ESPE Abstracts

Background: Disorders of androgen synthesis are rare causes of 46,XY disorder of sex development (DSD) that present with undervirilization or sex reversal.

Objective: A history of a female adolescent with 46,XY DSD, initially suspected to have complete androgen insensitivity is presented.

Methods: Patient history was obtained from the medical records. Urinary steroid profile was preformed using gas chromatography/mass spectrometry. The genetic analysis was performed by TruSight One sequencing panel using MiSeq desktop sequencer.

Results: The patient with prenatal karyotype 46,XY, born with female genital appearance, was first evaluated 3 days postnatally. She was found not to have Mullerian structures; the gonads were located in inguinal regions, with the ultrasound appearance of testes, and were left in situ. Testosterone (T) and dihydrotestosterone (DHT) were detected by immunoassay (T 0.6 nmol/L, DHT 1.1 nmol/L), and complete androgen insensitivity was suspected. No mutations or deletions in AR and SRD5A2 genes were identified. At presentation she was 12 years old and had no clinical signs of puberty or virilisation, but gonadotropins were in pubertal range (basal luteinizing hormone (LH) 5 kIU/L, peak 43,3 kIU/L). Adrenal androgen levels were very low basally and with adrenocorticotropin stimulation (T<0.1 nmol/L, dehydroepiandrosterone sulfate 0.5 μmol/L, androstenedione 0.2 nmol/L). There were no signs of gonadal failure (basal follicle-stimulating hormone (FSH) 2,3 kIU/L, peak FSH 4,5 kIU/L, Inhibin B 361 ng/L), salt loosing, salt retention or hypocorticism. The level of 17-OH progesterone was borderline elevated. No suspicious changes in the gonads were detected by ultrasound during regular follow-up. Urinary steroid metabolome analysis by gas chromatography-mass spectrometry (GC-MS) showed increased 17- deoxygenated steroids, normal glucocorticoids and subnormal sex hormones pointing to a general weakness of the 17-hydroxylase/17,20-lyase system with strongly impaired lyase function. This constellation was highly suspicious of “isolated” 17,20-lyase deficiency. Targeted genetic analysis showed that the patient is compound heterozygote for CYP17A1 gene (NM_000102: c.1040G>A (p.R347H; rs61754278) in exon 6 and NM_000102: c.1247G>A (p.R416H; rs104894155) in exon 8). Both variants are classified as pathogenic in ClinVar database.

Conclusion: A disorder of androgen synthesis due to isolated 17,20-lyase deficiency was identified in a patient with complete sex reversal. Unlike immunoassays,GC-MS urinary steroid metabolome analysis is independent of cross reactivity and also due to its high differential diagnostic potential is extremely helpful in the delineation of DSD.