Anetoderma

Etiology

Anetoderma has been classified into five different subtypes, including primary (idiopathic) anetoderma, secondary anetoderma from a preceding dermatosis, drug-induced anetoderma, familial anetoderma, and prematurity associated anetoderma. The primary type occurs in areas of previously normal skin, and this type is historically subdivided into the Jadassohn-Pellizzari type and the Schweninger-Buzzi type. The Jadassohn-Pellizzari type of anetoderma develops after preceding inflammatory or urticarial lesions transpire, while the Schweninger-Buzzi type develops in normal-appearing skin with no foreshadowing skin changes. The two primary types are identical histologically and have a similar disease course, and so these terms are now antiquated.[1]

The secondary type of anetoderma develops in areas of pathologic skin. The most common associated dermatoses are thought to be acne vulgaris and varicella but have also occurred with other disorders such as syphilis, sarcoidosis, tuberculosis, leprosy, Lyme disease, mastocytosis, prurigo nodularis, urticaria pigmentosa, granuloma annulare, insect bites, xanthomas, pilomatricomas, cutaneous B or T-cell lymphomas,[3] post-hepatitis B vaccination,[4] hamartomatous congenital melanocytic nevi, application of leeches, molluscum contagiosum, myxofibrosarcoma, and nodular amyloidosis.[1] There have been reports of primary and secondary anetoderma in association with HIV-1 infection and various autoimmune diseases such as systemic lupus erythematosus, Graves disease, Addison disease, antiphospholipid syndrome, Sjögren syndrome, and hemolytic anemia.[3]

Penicillamine is the sole medication linked to drug-induced anetoderma. Penicillamine is thought to inhibit aldol-cross-linking, which is important for elastic fiber formation.[1] The familial form of anetoderma is rare and has an autosomal inheritance pattern. The familial form generally develops in the first decade of life and might be evident as purely skin manifestations but can also be associated with bony, neurological, and ocular anomalies.[5] Anetoderma of prematurity is found in premature neonates that had been monitored in the neonatal intensive care unit with prematurity of twenty-four to twenty-nine weeks of gestational age.[1]

Epidemiology

Anetoderma is a rare disorder with an unknown accurate prevalence. Cases have been reported from all age ranges, but it most commonly occurs in adults 20 to 40 years old. Anetoderma is more common in females than males and has not been found to have a racial predilection.[1]

Pathophysiology

The exact pathophysiology of anetoderma is not certain. In all types of anetoderma, there is a decrease in elastic tissue hypothesized to be from a decrease in the production of elastin, an increase in elastin degradation through an increase in elastolytic enzymes, a decrease in elastolytic enzyme inhibitors, or increased elastin phagocytosis. In penicillamine drug-induced anetoderma, aldol cross-linking is inhibited, which does not allow elastic fibers to develop normally. It has been hypothesized in anetoderma of prematurity that tissue hypoxia secondary to adhesive medical devices causes degradation of elastin by producing an increase in the expression of matrix metalloproteinases.[6]

Histopathology

On microscopy, the skin of anetoderma shows nearly complete loss of elastic fibers in the layers of the papillary and reticular dermis. The histopathology of lesional skin can also show a dermal periadnexal and perivascular infiltrate with histiocytes and plasma cells.[7]

History and Physical

Early lesions of anetoderma are generally asymptomatic or pruritic erythematous macules, plaques, or nodules that enlarge until they reach their final size. They may also form in an area of pathologic skin, such as in the secondary type. The lesions may be single or multiple and are configured in discrete flaccid areas of loose, wrinkled skin that may be depressed or protruding bulges above the skin. With palpation of the lesion, a normal ring of the skin can be felt on the perimeter, and centrally the lesion will herniate inward with pressure. The lesions do not change over time once the lesions become end-stage.[1]

Evaluation

The diagnosis of anetoderma can be made clinically. However, if the diagnosis is not straightforward, a skin biopsy can be performed, preferably with a punch biopsy, in order to include the mid-dermis. The subtype of anetoderma should also be determined once diagnosed as anetoderma, aided by the patient’s history.

In addition to the histopathology on electron microscopy, elastophagocytosis and small fragmented elastic fibrils can be visualized in lesional skin.[8][9] Desmosine is a major amino acid in elastin and therefore has been used to measure the concentration of elastin in lesional skin, which is significantly reduced in anetoderma.[10]

Patients with primary anetoderma may require an additional workup to look for associated underlying diseases. The testing selected should be selected with suspicion for particular disorders based on the history and physical exam. Primary anetoderma has an association with antiphospholipid antibodies. Therefore they should always be tested for in patients diagnosed with primary anetoderma, even if history is negative for thrombotic disease or spontaneous abortions.[3]

Treatment / Management

There have been various medical treatments for anetoderma reported, but none have been effective in established lesions. Colchicine has been shown to prevent new primary anetoderma lesions from forming.[11] In secondary anetoderma, controlling the causative dermatoses should theoretically prevent new lesions from forming.(B3)

Other treatments that have been used with no studied efficacy include cryotherapy, intralesional steroids, colchicine, hydroxychloroquine, vitamin E, oral penicillin G, epsilon-aminocaproic acid, aspirin, niacin, dapsone, and phenytoin.[1] Established lesions can be excised for definitive treatment but will leave a permanent scar. Laser treatment may improve lesion appearance according to limited case reports.[12][13](B3)

Differential Diagnosis

Diseases commonly mistaken for anetoderma consist primarily of disorders of elastic tissue leading to cutaneous atrophy similar to that of anetoderma. Mid-dermal elastolysis has a loss of mid-dermal elastic fibers causing widespread, well-defined, thin, and wrinkled plaques commonly on the trunk and upper arms. In acquired cutis laxa, there is a loss of elastic fibers that cause the skin to have a widespread loose sagging appearance. Granulomatous slack skin disease is a rare variant of cutaneous T cell lymphoma with phagocytized elastic fibers causing findings of erythematous pendulous folds of loose skin. Atrophoderma of Pasini and Pierini present as brown, gray or violaceous macules or patches with a distinct drop-off sloping border on palpation most commonly located on the trunk.

Prognosis

After the development of anetoderma, the lesions remain stable and do not resolve over time.

Complications

In primary anetoderma associated with antiphospholipid antibodies, possible complications may occur years after diagnosis, which include thrombotic events, superficial phlebitis, and spontaneous abortions.[14] This is why it is important to serologically evaluate all patients with primary anetoderma for antiphospholipid antibodies irrespective of the history of thrombotic events.