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Background There is scant literature that documents pseudoxanthoma elasticum (PXE)–like histologic changes in the setting of inflammatory skin diseases. This article documents granulomatous dermatitis with PXE-like changes in a patient with cystic fibrosis. This is the first report of its kind, to our knowledge. Observations A 33-year-old woman with cystic fibrosis developed a papular eruption on the flexural surfaces of the upper and lower extremities, which was initially treated with prednisone. A punch biopsy showed granulomatous inflammation and associated PXE-like changes. The combined histologic and clinical findings were most consistent with granuloma annulare. There was no family history of PXE or clinical manifestations of PXE. The rash gradually resolved itself over the next several months. Conclusions There are few publications that document PXE-like changes in association with various inflammatory skin conditions. Thus, the clinical significance of this finding remains uncertain. This case and previous reports are discussed in the context of current molecular and genetic knowledge. It is hoped that greater awareness of this phenomenon will promote further investigation and elucidation of the clinical and biologic significance of PXE-like changes observed in biopsies of inflammatory skin disorders.

Objectives To illustrate a phenotypic overlap consisting of usual, but limited, or atypical manifestations of pseudoxanthoma elasticum (PXE) between heterozygous carriers of a single ABCC6 mutation and patients diagnosed with PXE, carriers of homozygous or compound heterozygous mutations. Design Evaluation for full and typical, incomplete, mild, or overlooked PXE during a 5-year period (2001-2005) based on the following 1992 expert consensus conference items: (1) yellowish papular skin eruption, (2) dermal elastorrhexis and mineralization of elastic fibers in lesional skin, and (3) angioid streaks. Testing for ABCC6 mutations was performed in all cases after informed consent. Setting French multidisciplinary outpatient clinic for patients with PXE. Participants Patients prospectively referred for PXE and first-degree relatives. Main Outcome Measure Prevalence of PXE with a limited or atypical phenotype and manifesting heterozygosity. Results Ninety-four patients were diagnosed as having PXE. Fifty-eight relatives were also examined, and none displayed the characteristic signs of the disease. Despite the histoclinical items and ABCC6 genotyping, we were unable to establish a definite diagnosis in 5 additional referred cases, ie, to distinguish between PXE with a limited or atypical phenotype and heterozygosity with skin and/or ophthalmologic and/or cardiovascular manifestations suggestive of PXE. Conclusions We assume that all categories established at the 1992 consensus conference correspond to PXE, but that the 5 patients reported herein also have PXE. Homozygous, compound heterozygous, or heterozygous individuals may fulfill only some of the clinical and/or histopathologic consensus criteria of PXE. They cannot be placed into any category. Expressivity is highly variable in carriers of 1 or 2 ABCC6 mutations, and the disease manifestations overlap between both genotypes. Physicians should thus be more cautious with respect to the prognosis when faced with heterozygous relatives of a patient diagnosed with undisputable PXE. Indeed, heterozygotes may uncommonly experience severe ophthalmologic complications. Whether they may also have cardiovascular complications related to or worsened by PXE remains to be determined.

General forms of loose and redundant skin have been described in pseudoxanthoma elasticum (PXE). 1,2 The wrinkled skin of PXE resembles that of cutis laxa and it is often hard to distinguish between these 2 conditions. We report a case of PXE with severe laxity of the skin.

Elastosis perforans serpiginosa (EPS) is a distinct entity. In this presentation a study of clinical features and histopathologic changes of EPS is made based on a review of 90 cases recorded in the literature and on observations of 11 additional cases. In 26% of the cases, EPS occurs in association with some type of systemic disorder such as mongoloid idiocy or disorders of the connective tissue, eg, Ehlers-Danlos syndrome, osteogenesis imperfecta, pseudoxanthoma elasticum, or Marfan's syndrome. An attempt is made to relate the histopathologic changes of EPS with other disorders of the skin through the interesting phenomenon of "transepithelial elimination."

Periumbilical pseudoxanthoma elasticum (PXE) with transepidermal elimination of altered elastica presented a distinctive clinical pattern in six middle-aged, multiparous women. Other sites usually affected in PXE were spared. The possible genetic predisposition to PXE of these patients found its expression in the periumbilical skin, a site exposed to the trauma of multiple pregnancies. The extruded elastica had tinctorial properties that were characteristic of PXE. The clinical picture in our cases differs from clasic PXE. A peculiar acquired cutaneous PXE is not excluded.

