Bilateral symmetric lipomatosis of the orbit in Madelung's disease.

Madelung's disease is a rare benign systemic lipomatosis, which often presents in the head, neck and upper trunk regions. The appearance of symmetrical, excessive adipose tissue in the subcutaneous layer is its clinical characteristic. Orbital involvement is unusual with only a few cases reported previously. In this study, we describe the clinical and radiological features of Madelung's disease in the orbits. A 42-year-old man with alcohol addiction presented with chronic bilateral masses of the lower eyelids and proptosis. Computed tomography (CT) scan showed excessive symmetrical non-encapsulated fat deposition in the orbital fat, lower eyelids, salivary glands, subcutaneous tissue along the neck and under the sternocleidomastoid muscles and supraclavicular areas bilaterally. Histopathological study of the orbital masses revealed mature adipose tissue interspersed with thin fibrous septae. He developed recurrent lipomatosis 1 year after surgical excision.

Madelung's disease in a non-alcoholic Ethiopian male patient mistaken for obesity: a case report.

BACKGROUND: Madelung's disease (MD) is a rare disorder of fat storage characterized by the presence of diffuse, symmetrical deposition of subcutaneous fat around the neck, shoulder, arm, trunk and thigh. Although its cause is not fully understood, this benign condition is commonly presented among adult males with Mediterranean origin and history of alcohol abuse. Patients often presents with compression of vital structures, cosmetic disfigurement and associated psychosocial problems and systemic comorbidities. It is often under-recognized by physicians, possibly due to obliviousness of the condition and often misdiagnosed as obesity. CASE PRESENTATION: We present a 65-year-old non-alcoholic black Ethiopian man, presented with a slowly growing body fat in his trunk and proximal limbs associated by multiple joint and back pain which got worse recently. He denied any history of chronic alcohol use. On examination, huge, bilateral, non-tender, soft, globular masses in his torso, shoulder, arm and thigh with bilateral breast enlargement. On investigation his biochemical profile was normal except hyperuricemia (10.6 mg/dl). Imaging of the cervical and lumbar vertebrae showed excess subcutaneous fat depositions with degenerative disc disease. Biopsy from the mass revealed non-encapsulated lipoma and he was diagnosed with type II MD. We treated his pain with supportive therapy and discharged in stable condition. The patient deferred surgical treatment. CONCLUSIONS: Madelung's disease is often reported among white adult males with chronic alcoholism. However, our case reported a black man without the typical risk factor which was misdiagnosed as obesity. Hence, clinicians should be aware of MD and need to consider it in their differential diagnosis when encountered with a patient having progressive centripetal fat deposition with or without a history of alcoholism and systemic comorbidities. As early detection of this disorder helps to avoid diagnostic delays and prevent complications through timely interventions which will in turn improves patient quality of life.

Madelung Disease Epidemiology and Clinical Characteristics: a Systemic Review.

BACKGROUND: Madelung disease is a rare lipid metabolic disorder, and most cases are sporadically reported. There are currently no systematic reviews summarizing the epidemiological and clinical characteristics of this disease. The purpose of the current article is to extract and analyze the existing evidence concerning Madelung disease derived from case series in order to provide adequate treatments for patients based on a more comprehensive understanding of the disease. METHODS: PubMed, Embase, and Web of Science databases were queried for relevant articles using the search terms "Madelung disease," "multiple symmetric lipomatosis," "Launois-Bensaude syndrome" and synonyms until Aug 31,2020. Data statistics of Madelung disease epidemiology and clinical characteristics are summarized in different tables or charts with Microsoft Office software. RESULTS: Patients exhibiting Madelung disease were mostly located in Europe, although some records existed in Asia as well. Average patient age was between 45 and 65 years old. Type I was the most common form of the disease, and the neck was the most common location for tumors. Madelung disease is associated with various metabolic disorders, and hematoma and seroma were the most common complications. Overall recurrence rate was 18.3%, with similar recurrence rates after lipectomy and liposuction. Fewer complications occurred after liposuction compared with lipectomy, but relapse was more common after liposuction. CONCLUSION: Madelung disease consists of specific epidemiological and clinical characteristics, knowledge of which can be helpful for diagnosis and cognition. Lipectomy and liposuction are considered to be the most effective treatment methods for Madelung disease; however, choice of surgery should be based on comprehensive consideration of the disease, such as severity, mass location, and patient expectations. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Mitochondrial DNA pathogenic mutations in multiple symmetric lipomatosis.

