Elastoma (elastic nevus, juvenile elastoma, ⁴⁰ nevus elasticus, connective tissue nevus of Lewandowsky type⁴¹) is a variant of connective tissue nevus (see p. 317) in which the predominant abnormality is an increase in dermal elastic tissue. ⁴² The lesions may be solitary or multiple^{40. and 43.} and in the latter circumstance they are often associated with multiple small foci of sclerosis of bone (osteopoikilosis). This association is known as the Buschke–Ollendorff syndrome44. ^{and 45.} and the cutaneous lesions as dermatofibrosis lenticularis disseminata. In several instances, the cutaneous lesions have shown abnormalities in collagen rather than elastic tissue (collagenomas)^{46.47. and 48.} and for this reason dermatofibrosis lenticularis disseminata is not entirely synonymous with the term ‘elastoma’. ⁴³

The Buschke–Ollendorff syndrome (OMIM 166700) is inherited as an autosomal dominant trait with variable expressivity. ⁴⁴ While most individuals with this syndrome have both skin manifestations and osteopoikilosis, some family members have only cutaneous lesions or only bony lesions, but not both.^{46.49.50.51. and 52.} The genetic defect in the Buschke–Ollendorff syndrome has now been determined. It involves loss-of-function mutations in the LEMD3 gene (also called MAN1), which encodes an inner nuclear membrane protein that influences Smad signaling.^{53. and 54.} Melorheostosis (OMIM 155950) appears to be allelic with this syndrome and the concurrence of the two diseases has been reported.^{54.55. and 56.} The cutaneous lesions (elastomas) may be widely distributed flesh-colored or yellowish papules or localized, asymmetrically distributed plaques on the lower trunk or extremities. ⁵⁷ These localized lesions are thought to represent type 2 segmental manifestations of an autosomal dominant trait. ⁵⁸ A large, multilobulated, exophytic variant has been reported. ⁵⁹ They develop at an early age. The nail–patella syndrome, another disorder of connective tissue, has been reported in a family with the Buschke–Ollendorff syndrome. ⁶⁰

Studies of the desmosine content of elastomas indicate a 3–7-fold increase in elastin. ⁶¹ There appears to be an abnormality of elastogenesis with faulty aggregation of elastin units associated with the overall increase in elastin.

Linear focal elastosis (elastotic striae) is a distinctive acquired lesion composed of palpable, stria-like, yellow lines that typically occur in the lumbosacral region,64.^{71.72.73.74.75.76. and 77.} but other sites, such as the face⁷⁸ and legs⁷⁹ may be affected. There is a predilection for males. It occurs at all ages, but predominantly in the elderly. ⁸⁰ This condition, which has been likened to a keloid of elastic fibers, may be an unusual form of striae distensae (see p. 319), ⁷⁵ but its pathogenesis is currently unknown. ⁸⁰

Focal dermal elastosis is a distinct entity of late onset, characterized by a pseudoxanthoma elasticum-like eruption.^{81.82.83. and 84.} The elastin content of the skin is significantly increased. ⁸⁵

Elastoderma, an exceedingly rare condition, is an acquired, localized laxity of skin resembling cutis laxa with lax, extensible, wrinkled skin.^{86.87. and 88.} The lesions are not indurated. The clinical presentation differs, therefore, from elastoma (elastic nevus).

Elastofibroma (elastofibroma dorsi) is a relatively rare, slowly growing proliferation of collagen and abnormal elastic fibers with a predilection for the subscapular fascia of older individuals, particularly females.^{84.89.90.91. and 92.} It is rarely found at other sites. Most elastofibromas are unilateral and asymptomatic. Multiple elastofibromas are rare. ⁹³ Nearly two-thirds of the 300 or more cases so far reported have been from southern Japan. ⁹⁴ Although an association with pseudoxanthoma elasticum has been recorded, there is no abnormality in the ABCC6 gene. ⁹⁵ The pathogenesis is unknown, but they may represent a reaction to prolonged mechanical stress, possibly involving disturbed elastic fibrillogenesis by periosteal-derived cells. ⁹⁶ Cytogenetic studies have found evidence of chromosomal instability and/or clonal changes suggesting a neoplastic process. ⁹⁷ Elastofibromas are gray-white or tan in color and measure 5–10 cm in diameter. Subclinical elastofibromas have been found at autopsy. ⁹⁸

