European Review for Medical and Pharmacological Sciences 2019; 23: 5581-5594 Genetics of lipedema: new perspectives on genetic research and molecular diagnoses S. PAOLACCI1, V. PRECONE2, F. ACQUAVIVA3, P. CHIURAZZI4,5, E. FULCHERI6,7, M. PINELLI3,8, F. BUFFELLI9,10, S. MICHELINI11, K.L. HERBST12, V. UNFER13, M. BERTELLI2; GENEOB PROJECT 1MAGI’S LAB, Rovereto (TN), Italy 2MAGI EUREGIO, Bolzano, Italy 3Department of Translational Medicine, Section of Pediatrics, Federico II University, Naples, Italy 4Istituto di Medicina Genomica, Fondazione A. Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy 5UOC Genetica Medica, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, Italy 6Fetal and Perinatal Pathology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy 7Department of Integrated Surgical and Diagnostic Sciences, University of Genoa, Genoa, Italy 8Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy 9Fetal and Perinatal Pathology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy 10Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal-Infantile Sciences, University of Genoa, Genoa, Italy 11Department of Vascular Rehabilitation, San Giovanni Battista Hospital, Rome, Italy 12Department of Medicine, University of Arizona, Tucson, AZ, USA 13Department of Developmental and Social Psychology, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy Abstract. – OBJECTIVE: The aim of this quali- Introduction tative review is to provide an update on the cur- rent understanding of the genetic determinants of lipedema and to develop a genetic test to dif- Lipedema is an underdiagnosed chronic debil- ferentiate lipedema from other diagnoses. itating disease characterized by bruising and pain MATERIALS AND METHODS: An electronic and excess of subcutaneous adipose tissue of the search was conducted in MEDLINE, PubMed, and legs and/or arms in women during or after times Scopus for articles published in English up to of hormone change, especially in puberty1. A defi- March 2019. Lipedema and similar disorders in- nition of lipedema has not yet been included in the cluded in the differential diagnosis of lipedema 10th revision of the International Classification of were searched in the clinical synopsis section of OMIM, in GeneCards, Orphanet, and MalaCards. Diseases (ICD) by the World Health Organization RESULTS: The search identified several ge- (WHO) although an ICD-11 code of EF02.2 has netic factors related to the onset of lipedema and been proposed. The first guidelines on lipedema highlighted the utility of developing genetic diag- were proposed in 2015 in Germany and by oth- nostic testing to help differentiate lipedema from ers in 2017 using the international classification other diagnoses. of functioning, disability and health2-4. Lipedema CONCLUSIONS: No genetic tests or guidelines for molecular diagnosis of lipedema are current- coexists frequently with obesity and can be easi- ly available, despite the fact that genetic testing ly confused with it. However, lipedema is distin- is fundamental for the differential diagnosis of li- guishable from obesity because it is located pri- pedema against Mendelian genetic obesity, pri- marily in the lower limbs and upper extremities mary lymphedema, and lipodystrophies. sparing the trunk; lipedema minimally responds to diets. Finally, women with lipedema can have a Key Words: normal Body Mass Index (BMI)5. Lipedema can Lipedema, Lipoedema, Differential diagnosis, Sub- cutaneous fat, Genetic diagnosis. be confused with lymphedema. There are sub- stantial differences between these two diseases: Corresponding Author: Stefano Paolacci, Ph.D; e-mail: [email protected] 5581 S. Paolacci, V. Precone, F. Acquaviva, P. Chiurazzi, E. Fulcheri, et al while lipedema is always bilateral, lymphedema MEDLINE, PubMed and Scopus, using different can be unilateral or bilateral; distinctive features combinations of the search terms and concepts “li- of lipedema are pain and bruising that are absent pedema”, “lipedema genes”,” lipedema etiology”, in lymphedema; and in lipedema, the Stemmer “lipedema differential diagnosis”, “lipedema and sign is negative6. Furthermore, lipedema may be obesity”, “lipedema and lymphedema”, “lipedema associated with multiple lipomas on the arms and/ and lipodystropy”, “clinical manifestations of li- or trunk which are not found in lymphedema5,6. pedema” and “lipedema genetic testing”. Articles The prevalence of lipedema has been reported to in English were first chosen by examining the title be 1-9/1000007. However, it is notable that epide- and abstract and, subsequently, analyzed by two miological data can fail to recognize lipedema or independent readings of the whole text. Reference include individuals who are