Testing whether all eigenstates obey the eigenstate thermalization hypothesis.

CONTINUING

MEDICAL EDUCATION

Acquired disorders of elastic tissue: Part II. Decreased elastic tissue Kevan G. Lewis, MS,a Lionel Bercovitch, MD,a Sara W. Dill, MD,a and Leslie Robinson-Bostom, MDa,b Providence, Rhode Island Elastic fibers in the extracellular matrix are integral components of dermal connective tissue. The resilience and elasticity required for normal structure and function of the skin are attributable to the network of elastic tissue. Advances in our understanding of elastic tissue physiology provide a foundation for studying the pathogenesis of elastic tissue disorders. Many acquired disorders are nevertheless poorly understood owing to the paucity of reported cases. Several acquired disorders in which loss of dermal elastic tissue produces prominent clinical and histopathologic features have recently been described, including middermal elastolysis, papular elastorrhexis, and pseudoxanthoma-like papillary dermal elastolysis, which must be differentiated from more well-known disorders such as anetoderma, acquired cutis laxa, and acrokeratoelastoidosis. (J Am Acad Dermatol 2004;51:165-85.) Learning objective: At the conclusion of this learning activity, participants should have an understanding of the similarities and differences between acquired disorders of elastic tissue that are characterized by a loss of elastic tissue.

I

n the first of this 2-part series, we reviewed the spectrum of acquired elastic tissue disorders that are characterized by an increase in elastic tissue, as well as the solar elastotic dermatoses. In this second part, we cover the family of acquired elastic tissue disorders in which loss of elastic tissue (elastolysis) results in distinctive clinical and histopathologic features (Table I).

NEVUS ANELASTICUS Definition. Nevus anelasticus is an elastic tissue nevus disorder characterized by perifollicular papules and fragmentation or absence of elastic tissue. History. Lewandowsky in 1921 described a subset of connective tissue nevi that commonly presents as grouped perifollicular papules on the pectoral region and that, at histopathologic examination, primarily or exclusively involves elastic tissue. He subsequently coined the term nevus elasticus.1,2 From the Departments of Dermatologya and Pathology,b Brown Medical SchooleRhode Island Hospital. Funding sources: Supported in part by an unrestricted grant from PXE International, Inc. Conflicts of interest: None identified. Reprint requests: Leslie Robinson-Bostom, MD, Department of Dermatology, Brown Medical School, Rhode Island Hospitale APC 10, 593 Eddy St, Providence, RI 02903. E-mail: [email protected]. 0190-9622/$30.00 ª 2004 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2004.03.016

Staricco and Mehregan in 1961 proposed the term nevus anelasticus to distinguish between connective tissue nevi in which elastic tissue is increased (nevus elasticus or elastoma) from connective tissue nevi in which there is loss of elastic tissue (nevus anelasticus).2 Epidemiology. Few cases of nevus anelasticus have been reported in the English language literature. Due to the asymptomatic nature of this disorder, affected persons may not seek medical attention. Hence the true prevalence may be underestimated. Etiology and pathogenesis. Both congenital and acquired forms of elastic tissue nevi have been reported. As a class, connective tissue nevi are dermal connective tissue hamartomas and are characterized by an accumulation of collagen, proteoglycans, or elastic tissue.3 As such, characterization of nevus anelasticus as a connective tissue nevus may not be appropriate. Clinical manifestations. Nevus anelasticus may present as multiple flat, pink or red, perifollicular papules a few millimeters in diameter and are typically distributed in asymmetric clusters over the upper trunk, especially the chest and arms.1 New lesions may occur over the course of several years. Histopathology. Histopathologic examination reveals loss of elastic tissue, with fragmentation of the residual elastic fibers in the upper and mid dermis and little or no change in collagen bundles.4,5 Associated conditions. Extracutaneous manifestations have not been reported. 165

166 Lewis et al

J AM ACAD DERMATOL AUGUST 2004

Table I. Disorders of decreased elastic tissue Disorder

Epidemiology

Nevus anelasticus

Few cases reported

Papular elastorrhexis

F [ M; 2nd decade

Perifollicular elastolysis

3 cases reported; may be associated with elastase-producing Staphylococcus epidermidis F [ M; children and adults

Anetoderma

Clinical Features

Histopathology

Multiple flat, pink to red papules in asymmetric clusters on upper part of trunk and on arms Asymptomatic, firm, nonfollicular, 1- to 5-mm-diameter white papules on trunk and upper extremities 1- to 4-mm-diameter, gray to white, finely wrinkled, round follicular papules on neck, earlobes, arms, and trunk Multiple 5- to 25-mmdiameter, round, finely wrinkled, atrophic, flaccid, saclike patches of skin

Loss of elastic tissue and fragmentation of elastic fibers in upper and mid dermis Fragmentation and loss of elastic tissue in reticular dermis; may see perivascular lymphohistiocytic dermal inflammation Loss of elastic fibers surrounding hair follicles; absence of inflammation

Acquired cutis laxa

M = F; adults [ children; no racial predilection

Insidious onset of pendulous, coarsely wrinkled skin on face; risk of systemic elastolysis

Postinflammatory elastolysis and cutis laxa

F [ M; infants and children; most cases in Africa and South America

White fibrous papulosis of neck

Ages 39e80 y; Japanese males; Western European and Middle Eastern females

PXE-like papillary dermal elastolysis

F [ M; 63e80 y

Middermal elastolysis

F [ M, 30e50 y

Bright red, pruritic, 2- to 10-cm-diameter plaque; resolves, leaving wrinkling and hyperpigmentation on face, ears, and neck Multiple (10e20) asymptomatic symmetric, discrete, 2- to 3-mm-diameter, nonfollicular, white or pale papules on neck Multiple yellow, symmetric, nonfollicular papules coalescing into plaques on neck, flexor forearms, or axillae Urticarial, erythematous plaques resolve, leaving asymptomatic, finely wrinkled patches on neck, trunk, upper extremities

Loss of elastic tissue; histopathologic study and EM may also show fragmentation of elastic fibers in papillary, mid, or deep dermis Fragmentation and loss of elastic fibers in papillary and reticular dermis; may see neutrophilic or lymphohistiocytic infiltrate with elastophagocytosis Granular degeneration and fragmentation; then nearly total loss of elastic tissue in upper and mid dermis

Fibrosis and elastic tissue loss in papillary and mid reticular dermis

Bandlike loss of elastic tissue in papillary dermis

Bandlike loss of middermal elastic fibers; may see perivascular lymphohistiocytic or neutrophilic inflammation and elastophagocytosis

EM, Electron microscopy; F, female prevalence; M, male prevalence.

Differential diagnosis. The differential diagnosis of nevus anelasticus includes middermal elastolysis, papular elastorrhexis, and collagenoma. Clinically, the perifollicular subtype of middermal

elastolysis may appear similar to nevus anelasticus. These 2 entities may be distinguished on the basis of histopathologic features, which include loss and fragmentation of elastic tissue throughout the dermis

Lewis et al 167

J AM ACAD DERMATOL VOLUME 51, NUMBER 2

Table I. Cont’d Disorder

Epidemiology

Upper dermal elastolysis

1 case reported: 86-year-old woman

Granulomatous slack skin

M [ F; 14e69 y; more common in whites

Acrokeratoelastoidosis

Bimodal: children and adults (54e77 y); no racial predilection

(nevus anelasticus) versus focal loss of elastic fibers confined to the midreticular dermis (middermal elastolysis). It has been argued that papular elastorrhexis and nevus anelasticus may both be variants of a common connective tissue nevus disorder, although lesions of the former typically are neither clustered nor perifollicular.6 At histopathologic examination, loss of elastic tissue is typically the most prominent feature of nevus anelasticus, whereas fragmentation of elastic fibers more aptly characterizes papular elastorrhexis. Collagenomas may also present as a collection of small papules on the trunk; changes in collagen seen at histopathologic examination predominate, however, and any perturbation of elastic tissue is thought to be a dilution effect resulting from increased collagen deposition.4 By contrast, nevus anelasticus is considered an abnormality primarily of elastic tissue. Treatment. There is no known treatment for nevus anelasticus.

PAPULAR ELASTORRHEXIS Definition. Papular elastorrhexis is characterized by asymptomatic papules and fragmentation of dermal elastic fibers. History. Papular elastorrhexis was described in 1987 by Bordas and colleagues.6 Their patient had a nonfollicular papular eruption over the abdomen, back, and chest, and the most prominent histopath-

Clinical Features

Small (2- to 5-mmdiameter) yellow papules on neck and trunk; may become more discrete over time Erythematous, tender, indurated plaques, nodules, scaly patches on axillae, groin, and trunk; become hyperpigmented and pendulous 2- to 4-mm-diameter, bilateral, yellow to white, horny umbilicated linear papules on radial and ulnar margins of hands

Histopathology

Loss of elastic fibers in upper dermis; may see elastophagocytosis

Full-thickness elastolysis and elastophagocytosis; diffuse lymphohistiocytic dermal infiltrate; atypical lymphocytes may show epidermotropism

Loss of elastic tissue and elastorrhexis in reticular dermis of lesional and normal-appearing skin

ologic change was intense fragmentation of elastic tissue that resulted in a speckled appearance. Epidemiology. Since 1987 there have been reports of approximately 13 cases of papular elastorrhexis, the majority of which (75%) occurred in females who presented during the second decade of life.3,4,6-8 However, a single case has been reported in a 45-year-old women.7 Etiology and pathogenesis. The cause and pathogenesis of papular elastorrhexis are largely unknown. Although the majority of cases have occurred in persons with no known family history of papular elastorrhexis, isolated cases of clustering within families suggests both acquired and familial forms of the disorder may exist.7 Clinical manifestations. Papular elastorrhexis typically presents as several asymptomatic, firm, nonfollicular, 1- to 5-mm-diameter, well-demarcated white papules distributed evenly over the trunk, including the chest, abdomen, back and shoulders, upper extremities, and, rarely, thighs (Fig 1, A).4,6,8,9 There is typically no history of antecedent trauma, local inflammation, or acne. Histopathology. Papular elastorrhexis is characterized by substantial fragmentation or nearly complete loss of elastic tissue in the reticular dermis (Fig 1, B).4,6,9 A perivascular lymphohistiocytic infiltrate in the superficial and deep dermis has been reported.8 Collagen bundles can be thickened and homogenized, or normal (Fig 1, C). Electron

168 Lewis et al


Fig 1. Papular elastorrhexis. A, Back showing a 4-mm-diameter, well-demarcated white papule. B, Fragmentation of elastic fibers throughout the dermis. (Elastic stain, original magnification 310). C, Thickened, homogenized collagen bundles throughout the dermis. (Hematoxylin-eosin stain; original magnification 310.) (Courtesy of Stanislaw Buechner, MD, University of Basel, Switzerland.)

