Atrophoderma of Pasini and Pierini

INTRODUCTION — Atrophoderma of Pasini and Pierini (APP) is a rare skin disorder affecting dermal collagen and presenting with dermal atrophy. The classic clinical manifestations of APP are hyperpigmented or hypopigmented, depressed areas of skin on the trunk or extremities (picture 1). It is unclear whether some cases of APP result from Borrelia burgdorferi infection. It is also uncertain whether APP is a distinct disease entity or a disorder on the spectrum of morphea (localized scleroderma).

The clinical manifestations, diagnosis, and treatment of APP will be reviewed here. Morphea is reviewed separately. (See "Pathogenesis, clinical manifestations, and diagnosis of morphea (localized scleroderma) in adults" and "Morphea (localized scleroderma) in adults: Management" and "Juvenile localized scleroderma".)

HISTORY — APP was described in 1923 by Pasini as "atrofodermia idiopathica progressiva" [1] and later by Pierini as a disorder affecting primarily females and consisting of single or multiple depressed patches with sharp, well-defined borders [2]. In 1958, Canizares coined the term "idiopathic atrophoderma of Pasini and Pierini," crediting both Italian doctors [3].

EPIDEMIOLOGY — APP is rare. The exact incidence and prevalence are unknown. Most cases have been reported in White persons, particularly in European countries. Whether this relates to a higher prevalence of Borrelia infection in Europe or speaks more to more frequent clinical recognition of this entity in individuals with lightly pigmented skin is not clear. (See 'Pathogenesis' below.)

APP tends to present in the second or third decade of life [3,4]. However, pediatric onset of the disease has been reported, including congenital presentations [5-8]. APP is seen more frequently in females than in males [9].

PATHOGENESIS — The pathogenesis of APP is poorly understood. An immunologic mechanism has been proposed based upon unusual staining of epidermal Langerhans cells and an abnormal T cell immunophenotype in the dermis [10,11]. The trigger for this immune reaction is unknown. B. burgdorferi infection has been proposed as a trigger based upon reports of APP occurring in the context of this infection. In a retrospective study of 34 patients with APP, 10 of 26 patients (38 percent) who were tested for antibodies against B. burgdorferi had elevated immunoglobulin G titers to B. burgdorferi compared with 14 percent of 43 healthy controls [9]. In addition, improvement in APP has occurred during treatment with doxycycline in a patient with immunoglobulin M antibodies to B. burgdorferi [12].

RELATIONSHIP WITH MORPHEA — The relationship between APP and morphea is controversial. Some authors propose that APP is a condition on the spectrum of morphea, representing the end result of the inflammatory process [13,14]. Arguments in support of this theory include reports describing the coexistence of the classic inflammatory and indurated plaques of morphea with APP, the progression of morphea plaques to APP, and clinical and pathologic similarities between APP and end-stage morphea [9,10,13,14]. (See 'Differential diagnosis' below and "Pathogenesis, clinical manifestations, and diagnosis of morphea (localized scleroderma) in adults".)

Evidence against the classification of APP as a manifestation of morphea includes an earlier average age of onset for pediatric morphea and longer disease course for APP than for morphea (an average active disease course of one to two decades versus five years); the subsequent development of induration in some cases of APP, which contradicts the theory that APP represents the end result of the inflammatory process in morphea; and pathologic differences [3,10,11,15]. Pathologically, APP may show decreased or clumped elastic fibers; in contrast, morphea may display inflammation and alteration of the appendageal structures [3,10,11]. (See "Pathogenesis, clinical manifestations, and diagnosis of morphea (localized scleroderma) in adults".)

CLINICAL MANIFESTATIONS — The clinical phenotype of APP consists of single or multiple well-demarcated, depressed areas of skin with dyspigmentation and an ovoid shape (picture 1). Individual depressed areas are generally a few millimeters to several centimeters in diameter and may coalesce to form larger depressions. The most common type of dyspigmentation is brown discoloration; however, primarily hypopigmented APP has also been reported [12,15]. Individual lesions tend to be symmetrical in nature.

The border between normal and affected skin is striking, creating a "cliff-drop" appearance [4]. This presentation has gained additional descriptors, such as "footprints in the snow" and "Swiss cheese."

Although APP may present anywhere on the body, the more common areas are the trunk (particularly the lumbosacral area) and/or extremities. The face is rarely affected. An unusual presentation consisting of widespread small lesions, "generalized lenticular APP," has been reported [16]. The involved areas of skin in APP are asymptomatic and functional impairment is not expected.

HISTOPATHOLOGY — Histologic changes, particularly in the early stages, may be minimal or nondiagnostic. The epidermis is normal. Dermal features consist of the flattening of the dermal papillae and rete pegs and a sparse perivascular and/or perifollicular lymphocytic infiltrate [9,17]. The collagen fibers may display clumping. The elastic fibers changes are variable, ranging from normal findings to fragmentation, and are best visualized with orcein stains [9].

