A recurrent familial partial lipodystrophy due to a monoallelic or biallelic LMNA founder variant highlights the multifaceted cardiac manifestations of metabolic laminopathies.

AIMS: LMNA-linked familial partial lipodystrophy type 2 (FPLD2) leads to insulin resistance-associated metabolic complications and cardiovascular diseases. We aimed to characterise the disease phenotype in a cohort of patients carrying an LMNA founder variant. METHODS: We collected clinical and biological data from patients carrying the monoallelic or biallelic LMNA p.(Thr655Asnfs*49) variant (n = 65 and 13, respectively) and 19 non-affected relative controls followed-up in Reunion Island Lipodystrophy Competence Centre, France. RESULTS: Two-thirds of patients with FPLD2 (n = 51) and one-third of controls (n = 6) displayed lipodystrophy and/or lean or android morphotype (P = 0.02). Although age and BMI were not statistically different between the two groups, the insulin resistance index (median HOMA-IR: 3.7 vs 1.5, P = 0.001), and the prevalence of diabetes, dyslipidaemia, and non-alcoholic fatty liver disease were much higher in patients with FPLD2 (51.3 vs 15.8%, 83.3 vs 42.1%, and 83.1 vs 33.3% (all P ≤ 0.01), respectively). Atherosclerosis tended to be more frequent in patients with FPLD2 (P = 0.07). Compared to heterozygous, homozygous patients displayed more severe lipoatrophy and metabolic alterations (lower BMI, fat mass, leptin and adiponectin, and higher triglycerides P ≤ 0.03) and tended to develop diabetes more frequently, and earlier (P = 0.09). Dilated cardiomyopathy and/or rhythm/conduction disturbances were the hallmark of the disease in homozygous patients, leading to death in four cases. CONCLUSIONS: The level of expression of the LMNA 'Reunionese' variant determines the severity of both lipoatrophy and metabolic complications. It also modulates the cardiac phenotype, from atherosclerosis to severe cardiomyopathy, highlighting the need for careful cardiac follow-up in affected patients.

Cushing's Syndrome Caused by a Well-Differentiated Ileal Neuroendocrine Carcinoma.

We report a very rare case of Cushing's syndrome caused by an ileal adrenocorticotrophin-secreting well-differentiated endocrine carcinoma with liver metastases. A 62-yr-old woman presented with clinical and biological signs suggestive of paraneoplastic Cushing's syndrome Radiological investigations, including magnetic resonance imaging of the pituitary gland, chest and abdominal computerized tomography scan, smalI bowel barium study and pancreatic endoscopic scan, 111 -pentetreotide scintigraphy (octreoscan), esogastroduodenoscopy, and colonoscopy did not detect the source of the ectopic adrenocorticotropic hormone (ACTH) secretior but showed a few liver nodules. Because a 10 mo-long ketoconazole treatment was not effective, a bilateral adrenalectomy was performed in order to control the Cushing's syndrome, and a liver nodule biopsy diagnosed a metastatic neuroendocrine tumor. Subsequently, a second laparotomy disclosed a 1.8 cm ileal neuroendocrine tumor, cosecreting ACTH and serotonin on immunohistochemistry with many liver metastases. ACTH and secretion by intestinal neuroendocrine tumors is rare, and the secretion is a most always clinicailly silent. Cushing's syndrome caused by an intestinal low grade neuroendocrine tumor is even rarer, with only two previous cases reported in the literature. Our observation underlines the difficulty of localizing the source of ectopic ACTI-I secretion in paraneoplastic Cushing's syndrome.