Endocrine Abstracts

Introduction: The prokinectin signalling pathway plays an important role in olfactory development, sexual development and fertility. The prokinectin receptor 2 (PROKR2) is associated with gonadotropin releasing hormone deficiency (isolated hypogonadotropic hypogonadism and Kallmann syndrome). Inheritance is autosomal recessive, requiring two copies of the gene mutation, one from each parent, to develop the disease (homozygotes). Disease can occur if the PROKR2 gene mutation is combined with a mutation in another gene (oligogenic inheritance) or a different mutation in the PROKR2 gene (digenic inheritance). Undescended testes (cryptorchidism) can also occur with varying frequency depending on the pattern of inheritance. We describe a man with cryptorchidism, primary hypogonadism who tested positive for the PROKR2 gene mutation.

Case study: A 32-year-old man presented with infertility due to azoospermia secondary to testicular failure (primary hypogonadism). Medical history included bilateral orchidopexy for cryptorchidism in childhood. He was not on any medication. He was born to a consanguineous marriage. He did not smoke or drink alcohol. Physical examination revealed bilateral small testes and gynaecomastia. He had normal body and fascial hair. Initial investigations demonstrated low testosterone levels with raised gonadotropin levels, characteristic of primary hypogonadism. Genetic testing demonstrated a PROKR2 missense variant of uncertain clinical significance. His mother demonstrated the same gene variant. The patient and his partner were referred to infertility clinic and medical genetics for further counselling and family screening.

Discussion: There are no previous reports of isolated cryptorchidism leading to testicular failure with elevated gonadotropin levels in relation to the PROKR2 gene mutation. Homozygotes with two copies of the PROKR2 gene mutation typically present with reduced gonadotropin levels due to gonadotropin releasing hormone deficiency. The man in this case may have another unknown gene mutation combined with the PROKR2 gene mutation contributing to this atypical presentation