Periumbilical pseudoxanthoma elasticum associated with chronic renal failure and angioid streaks—apparent regression with hemodialysis

Periumbilical pseudoxanthoma elasticum associated with chronic renal failure and angioid streaks— apparent regression with hemodialysis A. N. Sapadin,a M. G. Lebwohl,a S. A. Teich,b R. G. Phelps,a D. DiCostanzo,c and S. R. Cohenc New York, New York Pseudoxanthoma elasticum (PXE) is a heritable connective tissue disease involving progressive fragmentation and dystrophic calcification of elastic fibers. Periumbilical disease as the exclusive site of cutaneous involvement is most commonly seen in the rare entity termed periumbilical perforating pseudoxanthoma elasticum (PPPXE). Patients with this disorder are generally obese, middle aged, multiparous black women with hypertension. The cutaneous lesions are well-demarcated, hyperpigmented, periumbilical plaques with keratotic papules on the periphery. Extracutaneous manifestations have rarely been described. We describe a patient with periumbilical PXE associated with chronic renal failure and bilateral angioid streaks. Histopathologic examination demonstrated typical calcification of elastic fibers with additional amorphous calcium deposits in the superficial dermis. Transepidermal elimination was not present. Normalization of the serum calciumphosphate product resulted in regression of the lesions—both clinically and histopathologically. The relation between PPPXE and hereditary PXE is discussed. The role of chronic renal failure in precipitating PPPXE is considered. (J Am Acad Dermatol 1998;39:338-4.)

The common heritable form of pseudoxanthoma elasticum (PXE) is a systemic disorder involving elastic fiber fragmentation and calcification with major clinical manifestations in the cutaneous, ocular, and cardiovascular systems. Although it is a genetically heterogenous disease with either autosomal recessive1 or autosomal dominant2 inheritance, no single clinical feature or combination of features can reliably differentiate these forms.3 Reports of sporadic occurrences of This article is made possible through an educational grant from Ortho Dermatological. Presented in part at the Dermatologic Society of Greater New York’s Eighth Annual Conrad Stritzler Memorial Residents’ Competition, Lenox Hill Hospital, New York, N.Y., January 23, 1997; presented in part as a poster at the 55th Annual Meeting of the American Academy of Dermatology, San Francisco, Calif., March 21-26, 1997; presented in part as a poster at the International Centennial Meeting on Pseudoxanthoma Elasticum, Bethesda, Md., November 6-7, 1997. From the Departments of Dermatologya and Ophthalmology,b The Mount Sinai Medical Center; Department of Dermatology,c Beth Israel Medical Center. Reprint requests: Allen N. Sapadin, MD, Box 1048, The Mount Sinai Medical Center, One Gustave L. Levy Place, New York, NY 10029-6574. Copyright © 1998 by the American Academy of Dermatology, Inc. 0190-9622/98/$5.00 + 0 16/4/90389

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PXE are also common.4,5 Its prevalence is thought to be 1:100,000,6 but this is likely an underestimation. Although a locus for autosomal recessive PXE has recently been mapped to 16p13.1,7,8 the precise gene has not yet been identified. Cutaneous manifestations are characterized by yellow papules in a cobblestone pattern or plaques resembling “plucked chicken-skin” in flexural regions. Redundant folds of skin may develop in more advanced cases. The most frequent sites of cutaneous involvement are the neck, axillae, antecubital and popliteal fossae, inguinal region, and periumbilical area. Mucous membrane involvement occurs, most commonly on the inner aspect of the lower lip. Histopathologic findings in the skin are fragmentation, clumping, and calcification of elastic fibers in the middle and lower dermis. Calcification of elastic fibers also occurs in the ocular and cardiovascular systems. In the eyes, this leads to cracks in Bruch’s membrane, an elastic tissue-containing membrane that separates the vascular choroid from the retinal pigment epithelium. These cracks are known as angioid streaks and may be the only sign of the disease for years. In such patients, biopsy specimens of the mid portions of old scars that contain calcified and frag-

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Fig. 1. Periumbilical pseudoxanthoma elasticum. Immediately superior to umbilicus is well-demarcated, hyperpigmented plaque formed by confluence of several keratotic papules. Isolated papule is present inferior to umbilicus.

Table I. *Literature review of periumbilical perforating pseudoxanthoma elasticum Reference

Age

Race

MP

HTN

AS

FA

RF

HD

Paton,24 1972 Lund and Gilbert,18 1976 Schwartz and Richfield,22 1978 Hicks, Carpenter, and Reed,19 1979

