Anetoderma

Background

Anetoderma (anetos, Greek for slack) is a benign condition with focal loss of dermal elastic tissue, resulting in localized areas of flaccid or herniated saclike skin. The condition has been reported under various names, including macular atrophy, anetoderma maculosa, and atrophia maculosa cutis. Primary lesions consist of localized areas of flaccid skin, which can be macular, papular, or depressed. 

Historically, idiopathic lesions were classified based on a clinically inflammatory (Jadassohn-Pellizzari) or noninflammatory (Schweninger-Buzzi) onset. However, both types of lesions may be found in the same individual, and they are histologically similar. Currently, anetoderma is classified as either primary anetoderma, which is an idiopathic occurrence of atrophic lesions in areas of skin that appear normal prior to the onset of atrophy, or secondary anetoderma, which is preceded by an inflammatory, autoimmune, infectious, or neoplastic process. Both types may be associated with systemic diseases. A familial form that manifests as primary anetoderma has also been described.^[1]

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Pathophysiology

The exact cause of anetoderma is unknown. Possible explanations for the loss of elastic tissue include defective elastin synthesis, uncontrolled production of elastolytic enzymes, loss of elastolytic enzyme inhibitors, elastophagocytosis, or degeneration of elastic fibers secondary to local ischemia induced by microthromboses in dermal vessels.^[2] Some investigators have proposed a possible common epitope between elastic fibers and phospholipids as an explanation for an autoimmune-mediated process.^[2]

Elastolytic enzymes such as matrix metalloproteinases (MMPs) may be directly responsible for elastin degradation in anetoderma. Alternatively, they may act indirectly by modulating other inflammatory events, such as proteolytic activation of latent cytokines, which, in turn, may regulate the activity of other undiscovered elastolytic enzymes. Known elastolytic enzyme inhibitors include serine proteinase inhibitors (serpins) and tissue inhibitors of metalloproteinase (TIMPs).

An imbalance in levels of MMPs and TIMPs altering the rate of elastin turnover has been suggested as one explanation of the pathophysiology of anetoderma. Specifically, MMP-2 and MMP-9 have been suggested as possible culprits at the origin of elastic fiber destruction in anetoderma.^[3]

Furthermore, a 2016 study involving nine patients with idiopathic anetoderma found that the dermal expression of fibulin-4 (which binds tropoelastin and is involved in various aspects of elastic fiber development) was significantly decreased in anetoderma when compared with healthy controls. These findings suggest that in addition to elastolytic overactivity, altered reassembly of elastic fibers may also play a significant role in the pathogenesis anetoderma.^[4]

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Epidemiology

Frequency

The exact incidence of anetoderma is unknown, but secondary anetoderma is probably more common than the primary form. Familial anetoderma is uncommon, with only 12 families reported in the literature.^{[5, 6, 7, 8]} Inheritance may be autosomal dominant, autosomal recessive, or undefined.

Sex

Primary anetoderma occurs slightly more frequently in women than in men.

Age

Primary anetoderma usually presents between the second and fourth decades of life, although patients of all ages have been reported to develop anetoderma.^{[9, 10, 11]}

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Prognosis

Once developed, the lesions do not change over time.

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History

Initial lesions may be noticed as crops of 1-2 cm, asymptomatic erythematous macules, plaques, or nodules that enlarge over weeks, possibly reaching several centimeters in diameter. Lesions appear on the upper arms, the trunk, the thighs, and less commonly on the neck, face, and rarely on distal extremities. Comorbid lesions may already exist. End-stage lesions do not change over time, and new lesions may continue to develop over years.

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Physical Examination

Primary lesions of anetoderma present as discrete, flaccid areas of slack skin, which may be depressed, macular, or papular. Lesions may have overlying wrinkled skin. Lesions may be isolated or multiple. Lesions may slightly bulge like pouches and herniate into the skin upon palpation, a finding referred to as the "buttonhole" sign by some authors.^[12]  See the images below.

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Multiple lesions of anetoderma.

