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Late-onset focal dermal elastosis: Report of a case and review of the literature

Late-onset focal dermal elastosis is a rare cutaneous condition classified as an increased dermal elastic tissue disorder. It is distinguished clinically by multiple papules with a preference for the neck and other flexures, as well as histologically by focally increased elastic fibers in the reticular dermis. Several elastic tissue disorders in the skin have a similar clinical presentation. The distinction between late-onset focal dermal elastosis and other pseudoxanthoma elasticum mimickers is critical because they are not associated with systemic lesions. We present a case of late-onset focal dermal elastosis and conduct a literature review on this unusual condition.


Introduction
Several elastic tissue disorders share a similar clinical presentation in the skin, i.e. multiple small papules symmetrically distributed in the flexural areas. Pseudoxanthoma elasticum (PXE) represents the prototype of such clinical picture, but a number of other elastic tissue disorders may present with a similar appearance of "PXE-like" features. Late-onset focal dermal elastosis (LOFDE) is a rare, acquired cutaneous disorder first described in 1995, 1 characterized clinically by multiple papules in a PXE-like appearance, without systemic alterations, and histologically by focally increased elastic fibers in the reticular dermis. We report here on a case of LOFDE and review the scientific literature on this unusual condition.

Case report
A 70-year-old Italian woman presented with a 4-year history of a bilateral, slowly extending, papular eruption of the axillae. Cutaneous examination showed 2-4 mm firm, yellow white, partly coalescing, non-follicular papules symmetrically distributed along the posterior axillary folds (Figure 1). No other cutaneous folds were affected. The lesions were asymptomatic, but the patient referred that at first, they were itchy and erythematous. Her medical history revealed a primary cutaneous follicular non-Hodgkin lymphoma of the right groin 15 years previously, treated with surgery, chemotherapy, and radiotherapy. A grade 1 urinary bladder carcinoma was removed one year before. No ocular, cardiovascular, gastrointestinal or pulmonary symptoms were present.
A punch-biopsy of a representative papule showed dermal fibrosis at H&E staining. Verhoeff elastic tissue stain showed increase of thick, interlacing elastic fibers in the mid and deep reticular dermis. Fragmentation, calcification or phagocytosis of elastic fibers were no seen. Mild atrophy of the epidermis and edema in the papillary dermis were also evident ( Figure 2).