microscopy may reveal an absolute reduction of elastic tissue, with a relative increase in the fibrillar component of elastic fibers in comparison with normal fibers.7 Associated conditions. There have been no reports of systemic involvement. Differential diagnosis. The differential diagnosis of papular elastorrhexis includes nevus anelasticus, papular acne scars, collagenoma, anetoderma, and middermal elastolysis. Nevus anelasticus is characterized by perifollicular papules on the chest and focal attenuation and fragmentation of elastic fibers in affected areas, whereas papular elastorrhexis is classically nonfollicular and may occur on the arms, thighs, or abdomen. Papular acne scars are also in the differential diagnosis but typically are perifollicular and usually do not affect the abdomen and thighs.8 Collagenomas should also be considered; they may display apparent ‘‘loss’’ of elastic tissue, as discussed above.4 Anetoderma and middermal elastolysis may appear similar clinically but are usually characterized by elastolysis without elastorrhexis, and normal-appearing collagen. Treatment. There is no reliable treatment for papular elastorrhexis. One anecdotal report showed improvement after intralesional injection of triamcinolone.9 Oral antibiotics, oral isotretinoin, topical

tretinoin, and benzoyl peroxide have also been tried but are not effective.4

PERIFOLLICULAR ELASTOLYSIS Definition. Perifollicular elastolysis is an elastolytic disorder characterized by elastic tissue loss immediately surrounding hair follicles and balloonlike protrusions over affected areas. History. In 1968 Varadi first referred to this disorder as perifollicular macular atrophy and later reclassified it as perifollicular elastolysis to reflect the location and proposed mechanism of decreased elastic fibers.10 Epidemiology. There have been 3 reported cases of perifollicular elastolysis, occurring in women during the fourth decade of life.11 Additional cases may have been misclassified as noninflammatory Schweninger-Buzzi type anetoderma.10 Etiology and pathogenesis. The involvement of an elastase-producing variant of Staphylococcus epidermidis in the pathogenesis of perifollicular elastolysis has been suggested.11 Cell-free elastase isolated from S epidermidisecolonized hair follicles that were obtained from biopsy specimens of clinically involved skin was shown to selectively lyse elastic fibers of normal rabbit skin in vivo. The


Lewis et al 169

Fig 2. Anetoderma. A, Flank showing multiple discrete saclike bulging papules of the Schweninger-Buzzi type. B, Thigh showing multiple discrete, atrophic plaques with surrounding erythema of Jadassohn-Pellizzari type. C, Zone of elastolysis involving the papillary and reticular dermis. (Elastic stain; original magnification 310.) (A courtesy of Jorge Romanı´, MD, Hospital de Badalona, Barcelona, Spain. B and C courtesy of Marta Fernańdez-Galar, Clıńica Universitaria de Navarra, Navarra, Spain.)

molecular weight of one bacterial elastase enzyme has been estimated at 40 kd, small enough to potentially pass through an undamaged follicular wall. These results are consistent with a role for bacterial elastase in the pathogenesis of perifollicular elastolysis. Clinical manifestations. Perifollicular elastolysis may present as small (1 to 4 mm), gray or white, finely wrinkled, round or oval papules with a central hair follicle, occurring on the neck, earlobes, arms, and upper portion of the trunk without erythema. Balloonlike bulging or protrusion has been reported.11

Histopathology. Histopathologic examination reveals selective, nearly complete loss of elastic fibers immediately surrounding hair follicles in the absence of an inflammatory infiltrate, vascular involvement, and collagen loss.11 Associated conditions. There have been no reports of systemic involvement. Differential diagnosis. Disorders included in the differential diagnosis of perifollicular elastolysis include classic anetoderma, perifollicular anetoderma, middermal elastolysis, and papular elastorrhexis. Classic anetoderma shares some clinical features with perifollicular elastolysis, including

170 Lewis et al

atrophy, wrinkling, and pouchlike herniation. In contrast, anetoderma is typically characterized by larger lesions that are not associated with hair follicles. Perifollicular anetoderma is typically described as pea-sized, gray or red, delicately wrinkled, perifollicular ‘‘sunken’’ or atrophic lesions on the thighs of obese women.12 Histologically, lesions show protrusion of subcutaneous tissue into the dermis and no abnormality in elastic tissue, 2 features that contrast with perifollicular elastolysis. Middermal elastolysis may occur in a perifollicular pattern in a minority of cases but has not been associated with a bacterial cause. Papular elastorrhexis also presents as a papular eruption, but lesions are not associated with hair follicles; moreover, the most prominent histopathologic finding is elastic fiber fragmentation rather than loss, as seen in perifollicular elastolysis. Treatment. There is no known treatment for perifollicular elastolysis.

ANETODERMA Definition. Anetoderma (Greek anetos,‘‘slack’’), also known as macular atrophy, is characterized clinically by small, atrophic papules that herniate inward at palpation and histopathologically by loss of dermal elastic tissue. History. Anetoderma was described in 1892 by Jadassohn in an 18-year-old woman who presented with erythematous papules on the elbows that resolved with atrophy and wrinkling.13,14 Pellizzari described a similar condition under a different name in 1884.14,15 Epidemiology. Several hundred cases of anetoderma have been reported under a variety of names. The true prevalence is unknown, however, and it is likely that some cases of more recently described elastic tissue disorders were previously misclassified as anetoderma. Occurrence in women is reported more often than that in men. Both children and adults may be affected. Etiology and pathogenesis. Anetoderma is broadly categorized into 2 clinical types: Schweninger-Buzzi type (no preceding erythema) and Jadassohn-Pellizzari type (preceded by macular erythema or papular urticaria).16 Although several revisions in terminology have occurred, it is now generally accepted that secondary anetoderma refers to lesions that were preceded by an inflammatory dermatosis in the same location, whereas primary anetoderma refers to the occurrence of atrophic lesions in areas of skin that appeared normal prior to the onset of atrophy.14 Both types may be associated with systemic disease.


Clinical manifestations. Anetoderma may present as multiple round, nonfollicular, wellcircumscribed, 5- to 25-mm-diameter, finely wrinkled patches of skin that appear sunken, atrophic or flaccid, and saclike, and bulge outward (Fig 2, A). Many patients will have lesions that number in the hundreds. Palpation of flaccid lesions demonstrates inward herniation. Lesions typically appear on the upper part of the trunk and proximal portions of the extremities. The inflammatory stage of JadassohnPellizzari type resolves, leaving finely wrinkled, bulging areas of skin that were previously inflamed (Fig 2, B). The remaining types present as similarappearing papules without evidence of an antecedent dermatosis. Histopathology. The primary histopathologic feature is elastic tissue loss in the dermis (Fig 2, C). Light and electron microscopy may show fragmentation of remaining elastic fibers in the papillary and deep reticular dermis, although the midreticular dermis may also be involved.17,18 Elastophagocytosis may be present.19,20 Many cases of Jadassohn-Pellizzari type and some early cases of Schweninger-Buzzi type may reveal a perivascular lymphohistiocytic or neutrophilic infiltrate.21 Hence any distinction based on clinical signs of inflammation may be largely historical.22 Desmosine, a cross-linking compound found only in elastin, is reduced in lesional skin, indicating that mature elastin is also reduced.17 It has been suggested that anetoderma may result from an imbalance between metalloproteinases and inhibitors of metalloproteinases in lesional skin, resulting in degradation of elastic tissue.23 Associated conditions. Secondary anetoderma has been associated with urticaria pigmentosa,24 syphilis,25 acne,26 varicella,27 Lyme disease,28 leprosy,29 HIV infection,30,31 lymphoproliferative disorders,32,33 Langerhans cell histiocytosis,34 systemic lupus erythematosus,14,35,36 primary hypothyroidism,37 Graves disease,38 Addison disease,14 antiphospholipid syndrome,39 Sjo¨gren syndrome,40 prurigo nodularis,41 pilomatricoma,42,43 application of leeches,44 electrocardiographic lead placement,45 hepatitis B vaccination,46 chronic angular cheilitis,47 congenital melanocytic nevi with hamartomatous features,48 juvenile xanthogranuloma,49 and generalized granuloma annulare.50 Involvement of extracutaneous elastic tissue has not been reported. Differential diagnosis. The differential diagnosis of anetoderma includes numerous acquired disorders of elastic tissue. Although elastolysis is the principal histopathologic feature of anetoderma, the pattern of elastolysis is quite variable. By contrast, the histopathologic pattern of elastolysis seen in middermal elastolysis, pseudoxanthoma-like


papillary dermal elastolysis, and upper dermal elastolysis is both specific and diagnostic, as discussed below. Clinically, anetoderma is characterized by small, well-circumscribed lesions, whereas postinflammatory elastolysis and cutis laxa, acquired cutis laxa, and middermal elastolysis may be characterized by a more diffuse or generalized pattern of skin involvement. Treatment. Several anecdotal reports of treatment with aspirin,14 aminocaproic acid,51 phenytoin,14 dapsone,14 vitamin E,14 niacin,14 penicillin,14,52 colchicine,53 and hydroxychloroquine14 have shown variable short-term results; long-term outcome was generally unsuccessful, however.

ACQUIRED CUTIS LAXA Definition. Acquired cutis laxa is characterized by loose redundant skin folds, loss of dermal elastic tissue that results in ‘‘bloodhound-like’’ or lugubrious facies, and risk of systemic involvement. History. Marshall, Heyl, and Weber in 1966 first proposed a system of classification for cutis laxa that is widely accepted in the literature.54 The system distinguishes between acquired and inherited forms of the disease. Epidemiology. Acquired cutis laxa is a rare disorder that usually affects adults, although isolated cases in children have been reported. Men and women are affected equally, and there is no racial predilection. Etiology and pathogenesis. Skin laxity is preceded by an inflammatory phase of erythematous plaques in approximately half of cases. Additional cases of subclinical inflammation diagnosed histologically have also been reported.55 Adult-onset acquired cutis laxa (occurring in patients older than 20 years) has been associated with a high rate of systemic elastolysis, resulting in the formation of intestinal diverticula, inguinal and hiatal hernias, aortic rupture, emphysema, and cor pulmonale. In the small subset of patients with cardiovascular and pulmonary involvement, the risk of fatal outcome is extremely high (approaching 100%).56 It has been hypothesized that elastic tissue loss may result from decreased synthesis of serum elastase inhibitors such as alpha1-antitrypsin.57 Alternatively or in concert, the presence of neutrophil-derived elastase may result in increased elastolytic activity, although the presence of a neutrophilic infiltrate is variable.55,58,59 In addition, it has been shown that elastolytic activity in dermal fibroblasts is increased and that elastin gene expression is decreased in lesional skin.60,61 A deficiency in serum copper may lead to decreased synthesis of elastic fibers, which is regulated in part by copper-dependent lysyl oxidase.62,63 There have

