Abstract 119: Neuron derived neurotropic factor- A novel gene implicated in congenital hypogonadotropic hypogonadism

Background: Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by infertility and the absence of puberty. In patients with CHH, the genetic profile is heterogeneous, and more than 40 genes are involved either alone or in combination with one another. Mutations in the FN3 (fibronectin-3) superfamily of genes encode proteins involved in GnRH neuron ontogeny. One such gene is the NDNF (neuron derived neurotropic factor) gene which has been established in mouse and zebrafish knockout models to manifest with altered GnRH migration and also in humans recently as CHH with anosmia or hyposmia. Case Report: A male child aged seven years and three months, born of second-degree consanguinity, presented with complaints of small sized penis and bilateral undescended testes since birth. There was no significant antenatal history nor any history suggestive of salt wasting, virilization or failure to thrive in infancy. At nine months of age, he underwent diagnostic laparoscopy & bilateral orchidopexy. Child had normal developmental milestones and was cheerful and attentive in class. The child on examination had facial dysmorphism with triangular facies and prominent ears, normal vital signs and no midline defects. Anthropometry was essentially normal and SMR was notable for micropenis, 1cc right inguinoscrotal testis and non-palpable left testis with hypoplastic scrotum and an EMS of 6.5. He also had synkinesia with normosmia. Rest of the systemic examination was normal. Clinical diagnosis of congenital hypogonadotropic hypogonadism was considered. Review of prior investigations showed low gonadotropins recorded at mini-puberty, XY karyotype and an hCG stimulation test with non-stimulable testosterone (59.6 ng/dL). Prior USG showed right inguinal canal and left intra-abdominal testes with normal adrenals. The thyroid, GH and cortisol axes tested normal. Genetic analysis with whole exome sequencing showed heterozygous pathogenic mutation of exon 4 of NDNF gene. Conclusion: This case highlights thephenotypeofanovelmutation involving the NDNF gene that has been recently implicated in CHH in humans. This patient had clinical and biochemical features of hypogonadotropic hypogonadism with normosmia and synkinesia, along with facial dysmorphism. This phenotypic combination has not been described previously with this gene mutation.