Elastosis perforans serpiginosa (also known as perforating elastosis – OMIM 130100) presents as small papules, either grouped or in a circinate or serpiginous arrangement, on the neck, upper extremities, upper trunk, or face.^{100.101.102.103.104.105. and 106.} Rarely, the lesions are generalized.^{84.107. and 108.} There is a predilection for males, with the onset usually in the second decade. Familial cases have been reported.^{109.110. and 111.} An autosomal dominant mode of inheritance with variable expressivity of the trait has been suggested. ¹¹² In up to a third of cases there is an associated systemic condition or connective tissue disorder: these include Down syndrome,^{108.113.114.115. and 116.} osteogenesis imperfecta, ¹¹⁷ cutis laxa, ¹¹⁸ Ehlers–Danlos syndrome, Marfan’s syndrome, acrogeria, scleroderma,^{119. and 120.} an abnormal 47,XYY karyotype, ¹²¹ diabetes mellitus, ¹²² perforating folliculitis, ¹²³ and chronic renal failure. ¹²⁴

Similar cutaneous lesions have been reported in patients with Wilson’s disease and cystinuria receiving long-term penicillamine therapy.^{118.125.126.127.128. and 129.} In these patients, a local copper depletion or a direct effect of penicillamine on elastin synthesis may be responsible for the formation of the abnormal elastic fibers, which are then eliminated transepidermally.^{125. and 130.} Elastic tissue damage appears to occur in other organs as well, a feature generally lacking in the usual idiopathic form of the disease.^{130. and 131.} The nature of the defect in the idiopathic form is unknown, but it is possible that perforating elastosis is the final common pathway for more than one abnormality of elastic fibers.^{101. and 132.} This theory is compatible with the finding of a 67 kDa elastin receptor in keratinocytes immediately surrounding the elastic materials being eliminated in lesions of elastosis perforans serpiginosa.^{133. and 134.} The elastin receptor may be involved in the interaction between keratinocytes and elastin.^{133. and 134.}

Various therapies have been used including liquid nitrogen cryotherapy, isotretinoin, and imiquimod. ¹³⁵

Pseudoxanthoma elasticum (OMIM 264800) is an inherited disorder of connective tissue in which calcification of elastic fibers occurs in certain areas of the skin, eyes, and cardiovascular system.^{144.145.146.147.148. and 149.} Mutations in the ABCC6 gene on chromosome 16p13.1 are responsible for this condition. Over 60 different mutations of this gene have been reported.^{150. and 151.} Its incidence ranges from 1 : 70 000 to 1 : 100 000 live births. ¹⁵² Skin changes are usually evident by the second decade and consist of closely set yellowish papules with a predilection for flexural creases, particularly in the neck and axillae and less commonly in the groins, periumbilical area, and the cubital and popliteal fossae.^{145.146.147.153. and 154.} Oral lesions may occur. ¹⁴⁸ The skin becomes wrinkled and thickened and eventually may become lax and redundant, resembling cutis laxa.^{155.156.157. and 158.} Mental (chin) creases are common.^{159. and 160.} The calcium content of affected skin may be up to several hundred times normal. ¹⁶¹ Calcification occurring in the breast may lead to problems in the interpretation of mammograms. ¹⁶² Eye changes include angioid streaks and a degenerative choroidoretinitis which may lead to blindness. Angioid streaks can occur in the absence of pseudoxanthoma elasticum. ¹⁶³Calcification of elastic fibers in arteries and intimal and endocardial fibroelastosis develop. The vascular changes may lead to hypertension, sudden cardiac death, ¹⁶⁴ cerebrovascular accidents, and gastrointestinal hemorrhage.^{165.166. and 167.} Gastric bleeding may be increased in pregnancy, but most pregnancies in this condition are uncomplicated. ¹⁶⁸

Pseudoxanthoma elasticum has been associated with certain hemoglobinopathies such as β-thalassemia and sickle cell disease.^{152. and 169.} Nephrolithiasis is another rare association. ¹⁷⁰ Its occurrence is interesting as the ABCC6 gene encodes a transmembrane transporter protein ABCC6 (MRP6), a member of the ATP-binding cassette (ABC) superfamily. ¹⁷¹ This protein is strongly expressed in the liver and kidney, with a possible role in phosphocalcic metabolism. ¹⁷⁰ Hyperphosphatasia has been reported in several cases. ¹⁷² The administration of vitamin D₃ results in further deposition of calcium salts. ¹⁷³ Oral phosphate binders have been used in a small number of cases, with clinical improvement of skin lesions in half. ¹⁷⁴ Urinary glycosaminoglycan levels are elevated early in the disease. ¹⁷⁵ Polymyositis and lupus erythematosus are other associations, possibly due to chance.^{176. and 177.}

