cyclosporineA is ineffective or contraindicated. Apart from risks ofmalignancies and teratogenicity, azathioprine can inducesevere fatal myelosuppression in patients with thiopurinemethyltransferase (TPMT) deficiency more commonlyfound in Caucasians, or nucleotide diphosphatase(NUDT15) deficiency which is particularly relevant forAsians and our local Chinese population.91 FDArecommends prior laboratory screening for TPMTgenotype or phenotype and NUDT15 genotype beforeinitiation of treatment.92 Regular monitoring of completeblood profile and liver function tests are needed duringAzathioprine use.11,63

2.4 MethotrexateA few retrospective studies on low dose methotrexate

in children with AD demonstrated that it is safe and effectivewith similar efficacy compared to cyclosporin.63

Limited data is available for other systemic therapy likemycophenolate mofetil (MMF), interferon gamma,montelukast or immunoglobulins.11,63,90

3. BiologicsDupilumab is a fully human monoclonal antibody and


dual interleukin-4 (IL-4) and interleukin-13 (IL-13)receptor inhibitor. Since 2019, it has been the only biologicapproved for moderate-to-severe AD in patients 12 yearsand older who are not responsive to topical or systemictreatments in USA and Europe. Emollients and TCS or TCIshould be continued during subcutaneous dupilumab useand its maintenance effect has been shown to last for over1 year with minimal side effects.12,76 Off-label use ofdupilumab with injection every 2 weeks or 4 weeks inchildren <12 years old has been reported.93 Based on thepositive results of the phase 3 study for children 6 to11years old being treated for 16 weeks, US Food and DrugAdministration (FDA) lately approved the drug to be usedfrom 6 years old.94 Its clinical use is however limited bythe high cost.

Other biologics like rituximab, omalizumab orustekinumab are not recommended for AD, while someguidelines recommend short-term use of mepolizumab,an anti-interleukin-5 antibody, in selected cases.12

4. Allergen Specific Immunotherapy (ASIT)Subcutaneous immunotherapy ("SCIT") and sublingual

immunotherapy ("SLIT") are two regimens for treatmentof allergen sensitisation commonly used for allergicrhinitis and allergic asthma. There are some evidencessuggesting ASIT with house dust mite is an effectivetreatment for selected, highly sensitised patients withsevere AD flares after exposure.12 The Cochranesystematic review found only limited evidences thatASIT could be an effective treatment for AD and futurestudies with high quality allergen formulations weresuggested.95 Currently, ASIT remains an "off-label"treatment option and should only be considered whenclearly informed decision is made with patients andcaregivers.

5. Vitamin DCurrent data supports that vitamin D deficiency is

associated with AD severity especially in children.96,97 It isimportant to be alerted to vitamin D and other nutritionaldeficiency in AD and provide supplementation in cases ofdocumented def ic iency . Ef fec t s o f empi r i ca lsupplementation of vitamin D supplementation areinconsistent.96,98 Further research on dosage, timing,duration of vitamin D for management of various severityof AD are needed before specific recommendations couldbe made . The role of Vitamin D supplement for preventionof AD and allergic diseases is also uncertain.

6. Traditional Chinese Medicine (TCM)Various Traditional Chinese Medicine (TCM)

formulations are being used in our locality as an adjunctivetherapy or sole treatment for AD. A local study of a Chineseherbal concoction had shown efficacious improvement inquality of life and reduction in TCS use.99 Cochrane reviewof 28 randomised controlled trials was not able to drawdefinitive conclusions on the benefit of either oral ortopical TCM on AD for children and adults due to theheterogeneity and poorly designed studies.100 The NICEgu ide l ines s t r e s sed the poss ib l e p re sence o fhepatotoxic ingredients and the use of corticosteroidsin certain TCM preparations.3 Use of unfoundedcomplementary alternative medicine followed bycessation of original medical prescriptions may causeworsening of AD.11-13 Patients and caregivers are advisedto consult registered TCM practitioners for properassessment and prescription of TCM.

