Are You Confident of the Diagnosis?

In order to be confident in the diagnosis of a perforating disorder, one must acknowledge the historical ambiguity in classifying these disorders. In the past, these disorders have included elastosis perforans serpiginosum (EPS), reactive perforating collagenosis (RPC, pediatric and adult forms), perforating folliculitis (PF), Kyrle’s disease, perforating disorder of renal disease and other variants. However, the clinical and histologic similarities among the cases associated with diabetes and renal disease outweigh their differences and present a compelling reason to consider them variants of the same disease process. Acquired perforating dermatosis (APD), EPS (see separate chapter) and pediatric RPC are sufficiently different to be considered independent clinical entities.

What you should be alert for in the history

Acquired perforating dermatosis (APD) is strongly associated with pruritus, chronic renal failure, and/or diabetes mellitus. In the majority of cases, the chronic renal failure necessitating dialysis is due to diabetic nephropathy, although renal disease secondary to hypertension has also been described. Thus, the most important aspects on history are those of diabetes, renal failure, hemodialysis or peritoneal dialysis. A history of pruritus and chronic rubbing/scratching of the lesions is also important. Lesions may develop in scratch marks as a result of Koebner phenomenon and can have a striking linear configuration.

In establishing a diagnosis of a perforating disorder, in addition to the above historic features, it is important to consider the age of onset as reactive perforating collagenosis (RPC) and EPS tend to present in childhood while APD, including adult form of RPC, Kyrle’s disease (KD) and perforating folliculitis (PF) arise in adults. A history of preceding trauma is typical of RPC.

Characteristic features on physical examination

Umbilicated, dome-shaped, 1-10 mm keratotic papules with central keratinous crusts are the clinical hallmarks of all the perforating disorders (Figure 1. Lesions are preferentially localized over the extensor aspects of the arms and legs, but any cutaneous surface may be involved, including, but not limited to, trunk and scalp. Lesions on the conjunctiva and buccal mucosa have been described in a patient with Kyrle’s disease.

Figure 1.

Hyperkeratotic papules of APD.

If keratotic papules are seen in a periumbilical distribution, particularly in multiparous black women, a diagnosis of perforating periumbilical calcific elastosis (also known as periumbilical pseudoxanthoma elasticum) can be considered. Often, a “crunchy” or “grinding” sound is described during a biopsy of such lesions.

Pruritus is virtually universal in these patients, resulting in chronic rubbing/scratching which leads to hyperkeratotic papules and plaques. Removal of the central keratotic plug often leaves a small, bleeding crater, which may heal with a shallow scar or dyspigmentation. Lesions develop slowly over months to years and may be present in different stages of development, from pinhead-sized new lesions to older, verrucous, clefted, cherry-sized established lesions with central cone-shaped, horny mass.

Expected results of diagnostic studies

Histologically, the lesions of APD are also similar, each showing invagination of the epidermis around a central plug containing basophilic debris. In RPC, collagen bundles perforate through the epidermis, whereas in perforating folliculits there is follicular perforation and spilling out of follicular contents into the dermis. Occasionally, a hair can be seen and serial sectioning may be necessary to visualize a hair shaft. Patients have also been reported in whom lesions had variably showed the histology of PF, RPC, and KD. Elimination of both collagen and elastin has been documented in a number of cases, providing further support to the concept of a unified diagnosis of “acquired perforating dermatosis.”

When the underlying disease is not evident, additional laboratory investigations may include chemistry screen with BUN, creatinine, liver function tests, serum glucose levels and glucose tolerance tests.

Diagnosis confirmation

Clinical differential diagnosis of APD includes prurigo nodularis, hypertrophic lichen planus (however, a central hyperkeratotic plug is missing in these two), multiple keratoacanthomas, arthropod bites, folliculitis, phrynoderma of vitamin A deficiency, dermatofibromas and excoriated dermal diseases such as granuloma annulare. If there is evidence of Koebnerization, psoriasis, lichen planus and verrucae vugaris may be considered.

Diagnosis is made clinically and by skin biopsy. Differentiation between the different forms of perforating disorders can be accomplished with the use of Masson trichrome stains for collagen (RPC), Verhoeff-van Gieson stains for elastic tissue (EPS), and step-sectioning to visualize hair follicles (PF). Typically, a diagnosis of diabetes and renal failure will be known to the patient presenting with perforating skin lesions.

In the original description of RPC, renal failure and diabetes were not noted. However, most acquired perforating disorders are seen in association with kidney failure, diabetes or both. Other reported associations have included hypothyroidism, hyperparathyroidism, hepatic disorders, HIV infection as well as primary sclerosing cholangitis. Some of these reported associated conditions may be coincidental findings.