Lewis et al 171

been anecdotal reports of immunoglobulin G deposition on elastic fibers in patients with plasma cell dyscrasia and multiple myeloma, and of immunoglobulin A deposits on elastic fibers in a patient with blepharochalasis, suggesting that an immunologic mechanism may account for elastolysis in some persons.55,64-66 Marshall syndrome (acquired cutis laxa preceded by Sweet syndrome [acute neutrophilic dermatosis]) with coexistent alpha1-antitrypsin deficiency panniculitis has also been described.67 Clinical manifestations. Acquired cutis laxa may present without evidence of an antecedent dermatosis but has been reported in association with urticaria, eczema, and erythema multiforme.56,58,59,68,69 Lesions are commonly described as pendulous or redundant coarsely wrinkled areas of skin (Fig 3, A and B). The onset of disease may be insidious, developing over the course of several years. Classically, the face and particularly the earlobes are involved and lesions typically spread in a cephalocaudal direction.55,56 Isolated cases involving the palms and soles have also been reported.59,70 The extent of involvement ranges from localized areas of skin laxity to generalized, widespread wrinkling and systemic involvement involving the lungs, vasculature, and gastrointestinal tract.58,71 Histopathology. It has been suggested that the natural history of acquired cutis laxa may be divided into 4 histopathologic stages, although overlapping stages may be observed in the same biopsy specimen.72 Stage 1 lesions show mild fragmentation, shortening, or degeneration of elastic fibers. In stage 2, a neutrophilic or lymphocytic infiltrate is present (Fig 3, C). Stage 3 lesions show a predominance of histiocytes and phagocytosis of abnormal elastic fibers that results in depletion of elastic tissue in stage 4 (Fig 3, D). Though not well established empirically, this staging model suggests that elastic tissue derangement in acquired cutis laxa is a primary process, not simply the byproduct of inflammation. Elastic tissue loss may be observed throughout the papillary and reticular dermis, whereas the epidermis and appendages appear normal. Indirect immunofluorescence may show a reduction in papillary dermal fibrillin.73 Oxytalan and elaunin fibers may also be absent from lesional skin.69 Associated conditions. Acquired cutis laxa has been associated with many conditions, including plasma cell dyscrasia,55 multiple myeloma,64,71,74-76 lymphoma,77,78 dermatitis herpetiformis,79 sarcoidosis,79 amyloidosis,80 nephrotic syndrome,81 rheumatoid arthritis,82 systemic lupus erythematosus,62 reaction to isoniazid therapy,56 Borrelia burgdorferi infection,83 varicose veins,84 and alpha1-antitrypsin deficiency.67

172 Lewis et al


Fig 3. Acquired cutis laxa. Face (A) and upper arm (B) showing coarse wrinkling and pendulous skin in a 62-year-old woman. C, Sparse mixed perivascular infiltrate. (Hematoxylin-eosin stain; original magnification 320.) D, Complete loss of elastic fibers. (Elastic stain; original magnification 320.) (Courtesy of Thomas Helm, MD, Buffalo Medical Group, Buffalo, NY.)

Differential diagnosis. The differential diagnosis of acquired cutis laxa includes postinflammatory elastolysis and cutis laxa, anetoderma, middermal elastolysis, and granulomatous slack skin. Postinflammatory elastolysis and cutis laxa may be differentiated from acquired cutis laxa by the presence of an acute phase that is characterized by severe inflammation of affected skin and the presence of enlarging erythematous plaques. In addition, the acute phase of postinflammatory elastolysis and cutis laxa is manifest by systemic symptoms that include malaise, fever, and leukocytosis. In the chronic phase of postinflammatory elastolysis and cutis laxa, skin laxity is limited to areas of previous inflammation, in contrast to acquired cutis laxa, in which skin laxity may occur anywhere. Anetoderma presents as small, round, well-circumscribed areas of atrophy that herniate at palpation, in contrast to the larger, more generalized lesions of cutis laxa. Middermal elastolysis is more commonly characterized by fine rather than coarse

wrinkling; elastolysis is confined to the midreticular dermis. Neither anetoderma nor middermal elastolysis has been associated with systemic elastolysis. Granulomatous slack skin is characterized by patches and plaques that become manifest over time as pendulous skin folds but, unlike acquired cutis laxa, tend to occur preferentially in the axillae and groin. The histologic features of granulomatous slack skin are more distinct and may include diffuse granulomatous inflammation and lymphocytic epidermotropism. Treatment. There is no reliable treatment for acquired cutis laxa. Anecdotal evidence suggests that dapsone may improve urticaria but does not prevent progression of disease.59

POSTINFLAMMATORY ELASTOLYSIS AND CUTIS LAXA Definition. Postinflammatory elastolysis and cutis laxa is characterized by an acute papular eruption that resolves, leaving finely wrinkled skin and loss of dermal elastic tissue.


History. Postinflammatory elastolysis and cutis laxa were described by Marshall, Heyl, and Weber in 1966 in a series of five South African children who presented with an acute erythematous, infiltrated papular eruption.54 Epidemiology. Postinflammatory elastolysis and cutis laxa is a rare disorder that typically presents during infancy or childhood (1.5 to 4 years).54 Cases in persons of African or South American origin are most commonly reported, although one case in a child from North America has been reported.85,86 The disorder appears to be more common in females than in males. There is typically no family history of postinflammatory elastolysis and cutis laxa. Etiology and pathogenesis. It has been suggested anecdotally that postinflammatory elastolysis and cutis laxa may be the result of an idiosyncratic reaction to the bite of an arthropod.86 It has also been suggested that the high prevalence among young children is consistent with an environmental cause, such as exposure to grass, vegetation, or insects..86 Alternatively, postinflammatory elastolysis and cutis laxa may be the result of an idiosyncratic reaction to ultraviolet or infrared radiation in genetically predisposed persons.87 Clinical manifestations. Postinflammatory elastolysis and cutis laxa typically present with an eruptive phase that lasts several months to several years and resolves, leaving permanently wrinkled skin.54 The primary lesion has been described as a juicy, bright red papule that erupts quickly and becomes dark blue or red in the center as it expands peripherally. The lesion may be pruritic and continues to enlarge over the course of 1 to 2 weeks into a 2- to 10-cm-diameter, round or oval plaque with a collarette of scale surrounded by an active, 1-cm-wide, bright red cordlike border.54,86 As the primary lesion resolves, the center becomes wrinkled and hyperpigmented. Multiple lesions of different stages may be present, and adjacent lesions may become confluent.54 Lesions may be distributed anywhere on the body, although the face, ears, and neck are almost always affected, while the palms and soles are rarely affected.86 Skin laxity is apparent after resolution of previously active lesions.54 Mild cases may have a peau d’orange appearance, whereas severe cases result in coarse, deep wrinkles similar to those of acquired cutis laxa. The result is a profoundly aged appearance. Histopathology. Histologic examination during the acute phase reveals subepidermal edema, capillary dilation, and a polymorphonuclear and eosinophilic perivascular inflammatory infiltrate.86 Granular degeneration and fragmentation of elastic tissue are seen throughout the dermis; scattered necrotic foci may also be present.54 In the later

Lewis et al 173

phases, the dermis is atrophic; a lymphohistiocytic infiltrate and nearly complete loss of elastic tissue in the papillary and upper to mid reticular dermis may also be observed. Clinical and histologic findings resembling those of Sweet syndrome were noted in the original report about 5 African children who developed cutis laxa after an acute inflammatory cutaneous eruption.54 Associated conditions. Although there is no universal association, a significant number of those affected report a recent infectious illness (pneumonia, otitis media, conjunctivitis, acute bloody diarrhea) treated with an antibiotic.54 Leukocytosis with eosinophilia has been reported.86 In contrast to acquired cutis laxa, elastolysis in postinflammatory elastolysis and cutis laxa appears to be confined to the skin. Differential diagnosis. The differential diagnosis of postinflammatory elastolysis and cutis laxa includes anetoderma, acquired cutis laxa, and middermal elastolysis. Anetoderma is characterized by smaller (\5-cm-diameter) lesions that show a herniation at palpation, unlike postinflammatory elastolysis and cutis laxa.86 Acquired cutis laxa is associated with loose, pendulous folds of skin and systemic involvement, whereas postinflammatory elastolysis and cutis laxa is associated with fine wrinkling without systemic involvement. Middermal elastolysis can be distinguished from postinflammatory elastolysis and cutis laxa on the basis of the pattern of elastolysis, which is confined to the midreticular dermis. Also, middermal elastolysis tends not to affect the face, whereas postinflammatory elastolysis and cutis laxa usually does. Treatment. Antibiotics appear to have no effect on the course of disease.54

WHITE FIBROUS PAPULOSIS OF THE NECK Definition. White fibrous papulosis of the neck is characterized by a papular eruption on the neck with histologic evidence of fibrosis and variable loss of dermal elastic tissue. History. White fibrous papulosis of the neck was described by Shimizu, Nishikawa, and Kimura in 1985 in a series of elderly Japanese patients with asymptomatic white papules on the posterior portion of the neck.88 Epidemiology. Eighty-one percent of the initial series of 32 cases were in men.88 Subsequently, additional cases have been reported in persons residing in Western Europe and the Middle East, most of whom were women.89 The gender discrepancy has not been explained, although it is likely that the overall prevalence of this disorder is higher than published reports would suggest due to

174 Lewis et al

its asymptomatic nature. Patient age has ranged from 39 to 80 (mean, 62) years, suggesting that this disorder affects mostly middle-aged and elderly adults.90-92 Etiology and pathogenesis. The pathogenesis of white fibrous papulosis of the neck is poorly understood, but it has been speculated that it is an intrinsic manifestation of aging.89,91 Clinical manifestations. White fibrous papulosis of the neck is characterized by multiple (few to 100, usually 10 to 20), asymptomatic, symmetrically distributed, small (2- to 3-mm-diameter), round or oval, nonfollicular, discrete white or pale papules that are typically scattered about the neck (Fig 4).89-91,93 A few cases on the upper third of the trunk have also been reported.94 Histopathology. Histologic examination of affected skin reveals an unremarkable epidermis, although some reports have described a slight decrease in melanin content.93 While the main histopathologic change in the dermis is fibrosis consisting of areas of thickened collagen bundles in the papillary and midreticular dermis, loss of elastic tissue in the papillary and reticular dermis has also been noted.90,91,95,96 In particular, oxytalan and elaunin fibers may be completely absent.95 Electron microscopy may show a decrease in elastic tissue.93 In affected lesions, remaining elastin fibers appear smaller, fragmented, and cribriform.90 Associated conditions. There have been no reports of extracutaneous involvement in white fibrous papulosis of the neck. Differential diagnosis. The differential diagnosis of white fibrous papulosis of the neck includes acrochordons, anetoderma, perifollicular elastolysis, pseudoxanthoma elasticum (PXE), PXE-like papillary dermal elastolysis, dermatofibrosis lenticularis disseminata, and acquired connective tissue nevi. Like white fibrous papulosis of the neck, acrochordons may present around the neck of elderly persons but are pedunculated and often pigmented.93 Anetoderma may also affect the neck region. However, the most striking histopathologic characteristic of this disorder, as well as perifollicular elastolysis and PXE-like papillary dermal elastolysis, is elastolysis, whereas changes in elastic tissue may be more subtle or absent in white fibrous papulosis of the neck.93 Unlike white fibrous papulosis of the neck, PXE is characterized by calcification of dermal elastic tissue. Dermatofibrosis lenticularis disseminata presents as yellow 1- to 3-mm-diameter papules, and histopathologic examination reveals prominent thick, branching elastic fibers.93 In addition, it is often associated with osteopoikilosis. Acquired connective tissue nevi cannot be differen-


tiated from white fibrous papulosis of the neck on the basis of histopathologic examination; however, patients are typically younger and present with lesions on the back and extremities.90 Other disorders presenting as small papules, including eruptive vellus hair cysts, milia, and eruptive xanthomas, may be differentiated from white fibrous papulosis of the neck on the basis of age of onset, preferred anatomic site, and clinicohistologic features.90,93 Treatment. There is no known treatment for white fibrous papulosis of the neck.

