ESPE Abstracts

Background: Leptin receptor (LepR) deficiency is an autosomal-recessive rare condition causing early-onset severe obesity, hyperphagia, hypogonadotropic hypogonadism (HH), hypothyroidism, and/or growth hormone deficiency (GHD). Cohen syndrome is a variable autosomal recessive genetic disease caused by mutations in the VPS13B gene causing central obesity, characteristic facial features, hypotonia, non-progressive intellectual deficit, neutropenia, myopia retinal dystrophy and optic nerve atrophy,

Case Description: A 15-year-old female with morbid obesity, type 2 diabetes mellitus, obstructive sleep apnea and hypogonadotropic hypogonadism. She did not have facial features typical of a syndrome and no developmental delay. At age 16 y she was diagnosed with ACTH dependent cortisol deficiency and growth hormone deficiency. Her working diagnosis was ROHHAD syndrome with pituitary dysfunction, however sleep study showed no hypoventilation. The pituitary gland was of normal size, location and appearance on MRI, no neuroendocrine tumors were seen. She responded to metformin but continued with rapid weight gain, within 5 years her weight increased from 118 to 154 kg, BMI from 39.6 to 53 kg/m2. She subsequently required insulin for glucose control. She received setmelanotide for 3 months with no improvement. At 19 years of age, she presented in critical condition with COVID pneumonia, adrenal crisis, severe dehydration, hypernatremia and was diagnosed with central diabetes insipidus, which responded to DDAVP. Repeat MRI of pituitary showed a diminished bright spot. There was a new finding of bilateral optic nerve atrophy with dis-conjugate gaze. Ophthalmology evaluation is pending to evaluate pigmentary retinopathy.

Results: A genetic obesity panel identified a heterozygous mutation in the LEPR gene: p.Leu210Pro (c629T>C) (VUS) not previously described and not predicted to be pathogenic. In addition, three other VUS were found: heterozygous, not previously reported likely pathogenic mutation in VPS13B (c3082+1G>T), a heterozygous mutation VUS in ADCY3 (c2356G>A); and heterozygous, intronic variation in KIDINS220 (c1622-10_1622-9del).

Conclusion: This case is compelling because she shas some features of leptin resistance such as rapid weight gain, obesity, and late onset hypothalamic dysfunction. However posterior pituitary hormone deficiency and optic nerve atrophy have not been reported in LEPR mutations. She has neutropenia, a characteristic of Cohen syndrome; optic atrophy has been reported as well. Her VPS13B (c3082+1G>T) not previously reported however is reported to be likely pathogenic for Cohen syndrome. Both heterozygous variations in ADCY3 and KIDINS220 gene previously linked to high BMI. Further mutational analysis will need to be done to elucidate the role in hypothalamic weight-regulating pathways.