7. Other Complementary Alternative TherapyCurrently, there is no evidence to support the use of

probiotics or prebiotics, acupuncture, topical unsaturatedfatty acids, topical crude plant extracts, autologous bloodtherapy, bioresonance, homeopathy, aroma therapy,massage therapy, salt baths, avocado oil and vitaminsupplementation for treatment of AD.3,12,13

Referrals and Collaborations with OtherProfessionals

Collaborations between nurses, social workers, alliedhealth workers, psychologists and psychiatrists may beneeded especially for but not limited to severe cases.3,11

When AD is recalcitrant to treatment, referral todermatology specialists or specialised centres isrecommended for consideration of differential diagnoseslike contact dermatitis, cutaneous lymphoma or mycosisfungoides.3,4 Other specialists shall be involved whencomorbidities such as immunodeficiencies are suspectedor complications like retinal detachment, cataract, orstunting of growth have occurred.13

Prevention of AD and Atopic March

'Atopic march' refers to the progression of allergicconditions which often begins with AD in early infancy

Leung et al 53

followed by food allergy, allergic rhinitis and asthma inlater childhood. The skin barrier theory is being postulatedas the biological mechanism for atopic march. Thedisrupted epidermal barrier in AD, environmental factors,and infections predispose to cutaneous antigen penetration,which stimulates local Th2 immune responses andsubsequent development of other allergic diseases. Hence,intervention strategies targeting the skin to prevent atopicmarch are implicated.101 The concept of diseaseprogression in atopic march may in fact be more complexas heterogenous phenotypes of allergic diseases and co-manifestation of multiple allergic diseases are observed.There are ongoing studies on differential mechanisms,prognosis and development of targeted strategies to searchfor effective treatment and prevention of allergicdiseases.102

A group of local allergists published guidelines onm e a s u r e s f o r a l l e r g y p r e v e n t i o n i n c l u d i n grecommendations on diet for mothers and infants,environmental avoidance of smoking and air pollution,immunisation and judicious use of antibiotics. Theguidelines also suggest early treatment and control ofallergy diseases of which eczema is usually the first topresent in infants.103 Preventive strategies for infants atrisk of eczema include empirical emollients, modificationof maternal and infant diets, probiotics and prebiotics arediscussed in more details below.

1. Empirical EmollientsTwo earlier studies on empirical application of

emollients within the first month of life for at risk infantshave shown reduction of AD incidence at 6 months by 32-50%.104,105 Subsequently, various countries have carried outfurther studies. The PEBBLES pilot study (A randomisedcontrolled trial to prevent eczema, food allergy andsensitisation using a skin barrier improvement strategy)in Australia use ceramide containing emollients asprophylaxis for high risk neonates. The study did not showreduction in AD at 6 months and 1 year, while food allergensensitisation was reduced only in the subgroup withfrequent application of emollients five times per day.106

The Preventing Atopic Dermatitis and ALLergies inChildren (PreventADALL) study conducted in Sweden andNorway, with application of emollients from 2 weeks old,also failed to show any preventive effect of AD or foodallergy at 1 year old.107 The results of these two studieswere limited by problems of compliance. There are stillongoing research to investigate on the optimal timing,

frequency and type of emollients for this potentially safeand inexpensive strategy that could be beneficial in clinicalpractice.

2. Dietary InterventionInternational and local guidelines on allergy prevention

recommend no dietary restriction for breastfeedingmothers, exclusive breastfeeding for 6 months andsubstitution with hydrolysed milk formulas for high riskinfants if exclusive breastfeeding is not feasible.103,108

Historically, it was believed that delayed introduction ofantigenic foods exposure for high risk infants can preventdevelopment of allergic diseases including eczema.However, with recent publication of the landmark studiesLEAP (Learning Early About Peanut Allergy)109 and EAT(Enquiring About Tolerance)110 on food allergy prevention,the concept about food immune tolerance and sensitisationwith early exposure has changed dramatically. Thehypothesis of dual antigen exposure postulates thatimmune tolerance occurs as a result of oral exposure tofood antigens while sensitisation develops through skinexposure. Currently, most authorities support theintroduction of complementary foods from 4 months oldand should not be delayed beyond 6 months.108,111 Forinfants high risk for peanut allergy, it is recommended tointroduce peanuts at 4-6 months, while for infants with alow to moderate risk, peanuts can be introduced beforefirst year of life.108 Exclusion is only needed if there isdocumented adverse reactions. However, whether theserecommendations can be generalised to other foods andpopulations of different genetic and cultural backgroundis still uncertain. A study on earlier introduction ofcomplementary foods from 3 months old cannot preventeczema or subsequent food allergies.107 A recentsystematic review suggested that a diversity ofcomplementary foods in infancy may reduce developmentof allergy diseases in childhood.112 In practice,complementary foods as available in different cultures canbe introduced from 4 to 6 months when the child isdevelopmentally ready.