PSEUDOXANTHOMA ELASTICUMÿLIKE PAPILLARY DERMAL ELASTOLYSIS Definition. PXE-like papillary dermal elastolysis is an acquired disorder characterized by papules that resemble PXE clinically, and nearly complete loss of elastic tissue in the papillary dermis histopathologically. History. Rongioletti and Rebora in 1992 described PXE-like papillary dermal elastolysis in 2 female patients who presented with nonfollicular cobblestone-appearing papules that were coalescing into plaques on the neck; histopathologic examination showed elastolysis in the papillary dermis.97 No ophthalmic or cardiovascular complications were present. More recently, the term fibroelastolytic diseases of the skin has been used to suggest that PXElike papillary dermal elastolysis and white fibrous papulosis of the neck may be part of the same spectrum of disease.89 Epidemiology. PXE-like papillary dermal elastolysis is a rare disorder and typically affects women in late adulthood (ages 63 to 80 years).98 Most reported cases have been in women, although conclusive population-based prevalence data are lacking. Etiology and pathogenesis. The cause of PXElike papillary dermal elastolysis may be related to ultraviolet radiation, intrinsic aging (similar to white fibrous papulosis of the neck), or abnormal elastogenesis.89 However, there is typically no history of prolonged sun exposure, inflammation, or chemical exposure. If the disorder is one of intrinsic aging, men and women should be affected equally.99 The cobblestone pattern is thought to derive from defects in the underlying elastic fiber network, leading to minute foci of herniation in the skin, not unlike the lesions of anetoderma.98 No specific drug or chemical exposure has been implicated in the pathogenesis of PXE-like papillary dermal elastolysis. Clinical manifestations. PXE-like papillary dermal elastolysis may present as multiple, asymptomatic or pruritic, yellow or skin-colored, 2- to 3mm-diameter, nonfollicular, cobblestone-appearing

Lewis et al 175


Fig 4. White fibrous papulosis of the neck. Lateral view of neck (A) and close-up (B) showing multiple discrete white papules. (Courtesy of Hiroshi Shimizu, MD, PhD, Hokkaido University Graduate School of Medicine, Sapporo, Japan.)

papules that coalesce into large plaques distributed symmetrically over the supraclavicular, lateral, and posterior regions of the neck, the flexor aspect of the forearms, the axillae, the lower part of the abdomen, and the inframammary folds (Fig 5, A and B; unpublished observation).89,98 New lesions may appear over the course of months to years. Histopathology. Histopathologic examination reveals an atrophic epidermis and bandlike loss of elastic tissue in the papillary dermis (Fig 5, C).100 Clumping and fragmentation of elastic fibers may also be seen.98 The reticular dermis is largely unaffected but may show a mild reduction in elastic tissue.97 Loss of elaunin and oxytalan fibers in the papillary dermis of lesional skin, with granular and fibrillar degeneration of elastic fibers in perilesional areas, may also be seen.89 Elastophagocytosis has not been reported. Immunohistochemical staining may show loss of fibrillin-1 and -2 and microfibril-associated glycoprotein-1 and -2 in the papillary dermis.99,101 These elastogenic changes may reflect an active repair process of elastolytic damage and are thought to be consistent with intrinsic or chronologic aging.102 Associated conditions. PXE-like papillary dermal elastolysis is not associated with systemic involvement, as inherited PXE is. Differential diagnosis. Disorders included in the differential diagnosis of PXE-like papillary dermal elastolysis include PXE, white fibrous papulosis of the neck, late-onset focal dermal elastosis, upper dermal elastolysis, and middermal elastolysis. PXE shows fragmentation and calcification of elastic fibers primarily in the reticular dermis, in contrast to PXE-like papillary dermal elastolysis, which shows bandlike loss of papillary dermal elastic tissue and no calcification. In addition, PXE is associated with systemic complications, including angioid streaks and calcification of blood vessels, that lead to ischemic or hemorrhagic events. Similar to PXE-like

papillary dermal elastolysis, white fibrous papulosis of the neck commonly presents as nonfollicular papules around the neck. By contrast, white fibrous papulosis of the neck usually occurs in elderly men; also, lesions are not confluent, lack the characteristic cobblestone appearance, and are more pale than yellow, although some authors have considered these findings to represent variants of the same disorder.89 In addition, thickening of collagen bundles is the most consistent histopathologic feature of white fibrous papulosis of the neck, whereas papillary dermal elastolysis is a diagnostic feature of PXE-like papillary dermal elastolysis. Late-onset focal dermal elastosis may be distinguished from PXElike papillary dermal elastolysis by the presence of increased normal-appearing elastic tissue at histopathologic examination. The characteristic elastophagocytosis seen in upper dermal elastolysis has not been reported in PXE-like papillary dermal elastolysis. The perifollicular subtype of middermal elastolysis is characterized by perifollicular papules, whereas PXE-like papillary dermal elastolysis is characterized by nonfollicular papules.103 In addition, elastic tissue loss in middermal elastolysis is confined to the midreticular dermis. Treatment. One anecdotal report suggested that topical tretinoin was not effective.89

MID-DERMAL ELASTOLYSIS Definition. Mid-dermal elastolysis is characterized histopathologically by focal loss of elastic tissue in the midreticular dermis and is manifest clinically as patches and plaques of finely wrinkled skin. History. Shelley and Wood104 in 1977 described middermal elastolysis in a patient with a history of urticaria and endometriosis treated with oral contraceptives in whom histopathologic examination revealed the hallmark selective absence of elastic fibers in the mid-dermis. Contrary to their

176 Lewis et al


Fig 5. PXE-like papillary dermal elastolysis. Neck (A) and axilla (B) showing multiple white cobblestone-appearing coalescent papules. (B courtesy of Kenneth Becker, MD, Brown Medical School, Providence, RI.) C, Loss of elastic tissue in the papillary dermis, sparing the reticular dermis. (Elastic stain, original magnification 310.)

clinical suspicions, no inflammatory infiltrate was observed. On the basis of these findings, it was hypothesized that mid-dermal elastolysis is a noninflammatory dermatosis; more recent observations suggest the possibility of an inflammatory cause in some cases. Epidemiology. Mid-dermal elastolysis is a rare disorder that typically occurs in healthy young or middle-aged women (30 to 50 years of age), although isolated cases in men have been reported.105 Etiology and pathogenesis. Initial reports of mid-dermal elastolysis suggested that inflammation was not a prominent feature of the disease.106-113 More recently, several cases have been reported to follow urticaria, granuloma annulare, and exposure to ultraviolet radiation, suggesting that mid-dermal elastolysis may present in some cases as a postinflammatory elastolysis.114,115 It has also been reported to follow augmentation mammaplasty with silicone gelefilled implants.113 Exposure to ultraviolet radiation has been associated with middermal elastolysis.114-116 The age group, photodistribution of lesions, history of exposure to ultraviolet radiation, and absence of actinic

elastosis in most cases suggest that mid-dermal elastolysis may be the result of an idiosyncratic reaction to ultraviolet radiation rather than the cumulative effect of long-term sun exposure observed in actinic elastosis.114 Recent investigations suggest several mechanisms of elastolysis: experiments performed with dermal fibroblasts cultured from lesional skin demonstrate an 80% reduction in elastin messenger RNA level and a 2-fold increase in elastolytic activity compared with normal skin.117 One study performed with immunohistochemistry reported preferential damage to elastin but sparing of fibrillin.112 In addition, there is preliminary evidence that ultraviolet A stimulates the synthesis of elastase and cathepsin G, and that the production of matrix metalloproteinase 9, which is induced by ultraviolet radiation, is elevated in lesional skin of patients with middermal elastolysis.116,118 Clinical manifestations. Approximately 50% of cases of mid-dermal elastolysis are preceded or accompanied by burning or urticaria that is manifest as erythematous patches and plaques, perifollicular papules, and telangiectasia. Lesions usually resolve, leaving the classic asymptomatic, well-demarcated


patches of finely wrinkled skin with no pigmentary changes (Fig 6, A and B). Individual lesions may be stable over time or may enlarge slowly over several months. Lesions are typically found on the neck, trunk, and upper extremities but rarely involve the face. A subset of cases may present with perifollicular papules. Histopathology. Cases with an inflammatory clinical presentation have shown perivascular lymphocytic, monocytic, or neutrophilic infiltrates and phagocytosis of elastin by multinucleated giant cells.109,110,114,119-121 Electron microscopy studies have also reported phagocytosis of degenerated elastic fibers by macrophages,109,115,116,120,122 as well as loose assembly of skeleton fibrils and irregular aggregations of dense substance.108,109,119,122,123 In many cases, specimens stained with hematoxylin and eosin appear normal, however. Hence, the unifying histopathologic criterion for the diagnosis of middermal elastolysis is bandlike loss of middermal elastic fibers sparing the papillary and lower reticular dermis (Fig 6, C).104 In addition, elastic tissue appears normal around appendages, even in cases with perifollicular involvement.111 Associated conditions. Mid-dermal elastolysis is a localized elastolytic disorder and has not been associated with extracutaneous manifestations. There have been isolated reports of mid-dermal elastolysis in patients with autoimmune diseases, including systemic lupus erythematosus,124 Hashimoto thyroiditis,125 and rheumatoid arthritis.113 Differential diagnosis. Disorders commonly included in the differential diagnosis of mid-dermal elastolysis include anetoderma, perifollicular elastolysis, postinflammatory elastolysis and cutis laxa, and acquired cutis laxa. The diagnostic criteria of these elastolytic disorders are both clinical and histopathologic and are reviewed in their respective sections. Treatment. Current treatment options are empiric. Colchicine has been tried, with little response. Topical tretinoin has been reported to improve wrinkles but not does not appear to alter the natural history of the disease.120 Data about the use of oral and topical corticosteroids are anecdotal, but such agents do not appear to alter the disease course.

UPPER DERMAL ELASTOLYSIS Definition. Upper dermal elastolysis is characterized by a papular eruption and selective loss of elastic tissue in the papillary dermis. History. Upper dermal elastolysis was described by Hashimoto and Tye126 in 1994 in a patient with no known history of urticaria or unusual sun or chemical

Lewis et al 177

exposure, who presented with pruritus and small papules. Epidemiology. There has been one reported case of upper dermal elastolysis in an 86-year-old white woman. Etiology and pathogenesis. It has been suggested that lysis of elastic tissue may be a primary process or a reaction to an unknown irritant that results in activation of dermal phagocytes that recognize fragments of elastic fibers as foreign. Alternatively, activation of dermal phagocytes may be a primary inflammatory process that leads to elastolysis and engulfment of both normal-appearing and degraded elastic fibers.126 Clinical manifestations. Upper dermal elastolysis may present as myriad small (2- to 5-mmdiameter) yellow papules on the neck, shoulders, upper part of the chest, and back that become progressively more discrete over time.126 The lesions are not umbilicated, and the surrounding skin may appear depressed. Coarse furrows or wrinkles may also occur over affected areas. Fine wrinkling has not been reported. Histopathology. Histologic examination reveals an atrophic epidermis. Edema, capillary dilation, and perivascular lymphocytic infiltration in the papillary dermis may also be seen. Elastic fibers are markedly decreased or absent in the upper dermis; the mid dermis, deep dermis, and perifollicular dermis are grossly normal, although mild elastic tissue changes may be observed. Electron microscopy reveals a loose assembly of elastic fibrils and electron-dense substance aggregated between the loosely bound subunits. Elastophagocytosis of normal-appearing and abnormal fibers is seen.126 Associated conditions. Upper dermal elastolysis has not been associated with extracutaneous manifestations. Differential diagnosis. Disorders included in the differential diagnosis of upper dermal elastolysis are middermal elastolysis, PXE-like papillary dermal elastolysis, late-onset focal dermal elastosis, and white fibrous papulosis of the neck. Like upper dermal elastolysis, mid-dermal elastolysis may present as pruritic perifollicular papules, but histopathologic examination reveals elastolysis confined to the mid reticular dermis. In addition, mid-dermal elastolysis demonstrates fine wrinkling, in contrast to the coarse furrows or wrinkles seen in upper dermal elastolysis. PXE-like papillary dermal elastolysis typically presents as yellow papules that coalesce into cobblestone plaques, whereas upper dermal elastolysis is characterized by well-demarcated, non-coalescing papular lesions. In addition, elastophagocytosis has not been reported in

178 Lewis et al


Fig 6. Mid-dermal elastolysis. Antecubital fossa (A) and arch of foot (B) showing patches of finely wrinkled skin (arrows, B). C, Bandlike loss of elastic fibers in the midreticular dermis, sparing the papillary and deep reticular dermis. (Elastic stain; original magnification 310.) (A and B courtesy of Alan Boyd, MD, Vanderbilt University Medical Center, Nashville, Tenn.)

