Generalized elastolysis (cutis laxa)

Generalized Elastolysis (Cutis Laxa)

RUSSELL B. HARRIS, M.D. MICHAEL R. HEAPHY, M.D.* HAROLD 0. PERRY, M.D. Rochester, Minnesota

Generalized elastolysis is a rare and unique systemic disorder of connective tissue in which the elastic fibers suddenly become fragmented, disorganized and fewer in number with the resultant production of such entities as cutis laxa, emphysema, aortic aneurysms and bowel diverticula appearing in the organ system involved, that is, skin, lung, vasculature or gastrointestinal tract. Presented here are three cases that, illustrate the typical features of this condition. Jn addition, 14 more cases were retrieved from the literature and the information reviewed. Various etiologic factors relating to the synthesis and degradation of elastic tissue are discussed in light of recent findings in the biochemistry of connective tissue. Primary generalized elastolysis (cutis laxa) is a rare systemic disorder characterized by progressive looseness of the skin associated with widespread abnormalities of other organs and structures containing elastic tissue. It is a distinct entity from Ehiers-Danios syndrome, pseudoxanthoma eiasticum and Marfan’s syndrome, which it can resemble clinically in some respects. The usual form is genetically determined in one of several different patterns [ 1,2] with the dermai elastoiytic changes being present at birth or shortly thereafter. Until the summary article by Reed et al. [3] in 1971, the literature contained reports of only sporadic cases of generalized elastolysis occurring later in life. We wish to add three cases to the 14 cases reviewed in the literature and to discuss their clinical and morphologic significance in view of some of the more recent advances in the biochemistry of connective tissue. REPORT OF CASES Case 1.

A 44 year old housewife was seen at the Mayo Clinic in March 1977

for “loose skin.” In the spring of 1974, an erythematous the upper part of her chest and on her

From the Mayo Clinic and Mayo Foundation, Rochester, Minnesota. This paper was read at the meeting of the American Medical Association, Dermatology Section, St. Louis, Missouri, June 21-24, 1978. Requests for reprints should be addressed to Dr. R. B. Harris, c/o Section of Publications, Mayo Clinic, 200 First Street, SW, Rochester, Minnesota 5590 1. Manuscript accepted May 22, 1978. Present address: 1499 Arlington Drive, Lima, Ohio 45805. l

rash developed

on

neck; it lasted one month. Several

months later she noted that her skin was becoming undulywrinkled and loose, especially on the face and upper part of the trunk. Concomitantly, the patient began to note shortness of breath on exertion, which she thought was secondary to a pulmonary infection. She was given antibiotics on several occasions, which controlled her cough but not the gradually worsening dyspnea. She had no history of respiratory problems or smoking. Neither was there any history of cutis laxa or related skin diseases in her family. In May 1976, the patient underwent vaginal hysterectomy with anterior and posterior colporrhaphy for uterine procidentia, cystocele and rectocele. Physical examination showed the generalized lax skin (Figure 1) compared with a normal appearance at 25 years of age (Figure 2). Her joints and ocular fundi were normal. A pelvic examination revealed a “loose perineum with little support.”

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A work-up revealed normal values for urinalysis, hemoglobin, hematocrit, sedimentation rate, white blood cell and differential counts, chemistry group, alkaline phosphatase, cholesterol, triglycerides, albumin, globulin, serum protein electrophoresis, quantitative immunoglobulins, thyroxine, electrocardiogram, direct immunofluorescence on skin biopsy, serum zinc and copper, antinuclear antibodies and autoantibody screening. A chest roentgenogram showed evidence of scattered bullous changes in the bases of both lungs with linear fibrosis of the left apex, suggestive of an antitrypsin deficiency (Figure 3).

Ffgure 1. Prematurely agedappearance;wrinkledand facial and nuchal skin in a 44 year old woman.

of patient at 25 years of age.

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Results of pulmonary function studies were abnormal with a pattern consistent with diffuse obstructive pulmonary disease. Hyperinflation was present with rather severe reduction in maximal expiratory flows and an abnormal-appearing nitrogen washout. The maximal expiratory flows did not improve significantly after use of a bronchodilator, and the carbon monoxide-diffusing capacity was significantly reduced. The maximum flow static recoil (MFSR) curve had a normal slope but was shifted to the right, consistent with increased compliance of airways as well as the lung. The value for alpha,-antitrypsin @t-AT) was 462 mg/dl (normal range, 180 to 244 mg/dl). The phenotype was MM. Serum complement measurement caused agglutination of sheep red blood cells, but special autoantibody studies yielded negative results. A skin biopsy specimen stained for elastin revealed few, if any, elastic fibers in all dermal layers.

