Analysis of DAX1 (NR0B1) and steroidogenic factor-1 (NR5A1) in children and adults with primary adrenal failure: ten years' experience

Abstract

Context: Primary adrenal failure is a life-threatening condition that can be caused by a range of etiologies, including autoimmune, metabolic, and developmental disorders. The nuclear receptors DAX1 (NR0B1) and steroidogenic factor-1 (SF1/Ad4BP, NR5A1) play an important role in adrenal development and function, and mutations in these transcription factors have been found in patients with adrenal hypoplasia.

Objective: Our objective was to investigate the prevalence of DAX1 and SF1 mutations in children and adults with primary adrenal failure of unknown etiology (i.e. not caused by congenital adrenal hyperplasia, adrenoleukodystrophy, or autoimmune disease).

Patients: One hundred seventeen patients were included. Eighty-eight individuals presented in infancy or childhood with adrenal hypoplasia or primary adrenal failure of unknown etiology (n = 64 46,XY phenotypic males; n = 17 46,XY gonadal dysgenesis/impaired androgenization; n = 7 46,XX females). Twenty-nine individuals presented in adulthood with Addison's disease of unknown etiology.

Methods: Mutational analysis of DAX1 (NR0B1) (including exon 2alpha/1A) and SF1 (NR5A1) was done by direct sequencing.

Results: DAX1 mutations were found in 58% (37 of 64) of 46,XY phenotypic boys referred with adrenal hypoplasia and in all boys (eight of eight) with hypogonadotropic hypogonadism and a family history suggestive of adrenal failure in males. SF1 mutations causing adrenal failure were found in only two patients with 46,XY gonadal dysgenesis. No DAX1 or SF1 mutations were identified in the adult-onset group.

Conclusions: DAX1 mutations are a relatively frequent cause of adrenal failure in this group of boys. SF1 mutations causing adrenal failure in humans are rare and are more likely to be associated with significant underandrogenization and gonadal dysfunction in 46,XY individuals.

Fig. 1

Relative prevalence of different types of DAX1 mutations in A) this series compared to B) the published literature (excluding abstracts). Data shown represent the total number of different individuals or kindred with mutations. The historical literature has a bias towards cases of contiguous gene deletion syndrome where X-linked AHC has been reported together with glycerol kinase deficiency (GKD), Duchenne muscular dystrophy (DMD) and/or X-linked mental retardation. Our series focused on children with primary adrenal failure. In the two cases of contiguous gene deletion found, the diagnosis of a deletion of the DAX1 (AHC) locus was made before the clinical or biochemical diagnosis of GKD/DMD.

Fig. 2

A) Overview of nonsense (black) and frameshift (red) mutations in DAX1. Specific mutations identified by our centers are shown below the DAX1 model. Previously reported changes in the literature are shown above the DAX1 model by arrowheads. B) Naturally-occurring missense mutations in DAX1 cluster within the carboxyl-terminus of DAX1 in a region that is homologous to the ligand-binding domain of nuclear receptors. Mutations identified by our centers are shown in red, whereas mutations reported in the literature are shown in black. The three major cluster regions are indicated by black bars. Single amino-acid deletions (d269V, d430N) are included.

Fig. 3

Mutations in steroidogenic factor-1 (SF1, Ad4BP) associated with primary adrenal failure and 46,XY gonadal dysgenesis affect the P-box and A-box regions of the DNA-binding domain (G35E, R92Q). A heterozygous mutation has also been reported in a 46,XX girl with primary adrenal failure and apparently normal ovarian differentiation (R255L) (30). LBD, ligand-binding domain.