PXE-like papillary dermal elastolysis. It has been suggested that the papular elevations seen in upper dermal elastolysis are the result of focal edema caused by the underlying elastolytic process. By contrast, the fine wrinkling seen in mid-dermal elastolysis appears to result from degradation of the supporting elastic tissue network.126 Late-onset focal dermal elastosis may appear similar to upper dermal elastolysis clinically but is distinguished histopathologically by an increase in elastic tissue rather than a loss. White fibrous papulosis of the neck is characterized by an increase in dermal collagen with a variable decrease in elastic tissue, whereas collagen bundles appear normal in upper dermal elastolysis. Further characterization of upper dermal elastolysis is necessary to differentiate it from disorders with similar clinicohistopathologic features, including PXE-like papillary dermal elastolysis and white fibrous papulosis of the neck. Treatment. There is no known treatment for upper dermal elastolysis.

GRANULOMATOUS SLACK SKIN Definition. Granulomatous slack skin is a rare type of cutaneous T-cell lymphoma characterized by pendulous plaques and dermal elastolysis. History. Bazex, Dupre, and Chritol in 1968 described the disorder in a patient with hanging skin

folds and histologic evidence of granuloma formation.127 In 1978 Ackerman proposed the term granulomatous slack skin.128 Epidemiology. Granulomatous slack skin is a rare condition that has been reported in approximately 40 white patients, ranging in age from 14 to 69 years. Three times as many cases have been reported in males than in females.129 Etiology and pathogenesis. Granulomatous slack skin is classified as a lymphoproliferative disorder with clonal rearrangement of the T-cell receptor.130 Thus, granulomatous slack skin is considered an indolent form of cutaneous T-cell lymphoma. The propensity toward granuloma formation is not understood, but it has been postulated that antigenic stimulation of atypical lymphocytes may lead to the observed immunopathology. Dermal elastolysis may be an indirect consequence of aberrant cytokine production or a distinct antigenic target of a disordered immune response.131 Overexpression of matrix metalloproteinase-12 in multinucleated giant cells has been documented and may contribute to elastic fiber degradation and enhance recruitment of additional giant cells.132 Clinical manifestations. Granulomatous slack skin is a progressive disorder in which patients may present with a single or few well-circumscribed, poikilodermatous or erythematous, tender indurated

Lewis et al 179


plaques, nodules, scaly patches, or macules (Fig 7). Over time, lesions may become asymptomatic, mildly atrophic, hyperpigmented pendulous plaques and are located most often in the axillae, groin, and abdomen. Lesions on the thigh, knee, foot, forearm, face, shoulder, lower part of the back, buttock, and penile shaft have also been reported.133-136 Lesions may be bilateral or asymmetric.137 Persistent generalized pruritic erythroderma has also been reported.138 Histopathology. Histologic examination of the epidermis may show mild hyperkeratosis and focal parakeratosis.137 A diffuse perivascular or interstitial lymphohistiocytic dermal infiltrate with mildly to moderately hyperchromatic and pleomorphic nuclei as well as scattered neutrophils may also be seen.131,138 Atypical lymphocytes may demonstrate epidermotropism. Granuloma formation and multinucleated giant cells with more than 20 nuclei may be seen.130,134,135 Full-thickness elastolysis and elastophagocytosis of remaining fibers may also be seen. Electron microscopy may show multinucleated giant cells with numerous villous-shaped processes and intracytoplasmic lysosomes adjacent to degenerated elastic fibers in the dermis, suggesting the occurrence of elastophagocytosis.139 Associated conditions. Granulomatous slack skin is associated with lymphoproliferative disorders including Hodgkin and non-Hodgkin lymphoma and mycosis fungoides in approximately half of cases.131 The onset of granulomatous slack skin may follow, be concurrent with, or precede the associated malignancy by many years.131,134 Systemic involvement has been reported rarely, occurring in the lymph nodes, spleen, and submucosa of the bronchial tree.127,131,140,141 Differential diagnosis. The differential diagnosis of granulomatous slack skin includes middermal elastolysis, acquired cutis laxa, and granulomatous cutaneous T-cell lymphoma. Like granulomatous slack skin, middermal elastolysis may present clinically as axillary and inguinal lesions; histopathologic evidence of elastolysis is confined to the midreticular dermis, however. Clinically, lesions are more commonly described as finely wrinkled patches of skin, although coarse, pendulous folds have been reported.121 Acquired cutis laxa is also characterized by loose pendulous skin folds and dermal elastolysis but lacks the granulomatous infiltrate seen in granulomatous slack skin. Granulomatous slack skin may be differentiated from granulomatous cutaneous T-cell lymphoma by the presence of pendulous skin lesions and severe dermal elastolysis.140 In addition, patients with granulomatous slack skin are typically younger and carry

Fig 7. Granulomatous slack skin. Inguinal fold showing a large, well-demarcated, hyperpigmented pendulous plaque. (Courtesy of Françoise Poot, MD, Clinique Notre-Dame-de-Graˆce, Charleroi, Belgium.)

a significant risk for the development of a second malignancy. Histologically, the multinucleated giant cells seen in granulomatous slack skin are more evenly spaced and have more nuclei per cell compared with those of granulomatous cutaneous T-cell lymphoma.130,134,141 Treatment. There is no reliable treatment for granulomatous slack skin, although a variety of agents, including cyclophosphamide,134,142 adriamycin,142 vincristine,142 chlorambucil,138,142 procarbazine,131 busulfan,131 nitrogen mustard,131,135 corticosteroids,131,134,138,142,143 interferon-a or -g,129,131,132,143,144 surgery,129,135,145 psoralen plus ultraviolet A,131,132,144 and radiation therapy131,135 have been shown to control the progression of disease and flatten skin lesions with variable success.

ACROKERATOELASTOIDOSIS Definition. Acrokeratoelastoidosis (AKE) is a palmoplantar keratoderma characterized by a papular eruption and loss of elastic tissue. History. AKE was described by Costa in 1953 in an 18-year-old healthy white Brazilian woman who presented with a 3-year history of small asymptomatic papules on the palms and soles.146,147 Epidemiology. AKE is a rare disorder that commonly presents during childhood or adolescence, although presentation in adulthood (ages 54e77 years) has also been reported.148,149 There appears to be no racial or ethnic predilection.150 Etiology and pathogenesis. AKE is part of a class of disorders that includes palmar, plantar, and marginal papular keratodermas.146 In addition to presumptively acquired cases, both sporadic and autosomal dominant forms of AKE have been reported.146,148,151-155 There is some evidence to suggest that the pathogenesis of AKE may be due to a failure of elastic fiber synthesis rather than

180 Lewis et al


Fig 8. Acrokeratoelastoidosis. Thumb (A) and palm (B) showing scattered, polygonal, 2-mmdiameter, keratotic umbilicated papules (arrows, A). C, Loss of elastic tissue and elastorrhexis of remaining fibers in the reticular dermis. (Elastic stain; original magnification 310.) D, Amorphous, homogenized collagen bundles in the reticular dermis. (Hematoxylin-eosin stain; original magnification 310). (A courtesy of Shingo Tajima, MD, National Defense Medical College, Saitama, Japan. B courtesy of Dee Anna Glaser, MD, St. Louis University Health Sciences Center, St. Louis, Mo.)

degeneration. Results of an ultrastructural study showed that fibroblasts of lesional skin contain dense granules at the periphery of their cytoplasm, while extracellular elastic fibers are deficient; such findings are consistent with a defect in the secretion of elastic material.156 The formation of papules may be related to overproduction of filaggrin, which has been shown to accumulate in a dense band over the granular layer prior to its incorporation into the mature keratin matrix.150,154 Clinical manifestations. AKE typically presents as multiple, 2- to 4-mm-diameter, round to

polygonal, yellow or white, firm, horny papules with a keratotic, translucent, centrally depressed or umbilicated surface distributed bilaterally in a linear pattern or ‘‘paving stone’’ arrangement over the radial and ulnar margins of the hands, including the thenar and hypothenar eminences, volar aspect of the wrist, fingers (including the dorsal aspect of the interphalangeal joints), and the nail folds (Fig 8, A and B). The anterior surfaces of the ankles, the lateral and medial malleoli, and the dorsal and plantar surfaces of the feet and toes may be involved.150,157 Papules may be well circumscribed or coalesce into


plaques.157 Most cases are asymptomatic but may be associated with hyperhydrosis.146,158 Lesions may be stable in number, although rapid progression has been reported in pregnancy.158 Histopathology. Histologic examination of the epidermis reveals focal hyperkeratosis, acanthosis, and a prominent granular layer.146 Loss of elastic tissue and elastorrhexis of remaining elastic fibers, predominantly in the reticular dermis and sparing the papillary dermis, are typically seen in lesional skin but have been reported in nonlesional skin as well (Fig 8, C).152,157 Collagen fibers may be homogenized in lesional skin, and mild fibrosis may be observed in adjacent skin (Fig 8, D).159 Associated conditions. The preponderance of data suggest that there is no systemic involvement in AKE. One case in which medium and large arteries were affected has been reported, however.160 An association between AKE and systemic scleroderma has been suggested.159 Differential diagnosis. The differential diagnosis of AKE includes focal acral hyperkeratosis, degenerative collagenous plaques of the hands and keratoelastoidosis marginalis.146 AKE and focal acral hyperkeratosis have similar clinical features, but focal acral hyperkeratosis is found more often in black persons than in white, and histopathologic examination reveals no change in elastic tissue.161 Degenerative collagenous plaques of the hands and keratoelastoidosis marginalis are typically distributed over the index finger and the opposing margin of the thumb and occur in older white persons with a history of prolonged sun exposure or chronic trauma associated with manual labor. Treatment. There are no effective treatments for AKE. Use of topical tretinoin,148,162 salicylic acid,163 and cryotherapy163 have been reported anecdotally; none have been effective.

