Case presentation
This term baby boy was born from a healthy mother with an obstetrical
history notable for three early spontaneous abortions, two healthy-term
babies, and one child with Axenfield Riegers Syndrome (OMIM: 180500).
The prenatal course was complicated by severe fetal anemia at 26 weeks’
gestation (fetal hemoglobin of 39 g/L) requiring one intrauterine
transfusion. The mother’s blood group was A+.
Investigations for parvovirus, toxoplasmosis and cytomegalovirus were
negative. Routine serologies were protective. Non-invasive prenatal
testing (NIPT), rapid aneuploidy detection and chromosomal microarray
were normal. Several maternal IAT, done before and after the
intrauterine transfusion, were negative. The etiology of fetal anemia
remained unclear to the maternal-fetal medicine team. The patient was
not referred to hematology.
The baby was born at 37 weeks GA through induced vaginal delivery for
decreased fetal movement in the context of fetal anemia. Initial
complete blood count (CBC) showed hemoglobin of 65 g/L with an increased
MCV of 118 fL and reticulocytosis (574.2 X109/L). His
blood group was A+. The blood smear suggested
hemolysis (see figure 1A). LDH was elevated at 10 446 U/L (normal
< 1128 U/L). DAT and IAT were negative. He was transfused pRBC
(see Figure 1B). Pre-transfusion hemoglobin investigations were not
ordered. He developed early onset severe refractory unconjugated
hyperbilirubinemia (see Figure 1D), requiring 3 double volume exchange
transfusions in the first two days of life while under high-intensity
phototherapy. He required another pRBC transfusion after the first
exchange transfusion for mild anemia. He developed thrombocytopenia
within the first 24h, for which he received two platelet transfusions
(see Figure 1B). The thrombocytopenia resolved by DOL 4. An abdominal
ultrasound showed mild hepatosplenomegaly. Given the transfused status,
hemoglobin investigations and enzymopathy testing were not reliable. The
Kleihauer-Betke test from the placenta was negative for feto-maternal
hemorrhage. Further blood bank testing was obtained to rule out
alloimmunization. Maternal serum from the time of delivery was negative
for antibodies against low-frequency antigens. An eluate performed on
cord blood from delivery was negative. The maternal plasma was first
cross-matched against cord RBC, and then cross-matched against paternal
RBC, both of which showed no agglutination. Considering the inability to
test the baby’s endogenous blood for hemoglobinopathies, parents were
investigated with hemoglobin electrophoresis, CBC, reticulocyte and
ferritin levels; all tests were unremarkable.
Concomitantly, the baby’s refractory unconjugated hyperbilirubinemia
progressed to significant combined hyperbilirubinemia within the first
24 hours of life (see figure 1D, E). An extensive
gastroenterologic/metabolic work-up showed no primary liver disease. The
conjugated hyperbilirubinemia was thought to be inspissated bile duct
syndrome caused by overwhelming hemolysis. It improved with ursodiol. He
was discharged on DOL 10 with no transfusion requirement for one week.
The patient required pRBCs at two weeks of age and every two weeks
thereafter. At two weeks old, we performed alpha thalassemia gene
mapping, which came back normal, and sent a Invitae Hereditary Hemolytic
Anemia Panel (test code: 55679) genetic panel on mucosal cells. This
panel uses next-generation sequencing to analyze 40 genes involved in a
vast array of hereditary hemolytic anemias. At one month of age, his
genetic results yielded a KLF1 gene mutation C.973G>A, a
pathologic variant known to cause CDAIV. A bone marrow transplant
consultation was obtained. A fully matched sibling hematologic stem cell
transplant is planned once the patient is 1 year old.