Gilbert's syndrome accounts for the phenotypic variability of congenital dyserythropoietic anemia type II (CDA-II).

The molecular basis for the considerable variation of serum bilirubin levels and the incidence of gallstone formation in patients with congenital dyserythropoietic anemia (CDA) type II are unknown. We show that the combined effect of an increased bilirubin load caused by dyserythropoiesis in CDA II and decreased bilirubin conjugation caused by reduced expression of uridine diphosphate glucuronosyl transferase (UGT1A) would increase the risk of hyperbilirubinemia (P <.005) and gallstone formation (chi(2): P <. 001). The rate of gallstone formation in patients with CDA II is 4. 75-fold the rate of patients without Gilbert's syndrome, and gallstone diagnosis occurs at a younger age (P < 0.01). These findings should be considered during the follow-up of patients with CDA II.

High frequency of de novo mutations in ankyrin gene (ANK1) in children with hereditary spherocytosis.

OBJECTIVE: To evaluate the frequency of de novo monoallelic expression of the ANK1 gene in hereditary spherocytosis individuals appearing as recessive. STUDY DESIGN: We studied 40 unrelated children with spherocytosis and their normal parents. The genomic distribution of the ankyrin (AC)n dinucleotide repeats was evaluated in the patients showing combined ankyrin and spectrin deficiency. To search for the absence of mRNA derived from one of the two ANK1 genes, cDNA from the heterozygous patients was amplified using polymerase chain reaction. This was analyzed for the (AC)n dinucleotide repeats. RESULTS: Thirty-three hereditary spherocytosis subjects had variable degrees of combined ankyrin and spectrin reduction; 19 were found to be heterozygous for the AC repeat lengths and were further studied. In 12, we found a cDNA polymerase chain reaction product from one ankyrin gene alone. These findings strongly suggested the nonexpression of one of the two ANK1 genes because of the de novo mutational events. CONCLUSION: The de novo loss of an ankyrin allele expression is a frequent cause of hereditary spherocytosis in children with normal parents. Therefore the category of genuinely recessive hereditary spherocytosis cases is further reduced compared with spherocytosis cases because of de novo mutations. The determination of the (AC)n microsatellite polymorphisms appears as a helpful and reliable tool for the discrimination between these two categories.