3. Prebiotics, Probiotics and SynbioticsMicrobial dysbiosis of the gut has been linked to allergic

diseases including AD.113 Prebiotics, probiotics andsynbiotics have been shown to have mixed effects ontreatment and prevention of AD.11 The recently updatedCochrane review and a meta-analyses of paediatric studieson probiotics for treatment of AD showed no or little


evidence that probiotics are effective treatment forestablished AD.114,115 Studies on various prebiotics andsynbiotics combination are even more heterogenous andso far without definitive evidence of treatment benefit.

World Allergy Organisation (WAO) and McMasterUniversity published the Guidelines for Allergic DiseasesPrevention (GLAD-P) on probiotics and prebiotics in 2015and 2016 respectively.116,117 The guidelines recommend thatprobiotics may be used for prevention of eczema in (1)high risk infants and (2) their mothers during pregnancyand breastfeeding. For prebiotics, it is only recommendedin non-exclusively breast-fed high-risk infants. Theguidelines emphasized that the recommendations are onlybased on very weak evidences. Subsequent studies do notsupport the supplementation of probiotics for infants atrisk for eczema.118 These products are heterogenous andany clinical effects of one product shall not be generalisedfor another.

Conclusions

AD is a common chronic inflammatory skin diseasewith genetic predisposition and environmental aggravatingfactors characterised by atopic tendencies, skin barrierdysfunction and microbial dysbiosis. It has a large impacton the medical and psychological well-being of adeveloping child. With appropriate evidence-basedtreatment and patient education, symptoms of AD can bewell controlled. Despite availability of all the guidelines,health care providers shall devise individualisedmanagement plans according to the clinical needs andpreferences of patients and their caregivers. Theadvancement of new treatment modalities is intended tooffer more promising developments to improve the qualityof life of AD sufferers and their families in the near future.

Funding Statement

The authors received no funding for the work andpublication of this article.

Conflict of Interest Statement

The authors declare no conflict of interest in thematerials discussed in this manuscript.

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107. Skjerven HO, Rehbinder EM, Vettukattil R, et al. Skin emollientand early complementary feeding to prevent infant atopic dermatitis(PreventADALL): a factorial, multicentre, cluster-randomised trial.Lancet 2020;395(10228):951-61.

108. Greer FR, Sicherer SH, Burks AW; Comittee on Nutrition; Sectionon Allergy and Immunology. The Effects of Early NutritionalInterventions on the Development of Atopic Disease in Infantsand Children: The Role of Maternal Dietary Restriction,Breastfeeding, Hydrolyzed Formulas, and Timing of Introductionof Allergenic Complementary Foods. Pediatrics 2019;143:e20190281.

109. Du Toit G, Roberts G, Sayre PH, et al. Randomized trial of peanutconsumption in infants at risk for peanut allergy. N Engl J Med2015;372:803-13.

110. Perkin MR, Logan K, Marrs T, et al. Enquiring About Tolerance(EAT) study: Feasibility of an early allergenic food introductionregimen. J Allergy Clin Immunol 2016;137:1477-86.e8.

111. Fewtrell M, Bronsky J, Campoy C, et al. Complementary Feeding:A Position Paper by the European Society for PaediatricGastroenterology, Hepatology, and Nutrition (ESPGHAN)Committee on Nutrition. J Pediatr Gastroenterol Nutr 2017;64:119-32.

112. Venter C, Greenhawt M, Meyer RW, et al. EAACI position paperon diet diversity in pregnancy, infancy and childhood: Novelconcepts and implications for studies in allergy and asthma. Allergy2020;75:497-523.

113. Pascal M, Perez-Gordo M, Caballero T, et al. Microbiome andAllergic Diseases. Front Immunol 2018;9:1584.

114. Makrgeorgou A, Leonardi-Bee J, Bath-Hextall FJ, et al. Probioticsfor treating eczema. Cochrane Database Syst Rev 2018;11:CD006135.

115. Huang R, Ning H, Shen M, Li J, Zhang J, Chen X. Probiotics forthe Treatment of Atopic Dermatitis in Children: A SystematicReview and Meta-Analysis of Randomized Controlled Trials.Front Cell Infect Microbiol 2017;7:392.

