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Endocrine Abstracts (2022) 81 EP356 | DOI: 10.1530/endoabs.81.EP356

ECE2022 Eposter Presentations Diabetes, Obesity, Metabolism and Nutrition (318 abstracts)

A unique family with early-onset, severe obesity and hypopituitarism harboring different POMC pathogenic mutations.

Lauriane Le Collen 1,2,3 , Brigitte Delemer 1 , Christine Poitou-Bernert 4,5 , Vaxillaire Martine 1,2 , Jean Michel Petit 6 , Saveanu Alexandru 7,8,9 , Clement Karine 4,5 , Froguel Philippe 2,3 & Bonnefond Amélie 2,3

1University Hospital of Reims, Department of Endocrinology Diabetology, Reims, France; 2EGID/Pasteur Institute of Lille, Inserm/CNRS UMR 1283/8199, Lille, France; 3University of Lille, Lille, France; 4Pitié-Salpêtrière Hospital, Nutrition Department, Paris, France; 5Sorbonne Université, INSERM, NutriOmics Research Unit, Paris, France; 6University Hospital Dijon-Bourgogne, Dijon, France; 7Aix-Marseille Université Marseille Medical Genetics, Institut National de la Santé et de la Recherche Médicale (INSERM), U125, Marseille, France; 8Assistance Publique-Hôpitaux de Marseille, Centre de Référence des Maladies Rares de l’hypophyse HYPO, Marseille, France; 9Assistance-Publique des Hôpitaux de Marseille, Hôpital de la Conception, Laboratory of Molecular Biology, Marseille, France

Objective: We describe two first cousins presenting with neonatal corticotropic deficiency and severe, early-onset obesity. This study aims to identify the molecular etiology of these disorders in both cases and highlights the limits of genetic investigations.

Methods: We collected the clinical-biological data of the family and, more particularly, of the two first cousins (A and B). We performed several constitutive Next-generation Sequencing (NGS) protocols focused on genes causing monogenic forms of pituitary deficits or obesity. The pathogenicity of variants was assessed via the guidelines of the American College of Medical Genetics and Genomics.

Results: Patients A and B had very early-onset obesity (>+3DS at 1year) with neonatal corticotropic deficiency and Combined Pituitary Hormonal deficiency (CPHD). The initial sequencing of three genes causing pituitary deficiency ( TPIT, PROP1, LHX3) was negative. Then, by another targeted sequencing protocol, we found that Patient A carried a pathogenic compound heterozygous variant in POMC (NM_001035256.3: p.Tyr139* and p.Cys28*). However, Patient B only carried the POMC p.Tyr139* variant at heterozygous state, inherited from her mother (aunt of Patient A). Whole-exome sequencing in Patient B allowed us to identify a second pathogenic heterozygous variant in the proximal promoter of POMC (c.-11C>A) that was inherited from her father. This non-coding variant was previously reported pathogenic in the literature, with a deleterious effect on POMC activity according to in vitro analyses. Patient A is currently being treated effectively with an MCR4 agonist, decreasing BMI from 41.5 kg/m2 to 25 kg/m2 after three years.

Conclusions: We described the segregation of three different pathogenic POMC mutations within the same family with a CPHD phenotype and severe, early-onset obesity. One of them was challenging to identify because of the limitations of targeted NGS.

Volume 81

European Congress of Endocrinology 2022

Milan, Italy
21 May 2022 - 24 May 2022

European Society of Endocrinology 

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