Inherited Adrenal Hypoplasia: Not Just for Kids!

Lin Lin; John C. Achermann


Clin Endocrinol. 2004;60(5) 

In This Article

Recessive Adrenal Hypoplasia

The genetic basis of the recessive form of adrenal hypoplasia is not known, although adrenal hypoplasia has been described as part of the IMAGe syndrome (Intrauterine growth retardation, Metaphyseal dysplasia, Adrenal hypoplasia, and Genitourinary malformations; Vilain et al., 1999) and in individuals with certain chromosomal rearrangements (e.g. 5p dup, 11q-).

The orphan nuclear receptor steroidogenic factor-1 (SF-1, NR5A1) is a recessive (9p33) factor that plays a crucial regulatory role in the development and function of the adrenal and reproductive axes at many levels (Parker & Schimmer, 1997; Ozisik et al., 2003b). More than 40 different SF-1-responsive target genes have been described (e.g. MC2R, StAR, various steroid hydroxylases and many genes involved in reproductive development and function) and targeted deletion of the gene encoding SF-1 in mice (Ftzf1) results in adrenal agenesis, complete 46,XY sex reversal with persistent Müllerian structures, hypogonadotropic hypogonadism and obesity (Parker & Schimmer, 1997).

To date, we have described SF-1 mutations in two patients with primary adrenal failure, a female phenotype and uterus in the presence of a 46,XY karyotype (Achermann et al., 1999, 2002; OMIM 184757). In the first patient, a de novo heterozygous mutation (G35E) in the primary DNA-binding domain (P-box) of SF-1 severely affected binding to most target genes, resulting in a dosage-dependent reduction of SF-1 mediated transactivation (Ito et al., 2000). A second patient with a similar phenotype was found to have a milder loss-of-function mutation (R92Q) in the A-box region of SF-1 (Achermann et al., 2002). This region is a secondary DNA-binding domain, and a homozygous change was necessary for full expression of the phenotype in this patient (Fig. 6). Although rare, these naturally occurring mutations are therefore providing useful insight into nuclear receptor-DNA interactions and target gene regulation, and confirm the crucial role of SF-1 in human endocrine development and function.

Additional mutations in SF-1 have recently been described in a girl (46,XX) with primary adrenal failure (Biason-Lauber & Schoenle, 2000), and in a patient (46,XY) who presented in adulthood with clitoromegaly, primary amenorrhoea and impaired breast development but apparently normal adrenal function (Correa et al., 2001). These cases show that the phenotypes associated with changes in SF-1 can be quite variable. Given the diverse role that SF-1 plays in different endocrine systems, it is tempting to speculate that SF-1 mutations could be identified in patients labelled as having Addison's disease, or in other individuals with variable reproductive, adrenal or metabolic features.


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