gms | German Medical Science

Madelung’s disease (MD), a rare disorder of adipose tissue, is characterized by multiple, symmetrical, non-encapsulated adipose tissue deposition in typical locations [1]. MD is also known as benign symmetrical lipomatosis or Launois-Bensaude syndrome [1] and was first described by Benjamin Brodie in 1846 [2]. In 1888, Madelung published a series of patients with symmetrical fat deposition in the submental triangle [3], while 10 years later, in 1898, Launois and Bensaude published another series of cases with similar findings [4].

MD mainly affects middle-aged males (male/female ratio 15:1) of Mediterranean and Eastern European origin [1], whereas few cases from Asia are reported as well [5]. Interestingly, it has been suggested that the silhouette of an ancient Roman statue, the Capestrano Warrior, which dates back to 6^th century BC, mimics the fat distribution in MD [6]. This fact may indicate an inherited tendency in the Mediterranean region [6]. The incidence rate of the disease has been estimated as 1:25,000 men in the Italian population in 1984 [7], while the prevalence in the area of Bavaria in Germany was calculated as 1:24,274 people [8]. To the best of our knowledge, over 300 cases are described in the medical literature to date [9], [10], 106 of which were reported in a review published in 2018 [11]. The review included cases from 2000 to 2015 [11]. However, the exact number could be even higher as many undiagnosed cases may exist and therefore are not reported [1], [8].

The implicating pathogenetic mechanisms are still not well understood [1]. Although the relationship between MD and chronic alcohol consumption, especially red wine, is well known [12], cases without alcohol abuse have been described [13], [14]. It is generally believed that alcohol abuse impairs adrenergic lipolysis, leading to uncontrolled fat deposition in different areas of the body [1]. Moreover, a hypothesis that proliferation and differentiation of brown fat tissue has a key role in the pathogenesis of MD has been recently suggested [12]. Besides, mitochondrial dysfunction resulting from mutations of mitochondrial DNA has also been proposed as a trigger mechanism [15], [16].

The diagnosis of MD is based on medical history and the characteristic clinical presentation [8]. Imaging examination, such as ultrasound and magnetic resonance imaging, may be helpful; biopsy of the affected areas reveals the presence of non-encapsulated adipose tissue [1]. Herein, we present a case of a 70-year-old man with Madelung’s disease, who had recurrent fat depositions and a profound “pseudoathletic” phenotype reminiscent of anabolic steroid use.

A 70-year-old male patient was referred to the outpatient clinic for evaluation due to a 20-year history of recurrent lipomatous formations. During this 20-year period, he had undergone multiple surgical procedures but found no long-term relief. His past medical and family history were unremarkable, other than a 30-year long history of alcohol consumption. On physical examination, his body mass index was 27.3 kg/m² and he had a symmetrical enlargement of the superior part of the trunk, including the neck, shoulder girdle, upper arms, chest and upper back, giving the patient a “pseudoathletic appearance” (Figure 1 [Fig. 1]). The lesions were soft and painless. Both testes were normal. He denied having other symptoms such as dysphagia, hoarseness, muscle weakness, decreased libido, or erectile dysfunction. Biochemistry analysis including liver function tests, lipid profile and renal function was normal. Moreover, endocrine workup (prolactin, luteinizing hormone, follicle-stimulating hormone, estradiol, testosterone, dehydroepiandrosterone sulfate, insulin-like growth factor-I, 17α-hydroxyprogesterone, cortisol, haemoglobin A1c, thyroid functions tests and autoantibodies, thyroglobulin, calcitonin) and testing for hepatitis and HIV, was also unrevealing. Finally, previous pathology results revealed benign lipomas and the diagnosis of Madelung’s disease was made.

Madelung’s disease (MD), a rare disorder of adipose tissue, is characterized by multiple, symmetrical, non-encapsulated adipose tissue deposition in typical locations, such as the cervical area, shoulders, upper trunk, upper arms, the abdomen, hips and thighs. Enzi distinguishes two types of the disease:

1.

deposits in the area of the neck (Madelung’s collar), shoulders, supraclavicular triangle, and proximal upper limbs giving a “pseudoathletic appearance” and

2.

deposits in the thighs and abdomen, resembling generalized obesity [7], [12].

According to Enzi’s classification system, our patient has type 1 of MD. Another classification system, developed by Donhauser et al. in 1991, categorizes patients in 3 types. Type 1 involves cases with fat distribution in the area of the neck (horsecollar), type 2 in the upper trunk and arms (pseudoathletic phenotype), and type 3 in the thighs (gynecoid type) [17], [18]. Clinical overlap between the aforementioned types may be present [18]. Recently, a novel classification based on a cohort from Germany has been proposed [8]. This comprehensive classification system divides patients with Madelung’s disease into five subtypes (Ia, Ib, Ic, II, and III). More specifically, patients with multiple lipomas in the upper body are described as type I, those with lower body involvement (thighs and legs) as type II. Type I is further subdivided in Ia (lipomas in the area of the neck), Ib (neck, shoulders and arms) and Ic (neck, shoulders, arms and trunk). If fat deposition is generalized, the patient is considered as type III [8]. Therefore, based on Donhauser’s system, our patient is type II MD while type Ic MD, if the more recent classification system is applied.

