ESPE Yearbook of Paediatric Endocrinology

J Clin Endocrinol Metab. 2025; 110(4): e1261-e1271. PMID: 39500362 doi: 10.1210/clinem/dgae773. https://pubmed.ncbi.nlm.nih.gov/39500362/

Brief summary: This meta-analysis examined the relationship between CYP17A1 genotype and clinical presentation in a global cohort.

Comment: 17α-hydroxylase/17,20-lyase deficiency (17-OHD) accounts for only 1% of all cases of CAH. This enzyme catalyzes 2 distinct steps in steroidogenesis: 17α-hydroxylation of pregnenolone and progesterone to 17α-hydroxylated products and 17,20-bond cleavage of these products to the C19 androgen precursors, dehydroepiandrosterone and androstenedione (1-4). Homozygous pathogenic variants in CYP17A1 disrupt activity of the steroidogenic enzymes 17α-hydroxylase/17,20-lyase, resulting in the clinical syndrome of 17-OHD characterized by hypertension, hypokalemia, and disorders of sexual development. Pathogenic variants in CYP17A1 lead to complete or partial loss of enzymatic activity and clinical presentations of varying severity (5-8). This study examined the relationship between CYP17A1 genotype and clinical presentation in a global cohort.

The authors searched PubMed and Scopus for case reports and cohort studies published between 1988 and 2022 reporting clinical data on patients with 17-OHD. Of 451 studies, 178 met inclusion criteria comprising a total of 465 patients. They pooled patient data and examined associations between causative variants and their clinical presentations. There were 465 unique patients with mean age 18.9 (SD: 9.0) years, 52.5% (n=244) were XY and 6.4% (n=29) were phenotypically male. Common clinical presentations were hypertension (57.0%, n=256), hypokalemia (45.4% n=211), primary amenorrhea (38.3%, n=178), cryptorchidism (15.3%, n=71), and atypical genitalia (14.2%, n=66). Homozygous variants were seen in 48.0% (n=223) of patients. Frequently occurring variants included p.Y329Kfs (n=86), p.D487_F489del (n=44), and p.W406R (n=39). More severe variants, such as p.Y329Kfs, were associated with hypocortisolism (P<0.05), combined hypokalemia and hypertension (P<0.01), and disordered sexual development (P<;0.01).

In conclusion, 17-OHD is a rare, frequently misdiagnosed disease. Males are typically diagnosed earlier because of ambiguous genitalia associated with less severe variants, whereas females are typically diagnosed later because of primary amenorrhea and hypertension. Patients presenting with disordered sexual development and hypertension should be investigated for 17-OHD.

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