Shedding Light on Multiple Symmetric Lipomatosis: An Overlooked Syndrome in the Evaluation of Obesity

Background

Unlike obesity, lipomatosis is a rare disease of the adipose tissue that has been seldom reported [1,2]. It is defined by the simultaneous presence of several adipose tissue tumors in the body and it can be distinguished from the classical lipodystrophic syndromes because of the absence of the lipoatrophic component [2]. Multiple forms of lipomatosis have been described, some isolated and others as part of systemic syndromes [2].

Multiple symmetric lipomatosis (MSL), also known as Launois-Bensaude syndrome or Madelung’s disease, is a form of isolated lipomatosis that is frequently misinterpreted as simple obesity [2,3], although both conditions may coexist [4]. The most common and classical form of this disease was first described by Benjamin Brodie in 1846 [5] and later by Otto Madelung in 1888 and corresponds to a symmetrical submental fat deposition, commonly known as “Madelung’s collar” [6,7]. Pierre Emile Launois and Raúl Bensaude were the first physicians to acknowledge the disease’s heterogeneity and to name it “symmetrical adenolipomatosis” in 1898 [1,8]. Unlike common obesity, where total body fat is well distributed, patients affected by MSL typically present with symmetrical, painless fat masses that predominantly appear in the face, neck, occipital region, and supraclavicular fossa [9]. These masses differ from common lipomas because they are nonencapsulated [9,10]. The disease is benign by nature and mostly causes an esthetic impact but there have been descriptions of serious complications due to compression of the upper aerodigestive tract by the lipomatous masses [1,9].

Launois-Bensaude syndrome’s etiology is still poorly understood but it is believed that the lipomatous fat deposits derive from a defect in brown adipose tissue (impaired lipolytic activity by catecholamines) [11]. An association with alcohol use has been documented [4,10,12] and disturbances in mitochondrial DNA have also been associated with the disease [13]. MSL is mostly sporadic but familial forms have also been reported, both with autosomal dominant and mitochondrial inheritance pattern [7]. It is considered a rare disease, with an estimated prevalence of 1: 25 000 individuals, and predominantly affects Caucasian males (male to female ratio ranging from 1: 15 to 1: 30) aged 30 to 60 years [3,7]. It is also more common in the Mediterranean region or in people with Mediterranean ancestry [3,7,11].

There are 2 main classification systems for Launois-Bensaude syndrome based on the anatomical distribution of the lipomatous masses [14,15]. The first system was created by Enzi et al and considers 2 types: Type 1 – neck, shoulders and supraclavicular region affected; Type 2 – abdomen and thighs affected (similar to obesity) [14]. The second system was developed by Donhauser et al and divides MSL into 4 types: Type I – horsecollar type; Type II – pseudo-athletic type; Type III – gynecoid type; Type IV – abdominal type [15]. Recently, a third and new classification system was proposed by Schiltz et al which grossly divides patients into those with lipomatosis in an upper body location (Type I, with 3 different subtypes), lower body location (Type II), or general location other than the head, forearms, and legs (Type III) [7].

This report is of a 49-year-old woman who was identified as obese due to Launois-Bensaude syndrome.

Case Report

A 49-year-old woman was referred to our department due to obesity. She had a history of essential arterial hypertension for which she was chronically medicated with an angiotensin-converting enzyme inhibitor and a beta-blocker. The patient reported no other known health conditions, including sleep apnea.

She worked as a housewife and helped her husband with their farming and winery local business. She did not smoke but she reported drinking alcohol on a regular basis due to her occupation – at least 2 glasses of wine per day since she was 30 years old. The patient denied excessive consumption of sugary foods, fruits or fatty foods.

She had 2 sons. Her menses had spontaneously stopped by the age of 43 (early menopause of unknown etiology) and she complained of weight gain since then – before that age, she reported not having excess weight. The patient had tried to lose weight by herself many times through dietary changes but was unsuccessful. She reported maintaining a low-calorie dietary pattern but she admitted not exercising regularly.

At the first consultation in our department, she weighed 85 kg and had a body mass index of 39.8 kg/m2 (class II obesity). On the physical examination, she had no signs of hirsutism nor stigmata of endocrine disease, namely suggesting Cushing syndrome. However, when the patient got undressed, we noticed an unusual pattern of fat distribution – she had exuberant symmetrical fat masses that were localized in her arms and thighs and spared her face, neck, forearms and lower legs (Figure 1).

Upon inquiry, the patient reported that those masses had been growing for approximately the last 5 years, with a rapid progression at first which then evolved into slow progression/stabilization. They were painless and had a soft consistency, compatible with adipose tissue. She reported having no known family members with a similar phenotype.