116. Fiocchi A, Pawankar R, Cuello-Garcia C, et al. World AllergyOrganization-McMaster University Guidelines for AllergicDisease Prevention (GLAD-P): Probiotics. World AllergyOrgan J 2015;8:4.

117. Cuello-Garcia CA, Fiocchi A, Pawankar R, et al. World AllergyOrganization-McMaster University Guidelines for Allergic DiseasePrevention (GLAD-P): Prebiotics. World Allergy Organ J 2016;9:10.

118. Cabana MD, McKean M, Caughey AB, et al. Early ProbioticSupplementation for Eczema and Asthma Prevention:A Randomized Controlled Trial. Pediatrics 2017;140:e20163000.

119. MIMS, editor. MIMS pharmacotherapy guide to atopic dermatitisand Psoriasis (Singapore/Malaysia/Hong Kong 2018). Singapore:MIMS Pte Ltd; 2018.

HK J Paediatr (new series) 2021;26:58

What is the Diagnosis?

SSW CHENG, IFM LO, HM LUK

The clinical quiz was prepared by:SSW CHENG

IFM LO

HM LUK

Clinical Genetic Service, Department of Health, HKSAR

The proband is a 8 years old boy. He was born full termto a non-consanguineous Chinese couple in Hong Kong.Antenatal checkup showed small head circumference at3rd centile. His birth weight was 3.95 kg. Postnatally, hesuffered from failure to thrive without developmental delay.He was referred to genetic clinic for dysmorphism at 1 yearold. Physical examination at that time revealedmicrocephaly (41 cm, <3rd centile), short stature (70 cm,SD -2.2), low body weight (6.95 kg, SD-3.0 ), depressednasal bridge, antevertered nostrils, bulbous nasal tip, long

Answer to "Clinical Quiz" on Pages 62-64N.B. The Editors invite contributions of illustrative clinical casesor materials to this section of the journal.

Clinical Quiz

Figure (A) Facial profile at 1 years of age. (B) Left ankle region exostosis (arrow). (C) Facial profile at 8 years old (with consents for

publication by parents).

philtrum, thin upper vermillion border and righthypoplastic ear. He had right hearing loss. His hands, feetand genitalia were normal. Cardiovascular examinationand abdominal examination were unremarkable.Subsequently, he developed multiple exostoses at rightscapula and left distal tibia at the age of 2. He studied inmainstream primary school with average performance. Hehad sparse hair and eyebrows and short hands. Orthopedicsurgery was performed for exostoses on right knee at 7years of age.


MCQs

Instruction:1. Please use pencil to shade the box for the best and correct answer (only one answer for each question).2. Send back the answer sheet (see loose leaf page) to the Hong Kong College of Paediatricians. One point will be awarded

to each article if ≥3 of the 5 answers are correct. The total score of the 4 articles will be 4 CME points.

(A) Diagnostic Value of Procalcitonin andC-Reactive Protein Level for PredictingAppendiceal Perforation in Children

1. Which is the most common acute surgical abdomen inolder children?a. Acute appendicitisb. Intestinal obstructionc. Meckel's diverticulumd. Intussusceptione. Abdominal tumour

2. The clinical manifestation of acute appendicitis inyounger children, especially infants include?a. Irritabilityb. Anorexiac. Lethargyd. Fevere. All of above

3. Perforated appendicitis can result in a variety ofpotentially serious complications such as?a. Bacterial peritonitisb. Small bowel obstructionc. Abdominal abscess formationd. Septic shocke. All of above

4. The preoperative laboratory values for diagnosis acuteappendicitis in children include?a. White blood count (WBC)b. C-reactive protein (CRP)c. Procalcitonin (PCT)d. D-Dimere. All of above

5. Which of the following biochemical markers has thelargest area under receiver operating characteristic (ROC)curve in predicting appendiceal perforation?a. Procalcitonin (PCT)b. White blood count (WBC)c. C-reactive protein (CRP)d. Neutrophil counte. None of the above

(B) The Diagnostic Value of Serum Amyloid A inEarly-Onset Neonatal Sepsis in PrematureInfants

1. Which has the highest value in the diagnosis of neonatalsepsis?a. Positive multiple acute phase reactantsb. Consecutive CRP positivityc. Serum Amyloid A positivityd. Blood culture positivitye. Urine culture positivity

2. Which of the tests and acute phase reactants used in thediagnosis of early-onset neonatal sepsis provides theleast information?a. C-reactive proteinb. Serum Amyloid Ac. Procalcitonind. Blood culturee. Sepsis scoring systems

