17α-hydroxylase/17,20-lyase deficiency (17-OHD): A Meta-analysis of Reported Cases.

Purpose: Homozygous pathogenic variants in the CYP17A1 gene result in defective activity of the steroidogenic enzymes 17α-hydroxylase/17,20-lyase resulting in the clinical syndrome 17-OHD characterised by hypertension, hypokalaemia, and disorders of sexual development. Pathogenic variants of CYP17A1 lead to complete or partial loss of enzymatic activity and clinical presentations of varying severity. This study aimed to examine relationships between CYP17A1 genotype and clinical presentation in a global cohort.

Methods: We searched PubMed and Scopus for case reports and cohort studies reporting clinical data on patients with 17-OHD published between 1988 and 2022. Of 451 studies, 178 met inclusion criteria comprising a total of 465 patients. We pooled patient data and examined associations between causative variants and their clinical presentations.

Results: There were 465 unique patients with a mean age of 18·9 (9·0) years, 52·5% (n=244) were XY and 6·4% (n=29) were phenotypically male. Homozygous variants were seen in 48·0% (n=223) of patients. Common clinical presentations were hypertension (57·0%, n=256), hypokalaemia (45·4% n=211), primary amenorrhoea (38·3%, n=178), cryptorchidism (15·3%, n=71), and atypical genitalia (14·2%, n=66). 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 hypokalaemia and hypertension (p<0·01), and DSD (p<0·01).

Main conclusions: 17-OHD is a rare, frequently misdiagnosed disease. Male patients are typically diagnosed earlier due to genital dysplasia associated with less severe variants, while female patients are typically diagnosed later due to primary amenorrhoea and hypertension. Patients presenting with DSD and hypertension should be investigated for 17-OHD.