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Close-up view of a single lesion of anetoderma.

On pressure, a normal ring of surrounding skin is felt. The scalp, the palms, the soles, and the mucous membranes are usually spared. A few to hundreds of lesions may form. These may coalesce and become indistinguishable from acquired cutis laxa.

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Causes

Primary or idiopathic anetoderma originates from previously healthy skin with unknown pathogenesis. Various autoimmune, ocular, bony, cardiac, and other abnormalities have been reported with anetoderma, including the familial forms. Whether these findings are coincidental or related is unknown. Thus, a thorough history and a complete physical examination are essential.

The association with lupus erythematosus or other autoimmune disorders and primary anetoderma is well-established. This is owing to the frequent finding of antinuclear antibodies, antiphospholipid antibodies, hypocomplementemia, thyroid autoantibodies, and/or a positive lupus band test in patients who have anetoderma. However, criteria for diagnosis of systemic lupus erythematosus are typically not met.

Furthermore, studies have suggested a strong association between primary anetoderma and the presence of antiphospholipid antibodies, with or without a diagnosis of antiphospholipid antibody syndrome.^[13] Primary anetoderma may appear years earlier than the classic signs of an autoimmune syndrome. It is therefore recommended to search for clinical and laboratory signs of an autoimmune disorder in every patient presenting with primary anetoderma.^{[14, 15, 16]}

Familial anetoderma is a rare entity, which has only been reported in 12 families to date. Anetoderma was limited to the skin in some cases, while others were associated with extracutaneous abnormalities, particularly bone and/or cranial nerve anomalies.^[1]

Anetoderma of prematurity is yet another entity occurring in very-low-birth-weight infants in neonatal intensive care units. Lesions usually present on the trunk and have been linked to the use of monitoring leads, leading to local hypoxia secondary to pressure on immature skin, thereby representing an acquired disorder.^[17]

Additional associations that have been reported with primary anetoderma include the following:

• Autoimmune -Lupus erythematosus, antiphospholipid antibody syndrome, Addison's disease, autoimmune thyroiditis, Sjögren syndrome^[18]
• Eye - Cataract, keratoconus, blue sclerae, optic atrophy,^[19] subretinal neovascularization^[20]
• Bone - Calcifications, kyphoscoliosis, brachydactyly, congenital cervical fusions, spina bifida, osteopetrosis, metaphyseal dysplasia
• Blegvad-Haxthausen syndrome - Anetoderma, blue sclerae, osteogenesis imperfecta
• Cardiovascular -Mitral valve prolapse, aortic insufficiency, Wolff-Parkinson-White conduction disturbance, myocardial infarction
• Drugs- Cocaine^[21]
• Miscellaneous - Diverticulum of the mid esophagus, emphysema, protrusion of the teeth,^[22] myotonic dystrophy, focal sclerosing glomerulopathy, and decreased serum level of alpha1-antitrypsin
• Terminal osseous dysplasia with pigmentary defects^[23]

Secondary anetoderma has been associated with myriad inflammatory, autoimmune, infectious, and neoplastic dermatological conditions. Associations that have been well-documented in the literature include the following:

• Acne
• Acrodermatitis chronica atrophicans
• Amyloidosis
• Antiphospholipid antibody syndrome
• B-cell lymphoma^[24] (one case with concomitant Sjögren syndrome^[25] )
• Benign cutaneous lymphoid hyperplasia
• Cutaneous marginal zone B-cell lymphoma^{[26, 27]}
• Primary follicular center cutaneous B-cell lymphoma^[28]
• Dermatofibroma
• Herpes zoster^[29]
• Arthropod bites
• Leprosy
• Lupus: Systemic lupus erythematosus, discoid lupus, lupus profundus
• Lyme disease^[30]
• Lymphocytoma cutis
• Pilomatricoma^[31]
• Sarcoidosis
• Syphilis^{[32, 33]}
• Tuberculosis
• Urticaria pigmentosa
• Varicella

Additional conditions that have been reported to be associated with secondary anetoderma in isolated case reports include the following:

