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ONLINE FIRST

STUDY

Harlequin Ichthyosis

A Review of Clinical and Molecular Findings in 45 Cases

Shefali Rajpopat, MRCP; Celia Moss, DM, FRCP; Jemima Mellerio, MD, FRCP; Anders Vahlquist, PhD, MD;Agneta Ganemo, RN, PhD; Maritta Hellstrom-Pigg, PhD, MD; Andrew Ilchyshyn, FRCP; Nigel Burrows, FRCP;Giles Lestringant, MD; Aileen Taylor, FRCP; Cameron Kennedy, FRCP; David Paige, FRCP; John Harper, MD, FRCP;Mary Glover, FRCP; Philip Fleckman, MD; David Everman, MD; Mohamad Fouani, MSc; Hulya Kayserili, MD, PhD;Diana Purvis, MBChB, FRACP; Emma Hobson, MRCP, PhD; Carol Chu, MBChB, MD; Charles Mein, PhD;David Kelsell, PhD; Edel OToole, PhD, FRCP

Objective: To assess the clinical outcomes of 45 casesof harlequin ichthyosisandreview the underlyingABCA12gene mutations in these patients.

Design: Multicenter, retrospective, questionnaire-

based survey.

Setting: Dermatology research institute.

Participants: Patients with harlequin ichthyosis forwhom we had performed ABCA12 mutation analysis.

MainOutcomeMeasures: Referring physicians wereasked to complete a questionnaire using the patientsnotes, detailing the clinical outcome of the affected child.In each case, the causative ABCA12 mutation was iden-tified using standard polymerase chain reaction and se-quencing techniques.

Results:

Of the 45 cases, the ages of the survivors rangedfrom 10 months to 25 years, with an overall survival rateof 56%. Death usually occurred in the first 3 months and

was attributed to sepsis and/or respiratory failure in 75%of cases. The early introduction of oral retinoids may im-prove survival, since 83% of those treated survived,whereas 76% who were not given retinoids died. Recur-rent skin infections in infancy affected one-third of pa-

tients. Problems maintaining weight affected 44%. Threechildren developed an inflammatory arthritis, and de-velopmental delay was reported in 32%. Mutation analy-sis revealed that 52% of survivors had compound het-erozygous mutations, whereas all deaths were associatedwith homozygous mutations.

Conclusions: Harlequin ichthyosis should be regardedas a severechronic disease that is notinvariably fatal.Withimproved neonatal care and probably the early introduc-tion of oral retinoids, the number of survivors is increas-ing. Compound heterozygotes appear to have a survivaladvantage.

Arch Dermatol. 2011;147(6):681-686.Published online February 21, 2011.doi:10.1001/archdermatol.2011.9

HARLEQUIN ICHTHYOSIS(HI)(OMIM242500)isarare,severe form of congenitalichthyosis, which may befatal. The neonate is en-

casedinanarmorofthickscaleplatessepa-rated by deep fissures. There isbilateral ec-tropionandeclabium,andthenoseandearsareflattened andappearrudimentary.Con-

stricting bands around the extremities canrestrict movementand causedigital necro-sis. As the skin barrier is severely compro-mised, neonates are more prone to sepsis,dehydration, and impaired thermoregula-tion. Treatmentwithoral retinoidsencour-agessheddingofthegrosslythickenedskin. 1

Babieswhosurviveintoinfancyandbeyonddevelopskinchangesresemblingseverenon-bullous congenital ichthyosiform erythro-derma (NBCIE).2

Recessive mutations in the gene encod-ing the adenosine triphosphate (ATP)-binding cassette (ABC) transporter pro-tein ABCA12 (NCBI Entrez Gene 26154),localized to the lamellar granules of up-per epidermal keratinocytes, cause HI.3,4

Electron microscopy of lamellar granulesin HI skin has shown that they are ab-sent, abnormally shaped, or reduced in

number and that no intercellular lamel-lae are present.5 It is postulated thatABCA12 transports glucosylceramide intothelamellar granules, where it is then pro-cessed and secreted into the stratum cor-neum extracellular space to form lipid la-mellae.4 Expression of markers of lateepidermal differentiation is highly dys-regulated in HI skin, suggesting thatABCA12 may have a key role in keratino-cyte differentiation.6 Reports of HI to date

Author Affiliations are listed atthe end of this article.

