X-linked Adrenal Hypoplasia Congenita
The X-linked form of adrenal hypoplasia occurs due to mutations in the orphan nuclear receptor DAX1 [NR0B1, adrenal hypoplasia congenita (AHC); Muscatelli et al., 1994; Zanaria et al., 1994; Phelan & McCabe, 2001; Lalli & Sassone-Corsi, 2003; OMIM 300200]. DAX1 is expressed in the hypothalamus, pituitary gonadotropes, adrenal and gonad, and plays a key role in the development and function of the adrenal and reproductive axes.
More than 100 mutations in DAX1 have now been described in individuals or families with X-linked AHC (Fig. 4a; Reutens et al., 1998; Achermann et al., 2001a; Phelan & McCabe, 2001). Most of these mutations affect the structure and function of the DAX1 protein severely, and boys with this condition often present with primary adrenal failure and salt loss in the first weeks of life, or more insidiously with adrenal failure in childhood. As these boys reach adulthood, it is becoming increasingly clear that hypogonadotropic hypogonadism due to impaired gonadotropin synthesis and release is also an integral part of this condition, and testosterone replacement is usually necessary to induce signs of sexual maturation in these individuals.
Overview of DAX1 mutations. (a) More than 100 mutations have now been described in DAX1 (NR0B1), some of which are shown here. Most of these are frameshift or nonsense mutations (upper panel) that result in carboxyterminal truncation and significant loss of repressor function. Missense mutations in DAX1 (lower panel) are clustered in the putative ligand-like binding domain (LBD), and may interfere with protein stability and nuclear localization. Several missense mutations (e.g. Y380D, I439S) are associated with a milder loss of function and a delayed onset of adrenal failure in adulthood. Furthermore, patients with extreme amino-terminal nonsense mutations (Q37X, W39X) can also have an adult-onset form of the condition (b). This is likely to be due to 'phenotypic rescue' by an alternately translated DAX1 isoform from the methionine at codon 83, which has residual LXXLL domains capable of preserving partial function (reproduced with permission from Achermann et al., 2001b and Ozisik et al., 2003a).
Targeted deletion of the gene encoding Dax1 in the mouse produced only a subtle adrenal phenotype. Nevertheless, this model is revealing the importance of Dax1 in testis development and function (Yu et al., 1998). Hemizygous knockout mice are infertile, and testicular histology shows blockage of the rete testis and efferent ductules by aberrantly located Sertoli cells resulting in tubular dilatation; ectopic Leydig cell differentiation within seminiferous tubules; abnormalities in the basement membrane between the myoid and Sertoli cells; and interstitial Leydig cell hyperplasia (Jeffs et al., 2001; Meeks et al., 2003a, 2003b). Furthermore, one-third of animals develop sex-cord-stromal tumours by 1 year of age (Jeffs et al., 2001).
Limited data from adult patients with DAX1 mutations has shown a similar pattern of azoospermia, disordered tubular structure and Leydig cell hyperplasia, and a disappointing response to fertility induction with gonadotropin therapy (Fig. 5; Seminara et al., 1999; Tabarin et al., 2000; Mantovani et al., 2002), although apparently normal testicular histology has been reported in infancy in one patient (Brown et al., 2003). The tumour risk in humans or potential benefits of intracytoplasmic sperm injection (ICSI) are not yet known. However, the mouse model is providing important insight into some of the reproductive issues that need to be considered by physicians involved in the long-term care of adults with X-linked AHC, and caution may be needed before embarking on high-dose gonadotropin stimulation.
Histological features of the testis from a patient with X-linked AHC. Recently, the importance of Dax1 in testis development and spermatogenesis has been revealed from studies in the mouse. Although data from patients are limited, consistent features include oligo- or azoospermia, disruption of the normal tubular structure, ectasia of the rete testis (not shown), and abnormal proliferation of the interstitial tissue (including Leydig cell hyperplasia, inset) (reproduced with permission from Ozisik et al., 2003a) (magnification: main Fig. 50×, inset 200×).
Recently, we have reported several men who first presented in adulthood with mild adrenal insufficiency or partial hypogonadism due to DAX1 mutations. In two of these cases, point mutations in DAX1 (Y380D, I439S) produced only a partial loss of DAX1 repressor function, consistent with the late-onset phenotype in adulthood (Tabarin et al., 2000; Achermann et al., 2001b; Mantovani et al., 2002). In another case, alternate translation from an in-frame methionine (M83) was able to circumvent a nonsense mutation (Q37X) in the amino-terminus of DAX1, thereby producing a truncated protein with partial function (Fig. 4b; Ozisik et al., 2003a). In addition to highlighting some interesting genetic mechanisms of phenotypic expression, these cases clearly show that a diagnosis of X-linked AHC should be considered in all men presenting with primary adrenal failure, especially in the presence of partial hypogonadism or infertility.
Clin Endocrinol. 2004;60(5) © 2004 Blackwell Publishing
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