Importance of genetic diagnosis of DAX-1 deficiency: example from a large, multigenerational family.

Background: Inactivating mutations of DAX-1 give rise to the X-linked form of adrenal hypoplasia congenita (AHC). Affected fetuses are at risk of early postnatal Addisonian crisis, but the variable phenotypic expression of DAX-1 insufficiency renders this diagnosis challenging.

Methods: We describe the familial transmission of AHC over several generations. The proband was diagnosed with adrenal insufficiency at age 3.5 years: molecular analysis revealed a novel, 373-bp deletion including the second exon of DAX-1. Given the familial history of several unexplained deaths in male infants related to the proband via his maternal great-grandmother, we hypothesized that all these boys had been affected with AHC. Another female member of the family being pregnant with a male fetus at the time, we performed DAX-1 analysis on the mother and the newborn. The mother was heterozygous for the deletion, and the newborn hemizygous: he presented an adrenal crisis at 10 days of life, and is now doing well on hormone replacement therapy.

Conclusion: The unfortunate deaths of male infants at each generation of this family underlie the importance of early and precise diagnosis of this rare condition, stressing the value of genetic diagnosis in six potential female carriers of this family entering their reproductive years.