ARCH DERMATOL/VOL 147 (NO. 6), JUNE 2011 WWW.ARCHDERMATOL.COM681

2011 American Medical Association. All rights reserved.at , on June 22, 2011www.archdermatol.comDownloaded from
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have focused on the infant, and there is relatively littlein the literature about the outcome of older children andadult survivors. We have conducted a reviewof the clini-caloutcomes of HI cases referred to ourcenter forABCA12mutation analysis.

METHODS

Fifty-six referring physicians were identified from our data-

base andwith the consent of their patient(s) were askedto com-plete a detailed systems-based questionnaire. Ethical ap-proval was obtained from the local research ethics committee.

We have previously briefly reported the clinical outcomes of12 babies with HI.3 These brief questionnaire responses wereused in this review if the child was deceased at the time of theoriginal study or if no further information was available.

Primer design and polymerase chain reaction (PCR) con-ditions were the same as those described elsewhere, 7 withthe exception that a 15-L reaction volume was used. ThePCR products were purified and sequenced as describedpreviously.3

RESULTS

DEMOGRAPHIC AND MORTALITY DATA

Clinical data were obtained for 45 patients (eTable; http://www.archdermatol.com). This consisted of 33 com-pleted detailed questionnaires and 12 brief question-naires. In total, there were 25 survivors (56%) and 20deaths (44%). The mean gestational age at birth was 35weeks (range, 30 to 39 weeks). Sex was reported for 43patients (20 male and 23 female). The ages of survivorsranged from 10 months to 25 years. The children camefrom several different ethnic groups (eTable). The highincidence of Pakistani and Arab families probably re-flects the practice of consanguinity in these groups. In-deed, 38% of all parents were first cousins and 29% wereunrelated, and in 33% the information was not avail-able.However, 86% of thelatter showed homozygous mu-tations (the same mutation on bothABCA12 alleles) sug-gestive of consanguinity.

The mortality rate was 44% (20 of 45 patients), withthe age of death ranging from day 1 to day 52. Of the 20deaths, 15 (75%) were caused by fulminant sepsis (n=5[25%]), respiratory failure (n=5 [25%]) or a combina-tion of the 2 (n=5 [25%]). There was 1 stillbirth, and in4 cases the cause of death was unknown.

PRENATAL TESTING

Prenatal ultrasonography results were available for 6cases, all with previously affected children, from 22weeks onwards. Routine fetal anomaly scans used in theearly stages of pregnancy were not included. In 3 cases,features suggestive of HI were seen, including rudimen-tary ears, flexion contractures at the knees, and densefloating particles in the amniotic fluid. In the last case,previously described by Vohra et al,11 an open mouthwith a protruding tongue and echogenic amniotic fluidwere noted.

TREATMENT WITH RETINOIDS

Of 45 babies, an oral retinoid drug was given to 24, and20 (83%) survived. Among the 20 survivors, treatmentwas started within the first 3 days of life in 9 babies (45%)and between days 4 and 7 in 7 babies (35%) and was de-ferred until 2 years and 11 months in another case. Onebaby received a retinoid as a neonate, and in 2 cases thestart date was unknown. Four children died despite re-

ceiving a retinoid. Withinthisgroup, treatment wasstartedby day 3 in 3 babies (75%). Twenty-one babies did notreceive a retinoid, and within this group, 16 (76%) died.Of these 16 deaths, 10 (63%) occurred by day 3.

With the exception of 2 patients treated with etreti-nate and 2 with isotretinoin, the remainder (n=20) allreceived acitretin. The retinoid dose ranged from 0.5 to2.5 mg/kg (eTable). This was constant in 18 cases, butin 4 the dose was adjusted according to response and tol-erability. In 2 cases the dose was not stated. Among the20 survivors, 14 (70%) received 1 course of treatment, 4(20%) had 2 separate courses, and 2 (10%) received morethan 2 courses. Continuous treatment was given for upto 6 months in 13 cases, up to 1 year in 3 cases, up to 2

years in 3 cases, and from 3 to 7 years in 4 further cases.The length of treatment was unknown for 4 patients.

CLINICAL FINDINGS ASSOCIATED WITH HI

Skin Abnormalities

At Birth. All babies had the typical harlequin appearanceat birth, with truncal plates with fissuring, bilateral ectro-pion,andeclabium.Hyperkeratoticskinresultedinantevertednares and ears lacking retroaural folds. Of 45 children, 5developedautoamputationofdigitsduetoconstrictingskinbands. One child who subsequently died underwent afasciotomy for limb swelling due to constriction.