NA 48 59 58 55 58 57 56 57

NA NA NA AA AA AA AA AA AA

NA NA NA 11 19 11 15 NA 15

NA Yes Yes Yes Yes Yes Yes Yes No

Yes Yes OS No No No No No NA

ND ND ND ND ND ND ND ND ND

NA No No No No No No No No

NA No No No No No No No No

29

AA

5

Yes

No

ND

No

No

45

Indian

5

No

No

ND

No

No

62 50 66 68 58

AA NA AA AA AA

NA 9 4 13 9

Yes No Yes Yes Yes

Yes No No No Yes

ND ND ND ND D

Yes No Yes Yes No

Yes No No Yes No

61 57 57 77

AA 6 C 11 Korean 6 H 13

Yes No No Yes

No No NA Yes

ND ND ND D

No No No Yes

No No No Yes

Neldner and Martinez-Hernandez,21 1979 Premalatha, Yesudian, and Thambiah,25 1982 Nickoloff, Noodleman, and Abel26 1985 Somasundaram et al.,27 1987 Kazakis and Parish,28 1988 Toporcer and Kantor,29 1990 Goldstein and Lesher,30 1991 Pruzan, Rabbin, and Heilman,31 1992 Karp et al.,32 1996 Lee et al.,33 1996 Present case

MP, Multiparity; HTN, hypertension; AS, angioid streaks; FA, fluorescein angiography; RF, renal failure; HD, hemodialysis; NA, data not available; AA, African American; C, Caucasian; H, Hispanic; ND, not documented; D, documented. *Note: Excluding the first reference, these cases represent all of the cases cited in the literature since 1976 when Lundt and Gilbert distinguished perforating PXE from elastosis perforans serpiginosa, an entity with which it was previously confused.

mented elastic fibers may be diagnostic.9 Although angioid streaks are highly suggestive of PXE, these changes also occur in Paget’s disease of bone

and sickle cell anemia. Other ocular findings in PXE include optic disc drusen, a peau d’orange appearance of the fundus, mottling of the retinal

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Fig. 2. Initial punch biopsy specimen showing large amorphous basophilic globules of calcium in superficial dermis with raveled, calcified elastic fibers throughout dermis. (A, Hematoxylin-eosin stain; original magnification ×20. B, von Kossa stain; original magnification ×20.)

pigment epithelium or maculopathy.10 These are far less specific than angioid streaks. There are numerous other clinical features of PXE. Calcification of the internal elastic lamina of arteries may result in fatal gastrointestinal bleeding.11 Cardiovascular complications include angina, myocardial infarction, cardiac valvular disease,12 and intermittent claudication. Periumbilical lesions as the exclusive cutaneous manifestation of PXE are most commonly seen in so-called periumbilical perforating pseudoxanthoma elasticum (PPPXE). We describe a case of PPPXE. CASE REPORT

A 77-year-old Hispanic multiparous woman had uremic encephalopathy manifested by mental confusion, asterixis, and myoclonus. Her medical history included intermittent claudication, long-

standing hypertension, hypertensive nephropathy, and end stage renal disease, requiring hemodialysis. In addition, she had a painful periumbilical plaque that had enlarged during the past 2 weeks. Examination revealed a well-demarcated, hyperpigmented, rectangular-shaped plaque superior to the umbilicus that was formed by the confluence of several keratotic papules (Fig. 1). A solitary papule was present just inferior to the umbilicus. Multiple striae were present on the surrounding abdominal skin. Funduscopic examination identified a peau d’orange fundus, peripapillary degeneration, and angioid streaks. Serum calcium and phosphorus levels were 11.0 mg/dL (nl: 8.4 to 10.2) and 11.3 mg/dL (nl: 2.8 to 4.1), respectively. A skin biopsy specimen revealed clumping, fragmentation, and dystrophic calcification of elastic fibers in the reticular dermis without transepidermal elimination (Fig. 2). In addition,

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Fig. 3. Periumbical region 5 months later. Plaque had regressed, appearing flattened and less hyperpigmented. Isolated papule inferior to umbilicus is barely discernible.

deposits of amorphous calcium were apparent in the superficial dermis. Tissue specimens from the normal-appearing skin of the neck and axillae, as well as from an old scar, failed to demonstrate evidence of PXE. Renal function stabilized with hemodialysis. Five months later the periumbilical plaque appeared to have regressed and flattened to a hyperpigmented patch (Fig. 3). A biopsy specimen demonstrated residual dystrophic calcification of elastic fibers in the reticular dermis, but amorphous calcium was only minimally present (Fig. 4). A fluorescein angiogram highlighted the presence of angioid streaks in both eyes. Skull x-ray films revealed no evidence of Paget’s disease. A “sickle cell prep” was negative. DISCUSSION