Characterization of the gene mutations responsible for this condition have led to a change in our understanding of its inheritance. Previously it was believed that there were two variants with autosomal dominant inheritance and two with autosomal recessive inheritance. The clinical presentations and severity of these variants appeared to differ.^{178.179.180. and 181.} It was acknowledged that the interpretation of the genetic studies that resulted in these views was made difficult by the limited phenotypic expression of the disease in some individuals. ¹⁸² It is now believed that fewer than 2% of cases, if any, are autosomal dominant. In one study of 142 subjects, all cases were autosomal recessive in their mode of inheritance. ¹⁸³ Consanguinity was high. Homozygous patients had typical clinical appearances, including angioid streaks in the eye, although the severity of the disease varied. ¹⁸³ All 67 subjects that were heterozygous for the gene showed no cutaneous features of pseudoxanthoma elasticum, but few had skin biopsies. ¹⁸³ Heterozygotes may uncommonly experience severe ophthalmological complications. ¹²³ Whether they may have cardiovascular complications remains to be determined. Another study showed histological changes in dermal elastic fibers in heterozygotes but the authors still concluded that the relevance of performing a skin biopsy to detect heterozygous carriers remains to be determined. ¹⁷¹

Patients purported to have coexisting elastosis perforans serpiginosa and pseudoxanthoma elasticum have been reported; they are now regarded as having perforating pseudoxanthoma elasticum.^{184.185.186. and 187.} In such a case, associated with Moya Moya vasculopathy, amino acid substitutions were found in a region close to the ABCC6 gene site. ¹⁸⁷ Many of these patients have so-called ‘acquired pseudoxanthoma elasticum’ (see below).

The factors that lead to the calcification of initially normal elastic fibers in pseudoxanthoma elasticum are not known. ¹⁸⁸ The role of ABCC6 has not been delineated, and its substrate has not been identified. ¹⁷¹ Polyanionic material is deposited in association with the calcified material. Cultured fibroblasts from patients with this condition release a proteolytic substance and it has been postulated that this may cause selective damage to elastin, leading to calcification. ¹⁸⁹ Fibrillin appears to be abnormal in only isolated cases (unlike the findings in Marfan’s syndrome). ¹⁹⁰ Decreased deposition of fibrillin-2 has been reported in pseudoxanthoma elasticum. ¹⁹¹ These isolated findings have been replaced with a viewpoint that several structural proteins with an affinity for calcium (vitronectin, fibronectin, and bone sialoprotein) are increased in this condition and responsible for the calcification of the elastic fibers. ¹⁷¹

There has been one report of spontaneous resolution and repair of elastic tissue calcification. ¹⁹² There is one report of the successful treatment of this condition with oral tocopherol acetate and ascorbic acid, both antioxidants. ¹⁹³ It took 2 years of treatment for the papules to disappear. ¹⁹³

Elastic globes are small basophilic bodies, found in the upper dermis of clinically normal skin, which stain positively for elastic fibers (Fig. 12.11). They are considered with the other dermal cytoid bodies on page 387. Numerous elastic globes have been reported in a patient with epidermolysis bullosa whose skin was wrinkled²¹⁷ and in a patient with the cartilage–hair hypoplasia syndrome whose skin was hyperextensible. ²¹⁸

As the globes contain D-aspartyl residue-containing peptide, it has been postulated that they result from UV-induced skin damage. ²¹⁹

The usual clinical appearance of solar elastosis is thickened, dry, coarsely wrinkled skin with loss of skin tone. ²⁴⁴ Sometimes there is a yellowish hue. There may be some telangiectasia and pigmentary changes (poikilodermatous changes) in severe cases.^{245. and 246.} The best recognized clinical variant is cutis rhomboidalis in which there is thickened, deeply fissured skin on the back of the neck. Other clinical patterns include citrine skin, ²⁴⁷ Dubreuilh’s and other elastomas, ²⁴⁸ and solar elastotic bands of the forearm.^{249. and 250.} Elastotic bands are characterized by cordlike plaques across the flexor surfaces of the forearms. ²⁵¹ The author has seen a similar, but much milder phenomenon on the face of a colleague with severe solar damage. Bullous lesions are extremely rare.^{252. and 253.}