Infancy and Beyond. Babies who survived into infancyhad a severe ichthyosiform erythroderma. Of 25 survi-vors, 13 (52%) had a palmoplantar keratoderma. Plan-tar changes were associated with pain on weight bear-ing and delay in walking. Recurrent skin infections werereported in early childhood and affected 8 of 25 pa-tients. Among these 8 patients, cultured organisms in-cluded methicillin-resistant Staphylococcus aureus (n=5),Staphylococcus aureus (n=4), Streptococcus pyogenes(n=4), and Klebsiella (n=2). Both heat and cold intol-erance were reported in 9 of the 25 survivors (36%), aswas reduced sweating (n= 7 [28%]). Pruritus affected 11

of these 25 patients (44%). Photosensitivity was re-ported in 1 case, and widespread, pigmented maculeswereobserved in another patient. One patient had severalepisodes of widespread sterile pustulation attributed togeneralized pustular psoriasis, associated with nailshedding.

Hair and Nail Problems

Generalized poor hair growth affected 16 of the 25 sur-vivors (64%). In 1 patient, this was limited to the pari-




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etal and occipital scalp, and in another there was regres-sion of all the hair margins. One child aged 7 years hadno scalp hair. Nail deformities were observed in 16 of the25 survivors (64%). Among these 16 patients, 11 (69%)had abnormally shaped or small nails, 8 (50%) had thick-ened nails, and in 1 case, surgical amputation of the ter-minal phalanges of 2 fingers was required because of ony-chogryphosis.

Ophthalmological Problems

Persistent ectropion was found in 16 of the 25 survivors(64%) and was corrected in 5 patients. Among the 25 sur-vivors, epiphora wasreported in 12 (48%), recurrent con-junctivitisin 5 (20%),exposure keratitis in 3 (12%),squintin 2 (8%), and nystagmus in 4 (16%). The latter was notedin 1 child who survived a cardiac arrest and was unex-plained in the other 3 cases. Of the 25 patients, 1 eachhad corneal scarring and corneal perforation, 2 had punc-tate corneal erosions, and 1 developed cataracts while re-ceiving concomitant corticosteroid therapy and anotherwhile receiving acitretin.

Gastrointestinal Problems

Among the 25 survivors, problems maintaining weightdespite high-calorie supplements were reported in 11(44%). Two children required nasogastric feeding tubesin infancy, and1 child had overnight supplementary feed-ing via a gastrostomy tube, performed intermittently un-til the age of 6 years. This is probably an underestimatebecause we did not specifically enquire about the use offeedingtubes.Chronicconstipation requiring regular laxa-tives affected 11 of the 25 children (28%). Three chil-drenweretreated for gastroesophageal reflux. Finally, vi-tamin D deficiency causing rickets and osteomalacia was

reported in 3 patients, and 1 patient developed scurvyduringa 3-year period when thechild wasout of thecoun-try and lost to follow-up.

Height and Weight Abnormalities

Height and weight were both below average, lying be-tween the 0.4th and 25th percentiles, resulting in mostchildren being short and thin for their age. One child re-ceives regular somatotropin injections (started at age 9years and currently ongoing) to promote growth.

Locomotor Problems

Of the 25 survivors, 7 reported joint pain, most com-monly affecting the knees. In 3 cases this was associatedwith an inflammatory arthritis. One case was previouslyreported by Clement et al.12 The patient had juvenile id-iopathic arthritis and required systemic treatment withmethotrexate and the antitumor necrosis factor drugetanercept beforehaving bilateral hip arthroplasties at age17 years. The second casedeveloped an intermittent, pain-ful swollen right knee and ankles and was treated withnonsteroidal anti-inflammatory drugs for 1 year and cur-rently has nighttime splinting to prevent joint contrac-

tures. The final patient was noted to have erosions on ajoint radiograph, but detailsof further management werenotavailable. None of the patients were being treated withretinoids at the time of reporting the joint pain. In ad-dition, 4 of the 25 survivors (16%) required surgical cor-rection of contractures.

Neurological Problems

Developmental delay was reported in 8 of the 25 survi-vors (32%). This included delayed developmental mile-stones and fine and gross motor skills. Four children liv-ing in the United Kingdom required speech and languagetherapy. Of these, 1 child had cerebral palsy and 3 chil-dren showed significant developmental delay.

Respiratory Problems

Respiratory problems were most common in the neona-tal and early infancy periods and were a major cause ofdeath in neonates. Of the 25 children who survived, 3(12%) required mechanical ventilation and 1 had inter-mittent episodes of oxygen desaturation in the first 2

weeks. Another 3 patients (12%) had respiratory failuresecondary to respiratory syncytial virus, and 1 patient de-veloped pulmonary interstitial fibrosis.

