Endocrine Abstracts

JOINT231

Introduction: Congenital hypogonadotropic hypogonadism (CHH), whether or not associated with anosmia (Kallmann syndrome), is a rare genetic disorder characterized by the absence of pubertal development and infertility, caused by GnRH deficiency. Recently, neuron-derived neurotrophic factor (NDNF) has been identified as a novel factor involved in GnRH neuron ontogeny. NDNF enhances the GnRH neuron migratory route during embryological development and plays a role in GnRH release in the median eminence, suggesting a possible role in GnRH neuron biology beyond embryonic development.

Clinical case: A 16-year-old boy was referred to endocrinology because of the absence of pubertal development and anosmia. Medical history revealed bilateral cryptorchidism, treated with orchidopexy at 12 years of age. Testicular volume was 1 ml bilaterally, with Tanner stage 3 for pubic hair. Morning serum testosterone, FSH and LH were undetectably low, whereas the other pituitary hormones were normal. Testicular ultrasound confirmed prepubertal volumes of 14x10x5 mm and 11x3x4 mm. MRI of the brain showed an absent olfactory bulb, and normal anatomy of the pituitary gland and stalk. Bone age was more than 2 years delayed. Family history revealed cryptorchidism and late puberty in his father, without fertility problems. The clinical diagnosis of Kallmann syndrome was made and pubertal induction with gonadotropins was started. Gene panel testing for hypogonadotropic hypogonadism revealed a heterozygous variant in the NDNF gene, NM_02457.4:c.509_513dup p.(Pro172Ilefs*13). This variant is predicted to cause a frameshift in the last exon, presumably escaping nonsense-mediated decay leading to a truncated protein missing both C-terminal fibronectin type III domains, crucial for its migratory function. No other relevant variants in known CHH genes were detected.

Discussion/Conclusion: We describe a novel variant in the NDNF gene in an adolescent with Kallmann syndrome, contributing to the evidence of Ndnf as a novel factor involved in GnRH neuron ontogeny. A previously published gene-based burden test in a cohort of 240 CHH patients revealed 4 other NDNF rare likely pathogenic variants in 4 patients with hypogonadotropic hypogonadism with anosmia (OMIM # 618841), with in vitro analysis showing a loss of function of these variants. Three of these probands’ family members also carried the NDNF mutation and had partial and milder phenotypes, suggesting an autosomal-dominant inheritance with variable expression. Further research on the molecular role of NDNF on GnRH neuron migratory route and GnRH functioning is needed.