Figure 3. Roentgenogram showing evidence of scattered bullous changes in bases of both lungs, especially the left.

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Electron microscopy showed diminution of elastin as well as an apparent abnormality and uneven distribution of the dense granular substances that produce the bundles of efastin (Figure 4). The electron-dense amorphous matrix material of the elastic fiber was increased but did not form the dark bundles normally found in elastic fibers. Figure 4 reveals that the microfibrillary material within and about the elastic fiber is normal in structure but increased in amount, possibly because of decreased deposition of elastin. Finally, examination of many fields showed an over-all reduction in elastic fibers, and the dermis itself appeared to have a loose, almost depleted appearance. Case 2. In 1948, a 56 year old man consulted his physician concerning impotence. Benign prostatic hypertrophy was diagnosed, and the patient underwent transurethral prostatic resection. Postoperative complications included hemorrhage, phlebitis, pulmonary infarct and pneumonia. Subsequent to the postoperative complications, he began to notice a gradual drooping of the skin around his eyes. In November 1949, he had bilateral blepharoplasties. A right inguinal hernia had developed and was repaired in 1949. In March 1952 he was diagnosed as having an esophageal hernia, gallstones and pituitary or adrenal insufficiency or both. He was treated with

ELASTOLYSIS-HARRIS

ET AL.

penicillin and steroids. At no time did he have overt thyroid symptoms. The laxity of his skin became more generalized and continued to exacerbate. In 1952, he presented to the Mayo Clinic. On physical examination his condition was diagnosed as a classic example of cutis laxa with bloodhound facie% that is, a soft, velvety, pendulous skin of the eyelids, cheeks and neck, and also of the breast and scrotum. His skin was dry but not coarse; his voice was low and slightly hoarse; his reflexes were normal; and his blood pressure was 150170 mm Hg. He had a right inguinal hernia. Ocular examination revealed normal fundi. He was treated sequentially with neostigmine (Prostigmine), thyroid extract and methyltestosterone; all were without benefit. The results of most laboratory tests were normal; however, the following abnormalities were reported: the hemoglobin was 11.7 g/dl, sedimentation rate 37 mm in the first hour (Westergren), basal metabolic rate - 11 per cent, cholesterol 317 mg/dl, serum protein 4.2 g/dl with an albumin:globulin ratio of 2.7:1.5; albuminuria was 2i- with 2.3 g of protein loss per 24 hours; chest roentgenogram disclosed fibrosis at the base of the left lung, and stomach roentgenograms showed evidence of a large diaphragmatic hernia with much of the stomach situated intrathoracically.

Figure 4. Elastic fiber from anterior axillary fold of patient with acquired cutis laxa. Note aggregation of electron-dense amorphous substance and uncondensed micro fibrillary material around light bund/es of elastic fiber. The elastin itself seems reduced. Note also the focal aggregations of dense fibrillar material in sumn~nding dermis. Origiml magnification X 15; enlarged 2.5 times, reduced by 42 per cent.

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Figure 5. A, appearance of patient at 55 years of age after two surgical procedures to tighten drooping skin on chin and neck, Note extreme inelasticity of supraclavicular skin. 6, loose, pendulous abdominal skin.