Histologic paraffin sections of pseudoxanthoma elasticum (PXE)-involved skin of forearm and axilla were used for histochemistry and immunohistochemical and analytical electron microscopy to study the progressive mineralization in the dermis of patients with PXE. The von Kossa technique identified mineral deposits throughout the reticular PXE dermis. X-ray analysis revealed patterns of calcium and phosphorus deposition in the von Kossa-positive areas, and the immunohistochemical staining using monoclonal antibodies identified increased chondroitin-6-sulfate in these areas when compared with normal skin. Scanning transmission electron microscopy observation combined with X-ray dot mapping show calcium and phosphorus to be codistributed within the mineralized area. This study confirms by new methods the increase in chondroitin-6-sulfate, alterations in elastin and collagen, and a high calcium and phosphorus elemental distribution matching the mineralized area in the PXE dermis.

A patient with hypertension and chronic renal failure of an undetermined cause who was undergoing hemodialysis developed bilateral crusted, focally eroded plaques on her breasts. A biopsy specimen of the lesional skin revealed typical histologic changes of pseudoxanthoma elasticum, with epidermal perforation. A biopsy specimen of lesion-free skin revealed characteristics typical of pseudoxanthoma elasticum. Perforating pseudoxanthoma elasticum should be added to the growing list of cutaneous disorders that occur in patients with chronic renal failure who are undergoing hemodialysis.

The term nevus elasticus has been used in connection with 2 clinically and histologically different conditions, having in common only the fact of belonging to the group of connective-tissue nevi. The first to use the term nevus elasticus was Lewandowsky 1 who, in 1921, under the title of Naevus Elasticus Regionis Mammariae described a condition appearing in the pectoral regions and being characterized by groups of perifollicular papules which histologically showed disappearance and degeneration of the elastic fibers. Seventeen other cases have been published so far under a variety of names, such as ``dystrophia elastica follicularis thoracica,'' 2 ``naevus pseudocolloide parifolliculaire,'' 3 "nevus conjunctivus,'' 4,5 and finally, "nevus elasticus.'' 6-8 De Graciansky and Leclercq 9 recently, under the title of Le Naevus elasticus en tumeurs disseminees , described an entity previously called "juvenile elastoma'' by Weidman and co-authors. 10 This condition has also been described as ``Connective-tissue nevi" by Prakken

This paper is intended to emphasize the significance of the association of elastosis perforans serpiginosa with heritable disorders of connective tissue. A case is reported in which a patient with pseudoxanthoma elasticum developed multiple lesions of elastosis perforans serpiginosa. A review of the literature revealed only two such cases previously reported. The cases of elastosis perforans serpiginosa previously reported in association with other diseases are summarized. The case is that of a 35-year-old Caucasian male with the skin changes of pseudoxanthoma elasticum present since childhood. A sister also has this disease. Over the past seven years he developed multiple lesions of elastosis perforans serpiginosa which were located in the areas most affected by pseudoxanthoma elasticum. Seventeen such lesions were present at the time of examination. Histologic studies demonstrated the typical findings of both diseases.

The evidence that elastin is fundamentally different from collagen has been reviewed. With this background, a new classification based on etiology and distribution has been introduced for the dermal elastoses (those diseases associated with increased elastic tissue staining). Using the criteria which differentiate elastin from collagen, each of the elastoses has been evaluated. The elastotic fibers seen histologically in actinic elastosis and pseudoxanthoma elasticum are more characteristic of elastin than collagen.

