ESPE Abstracts

Introduction: Pathogenic MC4R gene variants result in hyperphagia and early onset obesity, but puberty is not usually affected. A 16-year-old male with repaired Tetralogy of Fallot, anosmia, autism, and anxiety, was referred with delayed puberty. Height was -1.31 SDS, BMI 30.7 kg/m². He had high-arched palate, normal skin and hair colour, mild hypertelorism, Tanner stage A2P1G1, 5ml testes.

Results: GnRH test showed borderline low peaks (LH 5.0U/L, FSH 2.6U/L) and inhibin B 108pg/mL (25-325pg/mL). MRI brain showed hypoplastic olfactory bulbs, absent olfactory sulci and normal pituitary. CGH microarray, karyotype and the UK hypogonadism gene panel were normal. Whole exome sequencing in the Genetic Factors Affecting Timing of Puberty Study showed no abnormalities in 52 known gene associated with GnRH deficiency but a previously described pathogenic heterozygous variant MC4R c.542G>A, p.Gly181Asp, (PM2,PS4,PS3), absent from control databases. No other variants of significance were detected. A Smell Identification Test confirmed anosmia. Testosterone was commenced but testicular size increased (10mL). Treatment was stopped but required restarting. Repeat investigations off treatment (aged 22 years): inhibin B 66pg/mL, testosterone 2nmol/L, LHRH test: baseline LH 2.4 U/L, peak 24.9 U/L, baseline FSH 1.2 U/L, peak 4.2 U/L. Aged 26 yrs, an 8 hr pulsatility study (10min sampling) demonstrated very small amplitude spontaneous LH pulses (7 pulses, max LH 0.5 IU/L). Further 8 hr sampling studies showed appropriate response to 100mcg GnRH stimulation (LH: 0.58 IU/L, peak 7.24 IU/L, FSH: 0.55 IU/L, peak 1.89 IU/L) but no increase in LH in response to Kisspeptin-54 (6.4nmol/kg), consistent with CHH due to hypothalamic dysfunction.

Discussion: Previous work showed complete loss of function of MC4R p.Gly181Asp due to reduced cell surface expression and reduced a-MSH binding. Heterozygous p.Gly181Asp variants have been described in several children/adults with obesity; but hypogonadism has not. 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, anosmia and hypoplastic bulbs. Interaction between POMC-MC-leptin circuits and Kisspeptin-GnRH circuits is recognised although not completely understood. Previous work has shown that a subset of kisspeptin neurons express MC4R and that KNDy neurons receive synaptic input from POMC neurons. In addition, inhibition of MC4R/MC3R delays puberty in rats. Our results support a role for MC4R in GnRH secretion and potentially olfactory/GnRH neuronal migration.