Case 3 (Figure 5). A 50 year old man was seen first at the Mayo Clinic in 1940 for looseness and swelling of the skin, especially around the eyes but also of the cheeks and chin, which had begun insidiously about two years earlier. By 1941, it involved not only his face but also his neck, upper part of the chest, back and shoulders, giving him a “Saint Bernard” appearance. Additionally, on his initial visit, he had a right inguinal hernia, gallbladder stones, benign prostatic hypertrophy without retention and possible myxedema. The patient underwent multiple operations to correct deformities secondary to loss of elastic tissue. In 1941 and 1943 he had plastic surgery to tighten the drooping skin on his neck and chin, respectively. In 1943, 1945 and 1949, he required blepharoplasties to correct the skin laxity around his eyes; however, the process continued to exacerbate and in 1952 he required a lid crutch that consisted of swimming goggles with a flange. In 1945 he underwent a full facelift. A right inguinal hernia was repaired in 1941, 1943 and 1950. In 1943, he underwent fascia lata repair of a ruptured right patellar tendon. Because of dysphagia and increasing emaciation, he had esophageal dilatations in both 1947 and 1950. The patient was seen last at the Mayo Clinic in 1952. On this admission he complained of progressive weakness, loss of weight, extreme dysphagia, shortness of breath, chronic constipation and continued drooping of his skin. A roentgenogram of the chest showed evidence of atelectasis of the upper lobe of the right lung. An x-ray series of the upper gastrointestinal tract revealed a huge pharyngoesophageal diverticulum with most of the stomach and part of the duodenum above the diaphragm. There was diffuse secondary dilatation, and spasms of the esophagus also were noted. Dysphagia was so severe that the patient could swallow only 1 or 2 ounces of the contrast material. Roentgenograms of the colon revealed evidence of widespread diverticulosis. An electrocardiogram showed low-voltage changes suggestive of diffuse myocardial disease. The remainder of the laboratory tests yielded normal results. The patient underwent another esophageal dilatation and

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was then dismissed. In December 1953, he died from a rupture of the thoracic aorta into the left pleural cavity. COMMENT Elastolysis is the term coined by Hult et al. [4] in which the elastic fibers become fragmented, disorganized and fewer in number. Among the diseases with acquired elastolysis, the most common is anetoderma or macular atrophy [5]. The disease is confined to the skin in well-localized areas, and the internal organs are free of conspicuous abnormalities. The primary process may be preceded by urticaria (Pellizari type), by red papules (Jadassohn type) or with no objective inflammatory signs (Schweniger-Buzzi type). Biopsy shows clumping, fragmentation and loss of elastic fibers in the corium [4,6,7]. Secondary anetoderma is seen with such widely divergent diseases as sarcoid, syphilis, pseudoxanthoma elasticum or neurofibromatosis [3]. Alibert [8], in 1835, was credited with the first description of cutis laxa, but in retrospect it was thought that Alibert’s patient had an unusual type of neurofibromatosis. Marshall et al. [9] in 1966 and Verhagen and Woerdeman [lo] in 1975 described an entity in which the clinical features were intermediate between anetoderma (macular atrophy) and generalized elastolysis. Because the destruction of elastic tissue was preceded by an inflammation of the skin, they termed this new entity “postinflammatory elastolysis and cutis laxa.” Their patients shared many features similar to those of patients with anetoderma (for example, predilection for the female sex; initial localization on the neck, shoulders and arms; chronic relapsing course; lack of internal involvement, and so forth) but differed in that anetoderma was more localized and less severe than postinflammatory elastolysis and cutis laxa. Because of the

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lack of internal involvement, the condition could be correctly designated as cutis laxa. At the far end of this spectrum of presentation (that is, widespread cutis laxa with internal involvement) is generalized elastolysis. This disease can be determined genetically in dominant, recessive [l] or X-linked recessive [2] forms, or it can be acquired with no apparent inherited pattern. Congenital generalized elastolysis is a slowly progressive disease without an initial localized inflammatory phase. Children with the dominant variety tend to have largely skin manifestations, a normal life span and few complications [ 11. Patients with the recessive form, however, are prone to severe complications and early death, usually from pulmonary or cardiovascular involvement. Acquired primary elastolysis closely resembles the congenital disease clinically, morphologically and pathologically. Reed et al. [3] reported two cases of cutis laxa in 1971: in one the patient had internal involvement (generalized elastolysis); in the other the patient had only dermal involvement (cutis laxa) and hence was excluded from this study. They also mentioned 11 cases of generalized elastolysis reported in the literature. Subsequently, two more cases have been reported [6,11]. We wish to add three more, making a total of 17 cases of generalized elastolysis in the literature. We reviewed several other cases reported in the literature [ 12- 161 but excluded them on the basis of no internal involvement or too little pertinent data for evaluation. Of the 17 patients, seven were female and 10 were male with an age range of 15 to 63 years. Our first patient presented with a well-defined erythematous rash preceding the onset of elastolysis. She had been taking penicillin for a chest infection at the time the rash erupted. Our second patient also was taking penicillin as was the patient in the case reported by Scott et al. [ 111. Four of the 12 patients in the group described by Reed et al. [3] had a previous rash described as eczema or persistent urticaria, and one had a definite penicillin reaction. All of the 17 patients (Table I) had cutis laxa or large loose folds of pendulous, redundant, inelastic skin, which gave them a lugubrious, prematurely aged appearance. The eyelids drooped, the facial skin sagged into jowls, and the skin of the neck and trunk hung in large, flaccid folds. Postinflammatory elastolysis and cutis laxa are characterized by a fine wrinkling and a more truly senile appearance, although, depending on position and manipulation, there may be folds [IO]. The nose appears normal in the acquired elastolysis, whereas a hooked nose and long upper lip typify the facial deformity in the congenital variety [ 11. The skin is the most commonly involved portion of the body. The pulmonary system ranked second with

TABLE I

ELASTOLYSIS---HARRIS

ET AL.

