The mild nonclassic form of steroid 21-hydroxylase deficiency is one of the most common autosomal recessive disorders in humans, occurring in almost 1% of caucasians and about 3% of Ashkenazi Jews. Many patients with this disorder carry a Val-281----Leu missense mutation in the CYP21 gene. This and most other mutations causing 21-hydroxylase deficiency are normally present in the CYP21P pseudogene and have presumably been transferred to CYP21 by gene conversion. To identify other potential nonclassic alleles, we used recombinant vaccinia virus to express two mutant enzymes carrying the mutations Pro-30----Leu (normally present in CYP21P) and Ser-268----Thr (considered a normal polymorphism of CYP21). Whereas the activity of the protein carrying the Ser----Thr mutation was indeed indistinguishable from the wild type, the enzyme with the Pro----Leu substitution had 60% of wild-type activity for 17-hydroxyprogesterone and about 30% of normal activity for progesterone when assayed in intact cells. When kinetic analysis of the latter mutant enzyme was performed in cellular lysates, the first order rate constants (maximum velocity/dissociation constant) for both substrates were reduced 10- to 20-fold compared with those for the wild-type enzyme. Pro-30 is conserved in many microsomal P450 enzymes and may be important for proper orientation of the enzyme with respect to the aminoterminal transmembrane segment. The Pro----Leu mutation was present in 5 of 18 patients with nonclassic 21-hydroxylase deficiency, suggesting that this mutation indeed acts as a nonclassic deficiency allele.

Nonclassic steroid 21-hydroxylase deficiency is an attenuated adrenal enzyme defect that is commonly the basis of hyperandrogenic syndromes. Inherited as an autosomal recessive trait, it is known to occur with high frequency in the general population and with increased frequency in a number of ethnic groups, including the Yugoslav population. Following expansion of the original data on 21 families in Croatia to a total of 49 Croatian and Serbian families, we establish that this enzymatic disorder is increased in this Slavic population and provide an updated estimate for the gene frequency of 0.092 (0.035\x=req-\ 0.149). Also in keeping with earlier reports, we continue to note the absence of association between nonclassic 21\ x=r eq-\ hydroxylase deficiency occurring among Yugoslavs and HLA-B14;DR1.Nonclassic steroid 21-hydroxylase deficiency is an autosomal recessive disorder that is known to occur with very high frequency generally, and which in addition shows increased prevalence in certain ethnic populations (1). This partial adrenal enzyme defect may or may not be clinically manifest in af¬ fected individuals, but can be identified by hor¬ mone criteria. Mild to moderate elevations of serum androgens result from increased secretion by the adrenal of androgens and of androgenic precursors which undergo peripheral conversion to active hormones. Biochemical indices of reduced adrenal 21-hydroxylation are serum elevations of the steroid intermediates 17a-hydroxyprogesterone (17-OHP), the principal substrate of 21-hy-droxylase, which fails to be converted to 11-deoxycortisol (compound S), the direct precursor of Cor¬ tisol, and also of A4-androstenedione (A4-A), im¬ mediately distal to 17-OHP in the androgenic pathway. Clinical effects arising from 21-hydroxy¬ lase deficiency vary between individuals and the different ages within the same individual.The first population genetic study on nonclassic 21-hydroxylase deficiency (1) identified an in¬ creased incidence among Yugoslavs, estimating the gene frequency among this population to be 0.125 (0.042-0.268 (95% confidence limits)) based on data from 21 families in Zagreb, SR Croatia, Yu¬ goslavia (1). This study observed that positive link¬ age disequilibrium between nonclassic 21-hydroxy¬ lase deficiency and HLA-B14;DR1 existing in other ethnic groups at increased risk, Ashkenazic Jews, Hispanics, and Italians, was absent in the Yu¬ goslav patient group.The population genetic analysis of the original study in 167 families was based on inference of genotype and gene counting as follows: Obligate hétérozygotes (the parents of affected offspring) in each pedigree were genotyped by HLA association and ACTH stimulation hormone testing. Occur¬ rence of the nonclassic deficiency trait in a tested parent identified the presence of a nonclassic de¬ ficiency alíele also on the second haplotype. Con¬ sidering that the second (nontransmitted) haplotypes of known hétérozygotes still represent a Klinika za djecje bolesti REBRO1 and Centar za tipizaciju tkiva REBRO2,

We describe two sisters (40 and 42 years old) heterozygous for adrenoleukodystrophy who have multiple endocrine disorders. In addition to the characteristic neurological symptoms, the younger patient has Addison disease and primary hypothyroidism attributable to autoimmune thyroiditis, and the older one has Graves disease. Both patients have loss of body hair and sparse scalp hair, which have not been reported previously in women heterozygous for adrenoleukodystrophy. After the institution of glucocorticoid replacement therapy, the younger sister, who has adrenal insufficiency, has shown unexpected neurological improvement.

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