Case of Severe Unconjugated Hyperbilirubinemia in a Neonate Heterozygous for Gilbert Syndrome

We present an unusual case of unconjugated hyperbilirubinemia in a 6 day old infant. The bilirubin peaked at 20.1/ 0.6 mg/dL. A work-up for a hemolytic process or metabolic disorder was negative. Crigler-Najjar was suspected. Phenobarbital was given for 3 days with no ������ change in bilirubin level. He was discharged home after 20 days of phototherapy with a bilirubin of 3.1/0.4 mg/dL. Five months later, his bilirubin was 0.2 mg/dL. His genetic testing came back positive for a heterozygous mutation for Gilbert Syndrome. In the UGT1A1 gene he had the following mutations: heterozygous *28 (TA 6/7) (c. 40-39insTA), heterozygous *60 (c-3275T>G), and heterozygous *93 (c.3152G>A). This result is consistent with a carrier state for unconjugated hyperbilirubinemia and may be associated with mild to moderate hyperbilirubinemia. The relevance of this haplotype of polymorphisms to hyperbilirubinemia in the neonate has not been established. Gilbert syndrome is the most common hereditary cause of increased bilirubin but is typically associated with mild hyperbilirubinemia, around 3 mg/dL. In the homozygous state, diminished bilirubin glucuronidation is observed but it is questionable if the same amount of decreased activity can be seen in the heterozygous state. It has been proposed that when additional mutations exist in conjunction with a heterozygous state, neonatal hyperbilirubinemia is more pronounced. We believe that unexplained unconjugated hyperbilirubinemia should raise the suspicion of a UGT1A1 gene mutation and should prompt genetic testing. Gilbert syndrome should be added to the differential of severe unconjugated hyperbilirubinemia in the neonate. *Corresponding Author: Rebecca Abell, Pediatric Gastroenterology, Hepatology, and Nutrition, Stony Brook Long Island Children’s Hospital, Stony Brook, NY, USA, Tel: 1-631-444-8115; Fax: 1-631-444-6045; E-mail: [email protected] Received March 06, 2012; Accepted July 26, 2012; Published July 28, 2012 Citation: Abell R, Monteleone B, Chawla A (2012) Case of Severe Unconjugated Hyperbilirubinemia in a Neonate Heterozygous for Gilbert Syndrome. Hereditary Genet 1:114. doi:10.4172/2161-1041.1000114 Copyright: © 2012 Abell R, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Introduction Jaundice is not an uncommon entity in the newborn and is encountered frequently by pediatricians. The differential diagnosis for indirect hyperbilirubinemia can be vast, making it imperative for the pediatrician to have an understanding of the different etiologies of increased bilirubin levels. Unconjugated hyperbilirubinemia can be caused by bilirubin overproduction (i.e. hemolysis), impaired hepatic bilirubin uptake (i.e. reduced hepatic blood flow or certain drugs), or impaired hepatic bilirubin conjugation (i.e. Gilbert syndrome and Crigler-Najjar syndrome Types I and II). If unconjugated hyperbilirubinemia is left untreated, it can have neurotoxic effects on the neonate with lifelong repercussions. Here we discuss a case of neonatal unconjugated hyperbilirubinemia with an unexpected diagnosis of Gilbert syndrome. Patient Presentation A six day old term infant presented with unconjugated hyperbilirubinemia. He had received phototherapy for two days while in the newborn nursery for a bilirubin of 14.5/0.4 mg/dL and was discharged home. Discharge bilirubin was 11.5 mg/dL. Bilirubin levels were followed daily. On day of life six his bilirubin was 19.4/0.6 mg/ dL, at which time he was admitted for phototherapy. Upon admission his vital signs were stable, he was in no distress, and was visibly jaundiced to the level of the torso. He had been feeding every three hours either breast milk or formula. His stools were yellow in color. Total bilirubin peaked the next day at 20.1 mg/dL with a direct bilirubin of 0.6. His hemoglobin was 16.1 g/dL at time of admission and dropped to 6.1,10 days later. He was transfused 15 cc/kg of packed red blood cells. Post-transfusion hemoglobin was 9.2 g/dL. Seven days later, his hemoglobin dropped again to 6.9 and he was transfused an additional 15 cc/kg of packed red blood cells. Throughout this period, he clinically remained stable. Reticulocyte count peaked at 9.9 and a peripheral smear demonstrated schistocytes and bite cells, suggesting a hemolytic process. However, Coomb’s test, haptoglobin, and G6PD screening were all within normal limits, essentially ruling out a hemolytic process. Ultrasounds of his abdomen and head were performed to look for a source of bleeding, and were both normal. Screening for metabolic disorders including plasma amino acids and urine organic acids was unremarkable. Crigler-Najjar was suspected. A trial of Phenobarbital was given for 3 days with no significant change in his bilirubin level. His hemoglobin remained stable and his bilirubin eventually decreased to 3.1/0.4 mg/dL after 20 days of phototherapy. He was discharged home. Five months later, his total bilirubin remains normal at 0.2 mg/dL. Several weeks after discharge, his genetic testing came back positive for a heterozygous mutation for Gilbert Syndrome, with an additional thymine and adenine (TA) base pair. In the UGT1A1 gene he had the following mutations: heterozygous *28 (TA 6/7) (c. 40-39insTA), heterozygous *60 (c-3275T>G), and heterozygous *93 (c.3152G>A). This result is consistent with a carrier state for unconjugated hyperbilirubinemia and may be associated with mild to moderate hyperbilirubinemia. This promoter TA7 repeat polymorphism when linked with these two addition alterations, (c-3275TG and c-3152GA), results in decreased glucuronidation capacity [1]. The *60 allele is associated with reduced transcription of UGT1A1 and reduced activity of the UGT1A1 enzyme in adult patients. [2,3] The relevance of this haplotype of polymorphisms to hyperbilirubinemia in the neonate has not been established.