The first description of an MC4R variant in a patient with Kallmann syndrome and obesity

slam isha A; Sharon Lim; Ruben Willemsen; Howard Sasha R; Evelien Gevers

doi:10.1530/endoabs.95.OC3.1

OC3.1

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Endocrine Abstracts (2023) 95 OC3.1 | DOI: 10.1530/endoabs.95.OC3.1

BSPED2023 Oral Communications Oral Communications 3 (3 abstracts)

The first description of an MC4R variant in a patient with Kallmann syndrome and obesity

Aisha A Aslam ¹ , Sharon Lim ² , Ruben Willemsen ¹ , Sasha R Howard ^1,3 & Evelien Gevers ^1,3

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¹Department of Paediatric Endocrinology, The Children’s Hospital at the Royal London Hospital, London, United Kingdom. ²Broomfield Hospital, Chelmsford, United Kingdom. ³William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University, London, United Kingdom

Introduction: Pathogenic MC4R variants result in hyperphagia and early onset obesity but puberty is not usually affected. We describe an MC4R variant in a patient with Kallmann syndrome and obesity.

Case: A 16 year old male with repaired Tetralogy of Fallot, anosmia, autism and anxiety, was referred with obesity and delayed puberty. Height was -1.31 SDS, BMI 30.7 kg/m2. He had a high arched palate, normal skin, normal hair colour, mild hypertelorism and upward slanting palpebral fissures. Pubertal staging was A2P1G1 5ml testes.

Results: LHRH test showed borderline low peaks (LH 5.0U/L, FSH 2.55U/L) and inhibin B 108pg/mL (25-325pg/mL). MRI brain showed hypoplastic olfactory bulbs and normal pituitary anatomy. CGH microarray, karyotype and R148 hypogonadism gene panel were normal. He underwent whole genome sequencing in the Genetic Factors Affecting the Timing of Puberty Study; no abnormalities in known genes associated with GnRH deficiency were found but detected a previously described heterozygous variant, MC4R c.542G>A, p.Gly181Asp, classified as pathogenic and not present in control databases.

Management: He was commenced on Testosterone but showed progression of testicular size to 10mL and testosterone was stopped but required restarting. Repeat investigations off treatment (aged 22 years, testes 15mL): inhibin B 66pg/mL, testosterone 2nmol/L, baseline LH 2.4U/L, stimulated peak 24.9U/L, baseline FSH 1.2U/L, stimulated peak 4.2U/L.

Discussion: Previous in vitro work has shown complete loss of function of MC4R p.Gly181Asp due to reduced binding to a-MSH and reduced cell surface expression. Heterozygous p.Gly181Asp have been described in several children/adults with obesity; but hypogonadism in heterozygous carriers has not. Homozygous MC4R p.Gly181Asp was found in a male with obesity and partial HH thought to be due to abnormal GnRH production but with normal olfactory bulbs. We are the first to describe a heterozygous MC4R p.Gly181Asp variant in a patient with partial hypogonadism and anosmia with hypoplastic bulbs in addition to obesity. Interaction between POMC-MC-leptin circuits and Kisspeptin-GnRH circuits is recognised although not completely understood. Our results support a role for MC4R in GnRH secretion and potentially olfactory cell/GnRH neurone migration. Screening for MC4R should be considered in cases of hypogonadism and early onset obesity.