Diseases of Subcutaneous Tissue

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Chapter 652 Diseases of Subcutaneous Tissue

Diseases involving the subcutis are usually characterized by necrosis and/or inflammation; they may occur either as a primary event or as a secondary response to various stimuli or disease processes. The principal diagnostic criteria relates to the appearance and distribution of the lesions, associated symptoms, results of laboratory studies, histopathology, and natural history and exogenous provocative factors of these conditions.

652.1 Panniculitis and Erythema Nodosum

Inflammation of fibrofatty subcutaneous tissue may primarily involve the fat lobule or, alternatively, the fibrous septum that compartmentalizes the fatty lobules. Lobular panniculitis that spares the subcutaneous vasculature includes post-steroid panniculitis, lupus erythematosus profundus, pancreatic panniculitis, α1-antitrypsin deficiency, subcutaneous fat necrosis of the newborn, sclerema neonatorum, cold panniculitis, subcutaneous sarcoidosis, and factitial panniculitis. Lobar panniculitis with vasculitis occurs in erythema induratum and, occasionally, as a feature of Crohn disease (Chapter 328.2). Inflammation predominantly within the septum, sparing the vasculature, may be seen in erythema nodosum (Table 652-1 and Fig. 652-2), necrobiosis lipoidica, progressive systemic sclerosis (Chapter 154), and subcutaneous granuloma annulare (Chapter 649). Septal panniculitis that includes inflammation of the vessels is found primarily in leukocytoclastic vasculitis and polyarteritis nodosa (Chapter 161).

Table 652-1 ETIOLOGY OF ERYTHEMA NODOSUM

VIRUSES

Epstein-Barr, hepatitis B, mumps

FUNGI

Coccidioidomycosis, histoplasmosis, blastomycosis, sporotrichosis

BACTERIA AND OTHER INFECTIOUS AGENTS

Group A streptococcus,* tuberculosis,* Yersinia, cat-scratch disease, leprosy, leptospirosis, tularemia, mycoplasma, Whipple disease, lymphogranuloma venereum, psittacosis, brucellosis

OTHER

Sarcoidosis, inflammatory bowel disease,* estrogen-containing oral contraceptives,* systemic lupus erythematosus, Behçet syndrome, severe acne, Hodgkin disease, lymphoma, sulfonamides, bromides, Sweet syndrome, pregnancy, idiopathic*

* Common.

image

Figure 652-2 Tender red nodules with indistinct borders in a teenage girl with erythema nodosum.

(From Weston AL, Lane AT, Morelli JG: Color textbook of pediatric dermatology, ed 3, St Louis, 2002, Mosby, p 212.)

Erythema Nodosum

Erythema nodosum is a nodular, erythematous hypersensitivity reaction that typically appears with multiple lesions on the exterior surfaces of the arms and legs in the pretibial area (more common) and less often in other cutaneous areas containing subcutaneous fat. The lesions vary in size from 1 to 6 cm, are symmetric, and are oval with the longer axis parallel to the extremity. They initially appear bright or dull red but progress to a brown or purple; they are tense and painful and usually do not ulcerate (see Fig. 652-2). Initial lesions may resolve in 1-2 wk, but new lesions may continue to appear for 2-6 wk. Repeat episodes may occur weeks to months later. Prior to or immediately at the onset of lesions, there may be systemic manifestations that include fever, malaise, arthralgias (50-90%) and rheumatoid factor negative arthritis.

The etiology is unknown in 30-50% of pediatric cases of erythema nodosum; other etiologies are noted in Table 652-1. Group A streptococcal infection and inflammatory disorders (inflammatory bowel disease) are common etiologies in children; sarcoidosis should be considered in young adults.

Treatment includes that of the underlying disease as well as symptomatic relief with nonsteroidal antiinflammatory agents. Salicylates, supersaturated solution of potassium iodide (oral), colchicine, intraintestinal injections of steroidsand, in severe, persistent, or recurrent lesions, oral steroids have been employed. The idiopathic form is a self-limited disorder.

Lupus Erythematosus Profundus (Lupus Erythematosus Panniculitis)

Subcutaneous Fat Necrosis

Clinical Manifestations

This inflammatory disorder of adipose tissue occurs primarily in the first 4 wk of life in full-term or post-term infants. Typical lesions are asymptomatic, rubbery to firm, erythematous to violaceous plaques or nodules on the cheeks, buttocks, back, thighs, or upper arms (Fig. 652-4). Lesions may be focal or extensive and are generally asymptomatic, although they may be tender during the acute phase. Uncomplicated lesions involute spontaneously within weeks to months, usually without scarring or atrophy. Calcium deposition may occasionally occur within areas of fat necrosis, which may sometimes result in rupture and drainage of liquid material. A rare but potentially life-threatening complication is hypercalcemia. It manifests at 1-6 mo of age as lethargy, poor feeding, vomiting, failure to thrive, irritability, seizures, shortening of the QT interval on electrocardiography, or renal failure. The origin of the hypercalcemia is unknown.

