Dermatologic Manifestations of Localized Lipodystrophy

Lipodystrophies are a heterogeneous group of diseases clinically characterized by a congenital or acquired loss of fat in circumscribed, partial, or diffuse areas of the body. As a rule, localized lipodystrophies are not associated with metabolic or systemic disorders, they tend to resolve spontaneously, and they have an excellent prognosis. The main concern is cosmetic when the lesions persist. Controversy exists in their classification, but three subsets can be identified based on the presence or the absence of preceding inflammation and the histologic findings. See the image below.

Localized lipoatrophy from a steroid injection. Courtesy of DermNet New Zealand (http://www.dermnetnz.org/assets/Uploads/dermal-infiltrative/lipoatrophy.jpg).

Centrifugal lipodystrophy or lipodystrophia centrifugalis abdominalis infantilis is the best-characterized subset. It affects children at a young age. It begins on the trunk, spreads for a few years to the neighboring abdomen or chest, and eventually resolves spontaneously in most patients.

The second group is defined by a lack of preceding inflammation and a common histologic pattern of involutional lipoatrophy. It includes such entities as lipoatrophia semicircularis; semicircular or annular dystrophy; and lipoatrophies linked to repeated trauma, pressure, or drug injections. A number of cases are idiopathic. Bleomycin, which is usually linked with flagellate erythema, may also be associated with acquired partial lipodystrophy.[1]

The third type represents a sequela from various types of panniculitis and is associated with preceding inflammation. It includes lipophagic granulomatous panniculitis and other types of panniculitis, primarily associated with connective-tissue disease.

Acquired partial lipodystrophy tends to be seen in women with late-onset lipodystrophy.[2] Some also have membranoproliferative glomerulonephritis, diabetes mellitus, and impaired autoimmune diseases such systemic lupus erythematosus, dermatomyositis, or rarely localized scleroderma.

Other Medscape articles on lipodystrophy include Dermatologic Manifestations of Generalized Lipodystrophy, Lipodystrophy in HIV, and Progressive Lipodystrophy.

The pathophysiology of localized lipodystrophy is unknown. The pathogenetic mechanism of inherited lipodystrophies at the molecular level has been linked to mutations of lamin A/C, peroxisome proliferator-activated receptor (PPAR-gamma), and other seemingly unrelated proteins.[3] In cases linked to injections of insulin, an immune response mediated by tumor necrosis factor-alpha has been hypothesized.[4, 5]

Familial partial lipodystrophy (FPLD) usually results from coding sequence mutations either in LMNA, encoding nuclear lamin A/C, or in peroxisome proliferator-activated receptor-gamma (PPARG), encoding PPAR-gamma. The LMNA form is called FPLD2 (Mendelian Inheritance in Man [MIM] 151660) and the PPARG form is called FPLD3 (MIM 604367). FPLD phenotype may be due to a single-base mutation in the DNA-binding domain of peroxisome PPAR-gamma.[6] A PPARG H449L mutation has been described in a Turkish family.[7] Impaired PPARG function through a mutation of a conserved salt bridge (R425C) producing FPLD has also been described.[8]  A multicenter prospective Turkish study of 56 FPLD patients delineated pathogenic variants of the LMNA gene in nine families, with typical exon 8 codon 482 pathogenic variants in four of them.[9]

Segmental lipodystrophy may result from mosaicism, a postzygotic mutation that may be a germline or a somatic phenomenon.[10] Mosaicism of adipocytes may be challenging to classify.

Lipophagic lobular panniculitis, an entity of unknown origin, may lead to circumferential fat atrophy of the ankles and may represent an end-stage manifestation of an idiopathic lobular panniculitis of children localized to the lower part of the lower limbs.[11]

The cause of centrifugal lipodystrophy is unknown.

In many cases, involutional lipodystrophy is idiopathic. In other cases, repeated trauma,[12] chronic pressure or compression, or local injections may be the cause. It has been reported to develop at the site of injection or in the surrounding area of injection with insulin,[13] intralesional or intra-articular steroids, antibiotics (eg, intramuscular benzathine penicillin),[14] vasopressin, and human growth hormone.[13] Localized lipoatrophy was also noted following intramuscular injection of amikacin.[15]

Localized lipoatrophy may represent the late or end stage of a preceding or concomitant panniculitis, which may be triggered by various underlying conditions. Connective-tissue disease–induced panniculitis is one of the main causes and may not be symptomatic at the time of presentation. Other causes of lipoatrophic panniculitis may include alpha-1-antitrypsin deficiency or cytophagic, factitial, and infectious panniculitides.

