Reactive Perforating Collagenosis
Updated: Feb 22, 2022
Author: Rachel M Fisher, MBChB, MRCP; Chief Editor: Dirk M Elston, MD
Overview
Practice Essentials
Reactive perforating collagenosis is a rare skin disorder characterized by the transepidermal elimination of altered collagen through the epidermis. The 2 distinct forms of are an inherited form that manifests in childhood and an acquired sporadic form that occurs in adulthood.
The lesions of reactive perforating collagenosis are intensely itchy, leaving some scarring after resolution. These lesions often occur on a background of very itchy skin.
The inherited form of reactive perforating collagenosis is not associated with any systemic complications. The acquired form of reactive perforating collagenosis occurs in patients with multiple medical problems, but whether the development of the lesions implies a poorer prognosis is unclear. Many patients with the acquired form have diabetes mellitus or renal failure.
The 4 primary perforating diseases are reactive perforating collagenosis, elastosis perforans serpiginosum, Kyrle disease, and perforating folliculitis, although whether perforating folliculitis is a primary perforating disease has been questioned, given that ruptured follicles are a feature of many infective conditions.
Some authors reserve the term reactive perforating collagenosis for the rare inherited form of the disease, preferring the term acquired perforating dermatosis for the acquired form. This article describes both inherited reactive perforating collagenosis and acquired reactive perforating collagenosis.
Flesh-colored, umbilicated, dome-shaped papules or nodules as large as 10 mm in diameter are typical. Lesions are most commonly found on the extensor surfaces of the limbs and the dorsa of the hands.
Urea and creatinine determinations are needed to detect any underlying renal impairment.
Histologically, early lesions show epidermal hyperplasia and established lesions show a cup-shaped depression of the epidermis.
Lesions tend to be self-healing but recurrent. Topical steroids are usually not helpful, but intralesional steroids have been successful.[1]
Pathophysiology
The major abnormality in reactive perforating collagenosis is focal damage to collagen and the elimination of the disrupted collagen through the epidermis.[2] Superficial trauma (eg, scratching) may contribute to the etiology of reactive perforating collagenosis, and reactive perforating collagenosis is frequently associated with pruritus. For example, a 58-year-old woman was diagnosed with acquired reactive perforating collagenosis manifesting on the bilateral lower extremities secondary to minor depilatory trauma.[3] Cold may precipitate the lesions, especially in the inherited form.
The acquired form usually occurs in patients with diabetes or chronic renal failure, especially those receiving dialysis. Other associations with systemic diseases, such as malignancy, have been reported.
Faver et al proposed diagnostic criteria for the adult (acquired) form of reactive perforating collagenosis, as follows[4] :
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Elimination of necrotic basophilic collagen bundles into a cup-shaped epidermal depression as seen in biopsy specimens
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Umbilicated papules or nodules with a central, adherent keratotic plug
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Onset of lesions after age 18 years
Epidemiology
Inherited reactive perforating collagenosis is a rare disorder. The acquired form of reactive perforating collagenosis is more common, occurring in as many as 10% of patients receiving maintenance hemodialysis.[5, 6]
No racial variations in the incidence of reactive perforating collagenosis are reported, and the sexual incidence of reactive perforating collagenosis is equal. The inherited form of reactive perforating collagenosis usually presents in infancy or early childhood, but the acquired form of reactive perforating collagenosis occurs in adults. In a series of 22 patients with acquired reactive perforating collagenosis, the mean patient age at presentation was 56 years.[4]
Presentation
History
Small, keratotic papules develop after minor trauma. The lesions start as pin-sized lesions, and they grow into larger papules/nodules over a few weeks. They heal with minor scarring. In acquired perforating collagenosis, patients typically present with umbilicated papules and plaques on the extremities and trunk.[7]
Intense pruritus is a feature of the acquired form of reactive perforating collagenosis. Many patients have diabetes mellitus or renal failure, and many will be on hemodialysis.
A positive family history may be elicited in the childhood form of reactive perforating collagenosis.
Physical Examination
Skin lesions of reactive perforating collagenosis
Flesh-colored, umbilicated, dome-shaped papules or nodules as large as 10 mm in diameter are typical. They have an adherent, keratinous plug. A giant variant of reactive perforating collagenosis has been described.[8]
Reactive perforating collagenosis lesions may occur in a linear configuration, exhibiting the Koebner phenomenon.
Residual scarring may be seen from previously healed lesions.
Skin distribution of reactive perforating collagenosis
Lesions are most commonly found on the extensor surfaces of the limbs and the dorsa of the hands. Reactive perforating collagenosis lesions may also occur on the trunk and the face.
(See the image below.)
Typical keratotic papules.
Causes
The childhood form of reactive perforating collagenosis is inherited.[9] A number of affected families have been reported. The mode of inheritance is not clear. Reports of affected families reveal autosomal dominant inheritance, autosomal recessive inheritance, and sporadic cases.
