301 Humans, Clinical Moura-Massari VO et al. Genotype and Hyperandrogenism in NC-CAH … Horm Metab Res 2013; 45: 301–307 received 03.05.2012 accepted after second revision 22.10.2012 Bibliography DOI http://dx.doi.org/ 10.1055/s-0032-1330007 Published online: January 15, 2013 Horm Metab Res 2013; 45: 301–307 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0018-5043 Correspondence T. S. Bachega Av. Dr. Enéas de Carvalho Aguiar n ° 155, 2 ° andar, bloco 6 Cerqueira César São Paulo, SP Brazil CEP: 05403-900 Tel.: + 55/11/2661 7512 Fax: + 55/11/2661 7519 tbachega@usp.br Key words ● ▶ 21-hydroxylase deficiency ● ▶ genotype/phenotype correlation ● ▶ hyperandrogenic manifestations ● ▶ allelic distribution ● ▶ nonclassical form CYP21A2 Genotypes do not Predict the Severity of Hyperandrogenic Manifestations in the Nonclassical Form of Congenital Adrenal Hyperplasia mildly affected phenotypes or in compound het- erozygosis with mutations corresponding to severely affected phenotypes. Several studies reported a modulatory effect of the severe allele on the phenotype of nonclassical patients because they presented with higher ACTH-stimulated 17OH-progesterone (17OHP) levels compared to individuals who were homozygous for mild mutations [8–12]. A modulatory effect on clinical manifestations was also investigated. In a cohort comprising 45 nonclassical patients, an earlier onset of pubarche in patients carrying the severe nonclassical genotype was observed, while no influence on clinical signs was observed in another series of 161 adult females [12, 13]. How- ever, to date, it is not possible to conclude whether impairment of 21-hydroxylase activity, as pre- dicted by nonclassical genotypes, also correlates with the severity of hyperandrogenic pheno- types. Such a correlation could be useful in clini- cal practice. Clinical manifestations of nonclassical CAH vary widely, ranging from premature pubarche associ- ated with bone age advancement to symptoms Introduction ▼ Congenital adrenal hyperplasia (CAH) is a fre- quent monogenic disorder due to 21-hydroxy- lase deficiency. It has a wide range of clinical manifestations, varying from prenatal external genitalia virilization in females, which can be with or without adrenal crisis (salt wasting or simple virilizing), to late onset hyperandrogenic symptoms (nonclassical form) [1, 2]. This spectrum of clinical manifestations reflects the existence of different mutations in the 21 -hydroxylase gene, CYP21A2, resulting in dif- ferent impairments of enzymatic activity. In CAH, there is a strong correlation between genotype and phenotype, that is, homozygous patients car- rying mutations resulting in severe ( < 7 %) and mild (20–50 %) impairments of enzymatic activ- ity develop classical and nonclassical forms, respectively. However, most CAH patients are compound heterozygous; in this case, clinical form correlates with the less affected allele [3–7]. Genotypes predicting the nonclassical form can be homozygous for mutations corresponding to Authors V. O. Moura-Massari 1 , D. D. G. Bugano 2 , J. A. M. Marcondes 1 , L. G. Gomes 1 , B. B. Mendonca 1 , T. A. S. S. Bachega 1 Affiliations 1 Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM 42, Disciplina de Endocrinologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil 2 Departamento de Clínica Médica, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil Abstract ▼ There is a strong correlation between the sever- ity of genotypes and 17OH-progesterone lev- els in patients with the nonclassical form of 21-hydroxylase deficiency (NC-CAH); however, there are few studies regarding the correlation with clinical signs. The aim of the study was to evaluate whether genotypes correlate with the severity of the hyperandrogenic phenotype. A cohort of 114 NC-CAH patients were diagnosed by stimulated-17OHP ≥ 10 ng/ml. CYP21A2 geno- types were divided into 2 groups according to the severity of enzymatic impairment; mild and severe. Clinical data and hormonal profiles were compared between the 2 groups. Age at onset of manifestations did not differ between children or adults carrying both mild and severe geno- types. Frequencies of precocious pubarche and hirsutism, with or without menstrual abnormal- ities, were similar between the 2 groups. There were no differences in basal testosterone lev- els of adult symptomatic females carrying both genotypes, but there were differences between adult females with (92.9 ± 49.5 ng/dl) and with- out hirsutism (43.8 ± 38 ng/dl) (p = 0.0002). Simi- lar frequencies of both genotypes were observed in asymptomatic females and in those with clito- romegaly. Nonclassical genotypes do not predict the severity of phenotype. Asymptomatic and virilized females carrying the same genotype suggest that there is a modulatory effect of genes involved in the androgen pathway on the phe- notype. Downloaded by: Dot. Lib Information. Copyrighted material.