Congenital adrenal hyperplasia

Did You Know?

• In extreme virilization, clitoromegaly with a phallic-like structure may occur, and labia may fully fuse into a scrotum with a penile urethra at the glans tip.
• Undervirilization in XY males can result in an apparent vulva.
• Crinecerfont (Crenessity) was approved for medical use in the United States in December 2024.

Types

The clinical presentation of CAH depends on the specific enzyme defect, precursor retention, and deficient products. Classical forms appear in infancy and are subdivided into salt-wasting and simple-virilizing forms based on the presence or absence of mineralocorticoid deficiency, though this distinction is often not clinically meaningful because all patients lose salt to some degree. In 75% of severe enzyme deficiency cases, insufficient aldosterone leads to salt wasting, failure to thrive, and potentially fatal hypovolemia and shock. In newborn females, the main feature is abnormal development of external genitalia with varying degrees of virilization. A nonclassical form exists, characterized by varying degrees of postnatal androgen excess, sometimes asymptomatic, which may be noticed in late childhood and can lead to accelerated growth, acne, hirsutism, premature pubarche, menstrual irregularities, and secondary polycystic ovary syndrome.

Genetics

CAH results from mutations in genes encoding enzymes for steroidogenesis. The most common type, 21-hydroxylase deficiency, involves the CYP21A2 active gene and the CYP21A1P pseudogene on 6p21.3; mutant alleles arise from recombination between these two genes. About 5% of cases are due to 11β-hydroxylase deficiency. Rarer forms are caused by mutations in HSD3B2, CYP17A1, CYP11A1, STAR, CYB5A, and CYPOR. The degree of enzyme inefficiency varies by allele: severe inefficiency produces fetal changes and prenatal or perinatal problems, milder inefficiency affects sex hormone effects in childhood or adolescence, and the mildest forms interfere with ovulation and fertility in adults.

Diagnosis

Female infants with classical CAH have ambiguous genitalia due to in utero androgen exposure; 21-hydroxylase deficiency is the most common cause of ambiguous genitalia in 46XX infants. Less severely affected females may present with early pubarche or symptoms of polycystic ovarian syndrome. Males with classical CAH generally show no signs at birth, though some may have hyperpigmentation and possible penile enlargement; diagnosis timing depends on aldosterone deficiency severity. Boys with salt-wasting disease present early with hyponatremia and hypovolemia, while those with non-salt-wasting disease present later with virilization. In rarer forms, males are undermasculinized and females have no signs at birth. Diagnosis can be made via ACTH stimulation test; in classical 21-hydroxylase deficiency, laboratory studies show hypoglycemia due to hypocortisolism.

Screening

In the United States and over 40 other countries, every newborn is screened for 21-hydroxylase CAH by detecting elevated 17α-hydroxyprogesterone (17-OHP). Early detection allows for medication and relatively normal lives. The screening has a high false-positive rate: in one study, only 111 true-positive cases occurred among 20,647 abnormal results (0.53% positive predictive value), meaning 200 unaffected newborns required follow-up for each true case. A 2020 study used deep learning to analyze facial morphology of 102 CAH patients and 144 controls, achieving a mean area under the receiver operating characteristic curve of 92% for predicting CAH from facial images, with the nose and upper face most contributory.