3. What is the cut off value for SAA with high specificityand sensitivity in the diagnosis of neonatal sepsis?a. 0.1 mg/Lb. 25 mg/Lc. 0.5 mg/Ld. 10 mg/Le. 2.5 mg/L

4. Which is correct for early-onset neonatal sepsis?a. Antibiotic therapy should be started only in culture

positive casesb. Acute phase reactants are generally normalc. Staphylococcus epidermidis is one of the common

causesd. In case of suspected early sepsis treatment should

always be given at least 7 dayse. Long-term antibiotic treatments are safe

60

5. Which of the following is the least common symptomin neonatal sepsis?a. Respiratory instabilityb. Vomitingc. Temperature instabilityd. Nutritional difficultye. Convulsion

(C) The Impact of Paediatric NeuromuscularDisorders on Parents' Health-Related Qualityof Life and Family Functioning

1. Which of the following statement is true?a. All hereditary neuromuscular diseases have similar

disease courseb. The motor function of children with Duchenne

muscular dystrophy is usually stable over time withoutmuch deterioration

c. Children with neuromuscular disorders could sufferfrom respiratory, cardiovascular, orthopaedic,nutritional and gastrointestinal complications.

d. There is curative treatment for most of theneuromuscular disorders

e. All of the above

2. Which of the following is an example of hereditarymotor neuron disease?a. Duchenne muscular dystrophyb. 5q spinal muscular atrophyc. Congenital myopathyd. Congenital myasthenic syndromee. None of the above

3. What is the first US Food and Drug Administration(FDA)-approved drug for treating spinal muscularatrophy?a. Steroidb. Nusinersenc. Coenzyme Q10d. Gene therapye. Tacrolimus

4. Which of the following aspects were included in theevaluation of parent health-related quality of life?a. Physicalb. Emotionalc. Sociald. Cognitive functioninge. All of the above

5. Which of the following could be a source of stress forparents of children with neuromuscular disorders?a. Loss of ambulation of their childrenb. Unavailability of effective treatmentc. Uncertain treatment outcomed. Lack of public awareness of neuromuscular diseasee. All of the above

(D) Does Subclinical Hypothyroidism Affect Lipidand Epicardial Fat Tissue Thickness in Children?

1. What is the definition of subclinical hypothyroidism?a. TSH high, fT4 normalb. TSH high, fT4 lowc. TSH normal, fT4 lowd. TSH normal, fT4 normale. None of the above

2. Which of the following is not associated withhypothyroidism?a. Dyslipidemiab. Atherosclerosisc. Increased risk of cardiovascular diseased. Obesitye. Increased HDL cholesterol

3. Which of the following does not play a role in therelationship between subclinical hypothyroidism andatherosclerosis?a. Increased body mass indexb. Increased visceral adipose tissuec. Insulin resistanced. Atherogenic dyslipidemiae. Hypocoagulability

4. Which of the following is the gold standard method forvisceral adipose tissue measurement?a. Magnetic resonance imagingb. Transthoracic echocardiographyc. Computerised tomographyd. Electrocardiographye. None of the above

5. Which of the following statements about subclinicalhypothyroidism is incorrect?a. It is more common in adultsb. It is more common in childrenc. It is usually detected incidentallyd. It may cause dyslipidemiae. It may cause atherosclerosis

Answers of October issue 2020

(A) 1. b; 2. d; 3. a; 4. d; 5. b

(B) 1. b; 2. c; 3. e; 4. d; 5. c

(C) 1. a; 2. b; 3. a; 4. d; 5. a

(D) 1. d; 2. e; 3. e; 4. e; 5. e

HK J Paediatr (new series) 2021;26:61

Our Fond Memoryof the Late Dr. Kelvin LIU Kam Wing ( )

MBChB (IREL) 1979, LLMRCP LLMRCS (IREL) 1979, BAO (NUI) 1979, FRCS (GLASG) 1984FRACS 1988, FCSHK 1990, FHKAM (SURGERY) 1993, FRCSEd 2003

President of the Hong Kong Paediatric Society (2010-2012)Honorary Life Member of the Hong Kong Paediatric Society (2012)

Founding President of the Hong Kong Society of Paediatric Surgery (2015-2019)Honorary Life Member of the Hong Kong Society of Paediatric Surgery (2019)

Dr. Kelvin LIU was graduated from the Royal College of Surgeons in Ireland and had been working in the UnitedKingdom, Ireland, Australia and Hong Kong. When he returned to Hong Kong, he joined the Department ofSurgery at the Chinese University of Hong Kong to start his professional life as clinician, academic, and teacherin Paediatric Surgery.