REPORT OF A CASE A 41-year-old woman presented with a three-day history of myalgias, headache, mouth pain, and a diffuse pruritic eruption. She was being followed up in our genetics clinic for pseudoxanthoma elasticum. Therapy consisted of dipyridamole, which she took intermittently. She was reticent about her history and refused a complete physical examination. Cutaneous examination revealed a diffuse eruption consisting of tender, erythematous macules and papules, some of which were eroded, whereas others were scaly (Fig 1). There were palmar and plantar lesions that were variably keratotic papules or deep-seated pustules (Fig 2). She also had nonulcerative, tender, oral erythematous macules. Laboratory tests included a complete blood cell count, which was within normal limits, and two serologic tests for syphilis, the results of which were negative. A skin biopsy specimen was obtained (Figs 3 and 4). What is your diagnosis? DIAGNOSIS: Secondary syphilis. TREATMENT AND CLINICAL COURSE

Pseudoxanthoma elasticum (PXE) with transepidermal elimination was observed in a patient and diagnosed histologically in a single cutaneous plaque; it was the only manifestation of her disease. Recently, Lund and Gilbert 1 clearly established that most cases of coexistent PXE and elastosis perforans serpiginosa (EPS) are, in fact, perforating PXE. We suggest that all patients with apparent EPS or with solitary verrucous plaques be carefully examined for possible PXE. Report of a Case A 59-year-old woman was first seen in August 1975 for evaluation of a periumbilical hyperpigmented plaque (Fig 1). In about 1970, the patient first noted the asymptomatic lesion, which had not changed in size, color, or other characteristics since. No other lesions were present. She was hospitalized in 1968 for epistaxis; no cause was found. In 1971 during an admission for atrial fibrillation, fluoroscopy showed no intracardiac or coronary artery calcifications. Her parents, three siblings, five children

Pseudoxanthoma elasticum (PXE) is a puzzling heritable disorder of elastic fibers. Even though the disease has been recognized for more than a hundred years, little is known of its natural history, and essentially no treatment is available. Moreover, this is a disorder that often goes undiagnosed for needlessly long periods, and, when diagnosed, either false or misleading information is often given to the patient, causing unwarranted anxiety. This sharply focused textbook addresses primarily the clinical facets of PXE. Specifically, the author, Dr Neldner, shares the wealth of his clinical expertise on this disease by summarizing data on 100 patientswith PXE who were followed up over the ten-year period from 1973 to 1983. The observations dispel many myths concerning PXE and clarify a variety of prognostic features, among which are the following: the overall survivorship is probably better than has been previously suggested; in most cases, PXE is inherited as an

• A patient with hypertension and chronic renal failure of an undetermined cause who was undergoing hemodialysis developed bilateral crusted, focally eroded plaques on her breasts. A biopsy specimen of the lesional skin revealed typical histologic changes of pseudoxanthoma elasticum, with epidermal perforation. A biopsy specimen of lesion-free skin revealed characteristics typical of pseudoxanthoma elasticum. Perforating pseudoxanthoma elasticum should be added to the growing list of cutaneous disorders that occur in patients with chronic renal failure who are undergoing hemodialysis. ( Arch Dermatol 1985;121:1321-1322)

Disseminate elastosis perforans serpiginosa (EPS) was found in a healthy white man without Down syndrome (mongolism) or pseudoxanthoma elasticum (PXE). No other connective tissue disease was found. We have found no similar cases in our review of the literature.

Periumbilical pseudoxanthoma elasticum (PXE) with transepidermal elimination of altered elastica presented a distinctive clinical pattern in six middleaged, multiparous women. Other sites usually affected in PXE were spared. The possible genetic predisposition to PXE of these patients found its expression in the periumbilical skin, a site exposed to the trauma of multiple pregnancies. The extruded elastica had tinctorial properties that were characteristic of PXE. The clinical picture in our cases differs from classic PXE. A peculiar acquired cutaneous PXE is not excluded. ( Arch Dermatol 115:300-303, 1979)

Elastosis perforans serpiginosa (EPS), a rare disease, has been associated with mongolism and several connective tissue disorders, including osteogenesis imperfecta, pseudoxanthoma elasticum, Marfan syndrome, and Ehlers-Danlos syndrome. The first description of EPS was made by Lutz in 1953.1Two years later, Miescher2presented a complete histopathologic study. The first cases of EPS in the United States were described by Hitch and Lund in 1959.3 To my knowledge, this is the third patient reported to have EPS coincident with osteogenesis imperfecta, which is a generalized disorder of connective tissue involving the fascia, ligaments, skin, sclera, tendons, inner ears, and bones, that typically results in the patient's having blue sclera and brittle bones.4 REPORT OF A CASE A 17-year-old boy had had blue sclerae since infancy. As a child, he had had several fractures, and x-ray films taken on each occasion were consistent with the diagnosis of osteogenesis

