diagnosis and management of hereditary spherocytosis in neonates israel neonatology...
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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
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?
Outline1. Hereditary Spherocytosis in Israel2. Pathogenesis & responsible mutations3. Making the diagnosis in the Newborn
Nursery or NICU4. Natural history during the neonatal
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
Outline1. Hereditary Spherocytosis in Israel2. Pathogenesis & responsible mutations3. Making the diagnosis in the Newborn
Nursery or NICU4. Natural history during the neonatal
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.
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. •Most neonates with HS are not anemic in the first week of life.
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. •Most neonates with HS are not anemic in the first week of life. •Jaundice is the most common presenting feature of HS in neonates.
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. •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.
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. •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.
Making the Diagnosis in a Neonate
• 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.
Making the Diagnosis in a Neonate
● 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
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
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
Making the Diagnosis in a Neonate
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
Outline1. Hereditary Spherocytosis in Israel2. Pathogenesis & responsible mutations3. Making the diagnosis in the Newborn
Nursery or NICU4. Natural history during the neonatal
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.
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. •Transfusions were rarely needed in the first week.•Thirty-one had pallor and dyspnea during the first month. .
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. •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.
Natural history during the neonatal period
Outline1. Hereditary Spherocytosis in Israel2. Pathogenesis & responsible mutations3. Making the diagnosis in the Newborn
Nursery or NICU4. Natural history during the neonatal
period5. Treatment
• Reports of recombinant erythropoietin therapy as an alternative or adjunct to transfusion.
Treatment
• Reports of recombinant erythropoietin therapy as an alternative or adjunct to transfusion.
• Rationale for rEPO - the relative hypoplastic phase of erythropoiesis during the first months after birth.
Treatment
• Reports of recombinant erythropoietin therapy as an alternative or adjunct to transfusion.
• Rationale for rEPO - the relative hypoplastic phase of erythropoiesis during the first months after birth.
• 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
• Reports of recombinant erythropoietin therapy as an alternative or adjunct to transfusion.
• Rationale for rEPO - the relative hypoplastic phase of erythropoiesis during the first months after birth.
• 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.
Outline1. Hereditary Spherocytosis in Israel2. Pathogenesis & responsible mutations3. Making the diagnosis in the Newborn
Nursery or NICU4. Natural history during the neonatal
period5. Treatment
Take Home Messages/Questions•What proportion of severe neonatal jaundice in Israel is caused by Hereditary Spherocytosis?
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?
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?
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?
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?
•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