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.