X-LINKED ADRENAL HYPOPLASIA IN A LARGE GREENLANDIC FAMILY - DETECTIONOF A MISSENSE MUTATION (N440I) IN THE DAX-1 GENE - IMPLICATION FOR GENETIC-COUNSELING AND CARRIER DIAGNOSIS

X-linked congenital adrenal hypoplasia (AHC) is a developmental disord er of the human adrenal gland that results in profound hormonal defici encies, which are lethal if untreated. Hypogonadotropic hypogonadism ( HHG) is frequently associated with this disorder. The gene (DAX-1) res ponsible for the disease has recently been isolated. It encodes a prot ein with large similarity to members of the nuclear hormone receptor s uperfamily. Several different mutations in this gene have been found i n patients suffering from AHC. We have identified a missense mutation (N440I) in three patients with AHC and HHG, all belonging to a large G reenlandic family. A total of 42 individuals has been tested for this mutation. We have diagnosed 10 women as carriers, and have excluded 22 women with a 25-50% risk from being carriers, emphasizing the rapid i mpact of molecular genetic techniques.