To the Editor.— Pseudoxanthoma elasticum (PXE) is a systemic heritable disorder aptly named for its xanthoma-like cutaneous lesions and its involvement of elastic tissue. Patients with this disease often have premature and severe vascular disease. It has been suggested that carriers of PXE may not be uncommon and that these people may also be prone to vascular disease and its complications.1 Altman and his associates evaluated the incidence of PXE in Seattle and found that it may be much more frequent than reported, with carriers representing a possible 1% or more of the general population. In the February issue of theArchives(114:279-280, 1978), PXE that was apparently limited to one organ system was reported. The authors of this report speculated that single-organ involvement may represent mosaicism, variable expressivity, or heterozygote expression, and that such involvement might also occur in the cardiovascular system elastic tissue, producing many patients with premature

Histologic paraffin sections of pseudoxanthoma elasticum (PXE)-involved skin of forearm and axilla were used for histochemistry and immunohistochemical and analytical electron microscopy to study the progressive mineralization in the dermis of patients with PXE. The von Kossa technique identified mineral deposits throughout the reticular PXE dermis. X-ray analysis revealed patterns of calcium and phosphorus deposition in the von Kossa-positive areas, and the immunohistochemical staining using monoclonal antibodies identified increased chondroitin-6-sulfate in these areas when compared with normal skin. Scanning transmission electron microscopy observation combined with X-ray dot mapping show calcium and phosphorus to be codistributed within the mineralized area. This study confirms by new methods the increase in chondroitin-6-sulfate, alterations in elastin and collagen, and a high calcium and phosphorus elemental distribution matching the mineralized area in the PXE dermis.

To the Editor.— Since elastosis perforans serpiginosa (EPS) was first described, it has been suggested that it is a phenomenon caused by a variety of abnormal elastic fibers. At least three etiologic types are now considered to be involved, ie, the idiopathic, the reactive, and the penicillamine-induced. 1-3 Previous ultrastructural investigations showed that the abnormal elastic fibers in the idiopathic type differ in structure from those of the penicillamine-induced type. 1,3-6 The reactive type, which is associated with different congenital disorders, mostly of the connective tissue, such as Down's syndrome, osteogenesis imperfecta, Marfan's syndrome, pseudoxanthoma elasticum, and Ehlers-Danlos syndrome (EDS), has not been as extensively studied. 7 It remains to be demonstrated whether it is a unique structural form of EPS. We performed an ultrastructural study in two patients with the reactive type of EPS. Report of Cases.—Case 1.— A 15-year-old girl presented with osteogenesis imperfecta, type Ia

Recent clinical examination of 140 British patients with pseudoxanthoma elasticum (PXE) showed both autosomal and recessive inheritance. Fifty-seven recessive families were studied and showed two disease patterns. Patients with type 1 recessive PXE had flexurally distributed rash, moderately severe retinal disease, and a particular predisposition to gastrointestinal bleeding. Type 2 recessive disease is much rarer and affects the entire skin which is loose-fitting, lax, and extensively infiltrated with degenerated elastic fibers. Pooled data for these two groups clearly support an autosomal recessive pattern of inheritance.

