Many diagnoses have similar symptoms as the symptoms experienced in Dercum’s disease. The diffuse types of Dercum’s disease have traits in common with conditions with general pain:
Endocrine disorders encompassing obesity and pain, e.g. Cushing’s syndrome and hypothyroidism
Primary psychiatric conditions encompassing pain, e.g. depression. Especially in combination with obesity.
The nodular type of Dercum’s disease has to be differentiated from conditions that may include lipomas or solitary deposits of excess fat that are sometimes painful:
Multiple symmetric lipomatosis (Madelung’s disease, Lanois-Bensaude syndrome)
Neurofibromatosis type I
Adipose tissue tumours
Multiple endocrine neoplasia I (MEN I)
Myoclonic epilepsy with red ragged fibres (MERRF)
Familial multiple lipomatosis
The similarities and differences of these conditions and Dercum’s disease are briefly presented below.
Fibromyalgia is a condition with widespread muscle pain and a painful response to pressure on at least 11 out of 18 specific tender point sites. It is associated with a range of other symptoms, such as sleep disturbances, fatigue, cognitive disturbances, and depressive symptoms . The aetiology is unknown [75, 76] and the demarcation from Dercum’s disease is sometimes arbitrary, especially in cases when the patient is obese.
Lipoedema is characterised by bilateral, symmetric lower extremity enlargement due to subcutaneous deposition of adipose tissue. The patients experience pain on palpation. The condition affects women almost exclusively. Typically, the disorder develops insidiously after puberty and progresses gradually. Moreover, patients with morbid obesity and longstanding lipoedema can develop a secondary mechanical insufficiency of the lymphatic system, producing a lipolymphoedema  due to associated difficulties with ambulation, which limits activation of the muscle pump in the lower extremities and subsequently leads to pitting oedema due to inactivity .
Panniculitis is a group of inflammatory conditions in which the principal focus is the subcutis. The condition encompasses painful subcutaneous masses and is therefore a possible differential diagnosis to Dercum’s disease. Panniculitis is classified according to which structure it affects: septal panniculitis denotes inflammation in the connective tissue septa, whereas lobular panniculitis refers to inflammation in the fat lobules. Panniculits occurs with or without accompanying vasculitis. Septal panniculitis without vasculitis (erythema nodosum) most commonly manifests itself as tender erythematous nodules on the lower extremity. As some nodules heal, others arise. Normally, all lesions heal without scarring within six weeks. Lobular panniculitis with vasculitis (erythema induratum, nodular vasculitis) presents itself with recurrent, tender, erythematous subcutaneous nodules on the lower extremity. The lesions frequently ulcerate, and they heal with atrophic scars. The condition may continue for several years. A special form of panniculitis is Pfeifer-Weber-Christian disease (idiopathic relapsing febrile lobular non-suppurative panniculitis).
A number of endocrine disorders can cause generalised pain in combination with obesity and psychiatric symptoms. For example, Cushing’s syndrome (corticotropin-independent adrenal hyperfunction) is characterised by aching joints, as well as a gradual onset of obesity, typically located around the face (‘moon face’), back (‘buffalo hump’), and trunk. In addition, the majority of patients suffer from psychiatric manifestations, including irritability, emotional labiality, and depression . Another endocrine disorder, encompassing weight gain and pain in the extremities, is hypothyroidism. If myxoedema develops, oedema of the face, hands and feet are added to the signs . Usually, the patients with endocrine disorders do not have painful adipose tissue.
Lipodystrophies are characterised by selective loss of body fat from different parts of the body. The adipose tissue loss can be limited, and result in well-demarked subcutaneous areas, or extensive, leading to widespread absence of body fat . There are different types of lipodystrophies, both congenital forms, such as Berardinelli-Seip syndrome, and acquired forms, such as Lawrence syndrome and Barraquer-Simons syndrome . On the other hand, localised excess deposition of fat is also a lipodystrophy and comprise most patients that have liposuction for cosmetic reasons. Furthermore, patients who have no pain and with lipoedema-like distribution of fat also belong to the lipodystrophies.
Patients with depression are often diagnosed with chronic pain conditions and vice versa . Both disorders activate common neurocircuitries, for example, the hypothalamic-pituitary-adrenal axis, limbic and paralimbic structures, ascending and descending pain pathways , and it is therefore sometimes difficult to determine whether the pain disorder or the psychiatric condition is the primary diagnosis.
Multiple symmetric lipomatosis is principally distinguished by large subcutaneous fatty masses distributed in a symmetrical fashion around the neck, shoulders, upper extremities, trunk, and sometimes intrathoracic. Epidemiologically, the incidence of the disorder is highest in males and is often associated with alcoholism. The majority of the patients are not obese. The fat accumulations are usually not experienced as painful . Sometimes multiple lipomatosis is inherited in an autosomal-dominant way, and is then referred to as familial multiple lipomatosis. The condition can be associated with an A to G mutation at position A8344 of mitochondrial DNA . The fatty masses in multiple symmetric lipomatosis are not painful and it is hence possible to differentiate from Dercum’s disease. Multiple symmetric lipomatosis is a separate entity from familial multiple lipomatosis.
Some patients with neurofibromatosis type 1 (von Recklinghausen’s disease) develop subcutaneous neurofibromas that cause pain and neurological symptoms . Neurofibromas are pathohistologically distinct from lipomas.
Benign adipose tissue tumours (solitary/multiple) are subcutaneous tumours composed of well-differentiated adipocytes. There are a number of varieties of lipomas, some of which are frequently painful . Malignant cutaneous adipose tissue neoplasms are exceptionally rare and are usually not experienced as painful. Such tumours include cutaneous angiolipoleiomyoma (‘angiomyolipoma’), adenolipoma of the skin, cutaneous spindle cell/pleomorphic lipomas, and liposarcomas . Tumours are normally easily differentiated from Dercum’s disease, as they are not painful.
Patients with multiple endocrine neoplasia I (MEN 1) sometimes exhibit several subcutaneous tumours, including multiple lipomas, which are, however, not painful . MEN 1 is easily differentiated from Dercum’s disease as the lipomas in MEN 1 are not painful.
Myoclonic epilepsy with ragged red fibres (MERRF), an inherited disease of the mitochondria, is sometimes accompanied by multiple symmetric lipomatosis. The most common cause is a mutation in position 8344 of the tRNA gene of mitochondrial DNA . MERRF is easily differentiated from Dercum’s disease, as the lipomas in MERRF are not painful.
In conclusion, the differential diagnosis is a challenge principally in cases where diffuse Dercum’s disease is one of the tentative diagnoses. All differential diagnoses have to be excluded before Dercum’s disease can be diagnosed.