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Lipodystrophy syndromes are rare diseases with defects in the development or maintenance of adipose tissue, frequently leading to severe metabolic complications. They may be genetic or acquired, with variable clinical forms, and are largely underdiagnosed. The European Consortium of Lipodystrophies, ECLip, is a fully functional non-profit network of European centers of excellence working in the field of lipodystrophies. It provides a favorable environment to promote large Europe-wide and international collaborations to increase the basic scientific understanding and clinical management of these diseases. It works with patient advocacy groups to increase public awareness. The network also promotes a European Patient Registry of lipodystrophies, as a collaborative research platform for consortium members. The annual congress organized gives an update of the findings of network research groups, highlighting clinical and fundamental aspects. The talks presented during the meeting in Cambridge, UK, in 2022 are summarized in these minutes.

Summary Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson–Gilford progeria syndrome, mandibuloacral dysplasia, atypical progeroid syndrome (APS) and generalized lipodystrophy-associated progeroid syndrome (GLPS). All of those syndromes are associated with some progeroid features, lipodystrophy and metabolic complications but vary differently depending on a particular mutation and even patients carrying the same gene variant are known to have clinical heterogeneity. We report a new 30-year-old female patient from Russia with an APS and generalized lipodystrophy (GL) due to the heterozygous de novo LMNA p.E262K mutation and compare her clinical and metabolic features to those of other described patients with APS. Despite many health issues, short stature, skeletal problems, GL and late diagnosis of APS, our patient seems to be relatively metabolically healthy for her age when compared to previously described patients with APS. Learning points Atypical progeroid syndromes (APS) are rare and heterogenic with different age of onset and degree of metabolic disorders, which makes this diagnosis very challenging for clinicians and may be missed until the adulthood. The clinical picture of the APS depends on a particular mutation in the LMNA gene, but may vary even between the patients with the same mutation. The APS due to a heterozygous LMNA p.E262K mutation, which we report in this patient, seems to have association with the generalized lipodystrophy, short stature and osteoporosis, but otherwise, it seems to cause relatively mild metabolic complications by the age of 30. The patients with APS and lipodystrophy syndromes require a personalized and multidisciplinary approach, and so they should be referred to highly specialized reference-centres for diagnostics and treatment as early as possible. Because of the high heterogeneity of such a rare disease as APS, every patient’s description is noteworthy for a better understanding of this challenging syndrome, including the analysis of genotype-phenotype correlations.

Generalized lipodystrophy (GL) syndromes are a group of rare heterogenous disorders, characterized by total subcutaneous fat loss. The frequency of GL is currently assessed as approximately 0,23 cases per million of the population, in Europe - as 0,96 cases per million of the population. They can be congenital (CGL) or acquired (AGL) depending on the etiology and the time of the onset of fat loss. Both CGL and AGL are often associated with different metabolic complications, such as hypertriglyceridemia, insulin resistance and lipoatrophic diabetes mellitus, metabolically associated FLD, arterial hypertension, proteinuria, reproductive system disorders. In this review we aimed to summarize the information on all forms of generalized lipodystrophy, especially the ones of genetic etiology, their clinical manifestations and complications, the perspectives for diagnostics, treatment and further research.

Incretin hormones analogues, including glucagon-like peptide type 1 (GLP-1), exhibit complex glucose-lowering, anorexigenic, and cardioprotective properties. Mechanisms of action of GLP-1 and its analogues are well known for pancreatic β-cells, hepatocytes, and other tissues. Nevertheless, local effects of GLP-1 and its analogues in adipose tissue remain unclear. In the present work effects of the GLP-1 synthetic analogue, liraglutide, on adipogenesis and insulin sensitivity of the 3T3-L1 adipocytes were examined. Enhancement of insulin sensitivity of mature adipocytes by the GLP-1 synthetic analogue liraglutide mediated by adenylate cyclase was demonstrated. The obtained results imply existence of the positive direct insulin-sensitizing effect of liraglutide on mature adipocytes.

The exact physiological basis for the suppression of growth hormone secretion by oral glucose intake remains unknown, despite the widespread use of the oral glucose tolerance test in endocrinology. Lack of growth hormone suppression by glucose occurs in about a third of patients with acromegaly, as well as in other disorders. It is currently known that the secretion of growth hormone is affected by various factors, such as age, gender, body mass index, and the redistribution of adipose tissue. There is also evidence of the impact of overeating as well as being overweight on the secretion of growth hormone. It is known that both of these conditions are associated with hyperinsulinemia, which determines the possibility of its predominant role in suppressing the secretion of growth hormone. The purpose of this review is to discuss the accumulated data on the isolated effects of hyperglycemia and hyperinsulinemia on growth hormone secretion, as well as other metabolic regulators and conditions affecting its signaling. Understanding of the pathophysiological basis of these mechanisms is essential for further research of the role of glucose and insulin in the metabolic regulation of growth hormone secretion. However, the studies in animal models are complicated by interspecific differences in the response of growth hormone to glucose loading, and the only possible available model in healthy people may be the hyperinsulinemic euglycemic clamp.

