Background: Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder resulting from resistance to the action of ACTH on the adrenal cortex to produce glucocorticoids. Affected individuals are deficient in cortisol and, if untreated, are likely to succumb to hypoglycemia or overwhelming infection in infancy or childhood. Mutations of the ACTH receptor (melanocortin 2 receptor, MC2R) or the melanocortin 2 receptor accessory protein (MRAP), FGD types 1 & 2 respectively, account for approximately 45% of cases. A further locus on chromosome 8 (8q 12.1 to 8q21.2), has been linked to the disease in 3 families (multipoint LOD scores 3.01,1.28 and 1.20).
Methods: Whole genome SNP analysis was undertaken, using the GeneChip mapping 10K array Xba131 (Affymetrix), on the probands from two 8q linked families.
Results: Reanalysis of the genotypes for these two individuals revealed a region of homozygosity on chromosome 8 larger than previously described, encompassing the steroid acute regulatory protein (StAR). We identified homozygous StAR mutations in both individuals (E169K and the novel mutation R192C). To ascertain whether other mild StAR mutations present as FGD, we screened our total FGD patient cohort. Homozygous, R188C StAR mutations were discovered in seven patients from three additional families. All affected individuals presented late (27 years of age) with an FGD-like phenotype and were phenotypically male if XY karyotype. In addition to cortisol deficiency, minor abnormalities of PRA were present in the absence of overt mineralocorticoid deficiency or electrolyte derangement.
Conclusions: Mutations in StAR usually cause lipoid congenital adrenal hyperplasia (LCAH), a severe disorder characterised by XY sex reversal and both gonadal and adrenal steroid insufficiency. Our results demonstrate that mild mutations in StAR can present as FGD.