ESPE Abstracts (2023) 97 P1-169

1Center for Medical Genetics Ghent, Ghent University Hospital; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. 2VIB-UGent Center for Medical Biotechnology, Ghent, Belgium; Department of Biomolecular Medicine, Ghent University, Gent, Belgium. 3Pediatric Endocrinology and Diabetology (DECCP), Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg. 4Paediatric Endocrinology Unit, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles (U.L.B.), Brussels, Belgium. 5Department of Paediatrics, Division of Paediatric Endocrinology, Antwerp University Hospital, Antwerp, Belgium. 6Department of Child Endocrinology, General Hospital Sint-Jan Bruges-Ostend, Brugge, Belgium. 7Department of Pédiatric endocrinology, CHU de Liège, Chênée, Belgium. 8Division of Pediatric Endocrinology and Diabetes, ZNA Queen Paola Children's Hospital, Antwerp, Belgium. 9Pediatric Endocrinology, Cliniques universitaires Saint Luc, Brussels, Belgium. 10Department of Pediatric Endocrinology and Diabetology, Jessa Hospital, Hasselt, Belgium. 11Department of Paediatric Endocrinology, University Hospitals Leuven, Leuven, Belgium. 12Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Department of Pediatrics, Division of Pediatric Endocrinology, Brussels, Belgium. 13Murdoch Children’s Research Institute, Royal Children’s Hospital & Department of Paediatrics, University of Melbourne, Melbourne, Australia. 14Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Australia. 15Department of Internal Medicine and Pediatrics, Ghent University, Department of Pediatric Endocrinology, Ghent University Hospital, Ghent, Belgium

Background/Aims: Cryptorchidism or undescended testis is a prevalent congenital urogenital condition affecting male newborns with an incidence rate ranging from 1.0 to 4.6%. Mouse models have implicated INSL3 and its receptor RXFP2 (formerly known as GREAT or LGR8) in the development of the condition. RXFP2 acts as a G protein-coupled receptor that triggers the generation of cAMP by binding INSL3. But despite the established role in testicular descent, so far only one family with cryptorchidism has been reported with defects in RXFP2.

Methods: Whole exome sequencing of the differences of sex development gene panel was carried out in an index case with bilateral cryptorchidism and infertility. Segregation analysis was performed in his brother with the same phenotype. Testicular biopsy in this brother showed a maturation arrest at the spermatocytes – spermatids stage. Single nucleotide variants were classified using the ACMG guidelines, and the exome data was analyzed for copy number variants using the Exome Depth algorithm. Further characterization was conducted through structural modeling and a cyclic AMP (cAMP) reporter gene assay. To examine the association with infertility, publicly available single-cell RNA (scRNA) sequencing data were used.

Results: An intragenic deletion of exon 1-5 in RXFP2 (NM_130806.5) was found in trans with a hemizygous missense variant c.229G>A, p.(Glu77Lys) in both brothers. The missense variant was classified as pathogenic based on in silico modeling and in vitro functional analysis. No changes in cell surface expression and ability to bind INSL3 were observed, but the absence of a cAMP signal in response to INSL3 indicated a loss-of-function, thereby confirming its causative role in the bilateral cryptorchidism of this family. Additionally, besides its role in testicular descent during fetal development, several animal studies have demonstrated a postnatal function of INSL3 and RXFP2 in germ cell survival. Furthermore, scRNA sequencing data shows expression of RXFP2 at the early spermatid stage which corresponds to the stage of maturation arrest as seen on the biopsy of one of the patients.

Conclusion: As the second report, this study further establishes RXFP2 as a cause for bilateral cryptorchidism in an autosomal recessive manner. RXFP2 should therefore be added to any gene panel testing for differences of sex development. Additionally, this study supports for the first time an association between RXFP2 and male infertility.

Volume 97

61st Annual ESPE (ESPE 2023)

The Hague, Netherlands
21 Sep 2023 - 23 Sep 2023

European Society for Paediatric Endocrinology 

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