Discussion
LOFDE is a rare cutaneous condition classified within the disorders of increased dermal elastic tissue. 2 Increase of dermal elastic tissue is a feature seen in a number of inherited and acquired disorders, including LOFDE, linear focal elastosis, elastofibroma, nevus elasticus, and Buschke-Ollendorff syndrome. Elastic tissue disorders presenting with a PXE-like appearance, i.e. symmetrical, non-follicular papules distributed along the major folds, often require histology and elastic tissue stains to be diagnosed. Distinction of LOFDE and other PXE mimickers from PXE is critical, as they are not associated to systemic lesions.
PXE is a genetic disease induced by autosomal recessive mutations in the ABCC6 gene, that make elastic tissue prone to mineralization. 3 The onset is in childhood or early adolescence, with yellowish papules appearing and coalescing on the major folds. Later on, skin laxity develops. Histology is characteristic, showing fragmentation of the elastic fibers and calcium deposits in the dermis. Internal organs may be affected. Mineralization of the Bruch membrane of the retina leads to angioid streaks and retinal hemorrhages. Involvement of the internal elastic lamina and tunica media of small-and mediumsized arteries may cause vascular disorders such as gastrointestinal bleeding, as well as cardiac and cerebral ischemia.
Other cutaneous conditions, without systemic involvement, share a similar clinical presentation with PXE, and must be considered in the differential diagnosis. PXE-like papillary dermal elastolysis (PXE-PDE) affects predominantly females in late adulthood. It is characterized by band-like loss of elastic tissue in the papillary dermis, with normal collagen fibers. White fibrous papulosis of the neck presents with multiple, symmetrical, non-confluent, whitish papules on the neck, caused by increase in the papillary dermal collagen and loss of elastic fibers in the papillary and reticular dermis. Because of the common characteristics, i.e. late onset, similar clinical presentation, histologic features typical of intrinsic aging (decreased elastic fibers in the papillary dermis with or without increased collagen fibers), these conditions Publisher's note: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
have been classified under the term "agerelated fibroelastolytic syndromes". 4 Nevus elasticus (or elastoma) is a connective tissue nevus, histologically featuring increased dermal elastic tissue. It is either congenital or appears during the first years of life as single or multiple, disseminated or clustered yellow papules or nodules in the face, trunk and extremities. The disseminated nodular form (dermatofibrosis lenticularis disseminata) may be heritable and in association with osteopoikilosis (focal addensation of bone tissue) constitutes the autosomal dominant Buschke-Ollendorff syndrome. Age of onset and the different distribution of the cutaneous lesions help to differentiate this syndrome from LOFDE. 2 Linear focal elastosis also displays a histologic picture of increased elastic tissue staining in the reticular dermis. Elastic fibers appear fragmented and aggregated. The clinical presentation displays asymptomatic, yellow or red, indurated and palpable linear cords, distributed symmetrically in the lumbar-sacral region and proximal extremities. It preferentially affects males and is not considered an age-dependent, nor actinic process. 2 Finally, a case of "papillary dermal elastosis" in a 33-year-old woman has been reported, characterized by scattered 1-2 mm white-to-yellow papules on the upper back and neck region. Histologically, foci of clumped, granular elastic tissue, alternating with foci of decreased elastic fibers were seen within the papillary dermis. Based on the focal clumping of elastic fibers and young age, it has been proposed that this case may be distinct from PXE-PDE. 5 LOFDE clinically presents with a longstanding history of progressively increasing, 2-4 mm flat-topped papules, symmetrically distributed in the flexural areas (neck, axillae, groin, popliteal and antecubital folds), which may coalesce in plaques. Lesions may be asymptomatic or pruritic. It is characterized histologically by focal increase, in the reticular dermis, of normal appearing elastic fibers, which present, with elastic tissue staining, as aggregates among collagen fibers without calcium deposition. The papillary dermis is unaffected. 1 LOFDE is not associated to systemic diseases; so far, no specific treatment has been described. LOFDE affects preferentially patients after the sixth decade, but a few reports relate to younger patients (18 years [6][7][8] The term "focal dermal elastosis" has been proposed as an update of the nomenclature to include also these earlier presentations. 9 However, the cases in younger patients differ also in other clinical features from classic presentation, e.g. association with acrogeria, 6 familiarity, 7 or acral distribution. 5,7 From a review of the cases reported in the literature ( Table 1) it appears that under the term of LOFDE have been grouped heterogeneous clinical presentations, solely on the basis of the histologic trait of increased dermal elastic tissue. The pathogenesis of LOFDE is still unclear. Clinical (late onset in nonexposed areas) and histologic features (absence of solar elastosis) suggest that the condition may result from an intrinsic aging process rather than from sun damage. It has been suggested that an increased elastin synthesis, rather than a reduction of elastin degradation, is involved in LOFDE, as mRNA levels of elastin as well as the expression of other molecules related to elastin metabolism, such as fibrillin-1, fibulin-5, latent transforming growth factor-ßbinding protein-2 (LTBP-2) and LTBP-4 are increased. 10,11 Location on flexural regions might suggest a role for repetitive mechanical stress. The condition may have a higher prevalence and be underreported, because it is clinically subtle and often asymptomatic, and histopathological recognition requires elastic fiber staining in addition to routine histology. In the first report of LOFDE, Authors stated that they had seen several similar cases in the elderly but could not confirm the diagnosis by histological examination. 1