A case has been described arising in a child with Down syndrome.[10]
The underlying cause of reactive perforating collagenosis is unknown, but an abnormal response to superficial trauma (eg, scratching) may be involved. Papules have been reported following scratches, acne spots, insect bites,[1] and scabies.[11] Lesions of reactive perforating collagenosis have been experimentally induced in susceptible skin by scratching.[12]
The acquired form of reactive perforating collagenosis may occur in association with chronic renal failure, often in a patient with underlying diabetes mellitus. In both the United Kingdom and the United States, the prevalence of this disorder in patients on dialysis is approximately 10%.[5, 6] While the pathogenesis of acquired perforating collagenosis is not well-understood, there appears to be a genetic component in some cases. Also, it has been suggested that microvasculopathy and trauma may act as triggers for collagen transdermal elimination and degeneration.[7]
The acquired form of reactive perforating collagenosis also can occur in association with other nephropathies without diabetes. Interestingly, both Akoglu et al and Bellinato et al found evidence that increased advanced glycation end-products may play a role in acquired perforating collagenosis pathogenesis.[13, 14] Akoglu et al reported discovering overexpression of the receptor for advanced glycation end-products in an analysis of 41 patients, independent of diabetes status.[13]
Acquired reactive perforating collagenosis has been reported in association with hypothyroidism, hyperparathyroidism, liver dysfunction,[4] dermatomyositis,[15] and rheumatoid vasculitis.[16] In a single case, a woman was initially diagnosed with polymorphic eruption of pregnancy at 17 weeks' gestation. Her skin condition evolved morphologically, and she was reevaluated at 24 weeks' gestation and diagnosed with acquired reactive perforating collagenosis.[17]
Malignancies, including lymphoma, hepatocellular carcinoma,[18] periampullary carcinoma,[19] and thyroid cancer,[20] have been associated with the acquired form of reactive perforating collagenosis.
Indinavir has induced reactive perforating dermatosis in 2 patients with HIV disease, and sorafenib was associated with acquired reactive perforating collagenosis in a single patient with HIV.[21, 22] . Ranibizumab injections have also been associated with acquired reactive perforating collagenosis, but the condition resolved after the patient was switched to aflibercept.[23]
DDx
Differential Diagnoses
Workup
Laboratory Studies
The purpose of any investigation is to search for underlying causes, particularly causes of pruritus.
Urea and creatinine determinations are needed to detect any underlying renal impairment. A creatinine clearance test and other more complex renal investigations may be required.
Ferritin levels and a full blood cell count can help detect anemia. Low iron stores can cause pruritus.
Random glucose testing can help detect diabetes.
Skin biopsy is essential to make a diagnosis.
Histologic Findings
The histology varies with the stage of the reactive perforating collagenosis. Early lesions show epidermal hyperplasia associated with underlying degenerate basophilic collagen fibers. In established lesions, a cup-shaped depression of the epidermis associated with a keratin plug containing parakeratosis, inflammatory debris and collagen fibers can be seen.
(See the image below.)
Cup-shaped invagination of the epidermis associated with a keratin plug containing inflammatory debris and collagen fibers.
Vertically orientated basophilic collagen fibers are seen in the underlying dermis, with focal extrusion through the epidermis.
Vertically orientated collagen fibers are extruded into the overlying keratin plug.
The epidermis is atrophic and may show ulceration. However, at the edges of the cup-shaped invagination, the epidermis is hyperplastic. Additionally, a mild perivascular lymphohistiocytic infiltrate can be seen.
Extruded collagen fibers may be demonstrated with elastic van Gieson (EVG) staining, which stains the fibers red. No extrusion of elastic fibers should be seen (staining black with EVG).
An elastic van Gieson stain demonstrating the expulsion of collagen fibers (red) into the overlying keratin plug.
Treatment
Medical Care
Treatment of reactive perforating collagenosis lesions is often unsatisfactory; in many cases, the lesions are self-healing, but usually are recurrent.
Anecdotal reports describe successful therapy for reactive perforating collagenosis with retinoids,[24] allopurinol,[25, 8] doxycycline,[26] UVB,[27] and psoralen ultraviolet light A.[28] Phototherapy is a good choice for patients with coexistent renal disease and associated pruritus. Narrowband UVB phototherapy has been helpful in a case of familial reactive perforating collagenosis in a child.[29] Narrowband UVB phototherapy combined with doxycycline was successful in treating acquired reactive perforating collagenosis in a 32-year-old male.[30]
Topical steroids are usually not helpful, but intralesional steroids have been successful.[1]
Emollients and systemic antihistamines seem helpful in controlling pruritus.
In cases of acquired reactive perforating collagenosis, García-Malinis et al recommend discontinuing treatment with biologics.[31] A 23-year-old patient with acquired reactive perforating collagenosis was successfully treated with an 8-week course of itraconazole, even though there was no fungal infection present.[32] Additionally, Ying et al report favorable results with dupilumab monotherapy in 2 elderly patients with acquired reactive perforating collagenosis associated with atopic dermatitis.[33]