Late-Onset, Cryptic and Classical 21-OH Deficiency: Allelic Variants

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HLA genotyping and hormonal studies in 9 females with non-classical steroid 21-hydroxylase deficiency (AAH) indicate that this disorder is due to an autosomal recessive gene linked to HLA, similar to classical and cryptic 21-hydroxylase deficiency (21-OH def). They had normal genitalia at birth and presented between 9 mos to 16 yrs with varying degrees of virilization. Hormonal studies of the families revealed 2 fathers and their HLA identical sisters with 21-OH def. The remaining parents and the sibs sharing one HLA haplotype with the AAH patient responded to ACTH stimulation as heterozygotes for classical or cryptic 21-OH def. Five sibs who were HLA identical to their affected sib also had findings diagnostic of 21-OH def. The hormonal response to ACTH of the patients with AAH and their HLA identical sibs was similar to that of patients with cryptic 21-OH def. Thus, individuals with these non-classical forms of 21-OH def and similar hormonal findings present with a clinical spectrum ranging from an asymptomatic deficiency to precocious pubic hair, acne, tall stature and advanced bone age, hirsutism, clitoromegaly and menstrual irregularities. The results of these studies support the concept that AAH, similar to classical and cryptic 21-OH def is due to an HLA linked autosomal recessive gene and that these disorders are due to allelic variants at the locus of steroid 21-hydroxylase.