Generalized Elastolysis-Systemic Involvement

System Involved Skin Pulmonary system Gastrointestinal tract Cardiovascular

No.

Per Cent ___-__

17117 11117 10117 7117

100 64 59 41

system Hernias (excluding hiatal)

6117

35

Genitourinary

417

57

tract, women

involvement in 11 of the 17 cases we reviewed; progressive emphysema was reported in eight and in the other three pneumothorax, fibrosis and tracheobronchiomegaly, respectively [ 3,171. The chest roentgenogram in our first case seemed to show evidence of alpha,-antitrypsin deficiency; however, this patient actually had double the normal amount of alpha,-antitrypsin. Seven of the 17 patients had cardiovascular involvement, which included cardiomegaly, congestive heart failure, car pulmonale, murmurs and electrocardiographic changes. Two patients with elastolysis of the aorta died from eventual rupture of the aorta; another had ectasia but died from an unrelated cause [ 31. Aortic dilatation and tortuosity were noted [3] and also peripheral pulmonary artery stenosis in patients with congenital generalized elastolysis [ 16-201. Involvement of the gastrointestinal tract is manifested largely by diverticula [21] that may involve the entire bowel from pharynx to colon but have little functional significance unless they bleed [ 161. Rectoceles, rectal prolapse, gallbladder prolapse, hepatomegaly, malrotation of the bowel and gastric ulcers also were seen. Of the 10 patients with gastrointestinal involvement, four had hiatal hernias with eventration of the diaphragm and evidence of esophagitis. In the third patient we examined, practically all of the stomach and a portion of the duodenum were supradiaphragmatic. In addition to hiatal hernias, femoral, inguinal, obturator or ventral hernias were seen in six patients. Four of the seven women had cystoceles and uterine prolapse. Diverticula of the urinary tract have been reported in patients with congenital elastolysis [22-241 but were not seen or sought in those with acquired elastolysis. Dilatation and tortuosity of the ureters also were noted in a patient with congenital elastolysis

[W.

Ruptured patellar tendons were seen in two patients, and associated multiple myelomas were encountered in two patients [6,11]. Loss of support of the uvula and soft palate was found in another. Most of the patients had had multiple gyneCOlOgiC, plastic or general surgical procedures in the manage-

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ment of their elastolysis. The skin changes in a patient described by Dingman et al. [26] became less severe as the patient aged; however, most patients show no improvement and the history of multiple unsuccessful surgical procedures is characteristic as is illustrated by our third case. In both congenital and acquired elastolysis, paraffin sections stained with hematoxylin and eosin showed no remarkable abnormalities; however, elastic fiber stain showed diminution or absence of elastic fibers from all dermal layers [4,6,7]. The clumped elastic fibers appeared fragmented and granular. These changes were similar in skin, lung and aorta [3,7]. On electron microscopy, elastin is diminished with the microfilaments being visible, particularly at the periphery [6]. There is an apparent abnormality and uneven distribution of the dense amorphous or granular substances that, under normal conditions, produce the dense bundles. From the electron microscope studies to date, it is difficult to say with certainty whether there is a deficient formation of elastic fibers in generalized elastolysis or whether there is an accelerated catabolism. A more detailed discussion of this proposal occurs later in the present review. ETWLOGIC ASPECTS Several theories have been postulated regarding the etiology of generalized elastolysis. In 1965, Goltz et al. [22] suggested a disturbance in the activity of the serum elastase inhibitor. The elastic fibers are made up of two components: a microfibrillar component and an amorphous component in which the fibrils are imbedded [6,27]. Neither the amorphous component nor the microfibrillar component contains hydroxylysine, thus distinguishing them from collagen. The specific activity of elastase is due to its action on the amorphous component of elastic tissue, since the microfibrils are susceptible to proteolytic digestion by other enzymes (for example, trypsin, pepsin). It is the amorphous component that gives the elastic fiber its rubberlike characteristics, so that alteration or partial destruction of the amorphous component would affect such things as skin tension or pulmonary compliance. The main elastase inhibitor is alpha,-antitrypsin [ 281. Alpha,-antitrypsin is known to be a protective protein secreted by the liver which acts to prevent autodigestion of pulmonary tissue by the proteolytic enzymes of phagocytic cells. In relative or absolute deficiencies of antitrypsin, proteolysis of pulmonary tissue may occur

