The impact of CYP21A2 (P30L/I172N) genotype on female fertility in one family

Background: The simple virilizing (SV) form of congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder usually caused by steroid 21-hydroxylase deficiency due to I172N missense mutation at the CYP21A2 gene. Clinical presentation encompasses virilization of external genitalia in newborn females and pseudoprecocious puberty in both sexes, due to reactive androgen overproduction. The aim of this study was to present two sisters with an SV form of CAH and distinctive genotype, detected and treated since childhood with a poor compliance and poor metabolic control hindering the fertility.

Case presentation: We retrospectively reviewed the clinical, biochemical, and molecular data of two sisters with CAH a 46,XX karyotype when they reached an age of 35 and 38 years, respectively, and were attempting conception for several years. They had been diagnosed with SV form of CAH at the age of 7 and 9 years, respectively, by the standard clinical and biochemical procedures, presenting with severe virilization due to androgen excess. Follow-up was performed through standard methods of measurement of 17-OHP, testosterone, and ACTH. Clitoroplasty with vaginoplasty was performed at the age of 18 in the older sister. Using PCR/ACRS, we performed molecular analysis of the nine most common point CYP21A2 mutations in the patients and family members. The P30L/II72N genotype was observed in both sisters. They had inadequate metabolic control due to noncompliance until decision to conceive. IVF was performed three times in the older sister without success. Sufficient follicles were harvested and fertilized; however, the embryos were lost 3-5 days after implantations. The younger sister is preparing for IVF. She underwent follicle harvesting and the embryos were frozen awaiting appropriate hormonal balance for embryo transfer. The I172N mutation in the heterozygote state was observed in their other two sisters, whose fertility was unaffected.

Conclusions: Despite significant improvements over the last years in achieving fertility in female patients with SV CAH, it is highly dependent upon the severity of virilization and the metabolic control. The role of P30L mutation in infertility and unsuccessfully assisted reproduction remains to be elucidated.