Ear, Nose, and Throat Problems

Deafness was reported in 1 of 25 survivors. Six childrenexperienced recurrent blockage of the external auditorycanal and required regular microsuctioning to removeskin debris.

Urological Problems

Surgical correction of phimosis in 1 patient and urinary

incontinence due to an unstable bladder in another pa-tient were reported. One child underwent circumcisionwithout any problems.

Biochemical Problems

Hypernatremia, hypocalcemia, and hypoglycemia werereported separately in 3 of 25 patients in early infancy.

Miscellaneous Problems

Hepatosplenomegaly attributed to infection was re-ported in 1 patient. In another case, hepatospleno-megaly was associated with lymphadenopathy, bonemar-

row fibrosis, and pancytopenia. Histopathologicexamination following splenectomy revealed splenicgranulomas. Severe anemia requiring blood transfusionwas reported in 3 of 25 cases.

EDUCATIONAL DEVELOPMENTAND AFFECTED SIBLINGS

Of the 17 school-aged children, 2 were in higher edu-cation, 9 attended a mainstream school, 2 attended aschool for children with special needs, and 1, who lived




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outside the United Kingdom, did not attend school; de-tails were unavailable for 3 children. In the United King-dom, many children (55%) needed a statement of spe-cial educational needs. This is the provision of additionalhelp for children who face difficulties in their ability tolearn owing to their disease.

Differences in phenotype within families (3 sibling-pair survivors)included cerebral palsy in the younger childof one pair and significant developmental delay in the

younger sibling of another pair.

MUTATION ANALYSIS

ABCA12 mutations were identified in 38 of 45 patients.In the remaining 7, no mutation was found in either al-lele by standard PCR and sequencing (n=3), DNA wasunavailable (n=2), or the analysis was performed else-where (n=2). Patients with mutations were classified ashomozygous if both alleles carried the same mutation(n=27) or compound heterozygous, indicating that dif-ferent mutations were seen on each allele (n= 11). All thedeaths were associated with homozygous mutations.Among the mutations found in 21 survivors, 11 (52%)

were compound heterozygous and 10 (48%) werehomozygous.

COMMENT

Harlequin ichthyosis is a rare disease, affecting all eth-nic groups, that is associated with substantial morbidityand mortality. Previous reports have shown that manybabies die soon after birth,13 but in our series the sur-vival rate is higher than 50%. Reasons may include greaterawareness of the condition, improved quality of care, andpossibly early treatment with oral retinoids. In the reti-noid-treated group,20 of 24 patients(83%)survivedcom-

pared with a 76% mortality rate in the untreated group(16 of 21 patients died). More than half of these deaths(10 of 16[63%]) occurred in the first 3 days of life. How-ever, only 45% of survivors received a retinoid within thistime. This suggests that many of these early deaths mayhave happened irrespective of treatment with a reti-noid. In some cases it may have been decided that pal-liative care only wasmore appropriate. A previous study14

showed that 6 of 7 cases of HI treated with an oral reti-noid survived beyond 1 year. Our results demonstratethat the majority of survivors were treated with a reti-noid and 80% started treatment by day 7. Liquid acitre-tin is not widely available and may take several days toobtain. We postulate that the introduction of oral reti-

noids, as soon as possible after birth, probably improvessurvival. However, we recognize that a more active man-agement approach overall also contributes to improvedsurvival.

The only potential retinoid related adverse effect inthis study was the development of a cataract in a childtreated with acitretin (0.5 mg/kg/d) for 4 months frombirth. Retinoid-associated cataracts have been reportedin adults but not in children.1 To minimize long-term toxiceffects, Brecher et al1 recommended that the retinoid doseshould be kept as low as possible, ideally close to 0.5 mg/

kg/d. Serum lipids and liver function tests should be per-formed at baseline, 1 month after initiation of treat-ment, andevery 3 monthsthereafter.Symptoms suggestiveof skeletal toxicity should be promptly investigated, par-ticularly in those children receiving doses greater than1.0 mg/kg/d.

