P-05 17Β-HYDROXYSTEROID DEHYDROGENASE 3 DEFICIENCY: TWO CASE REPORTS
Authors: Uzun Ilknur , Hacioglu Aysa , Karaca Zuleyha , Siraz Ulku Gul , Kiraz Aslihan , Unluhizarci Kursad 
Published: January 2025

Introduction

17-β-hydroxysteroid dehydrogenase type3 (17β-HSD3) is an enzyme that produces testosterone from androstenedione, encoded by the HSD17B3 gene. Its deficiency causes 46 XY disorder of sex development (DSD) with autosomal recessive inheritance. 46 XY individuals with this enzyme deficiency can exhibit a wide range of phenotypes, ranging from normal female external genitalia to ambiguous genitalia. In early childhood, the diagnosis might be clinically indistinguishable from other causes of 46 XY DSD such as partial androgen insensitivity syndrome (AIS) and 5α-reductase type 2 deficiency. Laboratory diagnosis is based on a low testosterone/androstenedione ratio. The diagnosis is confirmed by molecular genetic testing. If the diagnosis is missed in early infancy, patients present with severe virilization symptoms and amenorrhea during puberty. We present two siblings followed and managed with a presumed diagnosis of AIS until the genetic testing was performed.

Clinical Case 1

A 4-month-old patient with female external genitalia was operated on with suspicion of bilateral inguinal hernia, and pathologic investigation revealed immature testicular tissue. No uterus and ovaries could be detected by pelvic ultrasound. The karyotype analysis was consistent with 46 XY, and the patient was followed up with the diagnosis of AIS. The patient’s parents were first cousins. The patient was started on estradiol replacement when she was 13 years old. At the age of 21, she underwent vaginoplasty due to a 2 cm long vaginal canal. A genetic analysis was available when the patient was 21 years old. Next generation sequencing revealed a previously reported homozygous c.277+5g&gt;A mutation in exon 3 of HSD17B3 gene. The diagnosis was established as 17β-HSD3 deficiency.

Clinical Case 2

After the index case was diagnosed with AIS karyotype analyses were performed on three other siblings at the time. The patient’s 7 years old sibling, who had a complete female-appearing genitalia, had a karyotype of 46XY. As the presumed diagnosis was AIS, bilateral orchiectomy was performed after counselling. Estradiol replacement was started at the age of 14 and complete breast development was achieved. Vaginal length was reported as 8 cm. Further genetic analysis was performed at the age of 27 and it revealed that the two siblings shared the same genetic mutation. Both preferred to retain the female gender identity during adulthood.

Two other female siblings with a karyotype of 46XX and both parents had a heterozygous c.277+5g&gt;A mutation in the HSD17B3 gene.

Conclusion

Although clinical evaluation and laboratory test results might point out to 17-β-HSD3 deficiency, the definite diagnosis is established with genetic testing. As these patients might develop male gender identity, awareness of the disease and early genetic testing is of importance for the prevention of misdiagnoses, counselling for gender identity, deciding on surgical interventions, and management of these patients.