CONCLUSION Little is known about the cause and pathophysiology of many acquired disorders of elastic tissue. In this second of a 2-part review, we have covered acquired disorders that are characterized by loss or fragmentation of dermal elastic tissue. The clinical and histopathologic findings are diverse. Nevus anelasticus, papular elastorrhexis, perifollicular elastolysis, PXE-like papillary dermal elastolysis, and white fibrous papulosis of the neck appear to follow a benign course and to be of cosmetic concern only. By contrast, granulomatous slack skin and acquired cutis laxa can be associated with lifethreatening damage to elastic fibers in vital organs. Still other disorders may be harbingers of (anetoderma), be the consequence of (middermal

Lewis et al 181

elastolysis), or occur in conjunction with (acrokeratoelastoidosis) a systemic disease unrelated to elastic tissue. Treatment is largely anecdotal; data from randomized clinical trials are lacking. Continued research into the molecular and biochemical mechanisms, along with the addition of pertinent clinical and histopathologic observations to the literature, will facilitate a better understanding of the pathogenesis of acquired disorders of elastic tissue and suggest targets for therapeutic intervention. Glossary of terms: Elastosis: A degenerative change in elastic tissue; may also refer to degeneration of connective tissue fibers marked by altered staining properties resembling elastic tissue at histopathologic examination. Synonym: elastotic. Elastolysis: Dissolution of elastic tissue. Elastorrhexis: Fragmentation of elastic tissue in which the normal wavy strands appear shredded and clumped, and demonstrate basophilic staining. Fibrillin: Group of proteins that form microfibrils along with microfibril-associated glycoproteins. Microfibrils: Resilient components of elastic tissue, 10e12 nm in diameter, that form an envelope surrounding a central core of elastin. Elastin: Extensible components that make up 85% of mature elastic tissue and form an amorphous matrix with which microfibrils associate. Oxytalan fibers: Thin, superficial fibers consisting of microfibrils that form a network perpendicular to the dermal-epidermal junction. Elaunin fibers: Fibers in the papillary dermis consisting of a plexus composed primarily of microfibrils oriented parallel to the dermal-epidermal junction; elaunin fibers are connected to thicker elastic fibers in the reticular dermis. Elastic fibers: Thick fibers in the reticular dermis composed primarily of matrix elastin; microfibrils form a minor component.

REFERENCES 1. Lewandowsky F. Naevus elasticus regionis mammariae. Arch Clin Exp Dermatol 1921;131:90. 2. Staricco RG, Mehregan AH. Nevus elasticus and nevus elasticus vascularis. Arch Dermatol 1961;84:943-7. 3. Choonhakarn C, Jirarattanapochai K. Papular elastorrhexis: a distinct variant of connective tissue nevi or an incomplete form of Buschke-Ollendorff syndrome? Clin Exp Dermatol 2002;27:454-7. 4. Sears JK, Stone MS, Argenyi Z. Papular elastorrhexis: a variant of connective tissue nevus. Case reports and review of the literature. J Am Acad Dermatol 1988;19:409-14. 5. Crivellato E. Disseminated nevus anelasticus. Int J Dermatol 1986;25:171-3.

182 Lewis et al

6. Bordas X, Ferrandiz C, Ribera M, Galofre E. Papular elastorrhexis: a variety of nevus anelasticus? Arch Dermatol 1987; 123:433-4. 7. Schirren H, Schirren CG, Stolz W, Kind P, Plewig G. Papular elastorrhexis: a variant of dermatofibrosis lenticularis disseminata (Buschke-Ollendorff syndrome)? Dermatology 1994;189: 368-72. 8. Buechner SA, Itin P. Papular elastorrhexis. Report of five cases. Dermatology 2002;205:198-200. 9. Lee SH, Park SH, Song KY, Yoon TJ, Kim TH. Papular elastorrhexis in childhood improved by intralesional injections of triamcinolone. J Dermatol 2001;28:569-71. 10. Varadi DP. Elastase from Staphylococcus epidermidis. Nature 1968;218:468. 11. Varadi DP, Saqueton AC. Perifollicular elastolysis. Br J Dermatol 1970;83:143-50. 12. Streitmann R. Perifollikulare Anetodermie. Hautarzt 1966;17: 274. 13. Jadassohn J. Ueber eine eigenartige Form von ‘‘Atrophia maculosa cutis.’’ Arch Dermatol Syph 1892(Suppl 1):342-58. (From Venencie, Winkelmann, and Moore. Arch Dermatol 1984;120:1032.). 14. Venencie PY, Winkelmann RK, Moore BA. Anetoderma. Clinical findings, associations, and long-term follow-up evaluations. Arch Dermatol 1984;120:1032-9. 15. Pellizzari C. Eritema orticato atrofizzante: Atrofia parziale idiopatica della pelle. G Ital Mal Ven 1884;19:230-43. (From Venencie, Winkelmann, and Moore. Arch Dermatol 1984;120: 1032.). 16. Miller WN, Ruggles CW, Rist TE. Anetoderma. Int J Dermatol 1979;18:43-5. 17. Oikarinen AI, Palatsi R, Adomian GE, Oikarinen H, Clark JG, Uitto J. Anetoderma: biochemical and ultrastructural demonstration of an elastin defect in the skin of three patients. J Am Acad Dermatol 1984;11:64-72. 18. Misch KJ, Rhodes EL, Allen J, Kersey P. Anetoderma of Jadassohn. J R Soc Med 1988;81:734-6. 19. Kossard S, Kronman KR, Dicken CH, Schroeter AL. Inflammatory macular atrophy: immunofluorescent and ultrastructural findings. J Am Acad Dermatol 1979;1:325-34. 20. Zaki I, Scerri L, Nelson H. Primary anetoderma: phagocytosis of elastic fibres by macrophages. Clin Exp Dermatol 1994;19: 388-90. 21. Brownstein MH, Rabinowitz AD. The invisible dermatoses. J Am Acad Dermatol 1983;8:579-88. 22. Venencie PY, Winkelmann RK. Histopathologic findings in anetoderma. Arch Dermatol 1984;120:1040-4. 23. Ghomrasseni S, Dridi M, Gogly B, et al. Anetoderma: an altered balance between metalloproteinases and tissue inhibitors of metalloproteinases. Am J Dermatopathol 2002;24: 118-29. 24. Carr RD. Urticaria pigmentosa associated with anetoderma. Acta Derm Venereol 1971;51:120-2. 25. Clement M, du Vivier A. Anetoderma secondary to syphilis. J R Soc Med 1983;76:223-4. 26. Dick GF, Ashe BM, Rodgers EG, Diercks RC, Goltz RW. Study of elastolytic activity Propionibacterium acnes and Staphylococcus epidermidis in acne vulgaris and in normal skin. Acta Derm Venereol 1976;56:279-82. 27. Tousignant J, Crickx B, Grossin M, Besseige H, Lepine F, Belaich S. Post-varicella anetoderma. 3 cases. Ann Dermatol Venereol 1990;117:355-7. 28. Bauer J, Leitz G, Palmedo G, Hugel H. Anetoderma: another facet of Lyme disease? J Am Acad Dermatol 2003;48(Suppl 5): S86-8.


29. Khandpur S, Agarwal S, Reddy BS. Anetoderma secondary to lepromatous leprosy. Indian J Lepr 2001;73:51-4. 30. Ruiz-Rodriguez R, Longaker M, Berger TG. Anetoderma and human immunodeficiency virus infection. Arch Dermatol 1992;128:661-2. 31. Lindstrom J, Smith KJ, Skelton HG, Redfield R, Alving BM, Wagner KF, et al. Increased anticardiolipin antibodies associated with the development of anetoderma in HIV-1 disease. Military Medical Consortium for the Advancement of Retroviral Research (MMCARR). Int J Dermatol 1995;34:408-15. 32. Child FJ, Woollons A, Price ML, Calonje E, Russell-Jones R. Multiple cutaneous immunocytoma with secondary anetoderma: a report of two cases. Br J Dermatol 2000;143:165-70. 33. Kasper RC, Wood GS, Nihal M, LeBoit PE. Anetoderma arising in cutaneous B-cell lymphoproliferative disease. Am J Dermatopathol 2001;23:124-32. 34. Higgins CR, Tatnall FM, Leigh IM. Vesicular Langerhans cell histiocytosis—an uncommon variant. Clin Exp Dermatol 1994;19:350-2. 35. Fernandez-Galar M, Espana A, Lloret P. Systemic lupus erythematosuseassociated anetoderma and anti-phospholipid antibodies. Clin Exp Dermatol 2003;28:39-42. 36. Alvarez-Cuesta CC, Raya-Aguado C, Fernandez-Rippe ML, Sanchez TS, Perez-Oliva N. Anetoderma in a systemic lupus erythematosus patient with anti-PCNA and antiphospholipid antibodies. Dermatology 2001;203:348-50. 37. Bergman R, Friedman-Birnbaum R, Hazaz B, Cohen E, Munichor M, Lichtig C. An immunofluorescence study of primary anetoderma. Clin Exp Dermatol 1990;15:124-30. 38. Hodak E, Shamai-Lubovitz O, David M, Hazaz B, KatzenelsonWeissman V, Lahav M, et al. Immunologic abnormalities associated with primary anetoderma. Arch Dermatol 1992; 128:799-803. 39. Disdier P, Harle JR, Andrac L, Verrot D, Bolla G, San Marco M, et al. Primary anetoderma associated with the antiphospholipid syndrome. J Am Acad Dermatol 1994;30:133-4. 40. Jubert C, Cosnes A, Clerici T, Gaulard P, Andre P, Revuz J, et al. Sjo¨gren’s syndrome and cutaneous B cell lymphoma revealed by anetoderma. Arthritis Rheum 1993;36:133-4. 41. Hirschel-Scholz S, Salomon D, Merot Y, Saurat JH. Anetodermic prurigo nodularis (with Pautrier’s neuroma) responsive to arotinoid acid. J Am Acad Dermatol 1991;25:437-42. 42. Kelly SE, Humphreys F, Aldridge RD. The phenomenon of anetoderma occurring over pilomatricomas. J Am Acad Dermatol 1993;28:511. 43. Shames BS, Nassif A, Bailey CS, Saltzstein SL. Secondary anetoderma involving a pilomatricoma. Am J Dermatopathol 1994;16:557-60. 44. Siragusa M, Batolo D, Schepis C. Anetoderma secondary to the application of leeches. Int J Dermatol 1996;35:226-7. 45. Colditz PB, Dunster KR, Joy GJ, Robertson IM. Anetoderma of prematurity in association with electrocardiographic electrodes. J Am Acad Dermatol 1999;41:479-81. 46. Daoud MS, Dicken CH. Anetoderma after hepatitis B immunization in two siblings. J Am Acad Dermatol 1997;36:779-80. 47. Crone AM, James MP. Acquired linear anetoderma following angular cheilitis. Br J Dermatol 1998;138:923-4. 48. Cockayne SE, Gawkrodger DJ. Hamartomatous congenital melanocytic nevi showing secondary anetoderma-like changes. J Am Acad Dermatol 1998;39:843-5. 49. Ang P, Tay YK. Anetoderma in a patient with juvenile xanthogranuloma. Br J Dermatol 1999;140:541-2. 50. Ozkan S, Fetil E, Izler F, Pabuccuoglu U, Yalcin N, Gunes AT. Anetoderma secondary to generalized granuloma annulare. J Am Acad Dermatol 2000;42:335-8.