Management of HI in the neonate is largely supportiveand involves the input of a multidisciplinary team. Emol-lients and the early introduction of an oral retinoid at an

initial dose of 1 mg/kg/d encourage shedding of the thickarmor like plates. It is important to keep invasive pro-cedures to a minimum and to be vigilant for signs of sep-sis to avoid skin infection. An ophthalmologist should beinvolved at an early stageto minimizecomplicationscausedby the ectropion and ear, nose, and throat specialists foraural toilet to remove debris from the ears. Plastic sur-gery input may be needed to treat digital contractures ornecrosis. Baseline biochemical and hematological testsshouldbe carriedoutandabnormalities corrected.The ret-inoid dose can usually be reduced and after 6 monthsshould be guided by clinical response.

Survivors will have a life-long skin disease that re-sembles NBCIE. The mechanism behind this pheno-

typic recovery remains unclear. Yanagi et al15

recentlydemonstrated disrupted keratinocyte differentiation inneonatal epidermis and primary-culture keratinocytesfroman HI mouse model.With maturation, however, boththe skin graft and subcultured HI keratinocytes re-gained normal differentiation, suggesting that this maycontribute to the improvement in an HI survivors skin.Patients will still require frequent maintenance applica-tion of emollients, intermittent courses of oral retinoidsin some cases, and protection from extremes of tempera-ture. Vitamin D supplements will be required if skin ex-posure to sunshine is restricted. Patient support groupssuch as the Foundation for Ichthyosis & Related SkinTypes (FIRST) (United States) and the Ichthyosis Sup-

port Group (United Kingdom) provide valuable help tofamilies.Preservation of visual function is crucial in survivors.

Persistent ectropionis a frequentcomplication, and in thisstudy 20% underwent surgical correction. The lack of in-tact donor skin for grafting makes this more challengingin HI. Full-thickness autografts from the thigh16 and pos-terior auricular skin17 have been described in HI as wellas 1 case using engineered human skin.18 The long-termoutcome of surgery in these cases is not known, but wereport 1 case of epiphora postoperatively. Ectropion fre-quently recurs following surgical correction. An alterna-tive approach is topical periocular retinoid treatment.

Early input from a dietician is necessary, since in-

fants may have difficulty sucking because the jaw issplinted by thick scale, necessitating nasogastric feed-ing. Breastfeeding should be encouraged, particularly topromoteparental bonding. Young childrenmayneedfeed-ing via gastrostomy to maintain their calorific intake,whereas older children and adults are more likely to com-ply with high-calorie dietary supplements. To our knowl-edge, this is the first report of HI associated with rick-ets, although this haspreviously been reported in childrenwith ichthyosiform dermatoses.19,20 Possible mecha-nisms for this include defective vitamin D synthesis in




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the diseased epidermis and avoidance of exposure to UVradiation due to the disease.21

Juvenile idiopathic arthritis is a rare inflammatory ar-thritis. In addition to the 3 cases reported herein, an-other patient with HI aged 6 years is described in the lit-erature who developed rheumatoid factorpositivepolyarthritis.22 The coexistence of these 2 rare condi-tions suggests a common underlying etiology that is notyet understood.

Motor developmentaldelay wasreportedin almostone-third of the cases. Digital contractures and autoampu-tated fingertips can affect fine and gross motor skills, andthickened, fissured plantar skin may be painful and delaywalking. Many of the children have frequent hospital ad-missionsin infancy and, because of their disease, may alsohave fewer interactions with other children and adults,which affects their speech, language, and social skills.

Thecauseof deathin HI is oftenspeculative, sincepost-mortem examinations are not usually conducted. Re-view of the mortality data shows that respiratory failurecausesdeathas commonly as sepsis. This may simply arisebecause the thickened skin restricts chest wall move-ments or makes breathing too painful, resulting in poor

pulmonary ventilation. Opiate analgesia is given in theneonatal period to relieve this pain but may itself causerespiratory depression. Rajamani et al23 reported that as-piration of amniotic fluid rich in epithelial cells mighthave contributed to the development of pulmonary dis-ease in a child with congenital ichthyosis, which is alsoplausible in HI. Furthermore, ABCA12 is also expressedin the lungs, testis, and placenta.7 ABCA3 aids lipid se-cretion from type II alveolar cells via lamellar bodies.24

