Mutational analysis of DAX1 in patients with hypogonadotropic hypogonadismor pubertal delay

Although delayed puberty is relatively common and often familial, its molec ular and pathophysiologic basis is poorly understood. In contrast, the mole cular mechanisms underlying some forms of hypogonadotropic hypogonadism (HH ) are clearer, following the description of mutations in the genes KAL, GNR HR, and PROP1. Mutations in another gene, DAX1 (AHC), cause X-linked adrena l hypoplasia congenita and HH. Affected boys usually present with primary a drenal failure in infancy or childhood and HH at the expected time of puber ty. DAX1 mutations have also been reported to occur with a wider spectrum of cl inical presentations. These cases include female carriers of DAX1 mutations with marked pubertal delay and a male with incomplete BH and mild adrenal insufficiency in adulthood. Given this emerging phenotypic spectrum of clin ical presentation in men and women with DAX1 mutations, we hypothesized tha t DAX1 might be a candidate gene for mutation in patients with idiopathic s poradic or familial HH or constitutional delay of puberty. Direct sequencin g of DAX1 was performed in 106 patients, including 85 (80 men and 5 women) with sporadic HH or constitutional delay of puberty and patients from 21 ki ndreds with familial forms of these disorders. No DAX1 mutations were found in these groups of patients, although silent single nucleotide polymorphis ms were identified (T114C, G498A). This study suggests that mutations in DA X1 are unlikely to be a common cause of HH or pubertal delay in the absence of a concomitant history of adrenal insufficiency.