ESPE Abstracts (2022) 95 P1-580

ESPE2022 Poster Category 1 Sex Differentiation, Gonads and Gynaecology, and Sex Endocrinology (56 abstracts)

A rare case of 46,XY difference of sexual development (DSD) due to combined homozygous CYP17A1 and heterozygous CYP21A2 mutations with a unique phenotype and hormone profile

Aikaterini Stasinaki , Sarah Oberhauser & Dagmar l'Allemand-Jander


Children’s Hospital of Eastern Switzerland, St. Gall, Switzerland

Background: 17a-hydroxylase/17,20-lyase deficiency is a rare cause of congenital adrenal hyperplasia (CAH). 46,XY infants may present with ambiguous genitalia. Adrenal crises are rare due to compensatory glucocorticoid action of the overproduced corticosterone.

Case: A 3-month-old boy underwent a complication-free externalization of concealed penis and circumcision by a paediatric surgeon. At the age of 2.5 years, the boy was first presented to pediatric endocrinology because of mild penile hypoplasia (2.3 cm) and glandular hypospadias. The examination revealed non-familial tall stature, normal BMI and normally descended testes. A hypogonadotropic hypogonadism or testosterone synthesis defect were postulated due to normal basal LH and FSH and low testosterone 72 hours after 5000 IU/m2 HCG i.m. (3.72nmol/L). The stimulated testosterone/dihydrotestosterone ratio of 9 made 5a-reductase deficiency unlikely. Karyotype was 46,XY. Three testosterone enantate injections at 4-week-intervall resulted in penile growth up to 4.1 cm . At the age of 12 years, the buserelin test showed a normal LH rise and low stimulated testosterone at 24 hours (1.96nmol/L), possibly due to obesity. In the next two years, puberty progressed spontaneously (Pubic hair stage IV, testes 12ml), but due to hypoplastic penis (6.5 cm) and gynecomastia, testosterone synthesis defect was suspected and testosterone therapy initiated. In the presence of adynamia, ACTH testing (0.25mg/m2) confirmed partial adrenal insufficiency and hydrocortisone therapy was started. Blood pressure and electrolytes were always normal, as well as adrenal size in ultrasound, but ACTH was elevated (77pmol/L). Plasma and urine steroid profiling (LC-MS, CG-MS) indicated metabolite changes of 17a -hydroxylase and 21-hydroxylase deficiency fitting to P450 oxidoreductase deficiency. However, genetic analysis detected a heterozygous CYP21A2 mutation in exon 7 [c.844G>T p.(Val282Leu)], a pathogenic variant reducing 21-hydroxylase activity to 30-60% in vitro, and a homozygous CYP17A1 mutation in exon 3 [c.529A>G p.(Asn177Asp)]. The consanguineous Turkish parents were both asymptomatic heterozygous carriers of the above CYP17A1 mutation, whereas the mother was also heterozygous carrier of the above CYP21A2 mutation. The CYP17A1 variant has been classified as likely pathogenic, encoding a protein with 10% 17a-hydroxylase and 17,20-lyase activities (Biason-Lauber 2000).

Conclusion: The referral to paediatric endocrinologists after mini puberty and the atypical presentation complicated the diagnosis of this rare form of 46,XY DSD with combined homozygote CYP17A1 and heterozygote CYP21A2 mutations. Enzyme activities appear to overlap, resulting in mixed clinical and hormone findings; this hypothesis is being tested in expression studies. In complex DSD patients with inconclusive findings, genetic analysis should be considered as early as possible.

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

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