Ultrastructural analysis of these cells in an HI mousemodel has shown that lamellar bodylike organelles lackthe normal lamellar structure compared with wild-typemice, suggesting that ABCA12 protein may be involvedin generating the lipid component of pulmonary surfac-

tant.25

This would support our observation of a high in-cidence of respiratory-related deaths in HI.Mortality was associated with homozygous muta-

tions in this study. Unpublished work (2010) by our groupshows thatsome babieswith compound heterozygous mu-tations also die but are in the minority. The coexistenceof other serious recessive diseases may be one explana-tion. However, the nature of the ABCA12 mutation andits location within the protein may also affect the sever-ity of the disease. Homozygous missense mutations inABCA12 are known to cause type 2 lamellar ichthyosisin a subgroup of patients from Africa,7 as well as being amajor cause of NBCIE.26 Both type 2 lamellar ichthyosisand NBCIE have a much milder phenotype than HI, in

which most mutations are homozygous or compound het-erozygous deletions or truncations. ABCA12 mutationsin type 2 lamellar ichthyosis have been found exclu-sively in the first nucleotide-binding fold and in NBCIEhave been reported in the extracellular domain and sec-ond nucleotide-binding fold. Akiyama et al27 reported achild with HI of moderate clinical severity who hada ma-ternal deletion mutation of a highly conserved residuein exon 28 and a de novo missense mutation in exon 10,corresponding to the first nucleotide-binding fold andcytoplasmic domain, respectively. They argued that while

the missense mutation would not be expected to signifi-cantly affect the function of the protein, in combinationwith the deletion mutation, the HI phenotype still ap-pears but is of reduced clinical severity. In our series, 2missense mutations were identified, namely V1089F inexon 23 combined with a splice site mutation in exon33 in one patient, and G1179R (homozygous) in exon24 of another patient. Both of these substitutions wouldchange an amino acid residue in the first transmem-

brane domain of the protein. While neither patient hada milder form of disease, both have survived, and this maybe partly owing to the nature of their mutations. Fur-thermore, biallelic effects, as described in xerodermapigmentosum,28 may also occur in HI, where the inter-play between 2 heterozygous mutations determines theseverity of thedisease. In the3 casesin this series for whichno mutation was found, it is likely that there is a com-plex deletion or a mutation within an intron, promoter,or other regulatory component of thegene that is notame-nable to detection with conventional techniques. Muta-tion analysis is particularly important if preimplanta-tion or earlyprenataldiagnosis is beingconsidered in thefirst trimester. Knowledge of the familial mutation al-

lows earlier diagnosis by amniocentesis or chorionic vil-lous biopsy or in vitro fertilization followed by preim-plantation diagnosis.

Management of HI requires a multidisciplinary ap-proachfrom the outset. The disease is not alwaysfatal andis associated with extracutaneous manifestations. Al-though there is some delay in achieving developmentalmilestones, many children are able to attend a main-streamschool with appropriate support andadults canen-ter higher education and live independently. Awarenessof this information will provide greater understanding ofthe disease for those who care for patients with HI.

Accepted for Publication: December 14, 2010.

Published Online: February 21, 2011. doi:10.1001/archdermatol.2011.9Author Affiliations: Centre for Cutaneous Research, Bliz-ard Instituteof Cell and Molecular Science, Bartsand TheLondon School of Medicine and Dentistry (Drs Ra-jpopat, Kelsell, and OToole ), and The Genome Centre,John Vane Science Centre (Dr Mein ), Queen Mary, Uni-versity of London, London, England; Birmingham Chil-drens Hospital,Birmingham, England(Dr Moss); St JohnsInstitute of Dermatology, Guys and St Thomas NHSFoundation Trust, St Thomas Hospital, London(Dr Mel-lerio); Departments of Medical Sciences and Genetics andPathology, Uppsala University, Uppsala, Sweden (DrsVahlquist, Ganemo, and Hellstrom-Pigg); Department of

Dermatology, University Hospital Coventry, Coventry,England (Dr Ilchyshyn); Department of Dermatology, Ad-denbrookes NHS Trust, Cambridge, England (Dr Bur-rows); Department of Dermatology, Royal Victoria In-firmary, Newcastle upon Tyne, England (Dr Taylor);Bristol Dermatology Centre, Bristol Royal Infirmary, Bris-tol, England (Dr Kennedy); Department of Dermatol-ogy, Barts andtheLondon NHS Trust, London (Dr Paige);Great Ormond Street Hospital for Children, London (DrsHarper and Glover); Department of Dermatology, Uni-versity of Washington, Seattle (Dr Fleckman); Green-