In addition, the symmetrical fat distribution in this case was quite remarkable and profound; the clinical phenotype was reminiscent of anabolic steroid use as the areas of the upper trunk and arms were involved. Anabolic steroids are in demand among athletes and bodybuilders, leading to muscle hypertrophy, proliferation and strength increase [19]. This characteristic “pseudoathletic” or “bodybuilder’s” phenotype in combination with history (Mediterranean origin and chronic alcohol abuse) and histopathological examination facilitated the diagnosis of MD.

MD is also widely known as benign symmetrical lipomatosis [1]. However, MD is not always a “benign” disorder since associated complications and comorbidities may have a negative impact on prognosis [20], [21], [22]. Patients often present features of metabolic syndrome, such as diabetes mellitus, hyperuricemia and dyslipidemia, while other cases are related to secondary liver cirrhosis, peripheral (motor or sensory) and autonomy neuropathy [1], [21], [22], [23], [24]. Neuropathy, one of the most frequent chief complaints (85% of the cases) and possibly attributed to chronic alcohol abuse, is linked with increased cardiovascular morbidity and mortality [21], [24], [25]. Hypothyroidism, chronic obstructive pulmonary disease and adrenal dysfunction are also related to MD, whereas fat depositions may occur in HIV positive patients under treatment with protease inhibitors [1], [23], [24]. Furthermore, in some cases, symptoms of compression, such as hoarseness or dysphagia, may be present due to deep infiltration in the larynx and mediastinum [1], [21], [23]. On rare occasions, malignant transformation to intramyxoid sarcoma, liposarcoma and squamous cell carcinoma has also been reported [26], [27], [28]. Notably, despite the 30-year-alcohol consumption history, our patient did not show any sign of alcohol-induced liver disease or polyneuropathy. Also he did not develop any other MD related condition or complication.

The pathogenetic background of the disease has not been fully elucidated and several hypotheses have been developed. In this case, chronic alcohol intake is believed to be the inducing factor for developing MD, as the association between alcohol and impairment of adrenergic lipolysis is well known [1]. Furthermore, most MD cases, as ours, are sporadic, but some familiar cases, inherited in an autosomal dominant manner, are reported [29]. In familiar cases, mutations in mitochondrial DNA, which have maternal origin, have been identified [15], [16], [29].

Due to the existing knowledge gap regarding the etiology of the disease, any therapeutic intervention is characterized as palliative [1]. To date, surgical resection and liposuction are the only effective therapeutic approaches, yet with high recurrence rates, as complete resection is almost impossible [1], [11]. In fact, the risk of recurrence in lipectomy has been calculated at two-thirds of the cases, while at 95% in liposuction [1]. According to a recent systematic review of case series, liposuction was associated with better aesthetic results and higher recurrence risk, whereas patients subjected to lipectomy were more likely to suffer from post-surgical complications such as infection and hemorrhage [11]. The reported recurrence rates were lower compared to the study by Szewc et al. (5 out of 95 patients (5.3%) who had undergone lipectomy; 1 out of 18 (5.6%) who had undergone liposuction and 1 out of 11 (9%) who had undergone both lipectomy and liposuction). The latter, though, might be an underestimation of the real risk, taking into account the limitations of the study. Firstly, on some occasions, patients’ records were incomplete [11]. More importantly, follow-up duration was different in each case, ranging from one week to more than thirty years [11]. In view of the aforementioned complications, the indication for surgical intervention in Madelung’s disease should be taken with care and frequently will be seen in severe cases of compression related symptoms, such as trachea or pharynx obstruction. However, cosmetic deformity can also be seen as an indication for surgery in cases in which the patient presents with a certain level of suffering from the disease [1], [30].

Pre-, peri- and postoperative strategy in cases with MD is of cardinal importance [30], [31], [32]. Endotracheal intubation due to neck immobility or presence of macroglossia may be strenuous even for experienced anesthesiologists [31]. Moreover, the risk of postoperative bleeding or hematoma should be taken into account and patients should be monitored for indicative signs or symptoms [30]. Additionally, potential respiratory depression as a consequence of oversedation should also be considered in these cases [31]. Therefore, different interventions during airway management may be warranted [30], [31], [32]. For instance, awake fiberoptic intubation or awake videolaryngoscopy could be two effective alternatives, when general anesthesia is implemented [30], [31], [32].

Unfortunately, effective pharmacological agents are not available. Apart from surgical therapy, recommendation for alcohol abstinence and lifestyle modifications should also be examined [1], [30]. In our case, the patient was referred to the Plastic Surgery Department, where long-term follow-up was recommended as no symptoms of compression were present.

In conclusion, establishing the diagnosis of MD can be challenging, since clinicians may be unaware of this condition. The presence of comorbidities should be taken into consideration during management of these patients. Surgical resection and liposuction, the only effective therapeutic approaches, are recognized as palliative treatment due to the lack of efficient pharmacological agents. Future research should focus on the pathophysiology making more treatment options available.

The authors declare that they have no competing interests.

All authors cared for the patient and contributed equally to the preparation of the manuscript. All authors approved the final manuscript.

The patient provided written informed consent for publication of this case.