• Angular cheilitis^[34]
• Congenital melanocytic nevi with hamartomatous features^[35]
• Dermatofibrosarcoma protuberans^[36]
• Generalized granuloma annulare^{[37, 38]}
• HIV disease^[39]
• Juvenile xanthogranuloma
• Langerhans cell histiocytosis
• Mastocytosis^[40]
• Molluscum contagiosum^[41]
• Mycosis fungoides^[42]
• Myxofibrosarcoma^[43]
• Neuroblastomalike schwannoma^[44]
• Penicillamine^[45]
• Pityriasis versicolor
• Prurigo nodularis^[46]
• Reed syndrome^[47]
• Schwannoma^[48]
• Sjögren syndrome^[25]
• Stevens-Johnson’s syndrome^[49]
• Takayasu arteritis^[11]
• Wilson disease^[50]

Furthermore, external traumatic injuries that have been linked to the development of secondary anetoderma include the following:

• Electrodes (monitoring electrodes in premature infants), also known as iatrogenic anetoderma of prematurity^{[9, 51, 52]}
• Hepatitis B vaccination^[53]

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Laboratory Studies

Laboratory testing for the presence of thyroid autoantibodies^[55] and antiphospholipid antibodies in all patients who present with primary anetoderma is recommended. Antiphospholipid antibody tests include lupus anticoagulant, all isotypes of anticardiolipin, and anti-β2-glycoprotein I antibodies. The following laboratory tests may be considered if clinically indicated:

• Antinuclear antibody (ANA) test, complement (C3, C4)
• Other autoantibodies (anti-Ro, anti-La, antimitochondria, anti-smooth muscle)
• ACE level
• CBC count
• Lyme disease titers
• QuantiFERON assay
• Rapid plasma reagin (RPR)/Venereal Disease Research Laboratory (VDRL) test
• Sedimentation rate

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Histologic Findings

A perivascular and periadnexal lymphohistiocytic infiltrate is seen in the papillary dermis, upper reticular dermis, or both. Marked loss of elastic fibers is observed, although fine microfibrils may remain. Collagen fibers appear normal. Desmosine, a cross-linking compound found only in elastin, is reduced in lesional skin. Early lesions may show a pronounced monocytic infiltrate of predominantly T helper lymphocytes, but occasionally, the predominant cell types are histiocytes, neutrophils, or eosinophils. Scattered macrophages showing elastophagocytosis may be present. Microthromboses may be seen in individuals with anetoderma and antiphospholipid antibodies.

Direct immunofluorescence is usually not helpful, but findings similar to those of lupus erythematosus may be found,^[56] with granular deposits of immunoglobulin G (IgG), immunoglobulin M (IgM), and/or complement (C3) along the dermoepidermal junction and blood vessels. Sometimes, fibrillar immunoglobulin and complement deposits are present in the papillary dermis. This probably corresponds to deposition on elastic tissue, although indirect immunofluorescence studies have failed to demonstrate elastic fiber autoantibodies.

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Approach Considerations

To date, no effective treatment is available for anetoderma. Therapeutic options that have been used but have not shown consistent results include intralesional steroids, as well as systemic penicillin G, aspirin, phenytoin, dapsone, vitamin E, and niacin. Anecdotal reports have described topical epsilon-aminocaproic acid (an antifibrinolytic)^[57] and oral colchicine^[58] as potential treatments to prevent the development of new lesions.

Furthermore, isolated case reports have shown improvement of anetoderma lesions when treated with the following lasers:

• The 10,600-nm ablative carbon dioxide fractional lasers^{[29, 49]}
• Pulsed-dye lasers (10,600 and 595 nm) in conjunction with the 1550-nm nonablative fractionated laser^[59]

Surgical excision is an option if lesions are small and few in numbers.

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Long-Term Monitoring

For primary anetoderma, patients need periodic reevaluation for associated conditions not initially manifested. This evaluation includes a complete physical examination and appropriate screening laboratory tests.

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