Madelung's Disease - Symptoms, Causes, Treatment | NORD (2024)

Disease Overview

Summary

Madelung’s disease is a rare disorder of fat metabolism (lipid storage) that results in an unusual accumulation of subcutaneous fat (adipose tissue) deposits around the neck, shoulders, trunk, hips, upper arms and thighs. The fat masses can progress quickly over months or slowly over years. Face and legs are usually spared in this benign condition, and biochemical parameters can also remain within normal limits. Madelung’s disease can be mistaken for obesity due to the symmetrical deposition of fat. Although painless, the fatty tumors can affect the function of other structures in the affected area causing patients to have symptoms such as difficulty swallowing, speaking and breathing.

Adult males between ages 30-70 with a history of excessive drinking (chronic alcoholism) are most often affected, although females and people who do not drink alcohol can also get Madelung’s disease. This condition is more common in Mediterranean and European populations, and less frequent in Asian populations. The underlying causes of this condition aren’t fully understood, which can lead to limitations in treatment options. Scientists have suggested that a dysregulation in the fat breakdown (lipolytic) pathway could be the cause of the excessive growth and division of fat cells (adipocytes). Familial cases with an autosomal dominant inheritance pattern have also been noted. Currently, surgical removal of the fatty tumors through resection (lipectomy) or liposuction is the primary treatment. Unfortunately, the effectiveness of current treatment options is limited as the disease has a high tendency to reoccur.

Introduction

Madelung’s disease was first described by Benjamin Brodie in 1846, and then later as ‘fat neck’ (Fetthals) by Otto Madelung in 1888.

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Synonyms

• benign symmetrical lipomatosis (BSL)
• cephalothoracic lipodystrophy
• launois-bensaude syndrome
• multiple symmetric lipomatosis (MSL)

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Signs & Symptoms

Madelung’s disease is characterized by the presence of fatty tumors (lipomas) located symmetrically around the neck, shoulders, trunk, hips, upper arms and thighs. While these abnormal fatty tumors may grow over the course of months to years, the disease usually has a rapid progression at first and then slows down as the size of the fatty mass stabilizes. The rest of the body may be lean in contrast to the affected parts.

In 1984, Enzi classified two types of Madelung’s disease – type 1 and 2 – based on where the excess fat accumulated. The more frequent type 1 is common in males and manifests as fatty tumors primarily around the neck (known as ‘Madelung’s collar’) and upper shoulders with relative sparing of the trunk and arms. As a result, type 1 patients have a ‘pseudo-athletic’ appearance. In contrast, type 2 is observed in both males and females equally and resembles ‘generalized obesity’ as the fatty deposition occurs in the trunk, upper portion of arms, abdomen, hips and upper thighs. In 1991, type 3 (gynecoid type) was added to the classification and is characterized by fat accumulation primarily in the pelvic region.

Peripheral neuropathy, or impaired function of the nerves in the arms and legs, often accompanies Madelung’s disease, especially as the affected person grows older. However, these neurological deficits may be difficult to distinguish from the long-term effects of alcoholism when overuse of alcohol is a factor. Nevertheless, peripheral neuropathy may lead to decreased power in the muscles of the upper (proximal) portion of the arms and legs (myopathy). Symptoms can also arise from the fatty masses compressing important structures in the neck such as the airway (trachea), voice box (larynx), esophagus and carotid blood vessels. Depending on the severity of the disease, the fatty tumors may cause patients to have trouble breathing (dyspnea), swallowing (dysphagia) and speaking (dysphonia). The patient can present with limited mobility of the neck and may even develop sleep apnea as the disease progresses. It is important to note that the physical changes in a patient’s body resulting from the excessive fatty deposition can take a toll on the patient’s mental health and lead to depression. Social loss and difficulty performing or maintaining a job due to impaired mobility and other issues have been reported in patients.

There are metabolic abnormalities and other conditions usually associated with Madelung’s disease. These include diabetes mellitus, hypertension and liver disease. Most patients (~90%) diagnosed with Madelung’s disease have secondary (alcohol-induced) liver cirrhosis. Although rare, some patients have had malignant transformation and association of the disease with airway and digestive tract cancers.

