Juvenile Dermatomyositis Overlapping with Madelung Disease

Introduction

Dermatomyositis (DM) belongs to the heterogeneous group of idiopathic inflammatory myopathies [1]. It most commonly presents with progressive, symmetric, proximal muscle weakness, along with a group of characteristic cutaneous findings [1, 2]. Interstitial lung disease, constitutional signs and symptoms, dysphagia, and inflammatory arthritis may also be present with varying frequency in different serologic subsets defined by myositis-specific autoantibodies in dermatomyositis patients [1]. Additionally, there is an increased risk of underlying malignancy in these patients [1]. Juvenile DM is a systemic immune mediated vasculopathy, increasingly recognised as a group of distinct phenotypes with variable presentation and outlook [3].
Madelung disease, also known as Launois-Bensaude syndrome or multiple symmetrical lipomatosis, is a rare metabolic disorder characterized by symmetrical, non-encapsulated adipose tissue deposits [4–6]. In most cases, Madelung disease is an acquired condition; however, in very rare cases, it may be associated with MFN2 pathogenic variants [7]. The fat deposits typically involve the face, neck, and occipital region but can also extend to the shoulders, upper arms, pelvis, back, and thighs [4–6]. The adipose tissue can infiltrate deeper structures, including vessels, nerves, and muscles, leading to compression of internal organs such as the larynx, trachea, and esophagus [4]. According to Enzi et al., there are two types of the disease based on the localization of the fat tissue [8]. Type I is characterized by lipomas distributed in the nape of the neck, the supraclavicular, and deltoid regions (commonly referred to as Madelung’s collar) [8]. In contrast, type II lipomatosis involves extensive diffusion of fat tissue into the subcutaneous fat layer, giving the patient the appearance of simple obesity [8].
Data regarding the overlap of autoimmune diseases with Madelung disease are scarce [9]. To the best of our knowledge, this is the first reported case of a patient with a 35-year history of juvenile DM coexisting with Madelung disease.

Objective

The aim of the study was to present the case of dermatomyositis overlapping with Madelung disease and the concomitant diagnostic difficulties due to partial clinical and laboratory similarities.

Case report

A 42-year-old Caucasian woman, an abstainer from alcohol, was diagnosed with dermatomyositis at the age of 7. Her treatment included systemic glucocorticoids, up to 8 mg daily of methylprednisolone, except exacerbations of dermatomyositis when higher doses were administered. Additionally, she received azathioprine and intravenous immunoglobulins during juvenile DM exacerbations. The diagnosis was based on muscle weakness, characteristic skin changes (heliotrope rash on the upper eyelid, Gottron’s sign on the upper surface of the fingers and elbows) and laboratory findings indicating rhabdomyolysis. Further tests performed recently revealed the presence of positive antinuclear antibodies (ANA), specifically identified as PM-Scl 100 antibodies. The patient did not show any clinical signs of systemic sclerosis or scleromyositis, nor were such signs evident in imaging or laboratory tests. She was admitted to the Department of Clinical Immunology at the University Hospital in Krakow with a 2-day history of epigastric pain and vomiting. Over the years, she experienced numerous side effects from systemic steroid therapy, including cataracts, osteoporosis, diabetes mellitus, polyneuropathy, adrenal cortex insufficiency, arterial hypertension, pericardial effusion, hyperlipidaemia, and a left kidney tumour. Since 2014, she has undergone several abdominal surgeries, including appendectomy, abdominal abscess drainage, sigmoid colon resection with Hartmann’s procedure, segmental resection of the small and large intestine, and partial resection of the greater omentum.
Physical examination revealed muscle weakness, exophthalmos, orbital oedema, enlarged parotid and submandibular glands, increased neck and waist circumference, and palpable subcutaneous masses located on the face, neck, chest, abdomen, and limbs (figs. 1 A, B). Laboratory tests showed elevated serum levels of myoglobin (137.1 μg/l; normal range < 110.0), creatinine kinase (363 U/l; normal range: 20–180), alanine aminotransferase (64 U/l; normal range: 5–33), aspartate aminotransferase (34 U/l; normal range: 5–32), and triglycerides (3.64 mmol/l; normal range < 2.26); while the serum creatinine level has remained within the normal range (up to 68 μmol/l; normal: 44–80) for the past 11 years.
Computed tomography (CT) scans demonstrated disseminated symmetrical lipomatosis of the face, neck, chest, abdomen, and pelvis, leading to changes in shape and compression of internal organs (figs. 1 C–E). Additionally, imaging showed hypertrophy of lipid tissue in the salivary glands, particularly in the parotid glands, accompanied by glandular tissue atrophy. No typical signs of Sjögren’s syndrome were observed in imaging studies, nor were they detected clinically or through immunological tests. The patient did not meet the 2016 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for the diagnosis of Sjögren’s syndrome. The scan also revealed compression of internal organs, significant mediastinal lipomatosis, including adipose tissue proliferation within the pericardium, and hypertrophy of extrapleural adipose tissue. Based on these diagnostic imaging test results, clinical symptoms, and medical history, the Cushing’s syndrome was ruled out, and a diagnosis of Madelung disease was established. There were no similar cases reported in her family. The patient refused a biopsy of the pathological masses and further diagnostic procedures. She was treated with a zero-fat diet, intravenous fluids, analgesics, and anti-nausea medications, which led to an improvement of her condition. She was referred to the outpatient clinic for possible further surgical treatment. Fibrate therapy was initiated for the first time to prevent fat deposition associated with Madelung disease. However, due to unsatisfactory outcomes, the treatment was discontinued after 8 weeks. Notably, there was no increase in serum creatine kinase or myoglobin levels during fibrate therapy.

