ESPE Yearbook of Paediatric Endocrinology

JCEM Case Rep. 2025 Jan 20;3(2):luae245. doi: 10.1210/jcemcr/luae245

Brief Summary: This case report describes a 46,XY neonate born with ambiguous genitalia in whom 2 novel heterozygous variants in the HSD3β2 gene were found (c.779C > T/p.Pro260Leu and c.307 + 1G > A/p.Gly103Asp,fs29X), but only after age 5 y when she presented with premature pubarche and adrenarche, relative tall stature and +1.8 y advanced bone age. These novel variants were validated in vitro in transfected cells.

The midwife and pediatrician attending this infant after birth had noted increased 17-hydroxyprogesterone on neonatal screening, an External Genital Score of 6.5/12 with a 2.2 cm genital tubercle, scrotal hypospadias and echographically normal labioscrotal gonads with no uterus. Female sex of rearing was recommended. There was no evidence of adrenal failure and steroid studies in infancy, including mass spectroscopy (LC/GC MS), did not confirm a specific diagnosis.

At age 5 y, electrolytes, ACTH, testosterone and DHT remained normal, serum aldosterone was very low, and DHEA and DHEAS were elevated. A 0.25 mg Synacthen test showed an increased DHEA/androstenedione ratio– the clue to the enzymatic block - along with suggestive LC/GC-MS steroid features. Hydrocortisone (10 mg/m²/d) and fludrocortisone (0.05 mg/d) treatment was initiated. At age 7 y, the DSD team noted midpubertal status (P3, G3), stretched phallus length 6 cm, no gynecomastia, continued BA advancement but a predicted height within genetic target. There was no gender dysphoria although it was noted that the counselling was particularly sensitive given the extent of virilisation and context of autism and cognitive and language delay; options for management will continue to be discussed.

The most important contribution of this case report, besides adding novel, rigorously tested disease-causing variants in HSD3β2, is the excellent differential diagnostic table, and the discussion of the pitfalls involved in steroid measurements, particularly when there is some retention of enzyme activity as in this patient.