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 blocks in the metabolic pathway of cortisol, aldosterone, and androgen synthesis, leading to clinical manifestations of hormonal deficiency and excess. The most common 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 (DHEA-SO4), resulting in early hyperandrogenism. Patients are usually compound heterozygotes, where the less severe allele determines the phenotype. There are two forms: classic and non-classic (NC). The classic form may present as adrenal crisis in the newborn, with hyponatremia, hyperkalemia, hypoglycemia, metabolic acidosis, ambiguous genitalia in girls, enlarged phallus in boys, and increased pigmentation. In the NC form, 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 during childhood. Recognizing the wide clinical variability is essential for early diagnosis, appropriate sex assignment, and timely treatment. Genetic testing is crucial to confirm the diagnosis, identify the enzymatic defect, and provide appropriate genetic counseling, as in the presented case.