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Diagnostic Challenge in PLIN1-Associated Familial Partial Lipodystrophy

Authors :
Marie-Christine Vantyghem
Martine Auclair
Olivier Lascols
David B. Savage
Camille Vatier
Elise Bismuth
Isabelle Jéru
Sara Barraud
Pascale Cervera
Corinne Vigouroux
Centre de Recherche Saint-Antoine (UMRS893)
Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)
Université Sorbonne Paris Cité (USPC)
Université Pierre et Marie Curie - Paris 6 (UPMC)
Pathologie de l'Adipocyte et des Cellules Hepatiques
University of Cambridge [UK] (CAM)
Barraud, Sara
Source :
Journal of Clinical Endocrinology and Metabolism, Journal of Clinical Endocrinology and Metabolism, Endocrine Society, 2019, 104 (12), pp.6025-6032. ⟨10.1210/jc.2019-00849⟩, Journal of Clinical Endocrinology and Metabolism, 2019, 104 (12), pp.6025-6032. ⟨10.1210/jc.2019-00849⟩
Publication Year :
2019
Publisher :
HAL CCSD, 2019.

Abstract

Context Heterozygous frameshift variants in PLIN1 encoding perilipin-1, a key protein for lipid droplet formation and triglyceride metabolism, have been implicated in familial partial lipodystrophy type 4 (FPLD4), a rare entity with only six families reported worldwide. The pathogenicity of other PLIN1 null variants identified in patients with diabetes and/or hyperinsulinemia was recently questioned because of the absence of lipodystrophy in these individuals and the elevated frequency of PLIN1 null variants in the general population. Objectives To reevaluate the pathogenicity of PLIN1 frameshift variants owing to new data obtained in the largest series of patients with FPLD4. Methods We performed histological and molecular studies for patients referred to our French National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity for lipodystrophy and/or insulin resistance and carrying PLIN1 frameshift variants. Results We identified two heterozygous PLIN1 frameshift variants segregating with the phenotype in nine patients from four unrelated families. The FPLD4 stereotypical signs included postpubertal partial lipoatrophy of variable severity, muscular hypertrophy, acromegaloid features, polycystic ovary syndrome and/or hirsutism, metabolic complications (e.g., hypertriglyceridemia, liver steatosis, insulin resistance, diabetes), and disorganized subcutaneous fat lobules with fibrosis and macrophage infiltration. Conclusions These data suggest that some FPLD4-associated PLIN1 variants are deleterious. Thus, the evidence for the pathogenicity of each variant ought to be carefully considered before genetic counseling, especially given the importance of an early diagnosis for optimal disease management. Thus, we recommend detailed familial investigation, adipose tissue-focused examination, and follow-up of metabolic evolution.

Details

Language :
English
ISSN :
0021972X and 19457197
Database :
OpenAIRE
Journal :
Journal of Clinical Endocrinology and Metabolism, Journal of Clinical Endocrinology and Metabolism, Endocrine Society, 2019, 104 (12), pp.6025-6032. ⟨10.1210/jc.2019-00849⟩, Journal of Clinical Endocrinology and Metabolism, 2019, 104 (12), pp.6025-6032. ⟨10.1210/jc.2019-00849⟩
Accession number :
edsair.doi.dedup.....141b43b0bb1bc60cbab50eac296fb450