[=I. Aside from the pancreas, polymorphonuclear leukocytes in the blood are one of the large physiologic sources of elastase. Lazarus et al. [30] and Janoff and Scherer [31] discovered that the collagenase and elastase activities, respectively, reside within the granule

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fraction of human granulocytic leukocytes. Studies of leukocyte proteolytic enzymes have shown that they have the capability of attacking pulmonary tissue, causing emphysema, and that they can be blocked by alpha,-antitrypsin [32]. Human alveolar macrophages also have been found to contain proteolytic enzymes resembling those found in polymorphonuclear leukocytes. The specific enzymes actually differ, and it is not clear whether or not the elastase from alveolar macrophages is, in fact, inhibited by alpha,-antitrypsin [33]. Because of progressive emphysema associated with both congenital and acquired generalized elastolysis (cutis laxa), it is easy to understand why Goltz et al. [22] postulated an elastase inhibitor deficiency. This aspect has been considered by several investigators [6,1 l] including ourselves, but there seems to be no serum or tissue antielastase deficiencies. In fact, one of our patients (Case 1) had twice the normal amount of alpha,-antitrypsin, which leads one to wonder if the amount was increased secondary to the primary pathologic event. It is known that alpha,-antitrypsin increases in infections, inflammatory states, with injections of typhoid vaccine and with administration of diethylstilbesterol [34]. In a future study of Case 1, we hope to examine the elastase and ensure that the alpha,-antitrypsin is functional and capable of inhibiting elastase. In this event, high levels of elastase inhibitor also would be seen in the hypothetic situation in which an allosteric regulatory site on the elastase enzyme might be defective so that it could not be turned off by normal mechanisms. Ledoux-Corbusier and Achten [35] reported a case in which the patient had a total absence of serum alpha,-antitrypsin, chronic obstructive lung disease, hyperextensibility of the skin and hyperlaxity of the hand joints; because of the dissimilarity with our cases, this case suggests another mechanism. Just as it is not known whether alpha,antitrypsin inhibits alveolar proteolytic enzymes, an in-depth study of all the fixed and circulating elastolytic enzymes and inhibitors may provide clues to the pathogenesis of many collagen-related diseases. As previously mentioned, it is difficult to know whether generalized elastolysis represents a degradation problem or whether it represents a problem in synthesis. Recently, two male cousins with generalized elastolysis (cutis laxa) inherited in an apparent X-linked recessive pattern were reported to have deficient lysyl oxidase activity in cultures of their skin fibroblasts. The enzyme deficiency was more apparent when collagen instead of elastin was used as a substrate to assay the enzyme activity [ 21. The enzyme responsible for converting lysyl and hydroxylysyl residues to their aldehyde derivatives before cross-linking is lysyl oxidase. It does this by catalyzing oxidative deamination and thereby achieving

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tensile strength and integrity. It is not known whether there are distinct isoenzymes of lysyl oxidase in different tissues [27]. Ehlers-Danlos syndrome (type V) and Menkes’ (kinky hair) syndrome are also thought to result from defects in the same enzyme and are inherited in an X-linked pattern, suggesting that coding may be on the X chromosome [ 271. The different presentation of these three conditions may be explained on the basis of differing isoenzymes of lysyl oxidase. Lathyrogenic nitriles (for example, P-aminopropionitrile) prevent cross-linking of collagen and elastin by their inhibitory effect on lysyl oxidase with resultant aneurysms, reduced tensile strength of the skin, skeletal malformations, and so forth, in appropriate animal models [ 36,371. Lysyl oxidase is a copper-dependent enzyme [38]. There is a striking morphologic similarity between the elastica-containing tissues in Coulson’s copper-deficient swine and the tissues of the patient with generalized elastolysis [39]. The patients of Hajjar and Joyner [25] and of Scott et al. [ 1 l] had reduced serum copper levels and elevated ceruloplasmin levels. These facts were not substantiated in our patient (Case 1) of in the patients of Hashimoto and Kanzaki [6] or Chadfield and North [40] Elevated copper levels also have been reported [15]. Postulation of this tenet can be easily understood in congenital elastolysis, but why would the cross-linking mechanism suddenly become faulty in the acquired form?

