Nonclassical congenital adrenal hyperplasia in a prepubertal girl with no genital abnormalities: the importance of phenotype and genetic analysis

Abstract

Congenital adrenal hyperplasia (CAH) is a group of genetic disorders characterized by enzymatic blockages in the metabolic pathway of cortisol, aldosterone and androgen synthesis, which cause clinical manifestations of hormone deficiency and excess. The most frequent form is 21-hydroxylase deficiency (P450c21) caused by variants in the CYP21 gene, which leads to the accumulation of 17-OHP (17 hydroxyprogesterone) and dehydroepiandrosterone sulfate (DHESO4), causing early hyperandrogenism. Patients are usually compound heterozygotes, where the less severe allele determines the phenotype. There are two forms: Classical and non-classical (NC). The classical form may manifest as adrenal crisis in the neonate, with hyponatremia, hyperkalemia, hypoglycemia, metabolic acidosis, ambiguous genitalia in girls, macropenis in boys and increased pigmentation. In CKD there is postnatal hyperandrogenism, with symptoms such as peripheral precocious puberty, hirsutism, resistant acne, menstrual irregularities or primary amenorrhea; in some cases, signs are minimal in childhood. Recognizing the wide clinical variability is critical for early diagnosis, appropriate sex assignment and timely treatment. Genetic testing is crucial to confirm the diagnosis, identify the enzymatic defect and provide timely genetic counseling, as in the case presented.