diagnosis and management of hereditary spherocytosis in neonates israel neonatology...

Diagnosis and Management of Hereditary Spherocytosis in

NeonatesIsrael Neonatology Association Robert Christensen, MD

• A heterogeneous disorder where abnormalities of RBC structural proteins lead to loss of RBC membrane surface area.• Spherical-shaped, hyperdense, poorly deformable red cells with a shortened life span. • Occurs world-wide & affects all racial and ethnic groups. • A common genetic cause of extreme neonatal jaundice.

Hereditary Spherocytosis

STATE-OF-THE-ART REVIEW ARTICLE

A Pediatrician’s Practical Guide to Diagnosing and Treating Hereditary Spherocytosis in Neonates Robert D. Christensen, Hassan M. Yaish, and Patrick G. Gallagher

2015

Large Fresh Water Lake

Dead Sea

The River Jordan

Outline1. Hereditary Spherocytosis in Israel2. Pathogenesis & responsible mutations3. Making the diagnosis in the Newborn

Nursery or NICU4. Natural history during the neonatal

period5. Treatment

Ballin A, Waisbourd-Zinman O, Saab H, Yacobovich J

et al. Steroid therapy may be effective in augmenting hemoglobin levels during hemolytic crises in children with hereditary spherocytosis. Pediatr Blood Cancer. 2011 Aug;57(2):303-5

Department of Pediatrics, Edith Wolfson Medical Center, Holon, Israel.

118 children with Hereditary Spherocytosis cared for at Edith Wolfson Medical Center.

Streichman S, Gescheidt Y. Cryohemolysis for the detection of hereditary spherocytosis: correlation studies with osmotic fragility and autohemolysis.American J. Hematology 1998 Jul;58(3):206-12.

Department of Hematology, Rambam Medical Center, Haifa, Israel.

Developed a diagnostic test based on a unique sensitivity of HS cells to hypertonic cryohemolysis and analyzed blood samples of 55 HS patients.

Tamary H, Aviner S, Freud E, et al. High incidence of early cholelithiasis detected by ultrasonography in children and young adults with hereditary spherocytosis. J Pediatr Hematol/Oncol 2003 Dec;25(12):952-4.

Department of Hematology-Oncology, Schneider Children's Medical Center of Israel, Petah Tikva.

41% of patients with HS (18/44) developed cholelithiasis as demonstrated by gallbladder ultrasonography. In most patients (94%) the test first proved positive at age 4 to 13 years. Patients with HS and Gilbert syndrome tended to be younger at the time of cholelithiasis.

Did these children with HS have the typical course of severe neonatal jaundice? How many are autosomal dominant? Which mutations? How many are autosomal recessive varieties or de novo mutations? Would there be value in identifying these as newborns and providing anticipatory guidance regarding development of jaundice, anemia, gall bladder disease?



period5. Treatment

Spherocyte

HEREDITARY SPHEROCYTOSIS

Prevalence in the Utah, USA = 1/1000

Red Blood Cell Membrane Proteins

Protein Gene Chromosomal location

Percent of HS cases

Typical severity

Inheritance

Ankyrin-1 ANK1 8p11.2 40-50% Mild to moderate

Autosomal dominant

Band 3 SLC4A1 17q21 20-35% Mild to moderate

Autosomal dominant

Beta Spectrin

SPTB 14q23-24.1 15-30% Mild to moderate

Autosomal dominant

Alpha Spectrin

SPTA1 1q22-23 <5% Severe Autosomal recessive

Protein 4.2 EPB42 15q15-21 <5% Mild to moderate

Autosomal recessive



period5. Treatment

•First step in making the diagnosis of HS is considering it in the differential diagnosis.

Making the Diagnosis in a Neonate

•First step in making the diagnosis of HS is considering it in the differential diagnosis. •The triad of anemia, splenomegaly, and jaundice, found in older children and adults with HS, is rare in neonates.


•First step in making the diagnosis of HS is considering it in the differential diagnosis. •The triad of anemia, splenomegaly, and jaundice, found in older children and adults with HS, is rare in neonates. •Most neonates with HS are not anemic in the first week of life.


•First step in making the diagnosis of HS is considering it in the differential diagnosis. •The triad of anemia, splenomegaly, and jaundice, found in older children and adults with HS, is rare in neonates. •Most neonates with HS are not anemic in the first week of life. •Jaundice is the most common presenting feature of HS in neonates.


•First step in making the diagnosis of HS is considering it in the differential diagnosis. •The triad of anemia, splenomegaly, and jaundice, found in older children and adults with HS, is rare in neonates. •Most neonates with HS are not anemic in the first week of life. •Jaundice is the most common presenting feature of HS in neonates. •The typically sluggish erythropoietic response of neonates in the first months often renders the reticulocyte count low relative to the degree of anemia.