Dr. LIU was one of the pioneers to introduce paediatric minimal invasive surgery and paediatric liver transplantationin Hong Kong. In 1997, Dr. LIU worked as the team leader to set up the Cleft Lip and Palate Service MultidisciplinaryTeam (CLAPS) at the United Christian Hospital which has provided an one-stop holistic service for the treatmentof cleft deformity in children. He was the mentor of many paediatric surgeons trained in Hong Kong and hadinstrumental role in leading the development of paediatric surgery into a flourishing subspecialty. Dr. LIU wasthe Founding President of the Hong Kong Society of Paediatric Surgery and had actively involved in planningthe paediatric surgical services at the Hong Kong Children's Hospital. As an experienced paediatric surgeon, Dr.LIU always worked hand-in-hand with his paediatric colleagues to handle the complicated paediatric cases.

Being a close partner to paediatricians, Dr. LIU joined the Hong Kong Paediatric Society (HKPS) to promotechild health and served the Society for decades at different positions. He was the second paediatric surgeon electedas the President of HKPS. Dr. LIU had led our Society to celebrate the memorable 50th Anniversary duringhis Presidency in 2010-2012. His international connections also facilitated the Society to establish collaborativenetwork with many renowned institutes and global organizations such as Children's Hospital of Philadelphia (CHOP),the Boston Children's Hospital and American Academy of Pediatrics (AAP). In 2010, he represented HKPS tosign an MOU with AAP to start the collaborative relationship between the two parties.

We are so sad that Dr. LIU has left us. To the medical profession, we have lost a great leader, a respectableteacher, a close friend and a multi-talented colleague. To the children and families, they will forever miss thisdedicated and passionate doctor who has devoted his lifetime to work for the betterment of children. He hadindeed established a strong foundation for his successors to further develop quality services and training of paediatricsurgery in Hong Kong and demonstrated clear directions for his colleagues to follow. He will be eternally rememberedby all of us in the field.

Dr. LIU passed away peacefully on 18th October 2020 in Hong Kong. Memorial Service would be held at theUniversal Funeral Parlor, Hung Hom, Hong Kong on 25th November, 2020. To his family, we would like toconvey our most sincere condolences. To the medical professionals, we shall forever miss him!

Dr. Chok-wan CHANPresident of International Pediatric Association (IPA) (2007-2010)Honorary President of Asia-Pacific Pediatric Association (APPA)President of the Hong Kong Paediatric Society (1982-1985)20th November 2020, Hong Kong.


CLINICAL QUIZ (p58) ANSWER

What is the diagnosis?

The clinical features of this child (sparse hair, bulbous nasal tip, thin upper lip, short stature and multiple exostoses)were compatible with Trichorhinopharyngeal syndrome II (TRPSII). Trichorhinophalangeal syndrome (TRPS) is arare disorder characterised by distinctive craniofacial and skeletal abnormalities, first described in 1966 by Giedion,who named the syndrome on the basis of the three core features: sparse hair, bulbous nasal tip and short/deformedfingers.1 Under this entity, it contains three subtypes: TRPS I, TRPS II and TRPS III differing in clinical characteristicsand pattern of genetic alteration in the TRPS1 gene (OMIM*604386). All subtypes are characterised by differentinvolvement in craniofacial, ectodermal and skeletal systems TRPS II is featured by multiple exostoses/osteochondromas and an increased risk of mild-to-moderate intellectual disability. TRPS III is considered an extremeclinical spectrum of TRPS I, with more severe brachydactyly due to short metacarpals and severe short stature. Thisterm may not be used nowadays but may come across in old literature.

In view of multiple exostoses and facial dysmorphic features, our patient is likely suffering from TRPS II. He hadchromosomal microarray analysis performed at 2 years of age. The test showed a copy number loss at chromosome8q23.3q24.12, with a size of at least 6.99 Mb. The deletion encompasses the TRPS1 and EXT1 (OMIM*608177). Thedeletion is de novo. The haploinsufficiency or loss of function mutation of EXT1 gene is associated with multipleexostoses type 1 (OMIM#133700). Thus the diagnosis of TRPS II was substantiated in this child.