The subtle and variable histologic findings in APP were demonstrated in a retrospective study that found no abnormalities on hematoxylin and eosin staining in 12 of 17 specimens of APP [15]. The remaining five specimens showed a sparse superficial perivascular or perifollicular lymphocytic infiltrate. Elastic stains revealed a moderate to severe decrease in elastic fibers with fragmentation in six specimens.

DIAGNOSIS — The diagnosis of APP is made based upon the patient history and clinical findings. A biopsy is not necessary in most cases but may be employed to support the diagnosis in difficult cases. Laboratory investigations are not helpful for confirming the diagnosis but can identify patients with coexisting B. burgdorferi infection. Ultrasound examination with a 13 MHz probe may be capable of quantifying the degree of dermal atrophy in APP but is not necessary or routinely used in clinical practice [18].

History and physical examination — The progressive development of asymptomatic, depressed, ovoid areas of skin with sharply demarcated borders on the trunk or extremities strongly suggests APP when a history of inflammation or induration at affected sites is absent. Limitation of these features to a Blaschkoid distribution suggests the alternative diagnosis of linear atrophoderma of Moulin (figure 1).

A history of preceding skin inflammation and induration is suggestive of classic morphea. All patients should receive a full skin examination to evaluate for clinical manifestations of morphea. (See 'Differential diagnosis' below and "Pathogenesis, clinical manifestations, and diagnosis of morphea (localized scleroderma) in adults", section on 'Clinical manifestations' and "Juvenile localized scleroderma", section on 'Clinical manifestations'.)

Biopsy — The diagnosis of APP is primarily a clinical diagnosis. A skin biopsy may be used, particularly if morphea is in the differential diagnosis; however, the histologic changes may be subtle or nondiagnostic, particularly in early disease. (See 'Histopathology' above.)

The preferred type of biopsy in adults is a wedge (elliptical) biopsy or a 6 to 8 mm punch biopsy. In children, a smaller 4 mm punch biopsy may be preferable in order to limit scarring. Regardless of the type of biopsy performed, the specimen should include both affected and adjacent normal skin, and the specimen should be sectioned to include both portions. This facilitates the detection of subtle abnormalities within affected skin. (See "Skin biopsy techniques".)

Laboratory studies — There are no serologic markers that confirm a diagnosis of APP. Serologic evidence of inflammation is absent. Unlike morphea, there is no association with autoantibodies. (See "Pathogenesis, clinical manifestations, and diagnosis of morphea (localized scleroderma) in adults", section on 'Serum autoantibodies'.)

The relationship between B. burgdorferi infection and APP remains uncertain; therefore, the value of serologic testing for B. burgdorferi infection is unclear. It is our preference to obtain serologic testing in patients with recent-onset APP in areas where Lyme disease is endemic because of the potential benefit of antibiotic therapy. (See 'Treatment' below and "Treatment of Lyme disease".)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of APP includes disorders characterized by cutaneous or subcutaneous atrophy:

●End-stage morphea – The clinical course of morphea consists of an early inflammatory stage characterized by erythematous patches or plaques followed by sclerosis manifesting as firm, bound-down plaques and eventual progression (after months to years) to atrophic hypopigmented or hyperpigmented plaques (picture 2A-C). The atrophic stage of morphea may exhibit epidermal atrophy (shiny, thin epidermis), dermal atrophy (poorly demarcated skin depressions with visible veins), and/or subcutaneous atrophy (poorly demarcated, deep loss of tissue). In contrast, APP exhibits well-circumscribed atrophy with a cliff drop-like border. The preceding history of inflammatory and sclerotic stages also helps to distinguish morphea from APP. (See "Pathogenesis, clinical manifestations, and diagnosis of morphea (localized scleroderma) in adults", section on 'Clinical manifestations' and "Juvenile localized scleroderma", section on 'Clinical manifestations'.)

●Atrophoderma of Moulin – Atrophoderma of Moulin is a rare disorder that begins in childhood or adolescence. The disorder usually occurs on the trunk or extremities and presents with a unilateral band of hyperpigmented and atrophic plaques that follow the lines of Blaschko [19]. Inflammation is absent. The Blaschkoid distribution differentiates atrophoderma of Moulin from APP.