The frequency of dermatological manifestations in diseases due to mitochondrial DNA mutations is not well known, although multiple symmetric lipomatosis has been repeatedly associated to mitochondrial DNA mutations. Here, we present a patient suffering from multiple symmetric lipomatosis and other skin signs. We found a new mitochondrial DNA mutation, m.8357T>C, in the tRNALys -coding gene and, using a cybrid approach, confirmed its pathogenicity. A meta-analysis of the dermatological signs of the patient shows that they are not common in patients with confirmed mitochondrial DNA mutations and suggests that, in these cases, lipomatosis is not related to the oxidative phosphorylation dysfunction, but to an alteration of an additional function associated to particular mitochondrial tRNAs.

A case report of Multiple Symmetric Lipomatosis (MSL) in an East Asian Female.

BACKGROUND: Multiple Symmetric Lipomatosis (MSL) is a rare disorder related to fat metabolism and lipid storage. The condition results in characteristic depositions of fat, especially around the cephalic, cervical, and upper thoracic subcutaneous. It is much more common in adult males who live in the Mediterranean region and has only rarely been reported in Asian females. In this report, we present a case of an Asian female with MSL and also review the clinical features of the condition, including radiological and histological findings required for proper diagnosis and management. CASE PRESENTATION: A 59-year-old Korean female came in with a chief complaint of palpable mass present in shoulder and upper back regions. Images showed diffuse non-encapsulated adipose tissue in the subcutaneous layer of the suboccipital, posterior neck area. The patient wanted to remove the mass for cosmetic reasons and discomfort. Excisional biopsy was planned. Preoperative blood analyses showed deteriorated liver function, and the computed tomography findings were consistent with liver cirrhosis. Detailed history taking revealed that she consumed highly levels of alcohol. Lipectomy was performed and the histological findings demonstrated large dystrophic adipocyte morphology. The patient was recovered uneventfully. CONCLUSION: When patients have multiple symmetric lipomatous lesions, clinicians should suspect MSL and survey possible associated conditions, such as alcoholism, liver cirrhosis, dyspnea, and neuropathy in detail.

Adipose Tissue in Multiple Symmetric Lipomatosis Shows Features of Brown/Beige Fat.

INTRODUCTION: Multiple symmetric lipomatosis (MSL) (syn.: Launois-Bensaude Syndrome, benign symmetric lipomatosis) is a rare disease of fatty tissue. The pathophysiology of MSL still remains unclear, although several approaches have been described in order to understand it. Beside morphological characteristics and some molecular cell biological approaches, little is known about the histological and immunohistochemical characterization of adipose tissue from patients with MSL. METHODS: From the 45 patients with MSL in our database, 10 were included in the study. Fat tissue samples were collected from affected and unaffected areas. The forearm served as a control area as this area is not affected in MSL. The specimens were analyzed after selected stainings were taken (hematoxylin-eosin = HE, Elastica van Gieson, Ladewig, CD200, CIDEA, myf5, p107, Prdm16, Sca-1, syndecan, UCP1, MAC387, Glut4). RESULTS: In patients suffering from MSL, no macroscopic or microscopic morphological difference could be found between affected and unaffected adipose tissue in HE stainings. The majority of samples showed positivity for UCP1 (9/10 clinically affected tissues, 7/10 clinically unaffected tissues) and CD200. CONCLUSION: Marker profiles support the hypothesis that affected adipose tissue derives from brown or beige adipose tissue rather than from white fat. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

White Adipose Tissue Expansion in Multiple Symmetric Lipomatosis Is Associated with Upregulation of CK2, AKT and ERK1/2.

Multiple symmetric lipomatosis (MSL) is a rare disorder characterized by overgrowing lipomatous tissue (LT) in the subcutaneous adipose tissue (SAT). What LT is and how it expands are not completely understood; previous data suggested that it could derive from brown AT precursors. In six MSL type I patients, we compared LT morphology by histological and immunohistochemistry (IHC) analysis, gene expression, by qPCR, kinase activity, by Western Blot and in vitro assay to paired-control SAT using AT from patients with pheochromocytoma as a human browning reference. In the stromal vascular fraction (SVF), we quantified adipose stem cells (ASCs) by flow cytometry, the proliferation rate, white and beige adipogenic potential and clonogenicity and adipogenicity by a limiting dilution assay. LT displayed white AT morphology and expression pattern and did not show increased levels of the brown-specific marker UCP1. In LT, we evidenced AKT, CK2 and ERK1/2 hyperactivation. LT-SVF contained increased ASCs, proliferated faster, sprouted clones and differentiated into adipocytes better than the control, displaying enhanced white adipogenic potential but not increased browning compared to SAT. In conclusion, LT is a white AT depot expanding by hyperplasia through increased stemness and enhanced white adipogenesis upregulating AKT, CK2 and ERK1/2, which could represent new targets to counteract MSL.

