Hyperbilirubinemia, Transient Familial Neonatal

A number sign (#) is used with this entry because of evidence that transient familial neonatal hyperbilirubinemia can be caused by heterozygous or homozygous mutation in the uridine diphosphate-glucuronosyltransferase gene (UGT1A1; 191740) on chromosome 2q37.

Mutations in the same gene cause Crigler-Najjar syndrome types I and II (218800, 606785) and Gilbert syndrome (143500).

Clinical Features

Occasionally, severe neonatal unconjugated hyperbilirubinemia occurs without evident etiologic explanation. Lucey et al. (1960) and Arias et al. (1965) suggested that some of these cases may have a familial basis. The cause of transient neonatal hyperbilirubinemia may be steroidal substances in the plasma and milk of the mother that inhibit conjugation of bilirubin (Lucey et al., 1960). Arias et al. (1965) found a high level of a maternal serum substance that inhibits formation of the glucuronide of direct-reacting bilirubin and O-aminophenol by rat liver slices and homogenates. The inhibitor was present in these mothers in concentrations 4 to 10 times that in other pregnant mothers. The inhibitor is probably a progestational steroid. Arias et al. (1965) made reference to observations on 5 mothers who gave birth to a total of 16 infants, each of whom had severe transient neonatal hyperbilirubinemia. Three of the 16 died of kernicterus, and one was left with quadriplegic cerebral palsy. The mothers do not show hyperbilirubinemia, probably because of a large functional reserve. This is an interesting genetic disease of which there are few examples--one in which the genotype of the mother is responsible for the disease in the infant. Another example is mental retardation in the offspring of women with phenylketonuria (Mabry et al., 1963). The ethnic background of these mothers and the presence or absence of consanguinity in their parents would be of interest.

The same condition may be present in unusually high frequency in Yemenite Jews (Sheba, 1964).

Khoury et al. (1988) found that the risk of neonatal hyperbilirubinemia in newborns who had one or more prior sibs with this finding was 3.1 times higher than that of newborns who had prior sibs without this finding (10.3% vs 3.6%).

Breast Milk Jaundice

Transient nonhemolytic unconjugated hyperbilirubinemia is observed in breast-fed but not bottle-fed babies of mothers whose breast milk contains pregnane-3(alpha),20(beta)-diol that competitively inhibits hepatic glucuronyltransferase activity in vitro. Serum from these mothers contains no more inhibitory substance than does normal pregnancy serum. Kernicterus has not been observed, probably because severe jaundice does not develop until the seventh to tenth day, when the infant's blood-brain barrier has become relatively impermeable to unconjugated bilirubin (Arias et al., 1964; Arias et al., 1965).

Grunebaum et al. (1991) reported a follow-up of 60 infants with breast milk jaundice showing that there were 2 bilirubin peaks, on the fourth and fifth days and on the fourteenth and fifteenth days of life. In infants with uninterrupted breastfeeding, the hyperbilirubinemia disappeared slowly and could still be detected 12 weeks after birth. The familial incidence was 13.9%. Late neurodevelopmental or hearing defects were not observed, thus enabling the pediatrician to encourage continuation of breastfeeding in most cases of healthy infants with breast milk jaundice.

Sato et al. (2013) found that 56 (14%) of 401 Japanese neonates who were exclusively breastfed developed hyperbilirubinemia and required phototherapy. Neonates with a 10% or greater loss of body weight since birth had a significantly higher peak bilirubin level and incidence of hyperbilirubinemia, higher frequency of cesarean delivery, and shorter gestational period compared to those with less than 10% loss of body weight. Sex and body weight at birth were not significantly different between the 2 groups.

Molecular Genetics

Maruo et al. (2000) analyzed 17 breastfed Japanese infants with apparent prolonged jaundice (serum bilirubin greater than 10 mg/dL at age 3 weeks to 1 month). When breastfeeding was stopped, the serum bilirubin levels began to decrease in all cases, but when breastfeeding was resumed, the serum bilirubin concentration again became elevated in some infants. Serum bilirubin levels normalized by the time the infants were 4 months old. Sequencing of UGT1A1 revealed that 8 infants were homozygous and 7 heterozygous for a missense mutation (191740.0016) common in the East Asian population and found in Japanese patients with Gilbert syndrome (143500) or hereditary unconjugated hyperbilirubinemia. The authors suggested that breastfeeding jaundice may be an infantile and inducible phenotype of Gilbert syndrome. Another UGT1A1 missense mutation (191740.0017) was found in one of the homozygotes, an insertion in the TATA box of UGT1A1 (191740.0011) was found in one of the heterozygotes, and an enhancer region mutation (191740.0018) was found in a patient who did not carry the common mutation.

Sato et al. (2013) performed UGT1A1 genotyping of a cohort of 401 exclusively breastfed Japanese neonates, 56 (14%) of whom developed hyperbilirubinemia and required phototherapy, and found that the frequency of the G71R polymorphism (191740.0016) was 0.18 and was higher in neonates with body weight loss less than 10%. However, maximal body weight loss during the neonatal period was the only independent risk factor for the development of neonatal hyperbilirubinemia (odds ratio of 1.25). Although presence of the G71R variant was not a significant independent risk factor for neonatal hyperbilirubinemia overall, subgroup analysis revealed that G71R was a risk factor only in neonates with a 5% or greater maximal body weight loss, and the influence correlated with the degree of body weight loss. Sato et al. (2013) suggested that adequate feeding in the neonatal period may overcome the genetic predisposing factor of G71R to neonatal hyperbilirubinemia.