Loss-of-function mutations in the NR0B1 (DAX1) gene on chromosome Xp21 cause X-linked adrenal hypoplasia congenita (AHC). In males with X-linked AHC, the mature adult zone of the adrenal cortex fails to develop properly, resulting in a cortex that appears disorganized and contains large, cytomegalic cells that resemble cells in the fetal cortex. Typically, males with X-linked AHC develop salt-wasting primary adrenal failure in early infancy (~60%) or childhood (~40%), although later-onset cases presenting in adulthood have been described (Achermann et al., 2001; Mantovani et al., 2002). Individuals with mutations in the NROB1 gene also develop hypogonadotropic hypogonadism (HH), although the age of onset is variable. HH due to altered hypothalamic-pituitary-gonadal (HPG) activity may be observed in infancy, and greater than 10% of males with X-linked AHC have bilaterally undescended testicles. However, other individuals have normal HPG activity in infancy, and onset of HH is noted at the time of puberty. In rare cases, patients with DAX1 mutations have been reported with spontaneous onset of puberty, although pubertal development is incomplete. Most males have azoospermia and remain infertile even after treatment with gonadotropins (Mantovani et al., 2002), although a male with an NROB1 mutation was reported with preserved fertility (Merke et al., 1999). While mutations within the DAX1 gene result in isolated X-linked AHC, X-linked AHC may also occur as part of a contiguous gene deletion syndrome associated with mental retardation, glycerol kinase deficiency, and/or Duchenne muscular dystrophy, depending on the size of the deletion.
Most females who are heterozygous carriers of NROB1 mutations have normal adrenal function and no evidence of HH; however, several have been reported with delayed puberty (Seminara et al., 1999), and a female with a contiguous gene deletion including NROB1 had primary adrenal failure due to skewed X-inactivation (Shaikh et al., 2008). Additionally, one female was reported with a homozygous NROB1 mutation causing HH but apparently normal adrenal and ovarian function
(Merke et al., 1999).
Duplications of the NR0B1 gene and the surrounding genomic region, referred to as the dosage-sensitive sex reversal (DSS) region, do not cause X-linked AHC but instead result in a 46,XY disorder of sex development. Although most patients reported with duplications of the DSS region have complete gonadal dysgenesis causing XY sex reversal, partial gonadal dysgenesis with ambiguous genitalia has been described (Barbaro et al., 2008). Duplications of DAX1 in 46,XX individuals have no known clinical consequence, but the risk of transmission to 46,XY offspring is a significant consideration.