Phenotypic Heterogeneity and Fertility Potential of Patients With 17-Hydroxylase/17,20-lyase Deficiency

Abstract

Context 17α-Hydroxylase/17,20-lyase deficiency (17OHD) is caused by a human CYP17A1 gene mutation and has the classical phenotype of hypertension, hypokalemia, sexual infantilism, and primary amenorrhea in females (46,XX) and disorders of sexual development in males (46,XY). To date, few cases of 17OHD have been reported, and the likelihood of pregnancy has rarely been explored. Objective To study the clinical characteristics, phenotype heterogeneity, genotyping and the likelihood of pregnancy of patients with 17OHD. Design Genotype analysis was performed by direct sequencing of the CYP17A1 gene and next-generation sequencing in nonclassical patients. In vitro enzyme activity assays and three-dimensional structure observations were used to assess the function of 3 missense mutations of the CYP17A1 gene. Progestin-primed ovarian stimulation (PPOS) was chosen for ovulation induction in 2 patients. Results Eight mutations were identified from 13 patients, including the homozygous mutation p. N395D and p. R496C, compound heterozygous mutation p. Y329fs/p. A421A and p. I332T/p. D487_F489del in 4 nonclassical patients. For the three missense mutations, an in vitro functional study showed mild impairment of 17α-hydroxylase activities 15.3-25.0% but residual 17,20-lyase activities 6.6%-9.4%. Two 46,XX females succeeded in pregnancy by combined PPOS, IVF-ET and the use of low-dose dexamethasone. One patient successfully delivered 1 healthy baby. Conclusions Partial 17OHD present nonclassical clinical features, without hypertension and hypokalemia. Successful pregnancy in such 46,XX patients could be attained by the appropriate choice of ovulation induction regimen, precise dose of glucocorticoid to reduce progesterone levels, and the use of IVF-ET.

Reproductive endocrine characteristics and in vitro fertilization treatment of female patients with partial 17α-hydroxylase deficiency: Two pedigree investigations and a literature review

“…of literature associated with IVF-ET treatments on 17-OHD women, we listed the following cases in chronological order (Table 5): a 33-year-old woman with 17-OHD and IVF-donated oocytes resulted in a live birth in 2003 (17); in the same year, an infertile 17-OHD woman achieved pregnancy and delivered three healthy babies with the help of IVF using her own oocytes (14); a successful live birth in a 26-year-old woman with IVF was documented in 2016 (20); two consecutive live births of a 24-year-old 17OHD woman followed (19); another successful live birth in a 26-year-old woman with IVF using was recorded in 2018 (18); Blumenfeld et al described the achievement of the first successful pregnancy and delivery in a patient with 17,20-lyase deficiency (16); the first two Chinese cases of partial 17-OHD conceived and had a live birth through PPOS protocol (15). Notably, one of the cases in the last literature is just the proband 1 in our report (15). However, since the first report of this case did not include a complete pedigree survey and it was not centered on the patient's reproductive endocrine characteristics, we paid more attention to her infertility and IVF-ET treatment in this report and described this case in detail again (the detailed treatment records are shown in Supplementary Tables).…”

“…described the achievement of the first successful pregnancy and delivery in a patient with 17,20-lyase deficiency ( 16 ); the first two Chinese cases of partial 17-OHD conceived and had a live birth through PPOS protocol ( 15 ). Notably, one of the cases in the last literature is just the proband 1 in our report ( 15 ). However, since the first report of this case did not include a complete pedigree survey and it was not centered on the patient’s reproductive endocrine characteristics, we paid more attention to her infertility and IVF-ET treatment in this report and described this case in detail again (the detailed treatment records are shown in Supplementary Tables ).…”

Getting pregnant with congenital adrenal hyperplasia: Assisted reproduction and pregnancy complications. A systematic review and meta-analysis

“…Therefore, mutations in CYP17A1 could cause three different forms of enzymatic deficiency: 1) combined deficiencies of the two functions, which is the most common form, 2) isolated 17OH deficiency, and 3) isolated 17,20-lyase deficiency. Patients with double deficiency (39)(40)(41)(42)(43)(44)(45) suffer from hypertension and impaired glucocorticoid production. Low estradiol levels might lead to infantile genitalia.…”

Dexamethasone application for in vitro fertilisation in non-classic 17-hydroxylase/17,20-lyase-deficient women

“…To reduce dexamethasone-related side effects, Xu et al used dexamethasone before frozen embryo transfer and changed the glucocorticoid to prednisone after embryo transfer. However, the first pregnancy was terminated because the foetus had cleft lip and palate (19). Therefore, we stopped glucocorticoid administration once pregnancy was detected to promote pregnancy and avoid the side effects of administration on foetus.…”