51. Reiss F, Linn E. The therapeutic effect of epsilon-aminocaproic acid on anetoderma Jadassohn. Dermatologica 1973;146:35760. 52. Karrer S, Szeimies RM, Stolz W, Landthaler M. Primary anetoderma in children: report of two cases and literature review. Pediatr Dermatol 1996;13:382-5. 53. Braun RP, Borradori L, Chavaz P, Masouye I, French L, Saurat JH. Treatment of primary anetoderma with colchicine. J Am Acad Dermatol 1998;38:1002-3. 54. Marshall J, Heyl T, Weber HW. Postinflammatory elastolysis and cutis laxa. A report on a new variety of this phenomenon and a discussion of some syndromes characterized by elastolysis. S Afr Med J 1966;40:1016-22. 55. Nikko A, Dunnigan M, Black A, Cockerell CJ. Acquired cutis laxa associated with a plasma cell dyscrasia. Am J Dermatopathol 1996;18:533-7. 56. Koch SE, Williams ML. Acquired cutis laxa: case report and review of disorders of elastolysis. Pediatr Dermatol 1985;2: 282-8. 57. Goltz RW, Hult AM, Goldfarb M, Gorlin RJ. Cutis laxa. Arch Dermatol 1965;92:373-87. 58. Reed WB, Horowitz RE, Beighton P. Acquired cutis laxa. Primary generalized elastolysis. Arch Dermatol 1971;103: 661-9. 59. Fisher BK, Page E, Hanna W. Acral localized acquired cutis laxa. J Am Acad Dermatol 1989;21:33-40. 60. Olsen DR, Fazio MJ, Shamban AT, Rosenbloom J, Uitto J. Cutis laxa: reduced elastin gene expression in skin fibroblast cultures as determined by hybridizations with a homologous cDNA and an exon 1especific oligonucleotide. J Biol Chem 1988;263:6465-7. 61. Schwartz E, Cruickshank FA, Lebwohl MG. Elastase-like protease and elastolytic activities expressed in cultured dermal fibroblasts derived from lesional skin of patients with pseudoxanthoma elasticum, actinic elastosis, and cutis laxa. Clin Chim Acta 1988;176:219-24. 62. Randle HW, Muller S. Generalized elastolysis associated with systemic lupus erythematosus. J Am Acad Dermatol 1983;8: 869-73. 63. Fornieri C, Quaglino D, Lungarella G, et al. Elastin production and degradation in cutis laxa acquisita. J Invest Dermatol 1994;103:583-8. 64. Cho SY, Maguire RF. Multiple myeloma associated with acquired cutis laxa. Cutis 1980;26:209-11. 65. Gupta A, Helm TN. Acquired cutis laxa associated with multiple myeloma. Cutis 2002;69:114-8. 66. Grassegger A, Romani N, Fritsch P, Smolle J, Hintner H. Immunoglobulin A (IgA) deposits in lesional skin of a patient with blepharochalasis. Br J Dermatol 1996;135:791-5. 67. Hwang ST, Williams ML, McCalmont TH, Frieden IJ. Sweet’s syndrome leading to acquired cutis laxa (Marshall’s syndrome) in an infant with alpha 1eantitrypsin deficiency. Arch Dermatol 1995;131:1175-7. 68. Harris RB, Heaphy MR, Perry HO. Generalized elastolysis (cutis laxa). Am J Med 1978;65:815-22. 69. Bouloc A, Godeau G, Zeller J, Wechsler J, Revuz J, Cosnes A. Increased fibroblast elastase activity in acquired cutis laxa. Dermatology 1999;198:346-50. 70. Martin L, Requena L, Yus ES, Furio V, Farina MC. Acrolocalized acquired cutis laxa. Br J Dermatol 1996;134:973-6. 71. Hashimoto K, Kanzaki T. Cutis laxa. Ultrastructural and biochemical studies. Arch Dermatol 1975;111:861-73. 72. Nanko H, Jepsen LV, Zachariae H, Sogaard H. Acquired cutis laxa (generalized elastolysis): light and electron microscopic studies. Acta Derm Venereol 1979;59:315-24.

Lewis et al 183

73. Lebwohl MG, Schwartz E, Jacobs L, Lebwohl M, Sakai L, Fleischmajer R. Abnormalities of fibrillin in acquired cutis laxa. J Am Acad Dermatol 1994;30:950-4. 74. Scott MA, Kauh YC, Luscombe HA. Acquired cutis laxa associated with multiple myeloma. Arch Dermatol 1976;112: 853-5. 75. Ting HC, Foo MH, Wang F. Acquired cutis laxa and multiple myeloma. Br J Dermatol 1984;110:363-7. 76. McCarty MJ, Davidson JM, Cardone JS, Anderson LL. Cutis laxa acquisita associated with multiple myeloma: a case report and review of the literature. Cutis 1996;57:267-70. 77. Chartier S, Faucher L, Tousignant J, Rochette L. Acquired cutis laxa associated with cutaneous angiocentric T-cell lymphoma. Int J Dermatol 1997;36:772-6. 78. Machet MC, Machet L, Vaillant L, Esteve E, de Muret A, Arbeille A, et al. Acquired localized cutis laxa due to cutaneous lymphoplasmacytoid lymphoma. Arch Dermatol 1995;131:110-1. 79. Lewis FM, Lewis-Jones S, Gipson M. Acquired cutis laxa with dermatitis herpetiformis and sarcoidosis. J Am Acad Dermatol 1993;29:846-8. 80. Newton JA, McKee PH, Black MM. Cutis laxa associated with amyloidosis. Clin Exp Dermatol 1986;11:87-91. 81. Tsuji T, Imajo Y, Sawabe M, Kuniyuki S, Ishii M, Hamada T, et al. Acquired cutis laxa concomitant with nephrotic syndrome. Arch Dermatol 1987;123:1211-6. 82. Rongioletti F, Cutolo M, Bondavalli P, Rebora A. Acral localized acquired cutis laxa associated with rheumatoid arthritis. J Am Acad Dermatol 2002;46:128-30. 83. Ozkan S, Fetil E, Gunes AT, Bozkurt E, Sahin T, Erkizan V, et al. Cutis laxa acquisita: is there any association with Borrelia burgdorferi? Eur J Dermatol 1999;9:561-4. 84. Bayle-Lebey P, Periole B, Daste G, Sans B, Marguery MC, El Sayed F, et al. Acquired localized elastolysis associated with varicose veins. Clin Exp Dermatol 1995;20:492-5. 85. Lewis PG, Hood AF, Barnett NK, Holbrook KA. Postinflammatory elastolysis and cutis laxa. A case report. J Am Acad Dermatol 1990;22:40-8. 86. Verhagen AR, Woerdeman MJ. Post-inflammatory elastolysis and cutis laxa. Br J Dermatol 1975;92:183-90. 87. O’Brien JP. Is actinic (solar) damage the provoking cause of ‘‘post-inflammatory elastolysis and cutis laxa (PECL)’’? [letter]. Br J Dermatol 1976;95:105-6. 88. Shimizu H, Nishikawa T, Kimura S. White fibrous papulosis of the neck: a review of 16 cases. Jpn J Dermatol 1985;95:107784. 89. Rongioletti F, Rebora A. Fibroelastolytic patterns of intrinsic skin aging: pseudoxanthoma- elasticum-like papillary dermal elastolysis and white fibrous papulosis of the neck. Dermatology 1995;191:19-24. 90. Zanca A, Contri MB, Carnevali C, Bertazzoni MG. White fibrous papulosis of the neck. Int J Dermatol 1996;35:720-2. 91. Siragusa M, Batolo D, Schepis C. White fibrous papulosis of the neck in three Sicilian patients. Australas J Dermatol 1996; 37:202-4. 92. Vermersch-Langlin A, Delaporte E, Pagniez D, Piette F, Lecomte-Houcke M, Bergoend H. White fibrous papulosis of the neck. Int J Dermatol 1993;32:442-3. 93. Shimizu H, Kimura S, Harada T, Nishikawa T. White fibrous papulosis of the neck: a new clinicopathologic entity? J Am Acad Dermatol 1989;20:1073-7. 94. Redondo P, Vazquez-Doval J, de Alava E, Quintanilla E. White fibrous papulosis of the neck. Dermatology 1993;186:238-9.

184 Lewis et al

95. Balus L, Amantea A, Donati P, Fazio M, Giuliano MC, Bellocci M. Fibroelastolytic papulosis of the neck: a report of 20 cases. Br J Dermatol 1997;137:461-6. 96. Joshi RK, Abanmi A, Haleem A. White fibrous papulosis of the neck. Br J Dermatol 1992;127:295-6. 97. Rongioletti F, Rebora A. Pseudoxanthoma elasticumelike papillary dermal elastolysis. J Am Acad Dermatol 1992;26: 648-50. 98. el-Charif MA, Mousawi AM, Rubeiz NG, Kibbi AG. Pseudoxanthoma elasticumelike papillary dermal elastolysis: a report of two cases. J Cutan Pathol 1994;21:252-5. 99. Ohnishi Y, Tajima S, Ishibashi A, Inazumi T, Sasaki T, Sakamoto H. Pseudoxanthoma elasticumelike papillary dermal elastolysis: report of four Japanese cases and an immunohistochemical study of elastin and fibrillin-1. Br J Dermatol 1998; 139:141-4. 100. Vargas-Diez E, Penas PF, Fraga J, Aragues M, Garcia-Diez A. Pseudoxanthoma elasticumelike papillary dermal elastolysis. A report of two cases and review of the literature. Acta Derm Venereol 1997;77:43-5. 101. Akagi A, Tajima S, Kawada A, Ishibashi A. Coexistence of pseudoxanthoma elasticumelike papillary dermal elastolysis and linear focal dermal elastosis. J Am Acad Dermatol 2002; 47(Suppl 2):S189-92. 102. Tajima S, Ohnishi Y, Akagi A, Sasaki T. Elastotic change in the subpapillary and mid-dermal layers in pseudoxanthoma elasticum-like papillary dermal elastolysis. Br J Dermatol 2000;142:586-8. 103. Rebora A, Parodi A, Rongioletti F. Mid-dermal elastolysis and pseudoxanthoma elasticumelike papillary dermal elastolysis. Br J Dermatol 1995;132:487. 104. Shelley WB, Wood MG. Wrinkles due to idiopathic loss of middermal elastic tissue. Br J Dermatol 1977;97:441-5. 105. Rothfleisch JE. Mid-dermal elastolysis. Dermatol Online J 2001;7:15. 106. Rae V, Falanga V. Wrinkling due to middermal elastolysis. Report of a case and review of the literature. Arch Dermatol 1989;125:950-1. 107. Brenner W, Gschnait F, Konrad K, Holubar K, Tappeiner J. Noninflammatory dermal elastolysis. Br J Dermatol 1978;99:335-8. 108. Rudolph RI. Mid dermal elastolysis. J Am Acad Dermatol 1990; 22:203-6. 109. Ortel B, Rappersberger K, Konrad K. Middermal elastolysis in an elderly man with evidence of elastic fiber phagocytosis. Arch Dermatol 1992;128:88-90. 110. Kim JM, Su WP. Mid dermal elastolysis with wrinkling. Report of two cases and review of the literature. J Am Acad Dermatol 1992;26:169-73. 111. Maghraoui S, Grossin M, Crickx B, Blanchet P, Belaich S. Mid dermal elastolysis. Report of a case with a predominant perifollicular pattern. J Am Acad Dermatol 1992;26:490-2. 112. Thorneby K, Sakai L, Dahlback K. Middermal elastolysis. Report of a case and immunohistochemical studies on the dermal distribution of fibrillin, vitronectin and amyloid P component. Acta Derm Venereol 1991;71:1-5. 113. Kirsner RS, Falanga V. Features of an autoimmune process in mid-dermal elastolysis. J Am Acad Dermatol 1992;27:832-4. 114. Snider RL, Lang PG, Miaze JC. The clinical spectrum of middermal elastolysis and the role of UV light in its pathogenesis. J Am Acad Dermatol 1993;28:938-42. 115. Harmon CB, Su WP, Gagne EJ, Fransway AF, Zelickson BD. Ultrastructural evaluation of mid-dermal elastolysis. J Cutan Pathol 1994;21:233-8.