•First step in making the diagnosis of HS is considering it in the differential diagnosis. •The triad of anemia, splenomegaly, and jaundice, found in older children and adults with HS, is rare in neonates. •Most neonates with HS are not anemic in the first week of life. •Jaundice is the most common presenting feature of HS in neonates. •The typically sluggish erythropoietic response of neonates in the first months often renders the reticulocyte count low relative to the degree of anemia.•Sometimes in neonates with HS, spherocytes are not clearly discerned on the early blood smears.


• 65 percent of neonates with HS have a parent with HS.

• When a parent has HS it is important that this information be placed prominently in the prenatal record and communicated verbally, before birth, to the physicians and the hospital staff who will be providing neonatal care.

• Failure to communicate this information sometimes occurs when the affected parent has been asymptomatic since splenectomy as a child, and has all but forgotten about the condition and fails to consider that it might be problematic for their newborn infant.


● Follow the serum bilirubin level and treat according to the AAP guidelines during and for several days after the birth hospitalization as if this were a known case of hemolysis.● During the birth hospitalization initiate the evaluation (next slide) or as suggested by hematology consultation. ● Consider that the neonate could have more severe jaundice than the parent did as a neonate, particularly if there has been co-inheritance of a polymorphism retarding bilirubin uptake or conjugation.

Evaluating a neonate, during the birth-hospitalization, whose parent has HS

A screening test for HS in neonates

MCHC mean corpuscular hgb concentration (g/dL), the concentration of hemoglobin in an erythrocyte. The MCHC is HIGH in neonates with HS.

MCV mean corpuscular volume (fL = 10-15L), the size of circulating erythrocytes. The MCV is LOW in neonates with HS.

Dr. Maxwell M. Wintrobe

http://search.msn.com/images/results.aspx?FORM=IRPW&q=red%20blood%20cell

A screening test for HS in neonates

MCHC mean corpuscular hgb concentration (g/dL), the concentration of hemoglobin in an erythrocyte. The MCHC is HIGH in neonates with HS.

MCV mean corpuscular volume (fL = 10-15L), the size of circulating erythrocytes. The MCV is LOW in neonates with HS.

Dr. Maxwell M. WintrobeMCHC/MCV

http://search.msn.com/images/results.aspx?FORM=IRPW&q=red%20blood%20cell

BLACK LINE = neonates with HS GREY LINE = neonates who do not have HS

Neonate with MCHC/MCV

>0.37 98% sensitivity

98% specificity for HS

ORIGINAL ARTICLE

A Simple Screen to Detect Hereditary Spherocytosis in Jaundiced Newborn InfantsRD Christensen, HM Yaish, E Henry

Neonate with MCHC/MCV >0.37

98% sensitivity98% specificity for HS

Obtain CBC & Blood Smear

High MCHC/MCV ratio (≥0.37)

Intermediate (0.35-0.36) or Normal (<0.35) MCHC/MCV ratio

Spherocytes

No Spherocytes Likely to have

autosomal dominant HSMight have autosomal dominant HS

Less likely to have autosomal dominant HS (but sometimes spherocytes are not prominent on blood films of neonates with HS)

● EMA Flow● Incubated osmotic fragility● Hematology consultation

Evaluating a neonate with “problematic jaundice” where the etiology is unclear.

•Not all neonates with problematic jaundice have hemolytic jaundice.

•If hemolytic jaundice is suspected, the following algorithm for step-wise evaluation of etiology might be useful.

PROBLEMATIC NEONATAL JAUNDICE?To evaluate potential underlying causes, obtain blood group on mother and baby, DAT, and CBC with peripheral blood smear

DAT PositiveIn ABO hemolytic disease, if the jaundice is severe or atypical, consider the possibility of a co-existing condition – consider additional diagnostic testing sequencing

DAT Negative

Suspicious for HS?(MCHC/MCV >0.37)

RBC Enzymology or Other Intrinsic Defect

G6PDPyruvate Kinase

OtherEMA Flow or

Incubated osmotic fragilityPathogenesis Still Unclear?

● Additional diagnostic testing● Next generation DNA sequencing● Hematology consultation

ORIGINAL ARTICLE

Evaluating eosin-5-maleimide binding as a diagnostic test for hereditary spherocytosis in newborn infantsRD Christensen, AM Agarwal, RH Nussenzveig, N Heikal, MA Liew and HM Yaish

•EMA-flow on the blood of 31 neonates; 20 healthy newborns and 11 suspected of HS.

•The 20 healthy newborns and the 2 in whom HS was suspected but later excluded all had normal EMA-flow.