Who is at Risk for Developing this Disease?

Most acquired perforating disorders are seen in association with renal failure, diabetes, peritoneal dialysis or all of the above. APD affects about 10% of dialysis patients. Other, less common associations reported in the literature are hypothyroidism, hyperparathyroidism, liver disorders, HIV infection, Hodgkin disease, primary sclerosing cholangitis, and a number of other sporadic diseases. Several cases have been reported in association with scabies and are primarily attributable to scratching.

What is the Cause of the Disease?
Etiology

The perforating diseases of the skin are characterized by transepidermal elimination (TEE) of various dermal connective tissue components through the epidermis. The material extruded from the dermis through the epidermis may include collagen and elastin (in classic perforating dermatoses), but some authors extend the list to include inflammatory cells, red blood cells, microorganisms, calcified material, neoplastic cells and extracellular substances, such as mucin.

Historically, the four classic perforating dermatoses have included Kyrle’s disease (hyperkeratosis follicularis et parafollicularis in cutem penetrans), PF, RPC and EPS (considered in a separate chapter). Classification of these disorders is controversial, with many physicians now recognizing three main perforating disorders: elastosis perforans serpiginosa, pediatric reactive perforating collagenosis, and acquired perforating dermatosis. Thus, Kyrle’s disease, perforating folliculitis and adult reactive perforating collagenosis are considered on a spectrum of acquired perforating dermatosis as all three occur in patients with diabetes, chronic renal failure or on dialysis. However, perforating folliculitis, Kyrle’s disease, and RPC may be distinct entities when they occur outside the setting of renal dialysis and diabetes.

Pathophysiology

The precise mechanism of development of the perforating dermatoses is unknown. Trauma is a major trigger for all of the perforating dermatoses and in familial cases of RPC it is the most important factor. However, the molecular events to explain the development of lesions following trauma are unclear.

The term “perforation” implies an active process. However, it is difficult to envision elements of dermal connective tissue or hair shafts actively perforating into the epithelium and therefore the term “transepidermal elimination” is a more accurate concept where viable epidermis plays an active role in the process. Several factors have been implicated in the pathogenesis of acquired perforating dermatosis. Altered dermal collagen, either as a result of superficial trauma or a genetic susceptibility likely underlies the pathogenesis of RPC.

In patients with diabetes and uremia, the serum level and dermal matrix deposition of fibronectin is increased. Fibronectin plays a major role in cell adhesion, growth, migration, differentiation and wound healing. It interacts with type IV collagen, a constituent of basement membranes, as well as keratinocytes and may promote epithelial proliferation leading to formation of perforating channels.

Vitamin A metabolism may play a role as vitamin A levels are elevated during dialysis. Other proposed mechanisms include abnormal vitamin D metabolism, microvasculopathy and dermal microdeposits of crystalline substances, such as uric acid, hydroxyapatite and silicon in patients on dialysis.

Systemic Implications and Complications

The most important systemic associations are those of diabetes and chronic renal disease ,which is most often secondary to diabetic nephropathy. Thus, diagnosis and appropriate management of these underlying conditions is mandatory.

Treatment Options

Treatment options are summarized in Table I.

Table I.
Medical Treatment Surgical Procedures Physical Modalities
Minimize trauma and scratchingEmollients Surgical removal of lesionsRenal transplantation UVB phototherapyPUVACryotherapy
Topical corticosteroids with or without menthol and camphorKeratolyticsRetinoids    
AcitretinIsotretinoinDoxycyclineClindamycinAllopurinol    

PUVA, psoralen  plus ultraviolet A; UVB, ultraviolet B.

No specific therapy is uniformly effective for perforating disorders. The perforating disorders are notoriously difficult to treat. The prognosis is related to the underlying diseases, and treatment of the underlying cause can be effective.

Therapeutic options for perforating dermatoses include the following:

General measures involve protection from trauma and should include trimming of fingernails, avoidance of scratching, use of gloves to minimize scratching. Minimizing pruritus is important to control scratching. Pruritus can be managed initially with topical or intralesional corticosteroids, anesthetics, and counter-irritants (menthol or camphor). Oral antihistamines can be tried, but are usually minimally effective.

The topical regimen most commonly prescibed includes emollients, keratolytics, corticosteroids and retinoids.Topical application of retinoids, tretinoin 0.1% cream or tazarotene 0.1% gel, for 3 months can be tried first.

Physical modalities include broadband and narrowband ultraviolet B irradiation, psoralen plus ultraviolet A (PUVA), cryotherapy, as well as surgical removal of lesions combined with oral clindamycin. Ultraviolet B (UVB) phototherapy is dramatically effective for diminishing both pruritus and cutaneous lesions. UVB phototherapy sessions, three times a week for 6 weeks need to be carried out before therapy could be deemed ineffective. For limited disease, cryotherapy can be efficacious.