The origin of the elastotic material has been the subject of much debate. It has been attributed to the degradation of collagen or elastic fibers or both.^{254. and 255.} Alternatively, it has been suggested by others that the material results from the actinic stimulation of fibroblasts. ²⁵⁶ More recent work indicates that the elastotic material is primarily derived from elastic fibers.^{257. and 258.} The increased elastin appears to result from transcriptional activation of the elastin gene.^{259. and 260.} In contrast, various studies have clearly shown that in unexposed skin, elastin content decreases with age (−44%) between 50 and 70 years of age. Interestingly, the elastin content of moderately sun-exposed areas does not change during aging, which may be the result of age-induced reduction and sun-dependent increase in elastin. ²⁶¹ In addition to the increased production of elastin in sun-exposed skin, there is reduced human leukocyte elastase activity, possibly a consequence of increased lysozyme production which protects elastin from proteolysis. ²⁶¹ In contrast, neutrophil elastase is increased following experimental radiation to sun-protected skin. ²⁶² Clusterin, a glycoprotein, is markedly increased in solar elastosis. Its role is not completely elucidated. ²⁶³ A small amount of type I and VI collagen and procollagen type III are present, but the significance of this finding remains uncertain. ²⁵⁷ DNA photodamage and UV-generated reactive oxygen species are the initial molecular events that lead to most of the typical histological and clinical manifestations of chronic photodamage of the skin. ²⁶⁴ Photoaging results in the accumulation of glycosaminoglycans on the elastotic material in the upper dermis and not between collagen and elastic fibers as in normal skin.^{265. and 266.} Fibrillin is also increased. ²⁵⁸ Collagen VII is reduced and this may contribute to the formation of wrinkles by weakening the bond between the dermis and the epidermis. ²⁶⁷ D-aspartyl residues are increased in chronological and photo-induced aging. ²¹⁹ Matrix metalloproteinase-7 and -12 are increased in photodamaged skin; they may contribute to remodeling of elastotic areas.^{268. and 269.} Metalloproteinase-1 may be responsible for the degeneration and reduction in collagen.^{270.271. and 272.} Fibulin-2, which belongs to a novel family of extracellular matrix protein, is significantly increased in actinically damaged skin. ¹¹ Other consequences of photoaging are mutations in p53 and the partial loss of the ability of epidermal cells to differentiate normally. ²⁷³ The changes are qualitatively quite different from those seen in chronological aging,^{274. and 275.} contrary to the assertion of some. ²⁷⁶

Various therapies have been used in recent times to improve the clinical appearance of photoaged skin. ²²⁶ One such technique, dermabrasion, produces clinical improvement by the synthesis of type I collagen. ²⁷⁷ Another technique, the prolonged application of topical tretinoin (retinoic acid), produces epidermal thickening,^{225.278.279.280. and 281.} hypergranulosis, an increase in epidermal Langerhans cells, ²³¹ the deposition of collagen in the papillary dermis, ²⁸² and, sometimes, an increase in fine elastic fibers in the papillary dermis. ²⁸³ Carbon dioxide laser resurfacing, and the intradermal injection of crosslinked hyaluronic acid may also be used.^{226. and 284.} These changes may result in an improved clinical appearance,^{285. and 286.} although this has not occurred in all studies. ²⁸⁷ Imiquimod, tacrolimus ointment, topical 5-aminolevulinic acid, and topical estrogen creams have all been used successfully in the treatment of photoaging.^{288.289.290. and 291.} Over-the-counter preparations have had variable results. ²⁹² The prolonged use of sunscreens results in a significant reduction in the amount of solar elastosis and other harmful effects;^{293. and 294.} it is the single most cost-effective therapy.^{225. and 266.}

The solar degenerative condition, nodular elastosis with cysts and comedones, is also known as the Favre–Racouchot syndrome. ³⁰⁹ It occurs as thickened yellowish plaques studded with cysts and open comedones.^{310.311. and 312.} It involves the head and neck, but particularly the skin around the eyes. Lesions may extend to the temporal and zygomatic areas. A case involving the shoulder region has been reported. ³¹³ Rare cases are unilateral. ³¹⁴ There is a predilection for older males who have a history of prolonged solar exposure. Smoking may act in conjunction with solar damage to potentiate the development of this condition.315. ^{and 316.} A case precipitated by radiation therapy and successfully treated with low-dose isotretinoin has been reported. ³¹⁷ Another case was provoked by ultraviolet (UVA1 and UVB) radiation. ³¹⁸

Elastotic nodules are small, usually asymptomatic, pale papules and nodules found predominantly on the anterior crus of the antihelix in response to actinic damage.^{320.321. and 322.} They are often bilateral. There is a marked predilection for elderly white males. Rare cases develop on the helix, where they may be painful, simulating chondrodermatitis nodularis helicis. They may be diagnosed clinically as basal cell carcinoma, amyloid, or even small gouty tophi.