The patient firstly underwent a general blood workup and abdominal ultrasound. Her blood tests showed a high uric acid level of 6.1 mg/dL, with a reference range (RR) of 2.4–5.7 mg/dL, impaired fasting glucose (106 mg/dL), high HDL-cholesterol of 85 mg/dL (RR: 45–65 mg/dL) with adequate levels of triglycerides (138 mg/dL) and LDL-cholesterol (94 mg/dL), normal thyroid stimulating hormone (2.96 μUI/mL, RR: 0.30–3.94 μUI/mL), normal kidney function, high gamma-glutamyl transpeptidase (GGT) (150 U/L, RR: 6–29 U/L) with normal bilirubin and transaminase levels, and high ferritin (438 ng/mL, RR: 2.20–1.78 ng/ mL). Her abdominal ultrasound was conclusive for liver steatosis with no other relevant findings.

Afterwards, to better characterize the nature and the distribution of the fat masses, we asked for a whole body computed tomography (CT). The CT scan confirmed the presence of lipomatous masses in the posterior region of the arms and thighs and excluded other synchronous fat masses, namely near the mediastinum or the aerodigestive tract.

Due to evidence of pre-diabetes, she was started on metformin and due to the indirect signs of alcohol abuse (high GGT, HDL-cholesterol, and ferritin), she was advised to reduce alcohol intake.

Through the physical examination and CT scan, we concluded that our patient did not have simple obesity but Launois-Bensaude syndrome instead. The patient was referred to plastic surgery consultation for excision of the lipomatous masses.

Discussion

Our patient’s condition encompasses more than just simple obesity; it involves a distinct form of adiposopathy, MSL, that led to a completely different clinical approach. Launois-Bensaude syndrome, or MSL, is a rare disease that clinicians who treat obesity need to be aware of [16]. The most common types affect the face, cervical, and supraclavicular region and are easier to distinguish from simple obesity [9]. However, when MSL affects the lower body or has a more generalized distribution like in our clinical case, this distinction can be rather challenging [7]. The physical examination seems to be the key for clinical suspicion [10] and it is very important to examine the patient undressed. Laboratory workups and body imaging techniques (mostly CT or MRI) can support the diagnosis [3,10], as happened with our case. Definitive diagnosis can only be made by tissue biopsy [3], although this exam is frequently deemed unnecessary due to the strong correlation of the findings on physical examination and imaging techniques with the diagnosis [13]. Differential diagnosis can, however, be quite difficult since it is mainly clinical [10].

Besides simple obesity, other relevant differential diagnoses to consider are lipomas (encapsulated fat masses), lipodystrophy syndromes, Cushing syndrome, neurofibromatosis, lymphoma, and Frölich syndrome [1,2,11,17]. Despite the evident sparing of certain body regions in our patient, like the forearms and lower legs, she did not present a lipoatrophic component and did not have evidence of hypertriglyceridemia or marked insulin resistance, which we would expect to find in lipodystrophy syndromes [16].

Our patient had the typical manifestation of Launois-Bensaude syndrome: painless fat masses with a symmetrical distribution and a fast onset. Although she is a woman, which is not so typical, she fit the characteristic age range, she is from the Mediterranean region (Portugal), and there was a history of regular alcohol use (consistent with the European definition of excessive alcohol drinking for women: more than 2 units a day [18]). Furthermore, the patient was diagnosed with a glucose metabolism anomaly, hyperuricemia, and high levels of HDL-cholesterol, which have been commonly associated with Launois-Bensaude syndrome [2,3,7,16]. Other common associations with this syndrome that our patient did not present are primary hypothyroidism, renal tubular acidosis, and peripheral neuropathy [2,16]. According to Li et al, obesity may coexist with Launois-Bensaude syndrome in up to 16% of cases [4].

As for the classification, our patient seems to have an atypical distribution of the lipomatous masses that may fit MSL type 2 according to the Enzi et al classification, but does not seem to fully fit any of the categories proposed by Donhauser et al Interestingly, it seems to perfectly fit the Type III of the most recently proposed classification system by Schiltz et al – MSL with a general distribution except for the head, forearms, and lower legs [7]. This newer classification system is more complex than the previous ones since it includes 5 different types of MSL, but it also seems to be more precise and to better reflect this syndrome’s phenotypical heterogeneity.

We referred our patient to plastic surgery consultation, hoping that a surgical debulking of the lipomatous masses would help with the syndrome’s esthetic impact, which was cumbersome for her everyday life. However, the overall recurrence rate is quite high, happening in more than half of MSL patients [11,13,14]. Treatment with b2-agonists [19] and intralesional heparin [20] have been tried in some cases but the results were not consistent nor satisfactory, and thus surgery is the only approved treatment option so far [1,11,17]. We also recommended alcohol cessation and weight loss through diet and exercise but these interventions have not been shown to be associated with regression of lipomatosis [1,16,17].

Conclusions

Launois-Bensaude syndrome can easily be interpreted as common obesity. A detailed physical examination seems to be the key for clinical suspicion of this rare syndrome, which can be a true pitfall in obesity evaluation. Surgical debulking may be the only treatment to reduce the lipomatous masses. It is also important to incorporate the standard treatment measures for common obesity, such as adopting a balanced diet and a regular exercise routine.