The exact prevalence of TRPS is not available in literature.2 Around 100 cases of TRPS I and TRPS III and 100cases of TRPS II were published until June 2017.3 The clinical manifestation is highly heterogeneous. Given thewidely variable manifestations, many cases of TRPS probably remain undiagnosed. The condition is rare withestimated prevalence of 0.2-1 per 100,000 without ethnic group difference.2

How is the clinical diagnosis established in TRPS?

The diagnosis of TRPS relies on clinical suspicion and pattern recognition. There is no consensus diagnosticcriteria for TRPS. TRPS should be suspected if individuals having the following clinical or radiological findings:

Clinical features Radiological features

Characteristic facial features Cone-shaped epiphyses (detected >2 years old)

Skeletal anomalies Hip deformities

Ectodermal features (including hair, dental and nails) Secondary joint degeneration

Intellectual disability* Multiple osteochondromas*

*Detected in TRPS II only

Characteristic facial features include bulbous nasal tip, long flat philtrum, thin upper lip with vermilion borderand protruding ears. Ectodermal anomalies includes slow growing, fine and sparse scalp hair with receded medio-occipital hairline, thin eyebrows, dystrophic nails and dental anomalies, such as supernumerary teeth. Skeletalanomalies include short metacarpals or phalanges (ranging from mild to severe brachydactyly), ulnar or radialdeviation of the fingers, swelling of proximal interphalangeal joints (clinobrachydactyly), impaired small jointmobility, joint pain, cone-shaped epiphysis, short stature and osteopenia/decrease in bone mass.4 Hip deformities,e.g. coxa vara, coxa plana, and coxa magna, Perthes disease-like femoral head changes could be detected in TRPSpatients. Secondary joint degeneration Is characterised by joint space narrowing and subchondral sclerosis, involving

63

hips commonly but also found in other joints. Degenerative changes can be also be present in cervical spine, kneesand ankles. Clinical presentation of TRPS could vary widely, from mild change in the phalanges to osteopenia withfragility fractures.

For TRPS II, intellectual disability (usually mild to moderate) and multiple osteochondromas are unique featureswhich are not present in other two subtypes.

Molecular diagnosis of TRPS and Genetic counselling

The diagnosis of TRPS is established in a proband with typical clinical facial features, ectodermal manifestations,limb anomalies together with radiological findings. If the clinical phenotype is not distinct, the molecular diagnosiswould be helpful in establishing the diagnosis.

TRPS1 gene is located on chromosomal band 8q24.1. It encodes a transcription factor for a zinc-fingerprotein. Itrepresents a candidate gene for bone homeostasis regulation. It is believed to involve in regulation of boneperichondrium mineralisation and proliferation and apoptosis of chondrocytes.5

TRPS I is caused by heterozygous pathogenic variant of the TRPS1 gene, which leads to haploinsufficiency or lossof function of TRPS1. TRPS II, also known as Langer-Giedion syndrome, is a contiguous gene syndrome, caused bya larger deletion in the long arm of chromosome 8 (8q23.3-8q24.11) involving TRPS1 and EXT1 genes. The deletioncan be detected by chromosomal microarray or even karyotype if the size of deletion is bigger than 5 Mb. EXT1appears to have a regulatory effect on longitudinal bone growth and is involved in the development of exostoses.Mental retardation found to be correlated with the size of the interstitial 8q deletion.6

TRPS III is a variant of TRPS I, certain missense mutations of the same gene have been described in patients withTRPS III phenotype.7

TRPS is inherited in an autosomal dominant manner. The offspring of an affected individual is at a 50% risk ofinheriting the pathogenic variant. Once the pathogenic variant has been identified in an affected member, prenataltesting and preimplantation genetic diagnosis for a pregnancy at increased risk are possible. TRPS1 would have100% penetrance, although expressivity is variable and intrafamilial variation exists.

What are the management issues for TRPS?

Management of TRPS is principally supportive and prefers multi-disciplinary approaches involving pediatricorthopedic, endocrine, genetic, dental, physiotherapy and occupational therapy departments. For ectodermal aspect,advice about hair care and dental care (e.g. extraction of supernumerary teeth) can be given. For skeletal aspect, shortstature with or without growth hormone deficiency is major concern. The use of human growth hormone therapy hasvariable results and would need to be discussed on individual patient's basis. Joint pain is common among TRPSpatients. The main stay of treatment is use of analgesic, e.g. NSAID. Physiotherapy may help to improve the jointmobility. Occupational therapy can benefit the fine motor skills or task. In case of severe hip dysplasia, orthopedicsurgery, e.g. prosthetic hip implantation can be considered.

