Isolated 17,20-Lyase Deficiency in a CYB5A Mutated Female With Normal Sexual Development and Fertility

Abstract

Isolated 17,20-lyase deficiency may be caused by mutations in the CYP17A1 (coding for cytochrome P450c17), POR (coding for cytochrome P450 oxidoreductase) and CYB5A (coding for microsomal cytochrome b5) genes. Of these, mutations in the CYB5A gene have thus far only been described in genetic males who presented with methemoglobinemia and 46,XY disorders of sex development (DSD) due to 17,20-lyase deficiency. A 24-year-old Chinese woman presented to the hematology outpatient clinic with purplish discoloration of fingers, toes, and lips since childhood. Investigations confirmed methemoglobinemia. A homozygous c.105C>G (p.Tyr35Ter) nonsense mutation was detected in the CYB5A gene. Hormonal studies showed isolated 17,20-lyase deficiency. Interestingly, she had a completely normal female phenotype with no DSD, normal pubertal development, and spontaneous pregnancy giving birth uneventfully to a healthy female infant. The sex hormone-related features of genetic females with 17,20-lyase deficiency due to cytochrome b5 gene mutation appear to differ from that of females with 17,20-lyase deficiency caused by other genetic defects who presented with hypergonadotropic hypogonadism and infertility and differ from genetic males with the same mutation.

Isolated 17, 20 Lyase Deficiency Secondary to a Novel CYB5A Variant: Comparison of Steroid Metabolomic Findings with Published Cases Provides Diagnostic Guidelines and Greater Insight into Its Biological Role

“…We have included previously unpublished urine steroid data on the family described in a publication co-authored by one of us (NT [6]), hereafter called family 2, and detailed data for two single adult patients, which were obtained by essentially the same method and reported in summary, together with figures for the urine steroid chromatograms by Yeung et al [9] and Leung et al [10]. Serum steroid panelling involved the addition of a cocktail of deuterated internal standards for each target steroid, crashing with acetonitrile, extraction into ethyl acetate, and analysis by liquid chromatography-mass spectrometry (LC-MS)/MS [12].…”

“…Table 2 compares data on sibling 2 at the age of 17 years with that of the reported adults [9, 10]. Figure 7 compares their urine steroid chromatograms.…”

“…Isolated 17, 20 lyase deficiency occurs secondary to variants in genes encoding CYP17A1, POR, or CYB5A , with familial consanguinity being a common finding [3-10]. Due to androgen deficiency, 46 XY individuals display under-masculinization of varying severity at birth, with severe cases often presumed to be female.…”

“…Due to androgen deficiency, 46 XY individuals display under-masculinization of varying severity at birth, with severe cases often presumed to be female. Pubertal delay is frequently reported, with or without gynaecomastia [3-10]. 46 XX individuals do not present with ambiguous genitalia at birth but may be diagnosed following identification of an affected male sibling or during investigation of disrupted puberty [4].…”

“…Methaemoglobinaemia is specifically associated with isolated 17, 20 lyase deficiency secondary to a CYB5A gene variant due to the role of CYB5A in methaemoglobin reduction [2]. Only three different disease-causing variants in CYB5A have been described in association with isolated 17, 20 lyase deficiency in the published literature to date [6, 7, 9, 10].…”