Sclerema Neonatorum

652.2 Lipodystrophy

Several rare conditions are associated with loss of fatty tissue in a partial or generalized distribution.

Partial Lipodystrophy

Partial lipodystrophy may be familial or acquired. Loss of adipose tissue is not preceded by an inflammatory phase, and histopathologic examination reveals only absence of subcutaneous fat.

There are 3 forms of familial partial lipodystrophy (FPLD):

Type I (FPLD1Köbberlingg) is characterized by loss of adipose tissue confined to the extremities and gluteal region. Fat distribution of the face, neck, and trunk may be normal or increased. Hyperlipidemia, insulin-resistant diabetes mellitus, and eruptive xanthomas may be seen. The gene is unknown, but only females are affected.

Type 2 (FPLD2–Dunnigan) is caused by mutations in the laminin A/C gene. Fat distribution is normal in childhood, but atrophy commences with puberty. Lipodystrophy is seen in the trunk, gluteal region, and extremities. Adipose tissue accumulates in the face and neck and may also be seen in the axillae, back, labia majora, and infra-abdominal region. Insulin-resistant diabetes mellitus and hypertriglyceridemia develop, but high-density lipoprotein and cholesterol levels are low. Both males and females are affected, but the diagnosis may be more difficult in males owing to body habitus.

Type 3 (FPLD3) is caused by mutations in the peroxisome proliferation–activated receptor gamma (PPARG) gene. Lipodystrophy is seen in the limbs and gluteal region. Insulin-resistant diabetes mellitus, primary amenorrhea, acanthosis nigricans, hypertension, and fatty infiltration of the liver are present.

AKT2 and ZMPSTE24 mutations are newly recognized causes of partial lipodystrophy.

Acquired partial lipodystrophy (Barraquer-Simons syndrome) is caused by mutations in the LMNB2 gene. Females are more commonly affected. Fat loss begins in childhood or adolescence and affects the face, neck, arms, thorax, and upper abdomen. Excess fat is seen in the hips and legs, especially in females. Low levels of complement C3 are almost universally seen. C3 nephritic factor is also present. C3 nephritic factor stabilizes C3 convertase, allowing for unopposed activation of the alternate complement pathway and the decreased level of C3. Membranous proliferative glomerulonephritis and other autoimmune diseases may develop. Insulin-resistant diabetes mellitus is rare.

Generalized Lipodystrophy

Generalized lipodystrophy may also be congenital or acquired.

Congenital generalized lipodystrophy is seen in 3 forms:

Type 1 (Berardinelli-Seip congenital lipodystrophy type 1 [BSCL1]) is an autosomal recessive disorder caused by mutations in the 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT2) gene.

Type 2 (Berardinelli-Seip congenital lipodystrophy type 2 [BSCL2]) is also autosomal recessive and caused by mutations in the seipin gene.

Type 3 (CAV1) is autosomal recessive and caused by mutations in the caveolin 1 gene.

Marked lipodystrophy occurs at birth or in early infancy. Diabetes mellitus, hypertriglyceridemia, hepatic steatosis, acanthosis nigricans, and muscular hypertrophy occur. BSCL2 is a more severe phenotype, with premature death occurring in ≈ 15% of cases.

Acquired generalized lipodystrophy is more common in females. The most common associated disorder is juvenile dermatomyositis (78%). Panniculitis is seen in 17%. More than half of the children may have other complications, including acanthosis nigricans, hyperpigmentation, hepatomegaly, hypertension, protuberant abdomen, and hyperlipidemia.

Localized lipoatrophy is an idiopathic condition that manifests as annular atrophy at the ankles; a bandlike semicircular depression 2-4 cm in diameter on the thighs, abdomen, and/or upper groin or as a centrifugally spreading, depressed, bluish plaque with an erythematous margin.

Insulin lipoatrophy usually occur approximately 6 mo-2 yr after initiation of relatively high doses of insulin. A dimple or well-circumscribed depression at the site of injection is typically seen, although loss of fat may extend beyond the site of injection, leading to an extensive, depressed plaque. Biopsy reveals a marked decrease or absence of subcutaneous tissue, without inflammation or fibrosis. In some patients, hypertrophy occurs clinically. In these cases, the mid-dermal collagen is replaced by hypertrophic fat cells on histopathologic sections. The mechanism of insulin lipoatrophy may be cross-reaction of insulin antibodies with fat cells; the incidence of this condition has decreased since the implementation of widespread use of highly purified insulins. Lesions may also be prevented by frequent alteration of injection sites.