•All nine in whom HS was confirmed had abnormal EMA-flow results. 2015

NEXTGEN High Through-put Gene

Sequencing

Gene Symbol Gene Description OMIM ID Associated Hematological Disorder

SPTA1 Spectrin alpha 182860 Elliptocytosis, spherocytosis, pyropoikiolocytosis

SPTB Spectrin beta 182870 Elliptocytosis, spherocytosis

ANK1 Ankyrin 1 612641 Spherocytosis

SLC4A1 Erythrocyte membrane protein band 3 109270 Spherocytosis, stomatocytosis, ovalocytosis

EPB41 Erythrocyte membrane protein band 4.1 130500 Elliptocytosis

EPB42 Erythrocyte membrane protein band 4.2 177070 Spherocytosis

PIEZO1 Piezo-type mechanosenitive ion channel component 611184 Xerocytosis

CYB5R3 Cytochrome b reductase 3 613213 Methemoglobinemia type 1 and 2

G6PD Glucose-6-phosphate dehydrogenase 305900 G6PD deficiency

GPI Glucose phosphate isomerase 172400 GPI deficiency

GSR Glutathione reductase 138300 GSR deficiency

HK1 Hexokinase 1 142600 Hemolytic anemia

NT5C3 Pyrimidine 5’ nucleotidase 606224 Hemolytic anemia

PGK1 Phosphoglycerate kinase 1 311800 PGK1 deficiency

PKLR Pyruvate kinase (liver and red cell) 609712 PKLR deficiency

PKM Pyruvate kinase (muscle) 179050 Bloom syndrome

TPI1 Triosephosphate isomarase 1 190450 TPI1 deficiency

GSS Glutathione synthase 601002 GSS deficiency

ADA Adenosine deaminase 608958 ADA deficiency

AK1 Adenylate kinase 1 103000 AK1 deficiency

PFKM Phosphofructokinase (muscle) 610681 PFKM deficiency, Glycogen storage dis type 7

PFKL Phosphofructokinase (liver) 171860 ?

UGT1A1 UDP glycosyltransferase 1 family, polypeptide A1 19174 Crigler-Najar syndrome 1 and 2

UGT1A6 UDP glycosyltransferase 1 family, polypeptide A6 606431 UGT1A6 deficiency

UGT1A7 UDP glycosyltransferase 1 family, polypeptide A7 606432 UGT1A7 deficiency

SLCO1B1 Solute carrier organic anion transporter family, member 1B1 604843 Rotor Syndrome

SLCO1B3 Solute carrier organic anion transporter family, member 1B3 605495 Rotor syndrome

ORIGINAL ARTICLE

Causes of hemolysis in neonates with extreme hyperbilirubinemiaRD Christensen, RH Nussenzveig, HM Yaish, E Henry, LD Eggert, AM Agarwal

•12 neonates with bilirubin ≥ 25 mg/dL. •Explanations for the jaundice were found in all. •Five had hereditary spherocytosis, three of which also had ABO hemolytic disease. Two had pyruvate kinase deficiency. One had severe G6PD deficiency. The other four had ABO hemolytic disease. 2014


Could end tidal carbon monoxide measurement be of any value in treating jaundiced neonates?

HEME CO BILIRUBIN

CO in exhaled breath, minus ambient CO reflects the bilirubin production rate.

STUDY #1: Define the reference range for end-tidal CO in term neonates during the first days after birth. METHOD: Use an FDA approved CO detector to quantify end-tidal CO in neonates from first hours after birth to time of discharge home.

RESULTS: Upper limit 1.7 ppm in the first week, 1.0 ppm after two weeks.

STUDY #2: End-tidal CO in neonates and children with a known hemolytic disorder (n=20 CASES) vs. age-matched controls who do not have a hemolytic disorder (n=20 CONTROLS).

Cases: 1.2 – 6.6 ppm Controls: all ≤ 1 ppmHereditary Spherocytosis (n = 8; 1.2 - 6.6 ppm)ABO Hemolytic Disease (n= 6; 1.8 - 5.6 ppm)Pyruvate Kinase Deficiency (n = 3; 1.3 - 5.2 ppm)Hereditary Stomatocytosis (n = 1; 1.4 ppm)Beta Thalassemia (n = 1; 5.1 ppm)SCD + Alpha Thalassemia (n = 1; 1.6 ppm)

End Tidal Carbon Monoxide levels in 20 neonates and children with proven hemolytic conditions