Also known as ‘degenerative collagenous plaques of the hands’, ‘keratoelastoidosis marginalis’, and ‘digital papular calcific elastosis’, ³²³ collagenous and elastotic plaques of the hands is a slowly progressive, degenerative condition found predominantly in older males.^{324.325.326. and 327.} There are waxy, linear plaques at the juncture of palmar and dorsal skin of the hands. The condition particularly involves the medial aspect of the thumbs and the lateral (radial) aspect of the adjacent index finger. In this respect the lesions resemble in part those seen in the genodermatosis acrokeratoelastoidosis (see p. 261). ³²⁴ Physical trauma of a repetitive nature and prolonged actinic exposure may play a role in the etiology of collagenous and elastotic plaques of the hand.^{326. and 328.}

Erythema ab igne refers to the development of persistent areas of reticular erythema, with or without pigmentation, at the sites of repeated exposure to heat, usually from open hearths.330. ^{and 331.} Other cases have included frequent hot bathing, ³³² a laptop computer placed on the thighs, ³³³ and a heating pad. ³³⁴ The lower legs are usually involved. Erythema ab igne is now seen only rarely. ³³⁵ Keratoses and, rarely, squamous cell carcinomas may develop in lesions of long standing. ³³⁶

Nevus anelasticus is the term suggested by Staricco and Mehregan⁶⁶ for several cases reported in the earlier literature characterized by an absence or definite reduction and/or fragmentation of elastic fibers in cutaneous lesions of early onset. ³⁴⁰ Further cases have been reported in which multiple papular lesions have developed, particularly on the trunk.^{340.341.342. and 343.} The term papular elastorrhexis has been used for such cases; it has been regarded by some as a distinct variant of connective tissue nevus, ³⁴⁴ and not synonymous with nevus anelasticus. The author has been criticized in a recent paper for not separating cases of papular elastorrhexis from nevus anelasticus. ³⁴⁵ However, another recent paper by Ryder and Antaya has suggested that nevus anelasticus, papular elastorrhexis, and eruptive collagenoma are the same entity; their preference for a name for this composite entity was papular elastorrhexis. ³⁴⁶ The lesions are not perifollicular in distribution. Separation from the non-inflammatory type of anetoderma may be difficult (see below).

Perifollicular elastolysis is a not uncommon condition of the face and upper back in which 1–3 mm gray or white, finely wrinkled lesions develop in association with a central hair follicle.^{348. and 349.} Balloon-like bulging of larger lesions may develop. ³⁴⁸ The disorder is significantly associated with acne vulgaris.^{349. and 350.} An elastase-producing strain of Staphylococcus epidermidis was found in the hair follicles located within lesions in one report. ³⁴⁸

Anetoderma (macular atrophy) is a rare cutaneous disorder in which multiple, oval lesions with a wrinkled surface develop progressively over many years.^{351. and 352.} Individual lesions may bulge outwards or be slightly depressed. They usually herniate inwards with finger tip pressure. There is a predilection for the upper trunk and upper arms, but the neck and thighs may also be involved. Facial involvement may lead to chalazodermia. ³⁵¹ Onset of the lesions is in late adolescence and early adult life. Childhood cases have been reported. ³⁵³ Familial cases are quite rare.^{354.355.356.357.358. and 359.}

The onset of lesions may be preceded by an inflammatory stage with erythematous macules and papules (Jadassohn–Pellizzari type) or there may be no identifiable precursor inflammatory lesions (Schweninger–Buzzi type). ³⁵² These two types have been classified as primary anetodermas. As an inflammatory infiltrate may be present even in cases with no clinical inflammatory features, this classification is outdated. ³⁶⁰ Patients with primary anetoderma frequently have at least one prothrombotic abnormality, the most common being the presence of antiphospholipid antibodies.^{360.361.362. and 363.}Secondary anetodermas^{351. and 352.} develop during the course of other diseases such as syphilis, leprosy, sarcoidosis, granuloma annulare, ³⁶⁴ tuberculosis, varicella, ³⁶⁵ HIV infection,^{366. and 367.} folliculitis, ³⁶⁸ angular cheilitis, ³⁶⁹ Lyme disease, ³⁷⁰ acrodermatitis chronica atrophicans, ³⁵¹ lupus erythematosus, ³⁵¹ amyloidosis, lymphocytoma cutis, ³⁷¹ cutaneous B-cell lymphoma,^{372. and 373.} mycosis fungoides, ³⁷⁴ juvenile xanthogranuloma,^{375. and 376.} immunocytoma, ³⁷⁷ or following penicillamine therapy³⁷⁸ or hepatitis B immunization. ³⁷⁹ Patches of anetoderma may develop in extremely premature infants, ³⁸⁰ usually at the sites of attachment of gel electrocardiographic electrodes.^{381. and 382.} Anetoderma-like changes have been reported in a patient with the clinical features of atrophoderma. The term ‘atrophoderma elastolytica discreta’ was used for these lesions. ³⁸³ The association with urticaria pigmentosa may be coincidental. ³⁸⁴ Rarely, secondary anetoderma overlies a pilomatrixoma.^{385. and 386.} The lesions of secondary anetoderma do not always correspond with those of the primary disease process.