Frequency

Few cases have been reported internationally. Centrifugal lipodystrophy and the involutional type are rare. Lipoatrophy secondary to panniculitis is more frequent.

Race

No racial predilection exists except for centrifugal lipodystrophy, which has been described mainly in Asian children.

Sex

No difference in sex has been established, except for a female predominance in the involutional type. A female predominance is also observed in connective-tissue disorder–associated lipoatrophic panniculitis.

Age

No specific age of onset exists except for centrifugal lipodystrophy. In these cases, lesions appear before age 3 years, they stop spreading by age 8 years, and they tend to resolve by age 13 years.

Connective-tissue disorder–associated lipoatrophic panniculitis may be observed at any age, but it occurs most frequently in adults aged 20-60 years. Lupus erythematosus is the most common underlying disease.

The prognosis is excellent in the first two groups because they are limited disorders affecting only localized areas of subcutaneous tissue. The prognosis for patients with an underlying systemic illness follows that of the primary condition. Many patients show spontaneous regression.

Lipoatrophia semicircularis responds to basic measures, which when promptly and jointly applied, resulted in 90% of the cases resolving within 6 months in one large series.[16]

Localized lipodystrophies usually have little or no associated morbidity or mortality. They are circumscribed and tend to resolve spontaneously, although panniculitis may be chronic and relapsing. Usually, no associated systemic disorder is present, except in some cases of panniculitis induced by an underlying connective-tissue disorder. Even then, symptoms tend to be mild with an excellent overall outcome.

Lipodystrophia centrifugalis is defined by the appearance of cutaneous lesions surrounded by a peripheral erythematous border before age 3 years. They may progress centrifugally for as long as 10 years and tend to regress thereafter. Children who are affected are healthy.

Involutional lipoatrophy is characterized by one or a few circumscribed depressions of the skin affecting any part of the body in persons of any age, with or without a history of previous trauma, pressure, or previous injections in the area.[17] Clinically, it usually appears as a solitary, asymptomatic, well-demarcated, atrophic depression and often involves areas of antecedent intramuscular or intra-articular injections.[18, 19, 20] Overlying hypopigmentation and atrophy with morphealike changes may be noted with histology studies.

Panniculitis precedes the onset of lipoatrophy in the inflammatory subsets but may be asymptomatic clinically.

Lipodystrophia centrifugalis abdominalis infantilis, as originally described by Imamura et al[21] in 1971, presents as a round or oval depression in the skin, often in the groin or the axilla.[22] It is characterized by one or a few circumscribed depressions or indentations in the skin. The overlying skin is of normal texture and color except for the periphery, which may be erythematous and a little scaly. Lesions tend to spread centrifugally to adjacent areas, such as the chest and the abdomen, for several years. The face and the sacral area can also be involved. Regional enlarged lymph nodes can often be palpated. No other abnormal finding is present clinically.

The lesions are round, oval, bandlike, horizontal, annular, or semicircular in configuration. They are flesh colored and barely visible with normal overlying skin. The anterior parts of the thighs, the buttocks, or the lower parts of the limbs, including the ankles in some cases, as well as the arms, the neck, and the scalp may be involved, unilaterally or bilaterally. The lesions may be mildly tender at first. No associated finding and no preceding sign of inflammation are present.

Localized lipoatrophy may represent the late stage of panniculitis. Indurated, tender, erythematous, purplish or hyperpigmented subcutaneous nodules or plaques usually involving the extremities precede the onset of lipoatrophy at the same sites.

Fever and systemic signs may be present depending on the type of associated panniculitis.

Lipophagic panniculitis of childhood, first described in children and later in adults,[23] is characterized by its benign self-limited course. It presents with multiple, slightly tender, erythematous subcutaneous nodules and plaques, which precede the onset of lipoatrophy. The lesions mainly occur on the extremities. It may recur several times, and it may be associated with intermittent fever.