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wood Genetic Center, Greenwood, South Carolina (DrEverman); Department of Biochemistry, Faculty of LifeSciences, Tarbiat Modares University, Tehran, Iran (MrFouani); Medical Genetics Department, Istanbul Medi-cal Faculty, IstanbulUniversity, Istanbul, Turkey (Dr Kay-serili); Department of Paediatric Dermatology, StarshipChildrens Hospital, Auckland, New Zealand (Dr Pur-vis); and Departments of Clinical Genetics (Dr Hobson)and Clinical Genetics (Dr Chu), Chapel Allerton Hos-

pital, Leeds, England. Dr Lestringant is a consultant der-matologist (retired).Correspondence: Shefali Rajpopat, MRCP, Centre for Cu-taneous Research, Blizard Institute of Cell and MolecularScience, Barts andtheLondonSchool of Medicine andDen-tistry,Queen Mary, University ofLondon,4 NewarkSt,Lon-don E1 2AT, England ([email protected]).Author Contributions: Drs Rajpopat, Kelsell,and OToolehad full access to all of the data in the study and takeresponsibility for the integrity of the data and the accu-racy of the data analysis. Study concept and design:Rajpopat, Kelsell, Mein, and OToole.Acquisition of data:Rajpopat, Moss, Mellerio,Vahlquist, Ganemo, Hellstrom-Pigg, Ilchyshyn, Burrows, Lestringant, Taylor, Ken-

nedy, Paige, Harper, Glover, Fleckman, Everman,Fouani,Kayserili, Purvis, Hobson, Chu, Kelsell, and OToole.Analysis and interpretation of data: Rajpopat, Moss, Paige,Fleckman, Mein, Kelsell, and OToole. Drafting of themanuscript: Rajpopat, Kelsell, and OToole. Critical re-vision of the manuscript for important intellectual content:Rajpopat, Moss, Mellerio,Vahlquist, Ganemo, Hellstrom-Pigg, Ilchyshyn, Burrows, Lestringant, Taylor, and Ken-nedy, Paige, Harper, Glover, Fleckman, Everman,Fouani,Kayserili, Purvis, Hobson, Chu, Mein, Kelsell, andOToole. Statistical analysis: Rajpopat and OToole. Ob-tained funding: Rajpopat, Kelsell, and OToole. Adminis-trative, technical, and material support: Rajpopat, Hell-strom-Pigg, Kennedy, Paige, Fouani, Kayserili, and

OToole. Study supervision: Kelsell, Paige Lestringant,Mein, and OToole.Financial Disclosure: Dr OToole has a BSSRC industrialCASE studentship funded by Stiefel (GlaxoSmithKline).Funding/Support: This study was supported in part bygrants from the British Skin Foundation and Barts andthe London Charity. Dr Mellerio has received financialsupport from the Department of Health via the NationalInstitute for Health Research comprehensive Biomedi-cal Research Centre award to Guys and St Thomas NHSFoundation Trust in partnership with Kings College Lon-don and Kings College Hospital NHS Foundation Trust.Role of the Sponsors: The sponsors had no role in thedesign and conduct of the study; in the collection, analy-

sis, and interpretation of data; or in the preparation, re-view, or approval of the manuscript.Online-Only Material: The eTable is available at http://www.archdermatol.com.

REFERENCES

1. Brecher AR, Orlow SJ. Oral retinoid therapy for dermatologic conditions in chil-dren and adolescents. J Am Acad Dermatol. 2003;49(2):171-182.

2. Haftek M, Cambazard F, Dhouailly D, et al. A longitudinal study of a harlequin

infantpresentingclinicallyas non-bullouscongenitalichthyosiformerythroderma.

Br J Dermatol. 1996;135(3):448-453.

3. Kelsell DP, Norgett EE, Unsworth H, et al. Mutations in ABCA12 underlie the se-

vere congenital skin disease harlequin ichthyosis. Am J Hum Genet. 2005;

76(5):794-803.

4. Akiyama M, Sugiyama-Nakagiri Y, Sakai K, et al. Mutations in lipid transporter

ABCA12 in harlequinichthyosis andfunctional recovery by correctivegene transfer.

J Clin Invest. 2005;115(7):1777-1784.

5. Milner ME, OGuin WM, Holbrook KA, Dale BA. Abnormal lamellar granules in

harlequin ichthyosis. J Invest Dermatol. 1992;99(6):824-829.

6. Thomas AC, Tattersall D, Norgett EE, OToole EA, Kelsell DP. Premature termi-

nal differentiation and a reduction in specific proteases associated with loss of

ABCA12 in Harlequin ichthyosis. Am J Pathol. 2009;174(3):970-978.

7. Lefevre C, Audebert S, Jobard F, et al. Mutations in the transporter ABCA12 are

associated with lamellar ichthyosis type 2. Hum Mol Genet. 2003;12(18):2369-

2378.