Benign symmetric lipomatosis in the tongue: an uncommon case.

Symmetric lipomatosis of the tongue (SLT) is rare and characterized by diffuse growth and unencapsulated lipomas. An 87-year-old man was referred for evaluation of tongue lesions. Intraoral findings showed soft yellowish nodules with a smooth shiny surface diffusely on the lateral border of the tongue, bilaterally. Our clinical diagnosis was multiple tongue lipomas and an incisional biopsy was done. Histopathological examination revealed unencapsulated lobules of mature adipocytes with slight variation in the size and shape, confirming the diagnosis of lipoma. The final diagnosis was SLT. On follow-up at 6 months, the tongue findings were unchanged and no new lesions were observed.

Multiple symmetric lipomatosis of the male breast: An unusual mimic of gynecomastia.

Multiple symmetric lipomatosis (MSL) is a very uncommon disease. Its etiopathogenesis is uncertain, although it has been linked to a variety of factors. Its main characteristic is the overgrowth of fat in form of an unencapsulated lesion. Most of the cases reported are in the head and neck region. We report a case that occurred in the breasts of a 62-year-old man. A clinical diagnosis of gynecomastia was initially made. Partial mastectomy was done and MSL was reported on histopathologic examination. Our literature search revealed no previous case of MSL in the breast reported from our environment.

Madelung Disease: Analysis of Clinicopathological Experience in Taipei Veterans General Hospital.

BACKGROUND: The main feature of Madelung disease (MD), a rare condition, is the growth of adipose tissue without a capsule. Usually, this disease is known for its prominent features with fat deposition around the neck, shoulder, back, or chest wall. Clinically, the patient is likely to exhibit alcohol, neuropathy, and metabolic disorders; however, no clear cause has been confirmed. AIMS: The aim of this study was to analyze the morphological, pathophysiological, and various treatment methods of MD. We have presented and discussed 16 cases of treatment of this disease at our hospital and reviewed the literature on this subject. METHODS: We carried out a retrospective chart review of 16 consecutive patients with MD treated from 1989 through 2017. Patient demographic data, tumor size and location, and follow-up data were evaluated. Patients usually seek treatment because of the disfigured appearance, restricted range of the motion of the head and neck, inconvenience in daily activity such as eating or speaking, and worry about the mass effect. All patients underwent surgical resection and/or combined liposuction. RESULTS: Among the patients, 14 were men, aged 38 to 80 years, with a history of disease ranging from 6 months to 7 years. The mean duration from symptoms to diagnosis of MD was 4.4 years. The mean duration of follow-up was 82.8 months (range, 5-192 months). Three patients died of coronary artery disease at follow-up of 27, 78, and 141 months. The functional results were satisfactory in all patients. Severe complications were not observed. CONCLUSIONS: According to our experience, surgical resection is the main method of improving the appearance, ensuring eradication of the tumor, and reducing the possibility of recurrence. In addition, we have a case in which atypical changes were confirmed by histological examination in fractional surgery. A long follow-up period is recommended considering the high propensity and mean time to recurrence. Although malignant transformation of MD is rare occurrence, it occurred in 1 of the 16 patients.

Madelungs disease - a case report.

INTRODUCTION: Madelungs disease is a rare illness manifested by the uncontrollable proliferation of unencapsulated adipose tissue which accumulates symmetrically in the hypodermis in the area of the neck, shoulders, back and thighs. As part of differential diagnosis it is necessary to investigate tumours in the area of the neck, dysfunction of the thyroid gland, Cushings syndrome and rare lipomatosis. CASE REPORT: In the case report, the authors present the case of a 52-year-old male patient with a large formation on the neck, trunk and the scrotal area. A suspicion of liposarcoma was expressed based on the imaging examinations performed. RESULTS: Excisions of tumorous loci on several occasions were indicated for the patient. Lipomas without abnormalities were proven in all histolo-gical examinations. CONCLUSION: The diagnosis of Madelungs disease is based on the clinical findings, imaging (computed tomography CT, magnetic resonance imaging MRI) and biopsy examination. Laboratory methods tend to focus rather on associated internal diseases. Treatment is only symptomatic and consists in surgical removal of the foci. However, it is often associated with the risk of recurrence.

Intraneural lipomas: institutional and literature review.

