Dunnigan lipodystrophy syndrome: French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins)

Abstract

Dunnigan syndrome, or Familial Partial Lipodystrophy type 2 (FPLD2; ORPHA 2348), is a rare autosomal dominant disorder due to pathogenic variants of the LMNA gene. The objective of the French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins), is to provide health professionals with a guide to optimal management and care of patients with FPLD2, based on a critical literature review and multidisciplinary expert consensus. The PNDS, written by members of the French National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), is available on the French Health Authority website (in French). Dunnigan syndrome is characterized by a partial atrophy of the subcutaneous adipose tissue and by an insulin resistance syndrome, associated with a risk of metabolic, cardiovascular and muscular complications. Its prevalence, assessed at 1/100.000 in Europe, is probably considerably underestimated. Thorough clinical examination is key to diagnosis. Biochemical testing frequently shows hyperinsulinemia, abnormal glucose tolerance and hypertriglyceridemia. Elevated hepatic transaminases (hepatic steatosis) and creatine phosphokinase, and hyperandrogenism in women, are common. Molecular analysis of the LMNA gene confirms diagnosis and allows for family investigations. Regular screening and multidisciplinary monitoring of the associated complications are necessary. Diabetes frequently develops from puberty onwards. Hypertriglyceridemia may lead to acute pancreatitis. Early atherosclerosis and cardiomyopathy should be monitored. In women, polycystic ovary syndrome is common. Overall, the management of patients with Dunnigan syndrome requires the collaboration of several health care providers. The attending physician, in conjunction with the national care network, will ensure that the patient receives optimal care through regular follow-up and screening. The various elements of this PNDS are described to provide such a support.

A Very-Low-Calorie Diet Can Cause Remission of Diabetes Mellitus and Hypertriglyceridemia in Familial Partial Lipodystrophy

“…Hypoleptinemia affects the pulsatility of the hypothalamic-pituitary-gonadal axis, downstream of which results in hyperandrogenemia such that the reproductive problems in severe phenotypes seem inevitable [4, 8, 20]. Yet, the data on fertility in patients with FPLD2 are scarce [8, 10]. In a series of 14 female patients, 28% had infertility, and none with prepregnancy diabetes were able to conceive spontaneously, as was the case with our patient [8].…”

“…In a series of 14 female patients, 28% had infertility, and none with prepregnancy diabetes were able to conceive spontaneously, as was the case with our patient [8]. With the lack of recommendations regarding the safety of metreleptin during preconception and pregnancy, this dietary approach may be an acceptable option [1, 10]. Whether VLCD might be a successful intervention in all patients with lipodystrophy and how to sustain beneficial effects of reduced calorie state in the longer term both require further studies.…”

“…There is currently no treatment available for partial lipodystrophy syndromes in the USA; general measures are based on exercise and a balanced [2] diet. While metreleptin is the only drug approved specifically for generalized lipodystrophy in the USA [1, 5], its use in certain conditions, such as preconception or pregnancy, is still controversial [5, 10].…”

Enhancing diagnostic yield of monogenic diabetes through phenotypic and molecular reanalysis of 128 individuals with young onset hyperglycemia: highlighting the significance of accurate case characterization

“…Individuals with neonatal DM were considered typical if their hyperglycemia occurred in the first 6 months of life 2,3,6 . Individuals with suspected FPLD were identified as typical when their lower limbs fat was less than 25% 14,15 , as evaluated by dual-energy X-ray absorptiometry (DXA). Individuals suspected of Wolfram syndrome and mitochondrial DM, due to their syndromic phenotype, were all considered typical.…”

Diagnostic and referral pathways in patients with rare lipodystrophy and insulin-resistance syndromes: key milestones assessed from a national reference center

“…French national guidelines recommend that patients with lipodystrophy should be referred to a PRISIS competence or reference center to organize initial management and follow-up [ 16 ].…”