Systemic treatments, reported with inconsistent efficacy, include acitretin, 30mg daily, isotretinoin, 1 mg/kg in two divided doses daily, doxycycline, 100-200mg daily in two divided doses and allopurinol, 100mg daily.

Remissions following renal transplantation have been described.

Optimal Therapeutic Approach for this Disease

Since there are no randomized, placebo-controlled studies evaluating the efficacy of different treatment modalities, the current available evidence consists of isolated case reports or case series. The therapeutic ladder employed by many clinicians includes topical corticosteroids and UVB phototherapy. Typically, two to three weekly phototherapy sessions for 4-6 weeks are required to see improvement.

If UVB phototherapy and topical corticosteroids are ineffective, oral retinoids and allopurinol can be tried. It has been suggested that remissions in patients treated with allopurinol result from immunomodulating, pro-differentiation and antioxidative properties of allopurinol, besides its urocostatic effect.

Patient Management

It is important to educate the patient about the association with renal disease and diabetes and the need to be followed closely by a nephrologist and/or endocrinologist. Patients can be followed at reasonable intervals depending on degree of symptoms and should be informed that treatment options are not uniformly effective and may require a “trial and error” approach.

Unusual Clinical Scenarios to Consider in Patient Management

It should be remembered that, although rare, APD has been associated with hypothyroidism, hyperparathyroidism, liver disease, HIV, primary sclerosing cholangitis, and a number of other sporadic disorders. A careful review of systems may be used to determine if further physical examination or investigations are warranted.

What is the Evidence?

Chang, P, Fernandez, V. “What are the perforating diseases”. Int J Derm. vol. 32. 1993. pp. 407-8. (An overview of the main perforating dermatoses.)

Karpouzis, A, Giatromanolaki, A, Sivridis, E, Kouskoukis, C. “Acquired reactive perforating collagenosis: current status”. J Dermato. vol. 37. 2010. pp. 585-92. (The possible biochemical or immunological mechanisms of the systemic diseases potentially responsible for the development and appearance of acquired reactive perforating collagenosis, as well as treatment options are discussed.)

Ohe, S, Danno, K, Isei, T, Okamato, H, Horio, T. “Treatment of acquired perforating dermatosis with narrow band ultraviolet B”. J Am Acad Dermatol. vol. 50. 2004. pp. 892-4. (Effective narrowband treatment of acquired perforating dermatosis is described in five patients. Phototherapy was given 2 or 3 times weekly. The dose was started at 400 mJ/cm2 and increased to a maximum of 1500 mJ/cm2. All lesions disappeared completely after 10 to 15 exposures without adverse effects. Two patients with diabetes mellitus but without chronic renal failure experienced no recurrence until 5 and 10 months after stopping the phototherapy. One patient undergoing hemodialysis for chronic renal failure experienced a recurrence of pruritus and small papules after 1 month. Two patients undergoing hemodialysis showed no recurrence during narrowband UVB maintenance therapy until 7 and 8 months.)

Patterson, J.Y. “The perforating disorders”. J Am Acad Dermatol. vol. 10. 1984. pp. 561-81. (An excellent review of perforating dermatoses, describing the mechanisms, histopathological features, treatment modalities as well as some of the difficulties in classification of these disorders.)

Poliak, SC, Lebwohl, MG, Parris, A, Prioleau, PG. “Reactive perforating collagenosis associated with diabetes mellitus”. N Engl J Med. vol. 306. 1982. pp. 81(RPC lesions were found in 6 out of 15 patients witrh diabetes mellitus and chronic renal disease.)

Querings, K, Balda, BR, Bachter, D. “Treatment of acquired reactive perforating collagenosis with allopurinol”. Br J Dermatol. vol. 145. 2001. pp. 174-6. (A 57-year-old diabetic woman with RPC was treated with 100mg of allopurinol daily, with complete resolution of the lesions in 7 weeks.)

Rapini, RP, Herbert, AA, Drucker, CR. “Acquired perforating dermatosis. Evidence for combined transepidermal elimination of both collagen and elastic fibers”. Arch Dermatol. vol. 125. 1989. pp. 1074-8. (Histological features of all four classic perforating diseases are described as occuring in the same patients; thus a convincing argument is made to designate these patients as having acquired perforating dermatosis rather than subclassifying them into one of the four major perforating diseases.)

Saray, Y, Seckin, D, Bilezikci. “Acquired perforating dermatosis: clinicopathological features in twenty-two cases”. JEADV. vol. 20. 2006. pp. 679-88. (Cases of APD are described with systemic associations other than diabetes or renal failure.)

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