116. Fimiani M, Mazzatenta C, Alessandrini C, Paola M, Paola C, Andreassi L. Mid-dermal elastolysis: an ultrastructural and biochemical study. Arch Dermatol Res 1995;287:152-7. 117. Tajima S, Inazumi T, Kajiya H, Osakabe T, Seyama Y, Sakamoto H, et al. Elastin metabolism in skin fibroblasts explanted from a patient with mid-dermal elastolysis. Br J Dermatol 1999;140: 752-4. 118. Patroi I, Annessi G, Girolomoni G. Mid-dermal elastolysis: a clinical, histologic, and immunohistochemical study of 11 patients. J Am Acad Dermatol 2003;48:846-51. 119. Brod BA, Rabkin M, Rhodes AR, Jegasothy BV. Mid-dermal elastolysis with inflammation. J Am Acad Dermatol 1992;26: 882-4. 120. Sterling JC, Coleman N, Pye RJ. Mid-dermal elastolysis. Br J Dermatol 1994;130:502-6. 121. Lewis KG, Dill SW, Wilkel CS, Robinson-Bostom L. Middermal elastolysis preceded by acute neutrophilic dermatosis. J Cutan Pathol 2004;31:72-6. 122. Neri I, Patrizi A, Fanti PA, Passarini B, BadialieDe Giorgi L, Varotti C. Mid-dermal elastolysis: a pathological and ultrastructural study of five cases. J Cutan Pathol 1996;23:165-9. 123. Agha A, Hashimoto K, Mahon M. Mid dermal elastolysis: case report and review of the literature. J Dermatol 1994;21:760-6. 124. Boyd AS, King LE Jr. Middermal elastolysis in two patients with lupus erythematosus. Am J Dermatopathol 2001;23:1368. 125. Gambichler T, Linhart C, Wolter M. Mid-dermal elastolysis associated with Hashimoto’s thyroiditis. J Eur Acad Dermatol Venereol 1999;12:245-9. 126. Hashimoto K, Tye MJ. Upper dermal elastolysis: a comparative study with mid-dermal elastolysis. J Cutan Pathol 1994;21: 533-40. 127. Bazex A, Dupre A, Chritol B. Maladie de Besnier-BoeckSchaumann chalazodermique? Bull Soc Fr Dermatol Syphiligr 1968;75:194. 128. Ackerman AB. Granulomatous slack skin. In: Ackerman AB, editor. Histologic diagnosis of inflammatory skin diseases. Philadelphia. Lea & Febiger; 1978. 129. Clarijs M, Poot F, Laka A, Pirard C, Bourlond A. Granulomatous slack skin: treatment with extensive surgery and review of the literature. Dermatology 2003;206:393-7. 130. LeBoit PE, Zackheim HS, White CR Jr. Granulomatous variants of cutaneous T-cell lymphoma. The histopathology of granulomatous mycosis fungoides and granulomatous slack skin. Am J Surg Pathol 1988;12:83-95. 131. van Haselen CW, Toonstra J, van der Putte SJ, van Dongen JJ, van Hees CL, van Vloten WA. Granulomatous slack skin. Report of three patients with an updated review of the literature. Dermatology 1998;196:382-91. 132. Wada K, Maesawa C, Satoh T, Akasaka T, Masuda T. A case of primary cutaneous CD30+ T-cell lymphoproliferative disorder with features of granulomatous slack skin disease. Br J Dermatol 2002;147:998-1002. 133. Mouly F, Baccard M, Cayuela JM, Janssen F, Verola O, Flageul B, et al. Cutaneous T-cell lymphoma associated with granulomatous slack skin. Dermatology 1996;192:288-90. 134. DeGregorio R, Fenske NA, Glass LF. Granulomatous slack skin: a possible precursor of Hodgkin’s disease. J Am Acad Dermatol 1995;33:1044-7. 135. Helm KF, Cerio R, Winkelmann RK. Granulomatous slack skin: a clinicopathological and immunohistochemical study of three cases. Br J Dermatol 1992;126:142-7. 136. Pai K, Rao R, Devadiga R, Shenoi S, Pai S. Granulomatous slack skin. Int J Dermatol 2000;39:374-6.


137. Balus L, Bassetti F, Gentili G. Granulomatous slack skin. Arch Dermatol 1985;121:250-2. 138. Topar G, Zelger B, Schmuth M, Romani N, Thaler J, Sepp N. Granulomatous slack skin: a distinct disorder or a variant of mycosis fungoides? Acta Derm Venereol 2001;81:42-4. 139. Tsuruta D, Kono T, Kutsuna H, Yashiro N, Ishii M. Granulomatous slack skin: an ultrastructural study. J Cutan Pathol 2001; 28:44-8. 140. Noto G, Pravata G, Miceli S, Arico M. Granulomatous slack skin: report of a case associated with Hodgkin’s disease and a review of the literature. Br J Dermatol 1994;131:275-9. 141. LeBoit PE. Granulomatous slack skin. Dermatol Clin 1994;12: 375-89. 142. Tsang WY, Chan JK, Loo KT, Wong KF, Lee AW. Granulomatous slack skin. Histopathology 1994;25:49-55. 143. Kono T, Nagayasu TS, Nakanishi T, Tsuruta D, Ishii M, Taniguchi S, et al. Granulomatous slack skin: successful treatment with recombinant interferon-gamma. Br J Dermatol 2000;142:353-7. 144. Metzler G, Schlagenhauff B, Krober SM, Kaiserling E, Schaumburg-Lever G, Lischka G. Granulomatous mycosis fungoides: report of a case with some histopathologic features of granulomatous slack skin. Am J Dermatopathol 1999;21: 156-60. 145. Chen M, Qiu B, Kong J. Granulomatous slack skin: a case of unusual variant of mycosis fungoides. Chin Med J (Engl) 2000; 113:189-92. 146. Hu W, Cook TF, Vicki GJ, Glaser DA. Acrokeratoelastoidosis. Pediatr Dermatol 2002;19:320-2. 147. Costa OG. Acrokeratoelastoidosis. Dermatologica 1953;107: 164. 148. Parker CM. Tender linear lesions of the fingers. Acrokeratoelastoidosis (acquired type) or degenerative collagenous plaques of the hands. Arch Dermatol 1991;127:114-115, 117-8. 149. Helbling I, Tucker SC, Chalmers RJ. Acquired crateriform hyperkeratotic papules of the lower limbs: an unusual variant of acrokeratoelastoidosis of Costa. Clin Exp Dermatol 2001;26: 263-5.

Lewis et al 185

150. Abulafia J, Vignale RA. Degenerative collagenous plaques of the hands and acrokeratoelastoidosis: pathogenesis and relationship with knuckle pads. Int J Dermatol 2000;39:424-32. 151. de Boer EM, van Dijk E. Acrokeratoelastoidosis: a spectrum of diseases. Dermatologica 1985;171:8-11. 152. Shbaklo Z, Jamaleddine NF, Kibbi AG, Salman SM, Zaynoun ST. Acrokeratoelastoidosis. Int J Dermatol 1990;29:333-6. 153. Saruk M, Taylor MR, Rudolph RI, Parhizgar B, Wood MG. Acrokeratoelastoidosis. Cutis 1983;32:248, 250-1. 154. Bogle MA, Hwang LY, Tschen JA. Acrokeratoelastoidosis. J Am Acad Dermatol 2002;47:448-51. 155. Matthews CN, Harman RR. Acrokerato-elastoidosis in a Somerset mother and her two sons. Br J Dermatol 1977;97(Suppl 15):42-3. 156. Masse R, Quillard A, Hery B, Toudic L, Le Her G. Costa’s acrokerato-elastoidosis. Ultrastructural study [author’s transl]. Ann Dermatol Venereol 1977;104:441-5. 157. Fiallo P, Pesce C, Brusasco A, Nunzi E. Acrokeratoelastoidosis of Costa: a primary disease of the elastic tissue? J Cutan Pathol 1998;25:580-2. 158. Highet AS, Rook A, Anderson JR. Acrokeratoelastoidosis. Br J Dermatol 1982;106:337-44. 159. Tajima S, Tanaka N, Ishibashi A, Suzuki K. A variant of acrokeratoelastoidosis in systemic scleroderma: report of 7 cases. J Am Acad Dermatol 2002;46:767-70. 160. Scuderi G, Palazzolo A, Massimino SD, Micali G. Costa’s acrokeratoelastoidosis. Apropos of a sporadic case. G Ital Dermatol Venereol 1990;125:465-9. 161. Dowd PM, Harman RR, Black MM. Focal acral hyperkeratosis. Br J Dermatol 1983;109:97-103. 162. Nelson-Adesokan P, Mallory SB, Leonardi CL, Lund R, Lombardi C. Acrokeratoelastoidosis of Costa. Int J Dermatol 1995; 34:431-3. 163. Korc A, Hansen RC, Lynch PJ. Acrokeratoelastoidosis of Costa in North America. A report of two cases. J Am Acad Dermatol 1985;12:832-6.

Relevance of the eigenstate thermalization hypothesis for thermal relaxation.

Finite-size scaling of eigenstate thermalization.

Eigenstate thermalization and representative states on subsystems.

Testing the Penrose Hypothesis-Reply.

Testing Facet Joint Injections for Low Back Pain: Are We Testing Whether They Really Work or Whether They Work Better?

Testing the individual effective dose hypothesis.

Multiple hypothesis testing in genomics.

Technology: testing all possibilities.

The psychiatric examination in the walk-in clinic. Hypothesis generation and hypothesis testing.

Clinical trials of integrative medicine: testing whether magic works?

Regional anesthesia: testing whether it makes a difference.

CausalTrail: Testing hypothesis using causal Bayesian networks.

Diabetes and appendicectomy: testing a hypothesis.

Testing the adaptive radiation hypothesis for the lemurs of Madagascar.

Multiple hypothesis testing and Bonferroni's correction.

Hypothesis testing for differentially correlated features.

Exercise testing? Not at all.

Testing the activitystat hypothesis: a randomised controlled trial.

Testing the implicit processing hypothesis of precognitive dream experience.

Thermalization of entanglement.

Trust and health: testing the reverse causality hypothesis.

Testing the hypothesis of preferential attachment in social network formation.

Commentary: The Need for Bayesian Hypothesis Testing in Psychological Science.

Testing the null hypothesis in small area analysis.