Anetoderma

Etiology

Anetoderma is classified into 5 subtypes: primary (idiopathic), secondary to a preceding dermatosis, drug-induced, familial, and prematurity-associated. The primary type occurs in areas of previously normal skin and is historically subdivided into the Jadassohn-Pellizzari and Schweninger-Buzzi types. The Jadassohn-Pellizzari type develops after preceding inflammatory or urticarial lesions, while the Schweninger-Buzzi type arises in normal-appearing skin without prior changes. These subtypes are histologically identical and follow a similar disease course, rendering the terms obsolete.

The secondary type develops in areas of pathologic skin.[3] The most commonly associated dermatoses are acne vulgaris and varicella, but cases have also been reported with syphilis, sarcoidosis, tuberculosis, leprosy, Lyme disease, mastocytosis, prurigo nodularis, urticaria pigmentosa, granuloma annulare, insect bites, xanthomas, pilomatricomas, cutaneous B- or T-cell lymphomas, posthepatitis B vaccination, hamartomatous congenital melanocytic nevi, leech application, molluscum contagiosum, myxofibrosarcoma, and nodular amyloidosis.[4][5][6]

Reports have linked both primary and secondary anetoderma to HIV-1 infection and autoimmune diseases such as systemic lupus erythematosus (SLE), Graves disease, Addison disease, antiphospholipid syndrome (APS), Sjögren syndrome, and hemolytic anemia.[7][8] In recent years, anetoderma has also been associated with the COVID-19 vaccine and disseminated MPOX virus.[9][10]

Penicillamine is the only medication linked to drug-induced anetoderma, likely due to its inhibition of aldol cross-linking, a process essential for elastic fiber formation. The familial form of anetoderma is rare and follows an autosomal inheritance pattern, typically developing in the 1st decade of life. This form may present as isolated skin findings or occur with bony, neurological, and ocular anomalies.[11] Anetoderma of prematurity affects neonates born at 24 to 29 weeks of gestation who required monitoring while in the neonatal intensive care unit.

Epidemiology

Anetoderma is a rare disorder with an uncertain prevalence. This skin disorder has been reported across all age groups but most commonly affects adults aged 20 to 40 years. The condition is more frequent in female than male individuals and shows no racial predilection.

Pathophysiology

The exact pathophysiology of anetoderma remains uncertain. All forms of anetoderma involve a reduction in elastic tissue, potentially due to decreased elastin production, increased elastin degradation by elastolytic enzymes, reduced elastolytic enzyme inhibitors, or enhanced elastin phagocytosis. In penicillamine-induced anetoderma, inhibition of aldol cross-linking disrupts normal elastic fiber development. Anetoderma of prematurity is hypothesized to result from tissue hypoxia caused by adhesive medical devices, which may upregulate matrix metalloproteinase expression, leading to elastin degradation.[12]

Histopathology

Microscopically, anetoderma is characterized by focal loss or marked reduction of elastic fibers in the mid-to-reticular dermis, best visualized with special stains such as Verhoeff-Van Gieson or Orcein. The overlying epidermis remains unaffected, and the dermis may exhibit mild perivascular lymphocytic infiltration. Inflammatory variants show early elastophagocytosis by histiocytes or mast cells, whereas noninflammatory forms display passive elastic fiber loss. Collagen structure is typically preserved, though some cases demonstrate dermal atrophy. The absence of fibrosis distinguishes anetoderma from other elastolytic disorders, highlighting its unique pathophysiologic mechanism.[13]

History and Physical

Early lesions of anetoderma are typically asymptomatic or present as pruritic erythematous macules, plaques, or nodules that enlarge until reaching their final size. These manifestations may also be observed in areas of pathologic skin, as seen in the secondary type. Lesions can be solitary or multiple, appearing as discrete, flaccid areas of loose, wrinkled skin that may be depressed or protruding. On palpation, a normal skin ring is perceptible at the perimeter, while central pressure causes inward herniation. Once fully developed, lesions remain unchanged over time.

Evaluation

The diagnosis of anetoderma is primarily clinical. However, if uncertain, a skin biopsy, preferably a punch biopsy including the middermis, may be performed. Once diagnosed, the subtype should be determined based on the patient’s history.

On electron microscopy, lesional skin may show elastophagocytosis and small, fragmented elastic fibrils.[14][15] Desmosine, a major amino acid in elastin, has been used to quantify elastin concentration in affected skin, which is significantly reduced in anetoderma.[16]

Patients with primary anetoderma may require additional testing to identify associated underlying diseases. Workup should be guided by clinical suspicion based on history and physical examination. Given the association between primary anetoderma and antiphospholipid antibodies, testing is recommended in all cases, even in the absence of thrombotic disease or recurrent pregnancy loss.

Treatment / Management

Various medical treatments for anetoderma have been attempted, but none have proven effective for established lesions. Colchicine has demonstrated efficacy in preventing new primary anetoderma lesions.[17] In secondary anetoderma, controlling the underlying dermatosis may help prevent the formation of additional lesions.(B3)

Other treatments, including cryotherapy, intralesional steroids, hydroxychloroquine, vitamin E, oral penicillin G, epsilon-aminocaproic acid, aspirin, niacin, dapsone, and phenytoin, have been used but lack studied efficacy. Established lesions may be surgically excised for definitive treatment, though this approach results in permanent scarring. Laser therapy may improve lesion appearance, according to limited case reports.[18][19](B3)

Differential Diagnosis

Diseases commonly mistaken for anetoderma primarily involve disorders of elastic tissue that lead to cutaneous atrophy. Middermal elastolysis is characterized by the loss of middermal elastic fibers, resulting in widespread, well-defined, thin, and wrinkled plaques, typically on the trunk and upper arms. In acquired cutis laxa, elastic fiber loss causes generalized loose, sagging skin. Granulomatous slack skin disease, a rare variant of cutaneous T-cell lymphoma, presents with phagocytized elastic fibers and erythematous, pendulous folds of loose skin. Atrophoderma of Pasini and Pierini manifests as brown, gray, or violaceous macules or patches with a distinct sloping "cliff-drop" border on palpation, most commonly on the trunk.

Prognosis

The prognosis of anetoderma depends on its underlying cause. Primary anetoderma is typically benign, with lesions remaining stable or slowly progressing without systemic complications. In contrast, secondary anetoderma may indicate an associated autoimmune, infectious, or hematologic disorder, potentially contributing to morbidity and mortality. While skin lesions are irreversible, early identification and management of an underlying condition may prevent further progression. The psychosocial impact of disfigurement can be significant, warranting supportive care. Long-term follow-up is recommended, especially in cases linked to systemic disease, to monitor for progression or emerging comorbidities.

Complications

Complications of anetoderma primarily arise from its association with underlying systemic diseases rather than the skin lesions themselves. Secondary anetoderma may signal autoimmune conditions such as SLE or APS, where vascular thrombosis and systemic inflammation increase the risk of spontaneous abortion. Inflammatory or infectious causes, including syphilis and leprosy, can lead to progressive tissue damage if untreated. While lesions are typically asymptomatic, extensive involvement may result in cosmetic disfigurement and psychosocial distress. Rare cases of association with hematologic malignancies have been reported, necessitating thorough systemic evaluation in the presence of atypical features. Given the condition's chronic and often progressive nature, long-term monitoring is essential.[20]