Diabetes in pregnancy may be associated with monogenic defects of beta-cell function, frequency of which depends on ethnicity, clinical criteria for selection of patients as well as methods used for genetic analysis. The aim was to evaluate the contribution and molecular spectrum of mutations among genes associated with monogenic diabetes in non-obese Russian patients with diabetes in pregnancy using the next-generation sequencing (NGS). 188 non-obese pregnant women with diabetes during pregnancy were included in the study; among them 57 subjects (30.3%) met the American Diabetes Association (ADA) criteria of preexisting pregestational diabetes (pre-GDM), whereas 131 women (69.7%) fulfilled criteria of gestational diabetes mellitus (GDM). A custom NGS panel targeting 28 diabetes causative genes was used for sequencing. The sequence variants were rated according to the American College of Medical Genetics and Genomics (ACMG) guidelines. In total, 23 pathogenic, 18 likely pathogenic and 16 variants of uncertain significance were identified in 59/188 patients (31.4%). The majority of variants (38/59) were found in GCK gene. No significant differences in the number of variants among the two study groups (pre-GDM and GDM) were observed. The study suggests that frequency of monogenic variants of diabetes might be underestimated, which warrants a broader use of genetic testing, especially in pregnancy.

Lipodystrophy syndromes form a heterogenous group of inherited or acquired rare disorders, characterized by total (generalized lipodystrophy) or partial fat loss (partial lipodystrophy), usually accompanied by different metabolic disorders. Based on etiology lipodystrophies can be inherited or acquired. As a result of a significant progress in molecular genetics 20 new genes, associated with different lipodystrophy syndromes, were discovered during the last 20 years. However according to the majority of researchers data mutations in these causative genes are not found in approximately half of the patients. This might mean the need for both further molecular-genetic studies and the search for autoimmune factors playing a role in lipodystrophy syndromes etiology.

ClinicalTrials.gov (NCT03553420). Registered 14 March 2018, retrospectively registered Background: Lipodystrophy syndromes comprise a group of extremely rare and heterogeneous diseases characterized by a selective loss of adipose tissue in the absence of nutritional deprivation or catabolic state. Because of the rarity of each lipodystrophy subform, research in this area is difficult and international co-operation mandatory. Therefore, in 2016, the European Consortium of Lipodystrophies (ECLip) decided to create a registry for patients with lipodystrophy. Results: The registry was build using the information technology Open Source Registry System for Rare Diseases in the EU (OSSE), an open-source software and toolbox. Lipodystrophy specific data forms were developed based on current knowledge of typical signs and symptoms of lipodystrophy. The platform complies with the new General Data Protection Regulation (EU) 2016/679 by ensuring patient pseudonymization, informational separation of powers, secure data storage and security of communication, user authentication, person specific access to data, and recording of access granted to any data. Inclusion criteria are all patients with any form of lipodystrophy (with the exception of HIV-associated lipodystrophy). So far 246 patients from nine centres (Amsterdam, Bologna, Izmir, Leipzig, Münster, Moscow, Pisa, Santiago de Compostela, Ulm) have been recruited. With the help from the six centres on the brink of recruitment (Cambridge, Lille, Nicosia, Paris, Porto, Rome) this number is expected to double within the next one or 2 years. Conclusions: A European registry for all patients with lipodystrophy will provide a platform for improved research in the area of lipodystrophy. All physicians from Europe and neighbouring countries caring for patients with lipodystrophy are invited to participate in the ECLip Registry. E.S. has funding for lipodystrophy studies by the Russian Science Foundation,grantNo17–75-30035C.Vi. and C.Va. received funding by the French Ministry of Solidarity andHealth, Assistance-Publique Hôpitaux de Paris, Sorbonne Université, the Insti-tut National de la Santé et de la Recherche Médicale (Inserm), and CardioMe-tabolism and Nutrition University Hospital Institute (ICAN), grant ANR-10-IAHU, FranceD.B.S. is supported by the Wellcome Trust (WT 107064), the MRC MetabolicDisease Unit (MRC_MC_UU_12012/2), and The National Institute for HealthResearch (NIHR) Cambridge Biomedical Research Centre and NIHR RareDisease Translational Research Collaboration.D.A.-V. received funding by the Instituto de Salud Carlos III and the EuropeanRegional Development Fund, FEDER (grant number PI18/01890), by theConsellería de Industria, Xunta de Galicia (grant number ED341b 2017/19),and by Fundación Mutua Madrileña (Call 2015).E.S.-S. work was supported by Applied Molecular Biosciences Unit (UCIBIO),which is financed by national funds from FCT/MCTES (UID/MULTI/04378/2019). info:eu-repo/semantics/publishedVersion