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Causes

The exact cause of Madelung’s disease is not fully understood. The body’s inability to properly metabolize fat indicates that it may be an endocrine disorder. One theory is that a defect in the adrenergic (epinephrine or norepinephrine)-stimulated fat breakdown (lipolysis) process results in improper deposition of fat. Alcohol can also negatively impact the enzymatic processes in mitochondria (energy-supplying part of the cell) and can alter adrenergic lipolysis in the body. Radial red fibers in the muscles of Madelung’s patients have often been found, indicating a sign of impaired mitochondrial respiratory chain function. Some researchers have noted that the distribution and type of fat cells in the fatty tumors is similar to the brown fat found in infants. Linking this to the theory, one study suggested that the fatty tumors formed in Madelung’s disease result from impaired mitochondrial regulation in the brown fat, causing increased division of fat cells (adipocyte hyperplasia). While current research suggests adrenergic pathways and mitochondrial dysfunction to be implicated in Madelung’s disease, a clear picture of the pathogenesis is yet to be determined.

Most cases of Madelung’s disease are sporadic, but a few have been shown to run in families. Familial cases may be autosomal dominant and caused by variants in the MFN2 or LIPE genes while other cases are related to a rare mitochondrial gene variant called MTTT c.8344A>G.

Dominant genetic disorders occur when only a single copy of adisease-causing gene variantis necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.

Mitochondria are the cell structures that carry the body’s instructions for regulating energy production. Genes for mitochondria (mtDNA) are inherited from the mother. This is because the mtDNA in sperm cells is usually lost during fertilization. A mother with a gene variant in mtDNA will pass thevariant to all her children, and her daughters will pass thevariant to their children.

Normal mitochondrial genes and gene variants can exist in the same cell, a situation known as heteroplasmy. The number of mitochondria with thegene variant may be outnumbered by the number of mitochondria with a normal gene. Symptoms may not appear until a significant proportion of mitochondria havemtDNA with the gene variant. The uneven distribution of normal genes and gene variants in mtDNA in different tissues can affect different organs in members of the same family. This can result in a variety of different symptoms in affected family members.

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Affected populations

Madelung’s disease most frequently affects males between 30-70 years of age. The condition is most common in people who consume excessive amounts of alcohol (especially red wine), for a long period of time. However, this disease has also been diagnosed in females and persons who do not consume alcohol. For reasons that are unclear, the disorder appears to be more prevalent in Mediterranean and European population as compared to North American and Asian population.

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Disorders with Similar Symptoms

The differential diagnosis for Madelung’s disease includes lipomas, liposarcoma, lymphatic tumor, sialadenitis, neurofibromatosis, drug-induced lipomatosis (steroidal and antiretroviral drugs), angiolipoma and hibernoma. Some of these diseases are briefly described below:

Lipomas
Lipomas are single, painless lumps that most often appear in older females. Varying in size from a dime to a quarter, they are composed of fatty tissue and are slow growing, soft and movable.

Liposarcoma
Liposarcoma is a rare tumor derived from fat tissue that occurs in the “soft tissues” of the body (soft tissue sarcoma). It is classified as a cancer (malignancy) because of its potential to recur locally and spread to other areas of the body. It can arise in various locations throughout the body, although it is most frequently found in the extremities, particularly in the thighs. Some individuals with liposarcoma may not have symptoms in the early stages, but as the tumor grows and advances to later stages, it can potentially compress other tissues and cause pain. It is more common in middle-aged males from 50-65 years of age compared to females and is very rare in children. (For more information on this disorder, choose “Liposarcoma” as your search term in the Rare Disease Database)

Lymphatic Tumor
A lymphatic tumor is also called a lymphoma. It is a cancer involving cells of the lymphatic system. Hodgkin’s disease is the most common lymphoma in the general population. Among children, however, several other types of lymphoma classified together as non-Hodgkin’s lymphoma are more likely to occur. Unlike Hodgkin’s disease, non-Hodgkin’s lymphoma can run in families. Boys are affected more often than girls. Fortunately, this kind of lymphoma is highly treatable, and the cure rate is excellent, particularly if the illness is detected early. There are three major types of non-Hodgkin’s lymphoma, classified based on the type of lymphatic cell (lymphocyte) involved and the organs affected at the time of diagnosis. (For more information on this disorder, choose “Hodgkin’s Disease” as your search term in the Rare Disease Database)

Sialadenitis
Madelung’s disease is sometimes misdiagnosed as sialadenitis, an inflammation of the salivary glands, the glands that secrete saliva into the mouth. The inflammation may involve any of the glands that make up the salivary gland system (parotid, submandibular and sublingual glands). There are both acute and chronic forms. Sialadenitis is often associated with pain, tenderness, redness and gradual, localized swelling of the affected area. (For more information on this disorder, choose “Sialadenitis” as your search term in the Rare Disease Database)