BACKGROUND: Adipose lesions of nerve can be envisioned as a spectrum ranging from intraneural/extraneural lipomas to lipomatosis of nerve (LN). We have noticed that intraneural lipomas are not as a homogenous group as previously thought and demonstrate differences which have clinical implications. To better understand intraneural lipomas, we conducted a search of cases at our institution and published cases in the world's literature. MATERIALS AND METHODS: Mayo Clinic's database was searched between years 1994-2018. Published cases were identified using PubMed and Google Scholar databases. Following terms were used: intraneural lipoma, lipoma and nerve, lipoma and neuropathy, lipofibroma and nerve, fibrolipoma and nerve and neural lipoma as well as lipofibroma and fibrolipoma alone. Cases that could be clearly identified as intraneural lipomas by the location of the lipoma within the epineurium were included for analysis. These cases were then sub-classified as encapsulated intraneural lipomas or hybrid intraneural lipomas (demonstrating features of both intraneural/extraneural lipomas and LN) based on their characteristics. RESULTS: We identified 12 cases at our institution (8 encapsulated, 4 hybrid) and 24 published cases (21 encapsulated, 3 hybrid). The most commonly affected nerve was median both at our institution and in the published cases. Encapsulated cases were found to be relatively easy to resect. Hybrid cases demonstrated variable degree of interdigitating fat between the fascicles and were relatively difficult to resect. CONCLUSION: Intraneural lipomas exist as two separate entities with distinct clinical implications. Although rare, this should be taken in account when planning surgery. Terminology should be clarified to prevent ambiguity and confusion.

Homozygous mutations in MFN2 cause multiple symmetric lipomatosis associated with neuropathy.

Multiple symmetric lipomatosis (MSL) is a mitochondrial disorder with impaired brown fat metabolism that has been associated with MERRF mutations in some, but not all, patients. We studied a sibling pair and an unrelated indiviadual who presented with MSL and neuropathy to determine the genetic etiology of this disorder in patients who did not carry the MSL-associated MERRF mutation. Whole-exome sequencing was performed on the siblings, and a rare, shared homozygous mutation in MFN2 (c.2119C>T: p.R707W) was identified. The mutation was not present in their healthy siblings. In silico programs predict it to be pathogenic, and heterozygous carriers of the MFN2 p.R707W substitution are known to have Charcot-Marie-Tooth (CMT) disease. A third, unrelated patient with multiple symmetrical lipomatosis and neuropathy also harbored the same homozygous mutation and had been previously diagnosed with CMT. Functional studies in patient fibroblasts demonstrate that the p.R707W substitution impairs homotypic (MFN2-MFN2) protein interactions required for normal activity and renders mitochondria prone to perinuclear aggregation. These findings show that homozygous mutations at p.R707W in MFN2 are a novel cause of multiple symmetrical lipomatosis.

Homozygous LIPE mutation in siblings with multiple symmetric lipomatosis, partial lipodystrophy, and myopathy.

Despite considerable progress in identifying causal genes for lipodystrophy syndromes, the molecular basis of some peculiar adipose tissue disorders remains obscure. In an Israeli-Arab pedigree with a novel autosomal recessive, multiple symmetric lipomatosis (MSL), partial lipodystrophy and myopathy, we conducted exome sequencing of two affected siblings to identify the disease-causing mutation. The 41-year-old female proband and her 36-year-old brother reported marked accumulation of subcutaneous fat in the face, neck, axillae, and trunk but loss of subcutaneous fat from the lower extremities and progressive distal symmetric myopathy during adulthood. They had increased serum creatine kinase levels, hypertriglyceridemia and low levels of high-density lipoprotein cholesterol. Exome sequencing identified a novel homozygous NC_000019.9:g.42906092C>A variant on chromosome 19, leading to a NM_005357.3:c.3103G>T nucleotide change in coding DNA and corresponding p.(Glu1035*) protein change in hormone sensitive lipase (LIPE) gene as the disease-causing variant. Sanger sequencing further confirmed the segregation of the mutation in the family. Hormone sensitive lipase is the predominant regulator of lipolysis from adipocytes, releasing free fatty acids from stored triglycerides. The homozygous null LIPE mutation could result in marked inhibition of lipolysis from some adipose tissue depots and thus may induce an extremely rare phenotype of MSL and partial lipodystrophy in adulthood associated with complications of insulin resistance, such as diabetes, hypertriglyceridemia and hepatic steatosis. © 2016 Wiley Periodicals, Inc.

Madelung Disease Affecting Scrotal Region.

Madelung disease is an uncommon disease characterized by large subcutaneous adipose masses. Mediterranean countries show higher disease incidence. We review the current concepts concerning this pathology, including etiology, diagnosis, and treatment. Madelung disease usually affects the upper half of the body, but we describe a patient with scrotal lipomas. As this location is rare, we review the cases found in literature, as well as the specific nuances regarding local symptoms and treatment.