SUN-159 17-beta Hydroxysteroid Dehydrogenase 3 Deficiency in 1 Month Old Infant

Background: 17-beta hydroxysteroid dehydrogenase 3 deficiency is a rare autosomal recessive disorder caused by mutations in HSD17B3 encoding the enzyme which converts androstenedione to testosterone. It is characterized in 46, XY males by incomplete virilization, including micropenis and hypospadias. Clinical Case: We report a 1 month old infant who presented with ambiguous genitalia. Prenatal non-invasive screening showed a Y chromosome, however, fetal ultrasound revealed female genitalia. The infant was born with micropenis (~1.4 cm in length) and proximal hypospadius, with enlarged labioscrotal folds and palpable gonads bilaterally. The urethral meatus had been relocated surgically to the glans. There was an apparent vaginal orifice with a normally positioned anus. Initial testing revealed a normal serum 17-OHP (90 ng/dl, n<200 ng/dl) and normal electrolytes. Abdominal US showed normal kidneys. Pelvic US demonstrated no Mullerian structures; gonads thought to be testes were identified in the labioscrotal folds. At 3 months of age, the infant underwent a 3 day HCG stimulation testing with a borderline testosterone response to 132 ng/dl, androstenedione 78 ng/dl and DHT 25 ng/dl. T/A ratio was unremarkable at 1.7 (n>0.8). Thus, hormonal testing was unsupportive of a testicular steroidogenic enzyme deficiency or androgen insensitivity syndrome. Karyotype was confirmed as 46, XY with microarray evidence of multiple regions of homozygosity. Genotyping with a 46, XY DSD panel (GeneDx) revealed a homozygous pathogenic variant c.608 C>T (p.A203V) in exon 9 of the HSD17B3 gene, consistent with a diagnosis of autosomal recessive 17-beta hydroxysteroid dehydrogenase 3 deficiency. Parents are of Arabic descent and are consanguineous. An older brother was also born with ambiguous genital and was later found to be homozygous for the same mutation. This mutation has been identified in the homozygous state in several unrelated affected patients. Previously published functional studies demonstrated loss of enzymatic activity with this missense mutation (1). Male gender was assigned at birth, and parents wish to continue male sex of rearing. Conclusion: Molecular genetic analysis utilizing a commercially available candidate gene panel for 46, XY disorders of sex development diagnosed 17 beta-HSD3 deficiency in this case where hormonal testing was not informative. Early and correct diagnosis is key in planning medical treatment to facilitate pubertal development. References: (1) Geissler et al., 1994 Nature Genetics 7(1): 34-9.