Hibernoma
Hibernoma is a rare benign tumor that arises from the remaining parts of fetal brown adipose tissue. It is a slow growing tumor that can look like a malignancy clinically and on MRI. It occurs generally in the thigh but can also occur in the neck. There is a slight female predominance and patients are generally 40-50 years old. If large enough, hibernomas can compress vital structures in the body. Current treatment includes a complete excision of the tumor. As hibernomas have extensive vascularity, care should be taken during surgery to avoid post-operative bleeding.

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Diagnosis

The diagnosis of Madelung’s disease is based on a good clinical history, careful assessment of the appearance of the patient and imaging tests such as ultrasound, computerized tomography (CT)-scan or magnetic resonance imaging (MRI). Imaging tests can allow physicians to recognize the extent of fat deposition in the affected areas, appreciate compression of deeper structures and assess the presence of blood vessels in the fatty tumors. Imaging tests can also help rule out other diagnoses and provide insight for pre-operative surgical planning. Most patients come in with a complaint about their appearance due to the cosmetic deformity associated with Madelung’s disease. The diagnosis can be challenging in cases where the patient is obese from other factors (sedentary lifestyle, poor diet, etc.).

Clinical Testing and Work-Up

Clinical work-up involves physical examination and imaging of the affected area using ultrasound/sonography, CT-scan or MRI. A procedure known as fine needle aspiration (FNA) may be performed, involving insertion of a needle into the swelling, and obtaining a small sample of the tissue to be analyzed by pathology for fatty (lipomatous) lesion. FNA procedure may also help distinguish between benign and malignant forms of disease.

Nerve conduction and muscle function studies (electromyography) might be done to assess the degree of accompanying peripheral neuropathy for some patients.

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Standard Therapies

Treatment

Treatment usually consists of surgical removal of the fatty deposits from the affected areas. Treatment options include surgical resection of fatty tumor(s), liposuction or injection lipolysis. Surgical interventions may be complicated by the high number of blood vessels supplying the fatty tumor, as well as fat invasion into nearby tissues and deeper structures. Ultrasound-assisted liposuction has been used successfully to remove single fatty tumors.

The fat deposits never undergo spontaneous degeneration and can reoccur even after surgical removal. Therefore, frequent follow-ups are required after treatment. Fibrosis and adhesions can form after lipolysis injection and may interfere with subsequent surgical or liposuction treatment if the disease were to reoccur in the same area.

Unfortunately, drug therapy has not been highly effective in the treatment of Madelung’s disease thus far. The effectiveness of salbutamol in helping fat breakdown through beta-adrenergic receptor stimulation is being tested as a potential therapeutic agent, but results have been inconsistent.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email:prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact: http://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES
Cui Y, Cui X, Gao S, et al. Multiple symmetric lipomatosis with secondary laryngeal obstruction: A case report. Medicine (Baltimore). 2020;99(27):e21014.

Prahlow SP, Kosciuk P, Prahlow JA. Multiple symmetric lipomatosis. J Forensic Sci. 2018;63(1):312-315.

Szewc M, Sitarz R, Moroz N, et al. Madelung’s disease – progressive, excessive, and symmetrical deposition of adipose tissue in the subcutaneous layer: case report and literature review. Diabetes Metab Syndr Obes. 2018;11:819-825.

El Ouahabi H, Doubi S, Lahlou K, et al. Launois-bensaude syndrome: a benign symmetric lipomatosis without alcohol association. Ann Afr Med. 2017;16(1):33–34.

Wollina U, Heinig B. Madelung’s disease – case series and treatment by tumescent liposuction or lipectomy. Open Access Maced J Med Sci. 2017;5(4):427–431.

Zolotov S, Xing C, Mahamid R, et al. hom*ozygous lipe mutation in siblings with multiple symmetric lipomatosis, partial lipodystrophy, and myopathy. Am J Med Genet A. 2017;173(1):190–194.

Nisi G, Sisti A. Images in clinical medicine. Madelung’s disease. N Engl J Med. 2016;374(6):572.

Zielińska-Kaźmierska B, Lewicki M, Manowska B. Madelung disease. Postepy Dermatol Alergol. 2015;32(5):400-403.