The history of pseudoxanthoma elasticum and angioid streaks is presented, and the question of their pathogenesis is discussed. Complete agreement does not exist as to the pathological process involved. Four cases of pseudoxanthoma elasticum and angioid streaks (Gronblad-Strandberg syndrome) are presented plus a statistical review of 200 cases from the literature. Familial studies in the literature have all suggested a recessive inheritance in this disorder wth partial limitation to the female. The majority of cases have been reported in individuals beyond 30 years of age, but it is suspected that the syndrome often exists in an asymptomatic form from a much earlier age and is detected only when, for example, some circumstance such as trauma to an eye brings the individual to seek ophthalmological aid and the angioid streaks are then detected. The results of the statistical review herein presented suggest that cramps in the legs, gastrointestinal hemorrhage, and angina-like symptoms, otherwise unexplained, especially in the younger age groups, should at least suggest the possibility of this syndrome and that skin changes and angioid streaks should be looked for closely in these individuals. Visual difficulties, often severe, and hypertension also seem to be often encountered, but far more commonly in those affected individuals over 30 years of age. The visual difficulties appear to be casually related to retinal degeneration secondary to angioid streaks and tend to become more pronounced as the patient grows older, but the hypertension is far more difficult to evaluate, occurring mainly in an age group where hypertension is frequently seen due to other causes. Even so, it is suggested that more cases of "essential hypertension" may be on the basis of this disorder. Severe psychic disturbances are sometimes seen, but minor disturbances such as "neurasthenia" and slight memory loss seem to be common occurrences. The plethysmographic studies of our 4 cases show the usual variation from normal which has been described in these cases. It is felt that the diagnosis of pseudoxanthoma elasticum and/or angioid streaks warrants a complete vascular survey, including careful physical examination, ECG, x-rays of extremities for medial calcifications, and peripheral pulse and blood flow studies.

Angioid streaks of the fundus and pseudoxanthoma elasticum of the skin are rare diseases of apparently unrelated organs which only recently have been considered as related conditions, and possibly as manifestations of a single systemic disease. The first condition was described first by Doyne 1 (1889) and independently by Plange 2 (1892) and was given the name "angioid streaks" by Knapp (1892). 3 Balzar in 1884 (Ormsby 4 ) first described a rare disease of the skin which Darier later (1896) called pseudoxanthoma elasticum (Throne and Goodman 5 ). As early as 1903 Hallopeau and Laffitte 6 described the association of pseudoxanthoma elasticum with angioid streaks, but it was not until the work of Gronblad 7 (1929 and 1932) that the two diseases were generally associated and an attempt was made to correlate the etiologic factors in the two conditions. ANGIOID STREAKS Appearance .—On ophthalmoscopic examination angioid streaks appear as

A patient with pseudoxanthoma elasticum (PXE) and blue sclerae is described. This is believed to be the first report of this association, although blue sclerae are well recognized in other disorders of connective tissue.

PREVIOUS work 1 has demonstrated that patients with lupus erythematosus have an altered peripheral circulation, as demonstrated by changes in the form of the photoelectric plethysmogram of the fingers. It is the purpose of this paper to present evidence that the same kind of changes exist in the peripheral circulation of patients with psoriasis. This alteration in the peripheral circulation is similar to that reported in arteriosclerosis, 2 hypertension, 2 pseudoxanthoma elasticum, 3 and scleroderma. 4 MATERIAL AND METHODS Studies were made on 28 normal subjects and on 11 patients with psoriasis. The extent, acuity, or activity of the psoriasis was not recorded except to note that there was no clinical evidence of nail involvement at the time of the studies. Also, none of the patients had clinical or radiological evidence of hypertension or arteriosclerosis. The photoelectric plethysmograph used in this study was a modification of that described by Hertzman.

Skin from four patients with pseudoxanthoma elasticum is studied histochemically using stains for elastic tissue, calcium, and acid mucopolysaccharides. Skin from one of these individuals is studied biochemically with quantitation of total hexosamine, amino sugars, calcium, nonfibrous and fibrous proteins. Histologically and biochemically there is evidence of increased acid mucopolysaccharides which are hyaluronidase resistant and may be sulfated. It is postulated that the increased calcification seen in the lesions is related to this increased acid mucopolysaccharide. There is a reduction of collagen which appears to be primarily in the insoluble collagen fraction. The increased elastin-like protein isolated from pseudoxanthoma elasticum has an amino acid composition which is quite similar to normal human dermal elastin.

We report a patient with osteopoikilosis and dermatofibrosis lenticularis disseminata with unusual flexural location. The patient was undersized, had diabetes mellitus, and pronounced arteriosclerotic changes. Histologic examination showed the cutaneous lesions sharply demarcated with a pseudotumorous appearance. Electron microscopic studies of these lesions revealed some of the elastic fibers broken up, partly into big lumps consisting of the amorphous component, partly into smaller granular elements, presumably representing the fibrillar component. The collagen fibers were normal. A certain resemblance to pseudoxanthoma elasticum is discussed.