ET AL

For completeness, mention should be made of the hypothetic situation in which vitamin C or iron is deficient, thereby rendering the enzyme, protocollagen proline hydroxylase, ineffective with resultant diminution of pulmonary fibrous connective tissue and emphysema. This condition has been described in rats [ 411, but it is only theoretic in human beings. The last hypothesis deals with an immunologic mechanism or deficiency, which seems unlikely since the elastic generation occurs in virtual cellular seclusion [3]. The direct immunofluorescence in our first patient (Case 1) was negative, which also militates against an autoimmune hypothesis. Approximately a third of the patients had had an inflammatory rash; however, several seemed to have penicillin reactions. Of what importance is this, if any? Are mechanisms being incited to turn off lysyl oxidase and prevent the manufacture of elastin, or is elastase activity being increased with resultant degradation? The purpose of this communication is to promote interest, thought, investigation and interchange between internists, dermatologists and surgeons who will be confronted with the protean manifestations of primary generalized elastolysis. This is a model in man that shows how the destruction of elastic tissue may produce the myriad changes already enumerated. To discover the defects in the normal mechanisms responsible for the synthesis and secretion of connective tissue molecules, or the eventual degradation of these molecules, would have far-reaching effects.

REFERENCES

5.

6. 7.

8.

9.

Beighton P: The dominant and recessive forms of cutis laxa. J Med Genet 9: 216, 1972. Byers PH. Narayanan AS, Bornstein P, et al.: An X-linked form of cubs laxa due to deficiency of lysyl oxkfase. Birth Defects 12: 293, 1976. Reed WB, Horowitz RE, Beighton P: Acquired cutis laxa: primary generalized elastolysis. Arch Dermatol 103: 661, 1971. Hult AM, Goltz RW, Midtgaard K: The dermal elastic fibers in cubs hyperelastic (Ehlers-Danlos syndrome) and in cutis laxa (generalized elastolysis): a histological, histochemical and electron microscopical study. Acta Derm Venereol (Stockh) 44: 415, 1964. Fleischmajer R, Matus NR: Diseases of the corium and subcutaneous tissue. Dermatology, vol 2. (Moschella SL, Pillsbrrv DM. Hwtev HJ Jr. ed). Philadelohii W. B. Saunders Co., 1975,p961.* ” ’ Hashimoto K, Kanzaki T: Cubs laxa: ultrastructural and biochemical studies. Arch Dermatol 111: 661, 1975. Sayers CP, Goltz RW, Mottaz J: Pulmonary elastic tissue in generalized elastolysis (cubs laxa) and Marfan’s syndrome: a light and electron microscopic study. J Invest Dermatol 65: 451. 1975. Alibert JL: Histore d’un berger des environs de Gisors (Derrnatose hbtbromorphe). Classics in Clinical Dermatology, (Shelley WB, Crissey JT, ed), Springfield, Illinois, Charles C Thomas, 1953, p 40. Marshall J, Hey1 T, Weber HW: Postinflammatory elastolysis

10. 11.

12.

13. 14. 15. 16. 17.

16.

19.

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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 40: 1016, 1966. Verhagen AR, Woe&man MI: Post-inflammatory elastolysis and cutis laxa. Br J Dermatol 92: 183, 1975. Scott MA, Kauh YC, Luscombe HA: Acquired cutis laxa associated with multiple myeloma. Arch Dermatol 112: 653, 1976. Alberti E: lschaemic infarct of the brain stem combined with bisymptomatic Klippel-Trenaunay-Weber syndrome and cutis laxa. J Neurol Neurosurg Psychiatry 39: 518, 1976. Kuokkanen K: Cutis laxa. Acta Derm Venereol (Stockh) 51: 315,197l. Bernstein BA, Sorbera RS. Maloney PL, et al.: Cutis laxa: report of case. J Oral Surg 29: 201, 797 1. Ferreira MC, Spina V: A case of cutis laxa with abnormal copper metabolism. Br J Plast Surg 26: 283, 1973. Thaning 0, Beighton P: Alimentary bleeding in cutis laxa of late onset. S Afr Med J 46: 928, 1972. Wanderer AA, Ellis EF. Goltz RW, et al.: Tracheobronchiomegaly and acquired cubs laxa in a child: physiologic and immunologic studies. Pediatrics 44: 709, 1969. Balboni FA: Cubs laxa and multiple vascular anomalies including coarctation of the aorta, a case report. Bull St Francis Hosp 19: 26. 1963. Hayden JG, Talner NS. Klaus SN: Cutis laxa associated with pulmonary artery stenosis. J Pediatr 72: 506, 1968.

