Endocrine Abstracts

Introduction: Pathogenic MC4R gene variants result in hyperphagia and early onset obesity, but puberty is not usually affected. We recently assessed spontaneous LH and FSH pulsatility, response to LHRH and kisspeptin in a previously presented male with anosmia, delayed puberty (Tanner stage A2P1G1, 5ml testes) and obesity (BMI 30.7 kg/m²) and a MC4R variant.

Results: GnRH test showed borderline low peaks (LH 5.0 U/l, FSH 2.6 U/l) and inhibin B 108pg/mL (25-325 pg/ml). MRI brain showed hypoplastic olfactory bulbs, absent olfactory sulci and normal pituitary. CGH microarray, karyotype and the R148 hypogonadism gene panel were normal. Whole exome sequencing in the Genetic Factors Affecting Timing of Puberty Study showed no abnormalities in 52 known genes associated with GnRH deficiency but detected a previously described pathogenic heterozygous variant MC4R c.542G>A, p.Gly181Asp, (PM2, PS4, PS3), absent from control databases. University of Pennsylvania Smell Identification Test confirmed anosmia. Testosterone was commenced and stopped on progression of testicular size (10ml) but restarted due to failure to progress in puberty. Aged 26 years, an 8 hour pulsatility study (10 minute sampling) demonstrated low amplitude LH pulses (7 pulses, max LH 0.5 U/l). GnRH stimulation showed a normal pituitary response (LH peak 7.24 U/l, FSH peak 1.89 U/l). However, Kisspeptin-54 (6.4nmol/kg) stimulation demonstrated no increment in LH response, consistent with GnRH deficiency.

Discussion: MC4R(p.Gly181Asp) leads to complete loss of function due to reduced cell surface expression and a-MSH binding. Heterozygous p.Gly181Asp variants have been described in several children/adults with obesity. Homozygous MC4R p.Gly181Asp was found in a male with obesity and partial HH thought due to abnormal GnRH production. We are the first to describe a heterozygous MC4R p.Gly181Asp variant in a patient with obesity and partial hypogonadism due to absent hypothalamic response to kisspeptin, anosmia and hypoplastic bulbs. Interaction between POMC-MC-leptin circuits and Kisspeptin-GnRH circuits is recognised but not well understood. Kisspeptin neurons express MC4R and KNDy neurons receive synaptic input from POMC neurons. Our results highlight the value of kisspeptin testing for diagnosing GnRH deficiency and support a role for MC4R in GnRH secretion by affecting the kisspeptin-GnRH pathway and potentially olfactory/GnRH neuronal development.