Objective: Lipodystrophy syndromes are extremely rare disorders of deficient body fat associated with potentially serious metabolic complications, including diabetes, hypertriglyceridemia, and steatohepatitis. Due to their rarity, most clinicians are not familiar with their diagnosis and management. This practice guideline summarizes the diagnosis and management of lipodystrophy syndromes not associated with HIV or injectable drugs. Participants: Seventeen participants were nominated by worldwide endocrine societies or selected by the committee as content experts. Funding was via an unrestricted educational grant from Astra Zeneca to the Pediatric Endocrine Society. Meetings were not open to the general public. Evidence: A literature review was conducted by the committee. Recommendations of the committee were graded using the system of the American Heart Association. Expert opinion was used when published data were unavailable or scarce. Consensus Process: The guideline was drafted by committee members and reviewed, revised, and approved by the entire committee during group meetings. Contributing societies reviewed the document and provided approval. Conclusions: Lipodystrophy syndromes are heterogeneous and are diagnosed by clinical phenotype, supplemented by genetic testing in certain forms. Patients with most lipodystrophy syndromes should be screened for diabetes, dyslipidemia, and liver, kidney, and heart disease annually. Diet is essential for the management of metabolic complications of lipodystrophy. Metreleptin therapy is effective for metabolic complications in hypoleptinemic patients with generalized lipodystrophy and selected patients with partial lipodystrophy. Other treatments not specific for lipodystrophy may be helpful as well (eg, metformin for diabetes, and statins or fibrates for hyperlipidemia). Oral estrogens are contraindicated., Multiple worldwide endocrine societies developed practice guidelines for diagnosis and management of lipodystrophy syndromes based on current evidence.

We describe APS1 in a boy with generalized lipodystrophy, oral candidiasis, autoimmune hepatitis and adrenal insufficiency. It is the first time when generalized lipodystrophy is associated with APS1.

Background Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome (APS). Five of the 31 previously reported patients with APS harbored a recurrent de novo heterozygous LMNA p.T10I mutation. All five had generalized lipodystrophy, as well as similar metabolic and clinical features, suggesting a distinct progeroid syndrome. Methods We report nine new patients and follow-up of two previously reported patients with the heterozygous LMNA p.T10I mutation and compare their clinical and metabolic features with other patients with APS. Results Compared with other patients with APS, those with the heterozygous LMNA p.T10I mutation were younger in age but had increased prevalence of generalized lipodystrophy, diabetes mellitus, acanthosis nigricans, hypertriglyceridemia, and hepatomegaly, together with higher fasting serum insulin and triglyceride levels and lower serum leptin and high-density lipoprotein cholesterol levels. Prominent clinical features included mottled skin pigmentation, joint contractures, and cardiomyopathy resulting in cardiac transplants in three patients at ages 13, 33, and 47 years. Seven patients received metreleptin therapy for 0.5 to 16 years with all, except one noncompliant patient, showing marked improvement in metabolic complications. Conclusions Patients with the heterozygous LMNA p.T10I mutation have distinct clinical features and significantly worse metabolic complications compared with other patients with APS as well as patients with Hutchinson-Gilford progeria syndrome. We propose that they be recognized as having generalized lipodystrophy-associated progeroid syndrome. Patients with generalized lipodystrophy-associated progeroid syndrome should undergo careful multisystem assessment at onset and yearly metabolic and cardiac evaluation, as hyperglycemia, hypertriglyceridemia, hepatic steatosis, and cardiomyopathy are the major contributors to morbidity and mortality.

Hereditary lipodystrophies (HLD) are a heterogeneous group of rare diseases characterized by a complete or partial loss of subcutaneous fat and by the development of metabolic disturbances: diabetes mellitus with obvious insulin resistance and acanthosis nigricans, dyslipidemia, hepatic steatosis, hypertension, and polycystic ovary syndrome. The laminopathy variant familial partial lipodystrophy type 2 or Dunnigan syndrome (FPLD2) is the most common cause of partial LD. The paper describes a family (3 clinical cases) with FPLD2 caused by heterozygous R482W missense mutations in the gene encoding the protein lamin A/C (LMNA; 150330). This observation demonstrates that specialists should be more aware of this disease and make a timely diagnose in cases of concurrent severe metabolic disturbances at a young age, which contributes to more effective treatment of patients and to medical genetic counseling of their families.Наследственные липодистрофии (НЛД) представляют собой гетерогенную группу редких заболеваний, характеризующихся полной или частичной потерей подкожной жировой клетчатки, а также развитием метаболических нарушений: сахарного диабета с выраженной инсулинорезистентностью и acanthosis nigricans, дислипидемии, стеатоза печени, артериальной гипертонии, синдрома поликистозных яичников. Наиболее частой причиной парциальной липодистрофии (ЛД) является вариант ламинопатий, семейная парциальная ЛД 2-го типа (FPLD2), или синдром Dunnigan. Описана семья (3 клинических случая) с FPLD2, обусловленной гетерозиготной миссенс-мутацией R482W в гене, кодирующем белок ламин A/C (LMNA; 150330). Это наблюдение демонстрирует необходимость увеличения осведомленности специалистов о данном заболевании и своевременно установленного диагноза в случаях сочетания выраженных метаболических нарушений в молодом возрасте, что способствует более эффективному лечению пациентов и проведению медико-генетического консультирования их семей.