End Tidal CO in Well Babies with TSB >75th

percentileN=100

CO

CO

Feature Non-Hemolytic Jaundice

Hemolytic Jaundice

p-value

Number 63 37 <0.001

Birth weight (g) 3276±471 3416±525 0.172

Gestational age (wks) 39.0±1.6 38.4±1.2 0.566

Gender (% male) 40% 46% 0.584

Race (% non-Caucasian) *21% **30% 0.345

Age at qualifying bilirubin test (hrs) 34.6±16.7 33.5±13.6 0.442

Qualifying bilirubin value (mg/dL) 10.5±2.8 12.6±3.1 0.016

Mother blood group O 55% 62% 0.476

ETCOc (ppm) 1.5±0.3 2.6±0.8 <0.001

Received phototherapy in the hospital

45% 89% 0.003

Received home phototherapy after hospital discharge

18% 39% 0.005

Follow-up TB test was not obtained within 24 hrs of hospital discharge

16 1 <0.001

TB level RISK ZONE in the birth hospital

Number Day of life of hospital re-admission

TB level on re-admission(mg/dL)

Days of hospitaliz-ation(during the rehospitali-zation)

Number where readmission might have been averted by ETCOc testing

Test not done

2 5.0±1.4 21.0±3.6 3.0±2.8 ?

Low risk zone

6 5.6±1.8 18.8±1.9 1.8±1.0 0

Low-intermediate risk zone

34 4.5±1.2 19.2±1.8 1.3±0.4** 0

High-intermediate risk zone

22 4.1±0.8 19.9±2.6 1.8±1.3** 22

High risk zone

4 3.8±1.0 19.5±0.6 2.8±1.0 4

During the birth hospitalization, can we identify those jaundiced neonates with HEMOLYTIC jaundice and selectively involve them in a more rigorous bilirubin follow-up (<24 h after hospital

discharge?.....YES

QUESTIONS

By so doing, can we reduce hospital readmissions for extreme hyperbilirubinemia, and reduce the

risk of BIND and kernicterus….?

During the birth hospitalization, can we identify those jaundiced neonates with HEMOLYTIC jaundice and selectively involve them in a more rigorous bilirubin follow-up (<24 h after hospital

discharge?....YES

QUESTIONS



period5. Treatment

•Topic has received relatively little attention in published series or reviews. •Delhommeau et al. reported 34 infants with HS during their first year.

Natural history during the neonatal period

•Topic has received relatively little attention in published series or reviews. •Delhommeau et al. reported 34 infants with HS during their first year. •Neonatal jaundice was present in all and 3 received exchange transfusions.


•Topic has received relatively little attention in published series or reviews. •Delhommeau et al. reported 34 infants with HS during their first year. •Neonatal jaundice was present in all and 3 received exchange transfusions. •Transfusions were rarely needed in the first week.•Thirty-one had pallor and dyspnea during the first month. .


•Topic has received relatively little attention in published series or reviews. •Delhommeau et al. reported 34 infants with HS during their first year. •Neonatal jaundice was present in all and 3 received exchange transfusions. •Transfusions were rarely needed in the first week.•Thirty-one had pallor and dyspnea during the first month. •Twenty-six (76%) required one or more RBC transfusions during the first year; 12 had a single transfusion and 14 had two or more. •Six were splenectomized at 2 to 5 years.




period5. Treatment

• Reports of recombinant erythropoietin therapy as an alternative or adjunct to transfusion.

Treatment


• Rationale for rEPO - the relative hypoplastic phase of erythropoiesis during the first months after birth.

Treatment



• This phase might be related to the abrupt fall after birth from the highly-stimulated erythropoiesis during fetal life, the switch of EPO production from the liver to the kidney, the switch from fetal to adult hemoglobin, or the lower serum level of EPO in infants compared with older children.

Treatment



• This phase might be related to the abrupt fall after birth from the highly-stimulated erythropoiesis during fetal life, the switch of EPO production from the liver to the kidney, the switch from fetal to adult hemoglobin, or the lower serum level of EPO in infants compared with older children.

• We use Darbepoetin 10 µg/k sub Q if hgb <9 g/dL.

Treatment

•Erythrocyte transfusions.•Folic Acid. •Darbepoetin.•Iron status monitoring.•Splenectomy.

Treatment

Consistent approaches are needed to guide treatment of neonates. Organized study groups can make progress toward evidence-based improvements in outcomes and reductions in costs of care.



period5. Treatment

Take Home Messages/Questions•What proportion of severe neonatal jaundice in Israel is caused by Hereditary Spherocytosis?


•When a child here is found to have HS, what can we learn from the birth records about the natural history of bilirubin problems during the early days or transfusion needs in the early months of life?



•Are the cases of HS in Israel predominantly autosomal dominant? What are the responsible mutations?




•What percent of cases are autosomal recessive or de novo mutations? What are the responsible mutations?




•What percent of cases are autosomal recessive or de novo mutations? What are the responsible mutations?

•Can ETCO monitoring of provide any value?

•What “consistent approaches” (guidelines) can we write?

Diagnosis and Management of Hereditary Spherocytosis in Neonates

Israel Neonatology Association Robert Christensen, MD

Thanks for Your Kind Attention

diagnosis and management of hereditary spherocytosis in neonates israel neonatology...

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