ESPE Abstracts

Background: Idiopathic hypogonadotropic hypogonadism (HH) is highly genetically heterogeneous. To date, about 50 causative genes have been identified, estimated to account for up to 50% of hereditary cases. With next generation sequencing (NGS) technology now in wide clinical use, it is increasingly possible to determine the underlying genetic etiology of isolated and combined pituitary hormone deficiencies.

Objective: We report a case of two siblings with consanguineous parents, presenting with HH, growth hormone deficiency (GHD), intellectual disability and obesity in whom we performed NGS aiming to identify a genetic etiology.

Methods: Clinical, biochemical and hormonal assays as well as endocrine stimulation studies were performed, followed by whole exome sequencing (WES) and Sanger sequencing.

Patients: A 19-year-old male was referred for evaluation of short stature and hypogonadism with small intra-scrotal testes (2 ml), no pubic hair (P1), and micropenis. In addition, he had cognitive impairment, strabismus, obesity and marked acanthosis nigricans. Sense of smell was preserved. His sister was 16 years old at the time of presentation and similarly demonstrated short stature, delayed puberty (B1P2), cognitive impairment, strabismus and obesity.

Results: Hormone assays and endocrine stimulation tests revealed GHD and HH in both siblings. Using WES, we identified a likely pathogenic homozygous point mutation in the gene CCDC149: c.847G>T;p.Gly283* creating a stop codon in the 9th exon, in both siblings. The father was found to be heterozygous for the variant. Their mother passed away several years earlier however her sister was likewise found to be a heterozygous carrier. Several bioinformatics models identified the mutation as an extremely rare and likely pathological variant not previously reported in general population databases such as gnomAD. This gene codes for a highly preserved protein whose function in humans is presently unknown, although functional studies in the nematode C. elegans, suggest a possible association with ciliopathies such as in Bardet-Biedl syndrome.

Conclusion: We describe for the first time a homozygous variant in the CCDC149 gene associated with congenital hypopituitarism. Further investigation is required to determine the function of this gene and confirm its role in this genetic disorder.