Theoretically, anetoderma could result from increased degradation or reduced synthesis of elastic tissue. ³⁸⁷ It has been suggested that all cases have an inflammatory pathogenesis, which would tend to indicate that an elastolytic process is operative.^{21. and 388.} Increased expression of various metalloproteinases has been reported; they play an important role in the degradation of elastic fibers in anetodermic skin.^{19. and 389.} The concentration of elastin, as measured by the desmosine content of the skin, is markedly reduced. ³⁸⁷ Immunological abnormalities, the most common of which is a positive antinuclear factor, have been documented.^{390.391. and 392.}

The term ‘cutis laxa’ encompasses a group of rare disorders of elastic tissue in which the skin hangs in loose folds, giving the appearance of premature aging.^{347. and 399.} In many cases, there is a more generalized loss of elastic fibers involving the lungs, gastrointestinal tract and aorta, leading to emphysema, hernias, diverticula, and aneurysms.^{400.401.402. and 403.} It is an etiologically heterogeneous disorder.

Congenital and acquired forms exist. Congenital cutis laxa is genetically heterogeneous: there are several different autosomal recessive forms of the disease (OMIM 219100), one of which is associated with growth retardation.^{404.405.406.407. and 408.} These cases were reported in the earlier literature and may be examples of the De Barsy syndrome (see below). There is an autosomal dominant form (OMIM 123700) which is less severe. ⁴⁰⁹ One of the dominant forms is allelic to the Williams–Beuren syndrome and is related to mutations in the elastin (ELN) gene. ⁴¹⁰ The X-linked recessive variant (OMIM 304150), ⁴¹¹ in which there is a deficiency of lysyl oxidase, is now regarded as a variant of Menkes’ syndrome (OMIM 309400);^{410.412. and 413.} the two are allelic. ⁴¹⁰ It is caused by mutations in the ATP7A gene. ⁴¹⁴ The congenital forms are associated with a characteristic facies, with a hooked nose and a long upper lip (‘blood-hound’ facies). ⁴¹⁵ Congenital cutis laxa has been reported in a young male with the Kabuki make-up syndrome.^{416. and 417.} It has also been reported in a newborn with congenital hypothyroidism due to isolated thyrotropin deficiency. ⁴¹⁸

More than 50 cases of acquired cutis laxa have been described. The changes may be generalized or localized.^{419.420.421.422.423. and 424.} Localized cases may be acral or cephalic in distribution. ⁴²⁵ Acquired cutis laxa may be of insidious onset⁴²⁶ or develop after a prior inflammatory lesion of the skin⁴²⁷ which may take the form of erythema, erythema multiforme, urticaria,^{428. and 429.} a vesicular eruption, including dermatitis herpetiformis, ⁴³⁰ or Sweet’s syndrome. ⁴³¹ Several cases have followed an allergic reaction to penicillin,^{432. and 433.} while others have been associated with isoniazid therapy, ⁴³⁴ mastocytosis, ⁴³⁵ myelomatosis,^{436.437.438. and 439.} cutaneous lymphoma,^{440. and 441.} rheumatoid arthritis, ⁴⁴² systemic lupus erythematosus, ⁴⁴³ or the nephrotic syndrome. ³⁹⁹ In a case associated with celiac disease, deposits of IgA were present on the dermal elastic fibers. ⁴⁴⁴ Cutis laxa may occur as a manifestation of pseudoxanthoma elasticum. Late-onset cutis laxa also occurs in hereditary gelsolin amyloidosis (type V – familial amyloidosis of the Finnish type (OMIM 105120)) caused by a G654A or G654T gelsolin gene mutation on chromosome 9q34.^{445. and 446.} Gelsolin amyloid is deposited in dermal nerves, blood vessels, and appendages, and often encircles elastic fibers in the lower dermis leading to fragmentation and loss of fibers. ⁴⁴⁵

The congenital cases result from a defect in the synthesis or assembly of the components of the elastic fiber. All patients with the autosomal dominant form of cutis laxa who have had genetic sequencing studies performed have had mutations in the ELN gene localized to chromosome 7q11.2. ⁴⁴⁷ Its product, tropoelastin, is the most abundant component of elastic fibers.^{414. and 448.} Mutations in the ELN gene not only cause cutis laxa⁴⁴⁸ but also cause subvalvular aortic stenosis, ⁴⁴⁹ which may occur as an isolated disease or as part of the Williams–Beuren syndrome (Williams syndrome), a microdeletional syndrome that involves the deletion of one complete copy of ELN (see below).^{414. and 450.} The De Barsy syndrome appears to be another subgroup of cutis laxa that may involve a defect in elastin production with increased degradation. ⁴⁵¹ This syndrome is also characterized by progeroid features and mental retardation. ⁴⁵²