misdiagnosed with lists were scanned to retrieve other relevant arti- other similar diseases, most commonly obesity, cles. The reviewers assessed the full-text articles. lymphedema, and lipodystrophies. Lipedema can A search for lipedema and similar disorders that be considered as one component of a spectrum of overlap in the differential diagnoses was con- diseases that are characterized by the dysregu- ducted in the clinical synopsis section of OMIM, lated proliferation of adipose tissue and the pres- GeneCards, Orphanet and MalaCards. Orphanet ence of pain. The adiposis dolorosa (painful fat) GeneReviews, and Genetic Home Reference were spectrum of diseases includes: 1) “Generalized searched to find existing genetic diagnostic tests diffuse form of Dercum disease” where painful for lipedema. A general PubMed research was pearl-sized nodular subcutaneous adipose tissue used to investigate clinical, diagnostic and genet- is widespread throughout the body without larger ic testing guidelines regarding lipedema. Any dis- masses; 2) “generalized nodular form of Dercum agreements were solved through discussion until disease” where larger painful nodules are found consensus. on the arms, trunk, and thighs; 3) “lipedema”, a localized form of painful fat with characteristic distribution of pearl-sized nodular fat and larger masses on the limbs; 4) “localized nodular form Results of Dercum disease”, usually found around joints (juxta-articular type); and 5) “Madelung disease” Clinical Aspects of Lipedema or multiple symmetric lipomatosis with nodular Lipedema is a chronic condition of deposits of fat and lipomas on the upper aspect of the body painful fat, primarily in the gynoid region, occurring although a “gynoid type” has been identified8,9 at times of hormone change in women, especially (Figure 1). With a variety of diseases of painful at the time of puberty, that causes gait and joint ab- fat, diagnosing painful lipedema may be diffi- normalities, and which eventually can result in the cult; it would be useful to develop a genetic test development of lymphedema, called lipo-lymphede- that analyses all the genes known for Mendelian ma. Clinically, lipedema has several features: abnor- non-syndromic genetic obesity, primary lymph- mal and painful adipose tissue on the legs, thighs, edema, and lipodystrophies when trying to diag- buttocks, and on the arms in 80%, of cases with a nose a patient with lipedema, due to the clinical BMI that can be normal or increased without ab- findings these diseases hold in common10. This dominal obesity11; chronic pain that can significant- review aims to outline current knowledge about ly impact mobility; joint hypermobility associated the genetics of lipedema and highlights the im- with fatigue1,12,13; bruising due to increased capillary portance of genetic testing for a more precise di- fragility14; edema in advanced stages or longstand- agnosis of lipedema to separate it from similar ing lipedema15 and psychosocial stress and associ- appearing conditions. ated psychiatric disorders, especially anxiety and depression16. The main classifications of lipedema are Schingale classification (Types I, II, III, IV, and V) based on the different distribution of adipose tis- Materials and Methods sue2 and Schmeller and Meier-Vollrath classification (Stages I, II, III, and IV) depending on the sever- This is a “qualitative review” in which, infor- ity of the disease12. Conservative treatments of li- mation published about lipedema in referenced pedema include: manual lymphatic drainage as part scientific journals until March 2019 were col- of complex decongestive therapy, subcutaneous ad- lected. An electronic search was conducted in ipose tissue therapy to reduce fibrosis and increase 5582 Genetics of lipedema Figure 1. Depiction of phenotypic overlap of different conditions characterized by subcutaneous fat accumulation. fluid flow through the tissue, compression garment Etiopathogenesis of Lipedema therapy or wrapping to reduce tissue fluid, physical Lipedema is a chronic disease of lipid metab- activity and healthy food plans to reduce any obesity olism resulting in the symmetrical deposition of component of lipedema, medical foods and supple- subcutaneous adipose tissue associated with hy- ments (such as selenium, Butcher’s broom or dios- perplasia and/or hypertrophy of fat cells19. Etio- min), deep breathing and psychosocial counseling. pathogenesis is unclear but may be associated with For patients with minimal or no improvement with impairment of a hormonal axis, since lipedema conservative treatment, surgical treatments includ- mainly affects females and its onset is primari- ing liposuction and reductive surgery are needed2. ly around the time