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Mutational Analysis of DAX1 in Patients with Hypogonadotropic Hypogonadism or Pubertal Delay¹

Division of Endocrinology, Metabolism, and Molecular Medicine (J.C.A., W-X.G., T.J.K., J.J.M., L.P.S., R.L.H., J.L.J.), Northwestern University Medical School, Chicago, Illinois 60611; Reproductive Endocrine Unit (S.M.S., W.F.C.), Massachusetts General Hospital, Boston, Massachusetts 02114; London Centre for Paediatric Endocrinology (P.C.H.), University College London, London, United Kingdom W1N 8AA; Genetics and IVF Institute (D.P.B., R.J.S.), Fairfax, Virginia 22031; and Section of Reproductive Endocrinology and Infertility (L.C.L.), University of Chicago, Chicago, Illinois 60637

Address correspondence and requests for reprints to: J. Larry Jameson, M.D., Ph.D., Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School, 303 East Chicago Avenue, Tarry Building 15-709, Chicago, Illinois 60611.

Although delayed puberty is relatively common and often familial, its molecular and pathophysiologic basis is poorly understood. In contrast, the molecular mechanisms underlying some forms of hypogonadotropic hypogonadism (HH) are clearer, following the description of mutations in the genes KAL, GNRHR, and PROP1. Mutations in another gene, DAX1 (AHC), cause X-linked adrenal hypoplasia congenita and HH. Affected boys usually present with primary adrenal failure in infancy or childhood and HH at the expected time of puberty.

DAX1 mutations have also been reported to occur with a wider spectrum of clinical presentations. These cases include female carriers of DAX1 mutations with marked pubertal delay and a male with incomplete HH and mild adrenal insufficiency in adulthood. Given this emerging phenotypic spectrum of clinical presentation in men and women with DAX1 mutations, we hypothesized that DAX1 might be a candidate gene for mutation in patients with idiopathic sporadic or familial HH or constitutional delay of puberty. Direct sequencing 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 kindreds with familial forms of these disorders. No DAX1 mutations were found in these groups of patients, although silent single nucleotide polymorphisms were identified (T114C, G498A). This study suggests that mutations in DAX1 are unlikely to be a common cause of HH or pubertal delay in the absence of a concomitant history of adrenal insufficiency.

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