The molecular defects underlying the recessive forms of cutis laxa have recently been discovered.8. ^{and 9.} Mutations in the fibulin-5 gene (FBLN5) were the first identified. ⁴¹⁰ Mutations in this gene are also responsible for age-related macular degeneration, the leading cause of irreversible visual loss in the Western world. ⁴⁵³ A missense mutation in the fibulin-4 (FBLN4) gene has also resulted in cutis laxa. ¹² A congenital disorder of glycosylation involving a defect in the biosynthesis of N- and O-glycans has also been found in patients with cutis laxa. ¹⁷ Other rare syndromes associated with cutis laxa in which the mechanism of the decrease in fibers is not known include the Barber–Say syndrome (OMIM 209885), characterized by a dysmorphic face and hypertrichosis, ⁴⁵⁴ the SCARF syndrome (OMIM 312830), with skeletal abnormalities, ⁴⁵⁵ and geroderma osteodysplasticum (OMIM 231070). ⁴⁵⁶ It has been suggested recently that the elastic tissue abnormality in geroderma osteodysplasticum has overlap features between cutis laxa and wrinkly skin syndrome (OMIM 278250). ⁴⁵⁷

In those acquired cases associated with severe dermal inflammation, it has been suggested that granulocytic elastase may be responsible for the degradation of the elastic fibers. Cultured fibroblasts from one case showed increased elastase activity. ⁴²⁹ One report suggested that several factors, including high levels of cathepsin G, low lysyl oxidase activity, and a reduction in circulating proteinase inhibitor(s), could all contribute to the loss of elastin. ⁴⁵⁸ Collagenase and gelatinase A and B expression is up-regulated at the transcriptional level in cutis laxa. ⁴⁵⁹ This may explain the collagen abnormalities (see below) that are sometimes found. ⁴⁶⁰ A more recent paper has described missense alleles in both the elastin and fibulin-5 genes in a patient with acquired cutis laxa with inflammatory destruction of elastic fibers, suggesting an underlying genetic susceptibility in some patients with acquired cutis laxa. ⁴⁶¹

Localized areas of loose skin may develop in cutaneous lesions of sarcoidosis, syphilis, and neurofibromatosis. ⁴²⁶ Loose skin localized to the hands, feet, and neck, and deep palmar and plantar creases are seen in Costello syndrome (OMIM 218040) in which there are also characteristic facies, mental retardation, growth disorders, and, sometimes, hypertrophic cardiomyopathy.^{462.463. and 464.} Acanthosis nigricans may also be present. ⁴⁶⁵ There is an increased susceptibility to bladder cancers and rhabdomyosarcoma. It results from a functional deficiency in elastin-binding protein (EBP).^{7. and 462.} Mutations in the HRAS gene on chromosome 11p15.5 account for the majority of cases of Costello syndrome but other candidate genes have been mentioned sporadically.

Reduced elastic fibers were present in one case of the ‘Michelin-tire’ syndrome (see p. 846). ⁴⁶⁶

Williams–Beuren syndrome (OMIM 194050), also known as Williams’ syndrome, is a multisystem, congenital disorder characterized by craniofacial, neurobehavioral, cardiovascular, and metabolic changes.^{450. and 476.} It results from a microdeletion in the q11.23 region of chromosome 7, involving the elastin gene and up to 26 other genes such as the LIMK1 gene. ⁴⁷⁷ It is therefore a contiguous gene syndrome. Genes on other chromosomes have also been implicated. Its prevalence is approximately 1 in 10 000 births. Despite a moderate reduction in elastin deposition in the skin, the clinical changes are relatively mild with increased softness and mobility of the skin. ⁴⁷⁶

Papillary-dermal elastolysis is a rare disorder of elastic tissue characterized by clinical lesions resembling pseudoxanthoma elasticum, with small papules and cobblestone plaques on the neck and upper trunk.^{25. and 479.} Reported cases have occurred exclusively in females, but if the merged entity (see below) is accepted, both sexes may be involved. ⁴⁸⁰ Similar histopathological changes were present in a case presenting as a small, hyperpigmented plaque. ⁴⁸¹ It has been suggested recently that this condition is part of the spectrum of white fibrous papulosis of the neck (see p. 317), for which the term ‘fibroelastolytic papulosis of the neck’ has been suggested. ⁴⁸⁰ The pathogenesis of these two merged entities is unknown; it is possibly related to intrinsic aging.^{480. and 482.}

The coexistence of papillary-dermal elastolysis and linear focal dermal elastosis in the same patient has been reported. ⁴⁸³

Mid-dermal elastolysis, first described by Shelley and Wood in 1977, ⁴⁸⁷ is characterized by widespread patches of fine wrinkling due to a loss of elastic fibers from the mid dermis.^{487.488.489.490.491. and 492.} The clinical features can be quite subtle. ⁴⁹³ A few cases have shown a second clinical feature with looseness of the skin around hair follicles. ⁴⁹⁴ Other cases have had flesh-colored papules in a perifollicular distribution. ⁴⁹⁵ A third clinical pattern with a prominent reticular appearance has been reported. ⁴⁹⁶ It may represent the end stage of granuloma annulare. ⁴⁹⁶ Most cases have involved the upper extremities, neck, and trunk of women. It may represent a variant of anetoderma.