8. Thomas AC, Sinclair C, Mahmud N, et al. Novel and recurring ABCA12 muta-

tions associated with harlequin ichthyosis: implications for prenatal diagnosis.

Br J Dermatol. 2008;158(3):611-613.

9. Rajpar SF, Cullup T, Kelsell DP, Moss C. A novel ABCA12 mutation underlying a

case of Harlequin ichthyosis. Br J Dermatol. 2006;155(1):204-206.

10. Bojs G, Vrana I, Ganemo A, Vahlquist A. Neonatal acitretin treatment of harle-

quin ichthyosis. Retinoids. 2000;16(4):120-123.

11. Vohra N, Rochelson B, Smith-Levitin M. Three-dimensional sonographic findings

in congenital (harlequin) ichthyosis. J Ultrasound Med. 2003;22(7):737-739.

12. Clement SA, Burrows NP, Sansome A, Hazleman BL, Ostr AJ. Harlequin ich-

thyosisand juvenile idiopathic arthritis: a rare combination.ClinRheumatol. 2007;

26(3):460-462.13. Akiyama M. The pathogenesis of severe congenital ichthyosis of the neonate.

J Dermatol Sci. 1999;21(2):96-104.

14. Singh S, Bhura M, Maheshwari A, Kumar A, Singh CP, Pandey SS. Successful

treatment of harlequin ichthyosis with acitretin. Int J Dermatol. 2001;40(7):

472-473.

15. Yanagi T, Akiyama M, Nishihara H, et al. Self-improvement of keratinocyte dif-

ferentiation defects during skin maturation in ABCA12-deficient harlequin ich-

thyosis model mice. Am J Pathol. 2010;177(1):106-118.

16. Chua CN, Ainsworth J. Ocular management of harlequin syndrome. Arch

Ophthalmol. 2001;119(3):454-455.

17. Khan R, Arora S, El-Hindy N, Chang BY. Repair of cicatricial ectropion in a har-

lequin baby. J AAPOS. 2009;13(4):415-416.

18. Culican SM, Custer PL. Repair of cicatricial ectropion in an infant with harlequin

ichthyosis using engineered human skin. Am J Ophthalmol. 2002;134(3):442-

443.

19. Thacher TD, Fischer PR, Pettifor JM, Darmstadt GL. Nutritional rickets in ich-

thyosis and response to calcipotriene. Pediatrics. 2004;114(1):e119-e123.20. Sethuraman G, KhaitanBK, DashSS, et al.Ichthyosiform erythrodermawith rick-

ets: report of five cases. Br J Dermatol. 2008;158(3):603-606.

21. Milstone LM, Ellison AF, Insogna KL. Serum parathyroid hormone level is el-

evated in some patients with disorders of keratinization. Arch Dermatol. 1992;

128(7):926-930.22. Chan YC, Tay YK, Tan LK, Happle R, Giam YC. Harlequin ichthyosis in associa-

tionwith hypothyroidismand juvenile rheumatoidarthritis. Pediatr Dermatol.2003;

20(5):421-426.

23. Rajamani S, Birnkrant DJ, Rodgers M. Use of bronchoalveolar lavage to dem-

onstrate squamous epithelial aspiration in congenital icthyosis: a case report.

J Perinatol. 2000;20(5):329-330.

24. Yamano G, Funahashi H, Kawanami O, et al. ABCA3 is a lamellar body mem-

brane protein in human lung alveolar type II cells. FEBS Lett. 2001;508(2):

221-225.

25. Yanagi T, Akiyama M, Nishihara H, et al. Harlequin ichthyosis model mouse re-

veals alveolar collapse andseverefetalskinbarrierdefects.HumMolGenet. 2008;17(19):3075-3083.

26. Sakai K, Akiyama M, Yanagi T, et al. ABCA12 is a major causative gene for non-

bullous congenital ichthyosiform erythroderma. J Invest Dermatol. 2009;129

(9):2306-2309.

27. Akiyama M, Sakai K, Sugiyama-Nakagiri Y, et al. Compound heterozygous mu-

tations including a de novo missense mutation in ABCA12 led to a case of har-

lequin ichthyosis with moderate clinical severity. J Invest Dermatol. 2006;126

(7):1518-1523.

28. Andressoo JO, Jans J, de Wit J, et al. Rescue of progeria in trichothiodystrophy

by homozygous lethal Xpd alleles. PLoS Biol. 2006;4(10):e322.



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