Monogenic forms of lipodystrophic syndromes: diagnosis, detection, and practical management considerations from clinical cases

Abstract

Background: Lipodystrophic syndromes are rare diseases of genetic or acquired origin characterized by partial or generalized lack of body fat. Early detection and diagnosis are crucial to prevent and manage associated metabolic dysfunctions, i.e. insulin resistance, dyslipidemia, fatty liver, and diabetes, and to provide appropriate genetic counseling. By means of several representative case studies, this article illustrates the diagnostic and management challenges of lipodystrophic syndromes.

Review: Berardinelli-Seip congenital lipodystrophy (BSCL) is typically diagnosed at birth, or soon thereafter, with generalized lipoatrophy and hepatomegaly secondary to hepatic steatosis. Physicians must also consider this diagnosis in adults with atypical non-autoimmune diabetes, hypertriglyceridemia, and a lean and muscular phenotype. The BSCL1 subtype due to mutations in the AGPAT2 gene can have an unusual presentation, especially in neonates and infants. Particular attention should be paid to infants presenting failure to thrive who also have hepatomegaly and metabolic derangements. The BSCL2 sub-type due to mutations in the BSCL gene tends to be more severe than BSCL1, and is characterized by greater fat loss, mild intellectual disability, earlier onset of diabetes, and higher incidence of premature death. Effective management from an earlier age may moderate the natural disease course. Partial lipodystrophies may easily be confused with common central obesity and/or metabolic syndrome. In patients with unexplained pancreatitis and hypertriglyceridemia, lipodystrophies such as familial partial lipodystrophy type 2 (FPLD2; Dunnigan type, due to LMNA mutations) should be considered. Oral combined contraceptives, which can reveal the disease by inducing severe hypertriglyceridemia, are contraindicated. Endogenous estrogens may also lead to “unmasking” of the FPLD2 phenotype, which often appears at puberty, and is more severe in females than males.

Conclusions: Diet and exercise, adapted to age and potential comorbidities, are essential prerequisites for therapeutic management of lipodystrophic syndromes. Metreleptin therapy can be useful to manage lipodystrophy-related metabolic complications.

Keywords:

• Berardinelli-Seip congenital lipodystrophy
• Familial partial lipodystrophy
• Congenital generalized lipodystrophy
• Consanguinity
• Metreleptin

Transparency

Declaration of funding

Aegerion Pharmaceuticals, Cambridge, MA, the manufacturer of metreleptin (Myalept^®), provided financial assistance through an unrestricted educational program for presentation of clinical cases in this article.

Declaration of financial/other relationships

Camille Vatier has received personal fees for consultancy, travel, or accommodation from Aegerion Pharmaceuticals, Lilly, Novo Nordisk, Sanofi, Servier, and Vitalaire. Marie-Christine Vantyghem was invited by Aegerion for a conference on lipodystrophies at the Endodiabetes 2018 meeting (transportation and accommodation, with no other fee). Caroline Storey has received personal fees for travel or accommodation from IPSEN and Sanofi. Bruno Fève has received personal fees for consultancy, lecture, travel, or accommodation by Merck Sharp & Dohme, Novo Nordisk, Sanofi, and institutional research grants from Viiv-Healthcare and Merck Sharp & Dohme. Corinne Vigouroux has received personal fees for consultancy, lecture, travel, or accommodation from Aegerion Pharmaceuticals, Air Products, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Jansen-Cilag, Merck-Serono, Novo Nordisk, Orkyn, Sanofi, Servier, Viiv-Healthcare, and Vitalaire, and institutional research grants from Pierre-Fabre Médicament, Roche Diagnostics, and Servier. Elise Bismuth has received personal fees for consultancy, lecture, travel, or accommodation from Eli Lilly, Abbott Diabetes Care, and Medtronic. Other authors did not declare any conflicts of interest. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

The authors acknowledge the patients, the healthcare professionals at Saint-Antoine Hospital, Endocrinology and Molecular Biology Departments, and Robert Debré Hospital, Pediatric Endocrinology Department, and Assistance Publique-Hôpitaux de Paris and Lille University Hospital, Endocrinology Department; Dr Sylvie Falcon-Eicher and Profs Frédéric Huet, Jean-François Gautier, and Bruno Vergès, who contributed to the medical care of Patients 3 and 4; Amylin, Bristol-Myers Squibb, and AstraZeneca; and Aegerion, who provided metreleptin. Writing assistance, provided by Content Ed Net (Basel, Switzerland), with funding from Aegerion, was used in production of this manuscript.