Monitoring of linear growth and psychomotor developmental in childhood would be recommended. For TRPS IIpatients: X-ray evaluation of osteochondromas is recommended when the exostoses are symptomatic and at the timenear the end of puberty (when normal growth of osteochondromas has ceased) to provide a baseline for comparisonwith any future enlargement. Concerning the effect of growth hormone therapy on exostoses development, there isno concrete evidence to conclude it will lead to significant increase in size or number of exostoses.8 However,carefulclinical and imaging follow-up of exostoses is mandatory during the time of growth hormone use.

64 Clinical Quiz Answer

Acknowledgement

We would like to thank the patient and the family for their contribution.

References

1. Giedon A. Das tricho-rhino-phalangeal syndrome. Helv Paediatr Acta 1966;21:475-85.2. Maas S, Shaw A, Bikker H, Hennekam RCM. Trichorhinophalangeal Syndrome. GeneReviews [internet]. 2017 April [cited 2020

June 2]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK425926/.3. Prevalence of rare diseases: Bibliographic data, Orphanet Report Series, Rare Diseases collection, 2017, Number 1: Diseases listed

in alphabetical Order http://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_diseases.pdf.4. Trippella G, Lionetti P, Naldini S, Peluso F, Matteo DM, Stefano S. An early diagnosis of trichorhinophalangeal syndrome type

1: a case report and a review of literature. Ital J Pediat 2018;44:138.5. Dias C, Isidoro L, Santos M, Santos H, Marques JS. Trichorhinophalangeal syndrome type I: a patient with two novel and

different mutations in the TRPS1 gene. Case Rep Genet 2013;2013:748057.6. Riedl S, Giedion A, Schweitzer K, Müllner-Eidenböck A, et al. Pronounced short stature in a girl with trichorhino-phalangeal

syndrome II (TRPS II, Langer-Giedion syndrome) and growth hormone deficiency. Am J Med Genet A 2004;131:200-3.7. Lüdecke J, Schaper J, Meinecke P, et al. Genotypic and Phenotypic Spectrum in Tricho-Rhino-Phalangeal Syndrome Types I and

III. Am J Hum Genet 2001;68:81-91.8. Bozzola M, Gertosio C, Gnoli M, et al.Hereditary multiple exostoses and solitary osteochondroma associated with growth hormone

deficiency: to treat or not to treat? Ital J Pediatr 2015;41:53.


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making by analogy. N Engl J Med 1995;332:592-6.2. Organisation as author The Royal Marsden Hospital Bone-

Marrow Transplantation Team. Failure of syngeneic bone-marrow graft without preconditioning in post-hepatitismarrow aplasia. Lancet 1977;2:742-4.

3. No author given Coffee drinking and cancer of the pancreas[editorial]. BMJ 1981;283:628.

4. Issue with supplement Gardos G, Cole JO, Haskell D, MarbyD, Paine SS, Moore P. The natural history of tardive dyskinesia.J Clin Psychopharmacol 1988;8(4 Suppl):31S-37S.

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66

5. Type of article indicated as needed [i] Fuhrman SA, JoinerKA. Binding of the third component of complement C3 byToxoplasma gondii [abstract]. Clin Res 1987;35:475A. [ii]Feldman N. Laparoscopic nephrectomy [letter]. N Engl J Med1991;325:1110.

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8. Chapter in a book Steiner RE, Bydder GM. Clinical nuclearmagnetic resonance imaging. In: Dawaon AM, CompstonND, Besser GM, editors. Recent advances in medicine no.19. Edinburgh: Churchill Livingston, 1984:39-56.

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10. Dissertation Cairns R.B Infrared spectroscopic studies ofsolid oxygen [dissertation]. Berkeley, (CA): Univ. ofCalifornia, 1965.

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reading.

DistributionThe HKJP is published quarterly and adopts an open access

policy. Electronic copies of all articles are available online athttp://www.hkjpaed.org. Members of HKCPaed and HKPSwill receive quarterly e-mail notification of the Table ofContents in each of the Journal issues.

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