Insights on the phenotypic heterogenity of 11ß-hydroxylase deficiency: clinical and genetic studies in two novel families.

PURPOSE: 11ß-hydroxylase deficiency accounts for 5% of congenital adrenal hyperplasia cases. Diagnosis suspiction is classically based on the association between abnormal virilization, precocious puberty, and hypertension in 46XX or 46XY subjects. We investigated two families with siblings presenting with opposed clinical features, and provided a review of the mechanisms involved in mineralocorticoid-dependent phenotypic heterogeneity. METHODS: The coding region of the CYP11B1 gene of 4 patients was sequenced and familial segregation was confirmed. Clinical characterization and blood steroid profile were performed. RESULTS: Family 1 comprised a female and a male siblings who presented in middle childhood with genital ambiguity (Prader II) and precocious puberty, respectively, associated with hypertension. In the second decade of life, the woman had three full-term pregnancies, and then evolved normotensive with no treatment over a 5-year follow up. On the other hand, her brother had hypertensive end-organ damage at age 24. In family 2, a 2.9 year-old boy presented with precocious puberty and hypertension, whereas his 21 days-old sister had genital ambiguity (Prader III) and salt wasting. A homozygous exon 4 splice site mutation was identified (IVS4ds-1G > A; c.799 G > A) in family 1, while a nonsense mutation in exon 6 (p. Q356X; c.1066 C > T) was found in family 2. CONCLUSION: CYP11B1 mutations were associated with highly variable phenotypes, from mild to severe virilization, and early-onset hypertension or salt wasting. Further analysis of variants in other hypertension-related genes, steroid synthesis and metabolism compensatory pathways, and/or the investigation of chimeric CYP11B genes are needed to clarify the phenotypic heterogeneity in 11ß-hydroxylase deficiency.

Congenital hypokalemia with hypercalciuria in preterm infants: a hyperprostaglandinuric tubular syndrome different from Bartter syndrome.

A congenital hypokalemic tubular disorder is described with many features resembling Bartter syndrome. Additional features include prenatal onset with polyhydramnios and premature labor; failure to thrive; episodes of fever, vomiting, diarrhea, and renal electrolyte and water wastage; hypercalciuria; nephrocalcinosis; and osteopenia. Unlike Bartter syndrome, there is no defect in tubular reabsorption of chloride. Urinary levels of prostaglandin E2 and 7 alpha-hydroxy-5,11-diketotetranorprosta-1,16-dioic acid are selectively elevated, indicating marked stimulation of renal and systemic PGE2 production. Chronic suppression of PGE2 activity by indomethacin corrects most of the abnormalities, and there is an immediate decompensation of the disease on indomethacin withdrawal. We conclude that these preterm infants have a distinct variety of hypokalemic tubular disorders rather than a variant of Bartter syndrome, because renal and systemic hyperprostaglandinism ranks high in the pathogenic chain of events, and the suppression of PGE2 hyperactivity is associated with significant improvement in the development (and probably in the prognosis) of the affected children.