In nearly 50% of cases, erythema, urticaria, or burning precedes or coincides with the development of the lesions, suggesting that an inflammatory process may be involved in the pathogenesis. In some cases, the condition appears to be photoinduced or photoaggravated.^{495.497. and 498.} The onset has followed augmentation mammoplasty with silicone implants, ⁴⁹⁹ granuloma annulare,^{500. and 501.} and lupus erythematosus. ⁵⁰² Lesions may remain stable for many years. Mid-dermal elastolysis has been reported in one family with the Keutel syndrome (OMIM 245150), a rare autosomal recessive syndrome, characterized by abnormal cartilage calcification and due to mutations in the matrix Gla protein (MGP) gene. ⁵⁰³

There is some similarity to the cases reported from South Africa and South America, in young children, in whom wrinkling developed after a preceding inflammatory stage.^{504.505. and 506.}

An immunohistochemical study has shown enhanced expression of CD34⁺ and CD68⁺ cells and of matrix metalloproteinase-1 (MMP-1). ⁵⁰⁷ Another study confirmed the increase in CD68⁺ cells, but found that MMP-9 was present in epidermal keratinocytes and in large cells in lesional dermis. ⁴⁹⁵ This study of 11 patients concluded that the onset of the disease is strongly associated with UV exposure, which may induce fibroblast-like cells to express MMP-9 that in turn could be involved in the degradation of elastic fibers. ⁴⁹⁵ MMP-9 was also implicated in another study, in the destruction of the elastic fibers in this condition. ¹⁹³

Menkes’ kinky hair syndrome (OMIM 309400) is a rare multisystem disorder of elastic tissue transmitted as an X-linked recessive trait.^{513.514. and 515.} The defective gene (ATP7A) has been localized to chromosome Xq12–q13.^{516. and 517.} Characteristically the hair is white, sparse, brittle, and kinky. It looks and feels like steel wool. Pili torti and, occasionally, monilethrix are present. Neurodegenerative changes, vascular insufficiency, hypothermia, and susceptibility to infections are other manifestations of this syndrome.^{38. and 515.} Mild forms occur. ⁵¹⁸

The finding of reduced serum copper levels led to the view that Menkes’ syndrome was a simple copper deficiency state akin to that seen in copper-deficient sheep.^{519. and 520.} It is now thought to be due to a spectrum of mutations in the copper-transporting ATPase gene, ATP7A. ⁷ There is reduced activity of the copper-dependent enzyme lysyl oxidase in fibroblasts derived from the skin of patients with this syndrome. ⁵²¹ This enzyme is necessary for the crosslinking of elastin. ⁴ It has been suggested that this syndrome should be reclassified with Ehlers–Danlos syndrome type IX, in which a disorder of lysyl oxidase also occurs (see p. 328).

Fragile X syndrome (OMIM 300624), a rare X-linked form of mental retardation, is associated with a characteristic facies and connective tissue abnormalities which are clinically reminiscent of cutis laxa and the Ehlers–Danlos syndromes.^{522. and 523.} Most cases result from an increase in length of a stretch of CGG triplet repeats in the FMR1 gene situated on the long arm of the X chromosome (Xq27.3).^{524.525. and 526.} Rarely, the condition results from the deletion of all or part of this gene.^{525. and 527.} Attention deficit hyperactivity disorder is a frequent behavioral problem in young boys with fragile X syndrome. ⁵²⁸

Wrinkly skin syndrome (OMIM 278250) is a rare autosomal recessive disorder characterized by wrinkled skin with poor elasticity over the abdomen and on the dorsum of the hands and feet.^{529. and 530.} It has some features overlapping with cutis laxa type II. ⁵³¹ A recent study was unable to distinguish between wrinkly skin syndrome and cutis laxa with growth and developmental delay (OMIM 219200). ⁴⁵⁷ Increased palmar and plantar creases, a prominent venous pattern on the chest, microcephaly, and musculoskeletal abnormalities form part of the syndrome. There is overlap between wrinkly skin syndrome and geroderma osteodysplasticum (OMIM 231070).^{457. and 532.}