ESPE Abstracts

Introduction: 46,XY gonadal dysgenesis (GD) represents a heterogeneous group of disorders/differences of sex development (DSD) characterized by abnormal gonadal development leading to a wide phenotypic spectrum. Variable degrees of external genitalia undervirilization are observed, ranging from micropenis to female-like genitalia and partially or fully-developed Mullerian derivatives.

Case Report: A 6 years-old boy followed-up in our Pediatric Endocrinology clinic consultation due to bilateral cryptorchidism. At neonatal period, was evaluated by testicular hydrocele where testicular sonography reported as normal bilateral testis structure. There was not any personal or family history of interest. At physical examination testis were found in inguinal channel entrance of 0.5 cm3 with normal penis and no other dysmorphic features. Basal levels FSH were elevated, Inhibine-B and AHM were low consistent with low reserve of gonadal tissue. Karyotype show 46XY. Laparoscopic examinations were performed and no mullerian structure were found, in scrotum were observed hipotrophic testis (04.cc) and spermatic cords, also a left testis fragment was collected for histological study and spermatogonia was absent. A massive sequencing analysis of genes and regions associated with DSD in index case and parents aws performed and an heterozygous variant in the DHX37 gene, c.1261C>T; p.(Arg421Trp) in exon 9 with maternal origin was detected. This variant, missense, affects a highly conserved amino acid and has been classified as probably deleterious by bioinformatics tools. Following the ACMG variant classification recommendations, this variant was classified as a variant of uncertain significance (VOUS), but probably related to the phenotype present, although for the moment without sufficient evidence. DHX37 (DHEA-Box-Helicase-37) is an RNA helicase that plays a prominent role in the biogenesis of ribosomes. In relation to sexual development, DHX37 has been described as specifically expressed in the somatic cells of the gonads during testicular determination and development, although the exact role of DHX37 in testicular development is currently unknown. Recently, heterozygous variants have been identified in non-syndromic gonadal dysgenesis 46,XY and testicular regression syndrome. Therefore, DSD 46,XY due to heterozygous variants in DHX37 are characterized by absence or low reserve of gonadal tissue. The development and function of the ovary is apparently normal in mothers carrying pathogenic variants in DHX37.

Conclusion: DHX37 pathogenic variants are a new cause of an autosomal dominant form of 46,XY DSD, including gonadal dysgenesis and TRS, showing that these conditions are part of a clinical spectrum. This raises the possibility that some forms of DSD may be a ribosomopathy.