Localized lipoatrophy may be the only presenting feature in patients with an underlying or evolving connective-tissue disorder, such as lupus erythematosus, morphea profunda, dermatomyositis,[24] or overlap disease. In patients with lupus panniculitis, multiple, often painful subcutaneous nodules or plaques, with a predilection for the proximal extremities, may be observed in association with irregular, indurated depressions in the same areas. The overlying skin is often normal, or changes, such as atrophy, hyperkeratosis, telangiectasias, and/or ulceration, seen in discoid lupus erythematosus may be present. Arthralgias or Raynaud syndrome may be observed, but most patients show no evidence of severe systemic involvement, such as glomerulonephritis or neurologic complications.

No associated laboratory abnormalities are present in most cases of localized lipodystrophy.

Complete blood counts, chemistry, erythrocyte sedimentation rate, renal function tests, and serum antibody tests should be performed in search of an underlying autoimmune condition in cases associated with panniculitis.

A transient microcytic anemia, thrombocytosis, and elevated erythrocyte sedimentation rate have been reported in cases of lipophagic panniculitis.

Serum antinuclear antibodies may be positive in cases associated with an autoimmune disorder.

A skin biopsy of an affected area deep enough to include the subcutaneous tissue should be performed to confirm the diagnosis and to exclude underlying conditions. Direct immunofluorescence testing should be requested.

Centrifugal lipodystrophy is characterized by a loss of fat in the depressed area and evidence of panniculitis in the surrounding inflammatory area.

A pattern of involutional lipoatrophy is the common finding in the second subgroup, whether idiopathic or associated with a history of trauma, pressure, or local injections. Individual adipocytes and fat lobules are smaller and fewer, separated by hyaline material, with prominent and numerous capillaries, and minimal or no inflammation is present. No foreign body giant cell or lipophage is present.

Histologic evidence of panniculitis is usually present if a biopsy is performed on lesions early enough in the third subgroup. A combination of lipoatrophy and a predominantly lymphocytic or histiocytic infiltrate made of lipophages is most commonly found. Other features may vary with the underlying cause of panniculitis.

Lipophagic panniculitis is characterized by a panlobular panniculitis with a predominantly histiocytic infiltrate made of foamy and Toutonlike lipophages in the subcutaneous and periappendageal fat, giving it a granulomatous appearance. Immunofluorescence study findings are negative.

In cases of panniculitis associated with connective-tissue disorders, histopathologic findings may be diagnostic of lupus, scleroderma, dermatomyositis, or overlap disease, but they are not always specific. Lupus panniculitis is best defined as a mostly lobular panniculitis with a predominantly lymphocytic infiltrate. Lymphoid follicles with germinal centers around the septa and hyaline fat necrosis, when present, are characteristic. Changes may be confined to the subcutaneous tissue in about one half of cases, or the overlying epidermis and dermis may show evidence of discoid lupus erythematosus, such as epidermal atrophy, hyperkeratosis, hydropic degeneration of the dermoepidermal junction, and perivascular and appendageal lymphocytic infiltration of the overlying skin. Direct immunofluorescence findings are positive in most patients, with linear deposits of immunoglobulin M and C3 along the dermoepidermal junction.

Morphea profunda shows thickening and hyalinization of the septal panniculus and fascia. Small aggregates of lymphocytes and plasma cells as well as eosinophils may be observed and help in differentiating it from lupus.

No treatment is usually needed, and lesions tend to regress spontaneously in many cases. Intralesional steroids may be helpful in some cases. When associated with an autoimmune disorder, antimalarials or systemic corticosteroids may be needed.

No surgical care is needed as a rule. If cosmetically a problem, a combination of liposuction and localized fat transplantation may be used. Breast augmentation has been performed in selected patients with truncal lipoatrophy.[33] Simultaneous circumferential arm liposuction followed by brachioplasty is safe and effective in selected patients.[34]

Follow-up care may be useful to document spontaneous regression and/or to make decisions for further treatment. Patients may need to be monitored in cases preceded by panniculitis, particularly in cases associated with a connective-tissue disorder.

No medications are effective other than those indicated for a primary inflammatory panniculitis when present.