Nonclassical congenital adrenal hyperplasia (NCAH), an autosomal recessive disease, affects about 1 in 30 Ashkenazi Jews and 1 in 1,000 non Jewish Caucasians of mixed ethnicity [1]. It is commonly due to a mutation in the CYP21A2, a gene for steroid 21-hydroxylase [2]. Impaired enzyme activity (20-50% of wild type enzymatic action) leads to adrenal androgen excess. Unlike more severe forms of congenital adrenal hyperplasia (CAH), NCAH is rarely recognized in infants but may lead to premature adrenarche and pubarche, virilization in young women, and variable symptoms in young men [3]. Typically, infant girls do not have genital ambiguity but those who carry combinations of mild and severe mutant CYP21A2 alleles may have mild clitoromegaly or a partial urogenital sinus. In adolescence, females are more seriously affected than males, and may develop distressing features of androgen excess, such as hirsutism and acne. Oligomenorrhea, which is rare in adolescence, may be more severe in NCAH. Reproductive problems are also more common in NCAH women than in the general population [4]. Although there is no gender predilection for CAH, males are not readily detected with androgen excess after childhood. Oligospermia and infertility have been described, but less often than in classic CAH [5,6]. Differentiation of 21-hydroxylase deficiency from other enzyme defects is determined by the ACTH-stimulation test, which in patients with NCAH, raises serum levels of 17-hydroxyprogesterone (17OH-P) to 50-300 nmol/L [7].

The CYP21A2 gene is located on 6p21.3, within the class III region of the highly polymorphic HLA histocompatibility complex [8], with the pseudogene (CYP21A1P), with which it shares 98% homology in the exonic sequences. CYP21A2 consists of 3.2 kb pairs and contains 10 exons [9]. It is highly polymorphic, more than 100 alleles having been identified in patients and families with severe, moderate and mild forms of CAH [10,11].Few alleles are specifically associated with NCAH. Most commonly, late-onset 21-hydroxylase deficiency results from a homozygous conservative point mutation p.V281L, p.P30L, and p.P453S [12]. We used direct molecular detection of the p.P30L mutation in CYP21A2 in 11 Macedonian patients with NCAH and in an equal number of their relatives.