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Anetoderma

Anetoderma

Anetoderma also known as macular atrophy, anetoderma maculosa or atrophia maculosa cutis, is an uncommon benign skin condition in which the elastic tissue in the dermis is lost, resulting in a depression in the skin 1. Anetoderma more commonly affects women than men, and the usual age range is 15–25 years. There is perhaps an increased incidence in premature babies, especially those with very low birthweight and the lesions may develop where adhesives such as for monitoring leads had been attached. Once developed, anetoderma do not change over time. 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.

Anetoderma seems to be most commonly reported in Central Europe. There have been rare cases of anetoderma affecting family members including monozygotic (identical) twins.

Currently, there are two forms of anetoderma – primary and secondary.

The cause of the primary form is not known. Primary anetoderma, which is an idiopathic occurrence of atrophic lesions in areas of skin that appear normal prior to the onset of atrophy. Primary anetoderma occurs slightly more frequently in women than in men 1. A familial form that manifests as primary anetoderma has also been described 2. Familial anetoderma is uncommon, with only 12 families reported in the literature 3. Inheritance may be autosomal dominant, autosomal recessive, or undefined. Primary anetoderma usually presents between the second and fourth decades of life, although patients of all ages have been reported to develop anetoderma 4.

Secondary anetoderma occurs at the site of other unrelated skin conditions, which is preceded by an inflammatory, autoimmune, infectious, or neoplastic process:

  • Infections – chickenpox, syphilis
  • Tumors – pilomatrixoma, plasmacytoma, schwannoma, cutaneous B-cell lymphoma, juvenile xanthogranuloma
  • Infantile hemangioma
  • Inflammatory skin conditions – acne, granuloma annulare, lupus profundus

Both forms of anetoderma may be associated with systemic diseases including:

  • Infections – Lyme disease (Borrelia), leprosy, HIV infection
  • Inflammatory/autoimmune conditions – systemic lupus erythematosus (SLE), Graves disease, Addison disease, Sjögren syndrome,
  • Medications – penicillamine

There appears to be a particular association with the presence of anti-phospholipid antibodies, often without the other features required to diagnose anti-phospholipid syndrome.

The old classification of Schweninger-Buzzi and Jadassohn-Pellizari types, non-inflammatory versus inflammatory, is no longer considered useful as both types of lesion can be seen in the one patient and many clinically non-inflammatory lesions show inflammation on histology. This classification does not predict prognosis and is therefore no longer used.

There have been many theories proposed to describe the mechanism of development of anetoderma, but at this time this remains unknown.

There is no successful treatment to reverse the already formed lesions of anetoderma. Single lesions may be excised. Where an underlying condition has been diagnosed, successful treatment can prevent the formation of further lesions.

Figure 1. Anetoderma

Anetoderma

Anetoderma causes

The exact cause of anetoderma is unknown.

Primary anetoderma 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 5. 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 6.

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 2.

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 4.

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 7
  • Eye – Cataract, keratoconus, blue sclerae, optic atrophy 8, subretinal neovascularization 9
  • 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 10
  • Miscellaneous – Diverticulum of the mid esophagus, emphysema, protrusion of the teeth 11, myotonic dystrophy, focal sclerosing glomerulopathy, and decreased serum level of alpha1-antitrypsin
  • Terminal osseous dysplasia with pigmentary defects 12

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 13 (one case with concomitant Sjögren syndrome) 14
  • Benign cutaneous lymphoid hyperplasia
  • Cutaneous marginal zone B-cell lymphoma 15
  • Primary follicular center cutaneous B-cell lymphoma 16
  • Dermatofibroma
  • Herpes zoster 17
  • Arthropod bites
  • Leprosy
  • Lupus: Systemic lupus erythematosus, discoid lupus, lupus profundus
  • Lyme disease 18
  • Lymphocytoma cutis
  • Pilomatricoma 19
  • Sarcoidosis
  • Syphilis 20
  • 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 21
  • Congenital melanocytic nevi with hamartomatous features 22
  • Dermatofibrosarcoma protuberans 23
  • Generalized granuloma annulare 24
  • HIV disease 25
  • Juvenile xanthogranuloma
  • Langerhans cell histiocytosis
  • Mastocytosis 26
  • Molluscum contagiosum 27
  • Mycosis fungoides 28
  • Myxofibrosarcoma 29
  • Neuroblastomalike schwannoma 30
  • Penicillamine 31
  • Pityriasis versicolor
  • Prurigo nodularis 32
  • Reed syndrome 33
  • Schwannoma 34
  • Sjögren syndrome 14
  • Stevens-Johnson’s syndrome 35
  • Takayasu arteritis 36
  • Wilson disease 37

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 4
  • Hepatitis B vaccination 38

Anetoderma pathophysiology

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 39. Some investigators have proposed a possible common epitope between elastic fibers and phospholipids as an explanation for an autoimmune-mediated process 39.

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 40.

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 41. These findings suggest that in addition to elastolytic overactivity, altered reassembly of elastic fibers may also play a significant role in the pathogenesis anetoderma 41.

Anetoderma signs and symptoms

The typical clinical presentation of anetoderma is of isolated or multiple round well-defined 1–2 cm lesions with wrinkly skin overlying a palpable depression, the so-called “buttonhole” sign 42. A few to hundreds of lesions may form. These may coalesce and become indistinguishable from acquired cutis laxa.

Lesions may be flat, raised or depressed, skin-colored or bluish-white.

Anetoderma lesions are most commonly found on the chest, back, neck and arms, but any site can be affected. The scalp, the palms, the soles, and the mucous membranes are usually spared. They are not related to hair follicles.

Anetoderma diagnosis

Anetoderma needs to be considered clinically so the histopathologist knows to do the special stains on skin biopsy specimens. These are necessary to demonstrate the loss of elastic fibers in the upper to mid-dermis. On routine stains the skin looks relatively normal, perhaps with some signs of inflammation.

Laboratory studies

Laboratory testing for the presence of thyroid autoantibodies 43 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 (ESR).

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 44, 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.

Anetoderma treatment

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) 45 and oral colchicine 46 as potential treatments to prevent the development of new lesions.

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

Anetoderma laser treatment

Isolated case reports have shown improvement of anetoderma lesions when treated with the following lasers:

  • The 10,600-nm ablative carbon dioxide fractional lasers 35
  • Pulsed-dye lasers (10,600 and 595 nm) in conjunction with the 1550-nm nonablative fractionated laser 47
References
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  3. Patrizi A, Neri I, Virdi A, Misciali C, D’acunto C. Familial anetoderma: a report of two families. Eur J Dermatol. 2011 Jul 1.
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  41. Gambichler T, Reininghaus L, Skrygan M, Schulze HJ, Schaller J, Colato C, et al. Fibulin Protein Expression in Mid-dermal Elastolysis and Anetoderma: A Study of 23 Cases. Acta Derm Venereol. 2016 Jun 15. 96 (5):708-10.
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