Jang JH, Lee A, Han SA, et al. Multiple symmetric lipomatosis (madelung’s disease) presenting as bilateral huge gynecomastia. J Breast Cancer. 2014;17(4):397–400.

Ardeleanu V, Chicos S, Georgescu C, et al. Multiple benign symmetric lipomatosis – a differential diagnosis of obesity. Chirurgia. 2013;108(4):580–583.

Plummer C, Spring PJ, Marotta R, et al. Multiple symmetrical lipomatosis – a mitochondrial disorder of brown fat. Mitochondrion. 2013;13(4):269–276.

Yeh NC, Yang CY, Chou CW, et al. Madelung’s disease. J Clin Endocrinol Metab. 2012;97(9):3012–3013.

Medappil N, Vasu TA. Madelung’s disease: a spot diagnosis. Indian J Plast Surg. 2010;43(2):227-228.

Alameda YA, Torres L, Perez-Mitchell C, et al. Madelung disease: a clinical diagnosis. Otolaryngol Head Neck Surg. 2009;141(3):418-419.

Suresh Chandran CJ, Godge YR, et al. Madelung’s disease with myopathy. Ann Indian Acad Neurol. 2009;12(2):131-132.

Heike Z, Gudrun UM, Frank RD, et al. Multiple benign symmetric lipomatosis – a differential diagnosis of obesity: is there a rationale for fibrate treatment?. Obes Surg. 2008;18(2):240-242.

Colella G, Giudice A, Moscariello A. A case of Madelung’s disease. J Oral Maxillofac Surg. 2005;63(7):1044-1047.

Dabrowska A, Tarnowska C, Jałowinski R, et al. Tłszczakowatość uogólniona w otolaryngologii-jako problem diagnostyczny i terapeutyczny [Multiple symmetric lipomatosis in the otolaryngology as diagnostic and therapeutic problem]. Otolaryngol Pol. 2005;59(5):717-722.

Gonzalez-Garcia R, Rodriguez-Campos FJ, Sastre-Perez J, et al. Benign symmetric lipomatosis (madelung’s disease): case reports and current management. Aesthetic Plast Surg. 2004 May 28 [Epub ahead of print].

Busetto L, Strater D, Enzi G, et al. Differential clinical expression of multiple symmetric lipomatosis in men and women. Int J Obes Relat Metab Disord. 2003;27:1419-22.

Morelli F, De Benedetto A, Toto P, et al. Alcoholism as a trigger of multiple symmetric lipomatosis? J Eur Acad Dermatol Venereol. 2003;17:367-69.

Verhelle NA, Nizet JL, Van den Hof B, et al. Liposuction in benign symmetric lipomatosis: sense or senseless? Aesthetic Plast Surg. 2003;27:319-21.

fa*ga A, Valdatta LA, Thione A, et al. Ultrasound assisted liposuction for the palliative treatment of Madelung’s disease: a case report. Aesthetic Plast Surg. 2001;25(3):181-183.

Ujpal M, Nemeth ZS, Reichwein A, et al. Long-term results following surgical treatment of benign symmetric lipomatosis (BSL). Int J Oral Maxillofac Surg. 2001;30:479-83.

Enzi G, Busetto L, Ceschin E, et al. Multiple symmetric lipomatosis: clinical aspects and outcomes in a long-term longitudinal study. Int J Obes Relat Metab Disord. 2002;26:253-61.

Guastella C, Borsi C, Gibelli S, et al. Madelung’s lipomatosis associated with head and neck malignant neoplasia: a study of 2 cases. Otolaryngol Head Neck Surg. 2002;126(2):191-192.

Donhauser G, Vieluf D, Ruzicka T, et al. Benigne symmetrische Lipomatose Launois-Bensaude Typ III und Bureau-Barrière-Syndrom [Benign symmetric Launois-Bensaude type III lipomatosis and Bureau-Barrière syndrome]. Hautarzt. 1991;42(5):311-314.

Enzi G. Multiple symmetric lipomatosis: an updated clinical report. Medicine (Baltimore). 1984;63(1):56-64.

INTERNET
Multiple Symmetric Lipomatosis. Orphanet. Last update: October 2019.https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2398. Accessed Feb 28, 2024.

Lipomatosis, Familial Benign Cervical .Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Entry Number; 151800: Updated 06/02/2023.https://www.omim.org/entry/151800 Accessed Feb 28, 2024.

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