P3 - ECE_1584 - A novel homozygous mutation of CYP17A1 gene in a 20-year old 46, XY phenotypical male with hypergonadotropic hypogonadism and gynecomastia
TL;DR
The findings demonstrate that residual CYP17A1 activity can mask the classic phenotype, and 17-OHD should remain in the differential diagnosis of young men with unexplained hypogonadism, particularly when any features of disordered sex development are present.
Abstract
Congenital adrenal hyperplasia (CAH) comprises autosomal recessive disorders of adrenal steroidogenesis. 17α-hydroxylase/17, 20-lyase deficiency (17-OHD) is a rare subtype (~1% of CAH) caused by pathogenic variants in CYP17A1. In 46, XY individuals, complete deficiency typically leads to female or ambiguous external genitalia at birth and later hypertension and/or hypokalaemia. However, partial enzyme deficiency may preserve some androgen and glucocorticoid production, leading to atypical presentations and delayed diagnosis. A 20-year-old 46, XY phenotypic male was referred for progressive right-sided gynecomastia over five years and hypergonadotropic hypogonadism, initially suspected to represent Klinefelter syndrome. He reported impaired ejaculation with preserved erectile function and sparse facial hair. Past history included hypospadias repair in early childhood. Examination revealed normally virilized male genitalia without ambiguity, reduced penile length, and age-appropriate pubic and axillary hair. Biochemistry confirmed hypergonadotropic hypogonadism with low testosterone and elevated luteinizing hormone. Adrenal evaluation showed persistent ACTH elevation, markedly increased 17-hydroxyprogesterone, and low adrenal androgens, suggesting impaired steroidogenesis, while cortisol circadian rhythm was preserved. Renin was suppressed with normal aldosterone and normal blood pressure. Impaired glucose tolerance and osteopenia were also identified. Karyotype was 46, XY. Dynamic testing demonstrated minimal testosterone response to hCG and an abnormal Synacthen steroid profile with pronounced 17-hydroxyprogesterone elevation, supporting a congenital steroidogenic defect. Imaging showed pituitary changes consistent with hyperplasia and a left adrenal lesion compatible with adenoma. Breast biopsy was benign. Urinary steroid profiling revealed increased mineralocorticoid and progesterone metabolites with elevated 17-hydroxylated metabolites and normal cortisol metabolites, consistent with partial CYP17A1 deficiency, predominantly affecting 17, 20-lyase activity. Genetic testing identified a novel homozygous CYP17A1 missense variant (c.1234T>C, p.Phe412Leu; exon 7), classified as likely pathogenic and confirmed by Sanger sequencing. The variant has not been reported in major databases or the literature and is extremely rare in gnomAD (non-Finnish Europeans: 0.0000008993), with no previously described homozygous cases. This case expands the genotypic and phenotypic spectrum of partial 17α-hydroxylase/17, 20-lyase deficiency. The patient presented with hypergonadotropic hypogonadism and progressive gynecomastia despite normal blood pressure, preserved circadian cortisol rhythm, and no genital ambiguity, with only subtle signs of undervirilization. These findings demonstrate that residual CYP17A1 activity can mask the classic phenotype. Therefore, 17-OHD should remain in the differential diagnosis of young men with unexplained hypogonadism, particularly when any features of disordered sex development are present.