No abstract

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. (J Clin Endocrinol Metab 84: [4497][4498][4499][4500] 1999) T HE ASSOCIATION of DAX1 (AHC) gene mutations with X-linked adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HH) is well established (OMIM: 300200) (1, 2). More than 50 different mutations in the gene encoding DAX-1 have been reported in this condition (3-6). Affected boys typically present with primary adrenal insufficiency in infancy or childhood. HH usually becomes evident later in life with failure of pubertal development (7,8).DAX-1 is an orphan nuclear hormone receptor that is expressed in the adrenal gland, gonads, hypothalamus, and pituitary gonadotropes (9). The HH caused by DAX1 mutations seems to involve deficits at both hypothalamic and pituitary levels (10 -13). DAX-1 is also expressed in Sertoli cells (14), and male Ahch (Dax1) knockout mice have disordered spermatogenesis and infertility (15). DAX-1 has a crucial role, therefore, in the development and function of the reproductive axis at multiple levels. Different approaches to counseling and treatment are needed for patients with DAX1 mutations compared to those with hypothalamic forms of HH, such as Kallmann syndrome (3,16).Recently, DAX1 gene mutations have been found in several men and women who have less typical reproductive phenotypes. These cases include: 1) partial HH in a man who presented later in life with mild adrenal failure (13); 2) HH, but normal adrenal function, in a woman who is homozygous for a DAX1 mutation thro...