Discussion

We presented the patient with a long history of dermatomyositis, treated with steroids among other medications, who subsequently developed complications including weakness, myopathy, and muscle atrophy. Laboratory tests showed signs of rhabdomyolysis, while the clinical course and further lab results did not confirm an exacerbation of the dermatomyositis. Interestingly, a physical examination confirmed by CT revealed disseminated symmetrical lipomatosis throughout almost the entire body, leading to a diagnosis of Madelung disease type II.
The incidence of Madelung disease varies across different populations [9]. The highest incidence is reported in the Mediterranean region, particularly among the Italian population, with 4 cases per 100,000 inhabitants [10]. In contrast, only a few cases have been reported in Asia [10]. Whereas, the incidence of dermatomyositis in the adult population is up to 17 new cases per 1,000,000 inhabitants, with a prevalence ranging between 5 and 11 cases per 100,000 inhabitants [11]. Therefore, given the coexistence of these two diseases, the presented case appears to be unique. Similarly, in our patient, who was diagnosed with dermatomyositis at the age of 7 years and Madelung disease at 42 years, dermatomyositis shows two peaks of incidence: one in childhood between 4 and 10 years of age and the other in adulthood between 40 and 60 years [6, 11]. Madelung disease, on the other hand, mostly occurs in middle-aged individuals (30–60 years old) [6, 12]. In contrast to our case, Madelung disease is more prevalent in males, with the male to female ratio ranging from 15 : 1 to 30 : 1 [12, 13]. In our patient it can be incidental or associated with the higher female to male ratio ranging about 2 : 1 in dermatomyositis patients [11, 14]. The exact pathophysiology of Madelung disease still remains unknown [13]. The incidence of Madelung disease is known to be associated with a history of alcohol abuse in more than 90% of cases, according to Maximiano et al.; however, our patient was abstinent from alcohol [12, 13]. A reduction in β-adrenergic receptors and disruptions in mitochondrial DNA may explain the mechanism of alcohol-related etiology [13]. Several studies have noted an association with mitochondrial dysfunction, various metabolic disorders affecting liver cytochrome P450, lipid metabolism, carbohydrate metabolism, and steroid consumption [15]. Therefore, long-term steroid administration might be a potential trigger for Madelung disease in our patient. Patients with Madelung disease often present with concomitant features of type 2 diabetes mellitus, arterial hypertension, dyslipidaemia, hyperuricemia, liver cirrhosis, nephropathy, neuropathy, myopathy, gynecomastia and rarely malignant transformations, which was partly in line with symptoms present in our patient [13, 16–18]. Interestingly, reports regarding the overlap of autoimmune diseases with Madelung disease are scarce [9]. The diagnosis can be based on clinical features and imaging studies [13, 16]. Although alcohol withdrawal and weight loss are recommended, these procedures are not effective to reverse or to stop the progression of the disease [13, 15, 16]. Treatment mainly consists of surgical removal of fatty tissue or liposuction, as well as injection lipolysis, which has moderate and temporary efficacy [13, 15–18]. Recent studies suggest a possible role of pharmacological treatment (with fibrates, magnesium, and pyridoxine) for arresting the progression of Madelung disease [17].

Conclusions

The presented case underscores how long-term steroid therapy might trigger or aggravate the course of Madelung disease. Further studies are needed to confirm whether juvenile dermatomyositis can trigger or aggravate Madelung disease in the future.

Funding

No external funding.

Ethical approval

Not applicable.

Conflict of interest

The authors declare no conflict of interest.

References