●Disorders associated with subcutaneous atrophy – Dermal atrophy can be difficult to differentiate clinically from subcutaneous atrophy. Clinical signs that suggest subcutaneous atrophy rather than dermal atrophy secondary to APP include deep depressions, poorly demarcated borders, and a lack of pigmentary changes. Examples of causes of subcutaneous atrophy include local corticosteroid or insulin injections and chemical, physical, or inflammatory panniculitides (picture 3). The patient history is useful for identifying corticosteroid or insulin-related atrophy. A biopsy can be useful for diagnosing panniculitides. (See "Intralesional corticosteroid injection", section on 'Adverse effects and pitfalls' and "Panniculitis: Recognition and diagnosis".)

In addition, hyperpigmentation in APP should be distinguished from other causes of patchy cutaneous hyperpigmentation, such as lichen planus pigmentosus, erythema dyschromicum perstans (ashy dermatosis), and phytophotodermatitis. The presence of underlying skin depressions distinguishes APP.

TREATMENT — Although APP is a benign, asymptomatic, and non-life-threatening disorder, patients may seek treatment because of the disfiguring effects of APP. Treatment with topical corticosteroids, topical calcineurin inhibitors, oral antibiotics [9,12], or hydroxychloroquine [20] has been suggested based upon clinical experience; however, randomized trials are lacking and no treatment has been proven effective for improving the clinical manifestations or halting progression of the disease.

Cosmetic camouflage makeup can be used to decrease the appearance of APP [21]. A case report suggests that treatment of the associated hyperpigmentation with a Q-switched alexandrite laser may also improve the appearance of APP [22].

Treatment with an oral antibiotic regimen effective against B. burgdorferi infection is appropriate for patients with positive serology for B. burgdorferi infection. However, the efficacy of such a regimen is uncertain. In a retrospective study of 34 patients with APP (of which 10 of 26 patients tested for antibodies against B. burgdorferi with indirect immunofluorescence tested positive), 20 of 25 patients treated with oral penicillin (2 million units per day for two to three weeks), oral tetracycline (500 mg three times per day for two weeks), or both antibiotics showed clinical improvement and did not develop new active lesions during follow-up periods ranging from three months to eight years [9]. However, four of the six patients who did not receive antibiotic therapy and were available for follow-up also had no evident progression of disease. A separate case report describes improvement in the depth of APP lesions in a woman with positive serum immunoglobulin M antibodies to B. burgdorferi during treatment with doxycycline (200 mg per day for three weeks) [12].

There are insufficient data to determine the best approach to antibiotic treatment. Patients with recent onset of APP may be the best candidates for treatment. Standard early Lyme disease treatment protocols can be used. (See "Treatment of Lyme disease", section on 'Early localized disease (single erythema migrans)'.)

General principles of the management of B. burgdorferi infection are reviewed in detail separately. (See "Treatment of Lyme disease".)

PROGNOSIS — The long-term outcome of APP is usually good. It is likely that spontaneous improvement occurs over decades in many cases.

FOLLOW-UP — Given the potential overlap between APP and morphea, long-term periodic follow-up of patients with APP to assess for signs of morphea (ie, skin inflammation, induration, and thickening) is prudent. Follow-up visits are also useful for monitoring disease progression and addressing patient (or parent/caregiver) questions and concerns, particularly for patients with recent-onset APP and pediatric APP. We suggest performing a skin examination at least once yearly.

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Atrophoderma of Pasini and Pierini (APP) is a rare cutaneous disorder characterized by dermal atrophy. APP can occur at any age but most often begins in the second or third decade of life. (See 'Epidemiology' above.)

●Pathogenesis – The pathogenesis of APP is unclear. An immunologic mechanism has been proposed. Borrelia burgdorferi infection may also be a contributor. (See 'Pathogenesis' above.)

●Relationship with morphea – The relationship between APP and morphea is controversial. Some authors consider APP a distinct disease entity, whereas others consider it a condition on the spectrum of morphea. (See 'Relationship with morphea' above.)

●Clinical manifestations – The classic clinical findings of APP are ovoid, depressed areas of skin with sharply demarcated "cliff-drop" borders (picture 1). Dyspigmentation, particularly hyperpigmentation, is usually present. Inflammation and skin induration are absent. The trunk and extremities are the most common sites of involvement. (See 'Clinical manifestations' above.)

●Diagnosis – A diagnosis of APP usually can be made based upon the patient history and skin examination. A biopsy may be helpful for supporting the diagnosis in difficult cases. Testing for B. burgdorferi infection is indicated in Lyme disease endemic areas. (See 'Diagnosis' above.)

●Treatment – APP is a benign disorder; however, APP can be disfiguring. No treatment has been proven effective for APP. For patients found to have positive serology for B. burgdorferi infection, we suggest antibiotic therapy (Grade 2C). (See 'Treatment' above.)

●Prognosis and follow-up – Spontaneous improvement in APP may occur over decades. Given the potential relationship between APP and morphea, patients with APP should be examined periodically for clinical signs of morphea. (See 'Prognosis' above and 'Follow-up' above.)