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20.

21.

22.

23.

24. 25. 26.

27.

28.

29. 30. 31.

822

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ET AL.

Wagstaff LA, Fir-th JC, Levin SE: Vascular abnormalities in congenital generalized elastolysis (cutis laxa): report of a case. S Afr Med J 44: 1125, 1970. Lally JF, Gohel VK, Dalinka MK, et al.: The roentgenographic manifestations of cutis laxa (generalized elastolysis). Radiology 113: 605, 1974. Goltz RW, Hult A-M, Goldfarb M, et al.: Cutis laxa: a manifestation of generalized elastolysis. Arch Dermatol 92: 373, 1965. McKusick VA: Heritable Disorders of Connective Tissue, 4th ed. St. Louis, C. V. Mosby Co., 1972, p 372. Schreiber MM, Tilley JC: Cutis laxa. Arch Dermatol 84: 266, 1961. Hajjar BA, Joyner EN Ill: Congenital cutis laxa with advanced cardiopulmonary disease. J Pediatr 73: 116, 1968. Dingman RO, Grabb WC, Oneal RM: Cutis laxa congenitageneralized elastosis. Plast Reconstr Surg 44: 431, 1969. Uitto J, Lichtenstein JR: Defects in the biochemistry of collagen in diseases of connective tissue. J Invest Dermatol 66: 59, 1976. Senior RM, Huebner PF, Pierce JA: Serum elastase inhibitory capacity as a measure of serum alphat-antitrypsin concentration. Pulmonary Emphysema and Proteolysis, (Mittman C, ed), New York, Academic Press, 1972, p 179. Lieberman J: Elastase, collagenase, emphysema, and alphat-antitrypsin deficiency. Chest 70: 62, 1976. Lazarus GS, Brown RS, Daniels JR, et al.: Human granulocyte collagenase. Science 159: 1483, 1968. Janoff A, Scherer J: Mediators of inflammation in leukocyte lysosomes. IX. Elastinolytic activity in granules of human

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32.

33.

34. 35. 36.

37.

38.

39.

40. 41.

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polymorphonuclear leukocytes. J Exp Med 128: 1137, 1968. Kaplan PD, Kuhn C, Pierce JA: The induction of emphysema with elastase. I. The evolution of the lesion and the influence of serum. J Lab Clin Med 82: 349, 1973. Janoff A, Rosenberg R, Galdston M: Elastase-like, estroprotease activity in human and rabbit alveolar macrophage granules. Proc Sot Exp Biol Med 136: 1054, 1971. Kueppers F, Black LF: cut-Antitrypsin and its deficiency. Am Rev Respir Dis 110: 176. 1974. Ledoux-Corbusier M, Achten G: cY1-Antitrypsin deficiency and skin abnormalities. J Cutan Pathol 2: 25, 1975. Siegel RC, Pinnell SR, Martin GR: Cross-linking of collagen and elastin: properties of lysyl oxidase. Biochemistry 9: 4486, 1970. Pinnell SR, Martin GR: The cross-linking of collagen and elastin: enzymatic conversion of lysine in peptide linkage to cY-aminoadipic-&semialdehyde (allysine) by an extract from bone. Proc Natl Acad Sci USA 61: 708, 716, 1968. Papajiannis SP, Spina M, Gotte L: Sequential degradation and phagocytosis of heterologous elastin. Arch Pathol89: 434, 1970. Shields GS, Coulson WF, Kimball DA, et al.: Studies on copper metabolism. XXXII. Cardiovascular lesions in copperdeficient swine. Am J Pathol 41: 603, 1962. Chadfield HW, North JF; Cutis laxa-a report of three cases. Trans St Johns Hosp Dermatol Sot 57: 18 1, 197 1. Halme .J, Uitto J, Kahanp%i K, et al.: Protocollagen proline hydroxylase activity in experimental pulmonary fibrosis of rats. J Lab Clin Med 75: 535, 1970.