Cases of perforating PXE were originally thought to represent PXE coexisting with elastosis perforans serpiginosa (EPS).13-17 Lund and Gilbert18 analyzed 7 of these cases and found that their coexistence was established in only 1 case. In EPS, the abnormal elastic fibers are located superficially and appear coarse, straight, and unmineralized (eosinophilic). In contrast, perforating PXE is characterized by the transepidermal elimination of fragmented, clumped, and calcified (basophilic) elastic fibers that are predominantly located in the mid and lower dermis. Patients with PPPXE are generally obese, mid-

dle aged, multiparous black women with hypertension.19 The cutaneous lesions are well-demarcated, hyperpigmented, periumbilical plaques with keratotic papules at the periphery.20 Extracutaneous manifestations of PPPXE have rarely been described. The histopathology reveals morphologically altered and calcified elastic fibers throughout the dermis that are extruded to the skin surface by transepidermal elimination. The classification of PPPXE has been a matter of controversy. Some suggest that PPPXE be considered a separate entity from hereditary PXE because of its distinct clinical features and its presumed lack of association with systemic disease. They postulate that localized PXE is an acquired lesion that develops locally in predisposed persons. Cutaneous trauma from obesity and multiple pregnancies,19 acscites,21 and multiple abdominal surgeries20 have also been cited as predisposing to PPPXE. An opposing theory suggests that localized periumbilical PXE may represent limited cutaneous expressivity of hereditary PXE.22 The presence of known cardiovascular (hypertension and claudication) and ophthalmologic (angioid streaks) complications of hereditary PXE in our patient supports this view. The family history of PXE was negative, although her mother died of a sudden cardiovascular event at age 40, encouraging speculation about occult PXE.23 A review of the PPPXE literature also supports

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Fig. 4. Biopsy specimen after 5 months of hemodialysis shows some residual abnormal and calcified elastic fibers throughout dermis. Amount of amorphous deposits has substantially decreased. (A, Hematoxylin-eosin stain; original magnification ×20; B, von Kossa stain; original magnification ×20.)

the theory advocating heritability (Table I). Including our patient, 14 of 19 patients (74%) had a history of hypertension. Although hypertension is not uncommon in the general population, the majority of patients with angioid streaks have systemic PXE,34 rendering it a more specific finding, although not pathognomonic. Six of the 18 (33%) patients in whom a funduscopic examination was recorded had angioid streaks. This is likely an underestimation because breaks in Bruch’s membrane may be subtle and easily missed on funduscopic examination alone. Fluorescein angiography was performed in only 1 of the previously reported patients, who also showed angioid streaks.30 Hicks et al.19 first coined the term periumbilical perforating pseudoxanthoma elasticum in 1979, acknowledging calcific elastosis as an acceptable substitute. Lever and Schaumburg-Lever35 pre-

ferred the latter term. Neldner and MartinezHernandez21 proposed the term localized acquired cutaneous pseudoxanthoma elasticum, objecting to PPPXE because it did not emphasize the “acquired nature of the process,” or the “absence of systemic manifestations.” At present, it may be useful to consider PPPXE as a nosologic bridge between the pure acquired form (i.e., “localized acquired” PXE) and the pure inherited form (i.e., hereditary PXE). Some cases are closer to the “acquired” end of the spectrum, having no systemic manifestations of PXE, whereas others have 1 or more extracutaneous manifestations of PXE and lie closer to the “inherited” end of the spectrum. At the time of presentation, our patient had been inadequately dialyzed and had uremic encephalopathy. After 5 months of hemodialysis, the periumbil-

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ical plaque completely regressed. The histopathology disclosed that amorphous calcium deposits located in the superficial dermis almost completely disappeared. We suspect the presence of altered elastic fibers in a patient with an increased phosphate-calcium product provided a nucleation site for these additional foci of calcification.36 As is the case for calciphylaxis, damaged tissue, on the basis of an altered local microenvironment, is susceptible to calcium deposition in patients with an abnormal phosphorous-calcium product.37 Although reversal of the pathologic changes was not absolute (i.e., some calcification of elastic fibers in the mid and lower dermis persisted), the clinical regression was striking. Complete histopathologic regression is unexpected because pathologic changes in the elastic fibers may be present in clinically normalappearing skin in patients with PXE.9 Three other patients with PPPXE described in the literature since 1976 had chronic renal failure. Two of these also required hemodialysis (Table I). In addition to physical factors such as multiparity and ascites, renal failure and metabolic disturbances may be precipitating factors in some patients who are genetically predisposed to develop this disorder. Acquired perforating dermatosis also features perforating lesions in the setting of chronic renal failure,38-39 but calcification of elastic fibers is not seen. To our knowledge, only one other instance of PXE regression has been documented.40 The only therapeutic intervention was an 800 mg/day dietary calcium restriction. The major significance of that case was the demonstration that the calcified elastic fibers of PXE are not irreparable and may be reversible in some patients. REFERENCES 1. Pope FM. Two types of autosomal recessive pseudoxanthoma elasticum. Arch Dermatol 1974;110:209-12. 2. Pope FM. Autosomal dominant pseudoxanthoma elasticum. J Med Genet 1974;11:152-7. 3. Lebwohl M, Neldner K, Pope FM, DePaepa A, Christiano AM, Boyd CD, et al. Classification of pseudoxanthoma elasticum: report of a consensus conference. J Am Acad Dermatol 1994;30:103-7. 4. Neldner KH. Pseudoxanthoma elasticum. Clin Dermatol 1988;6:83-92. 5. De Paepe A, Viljoen D, Matton M, Beighton P, Lenaerts V, Vossaert K, et al. Pseudoxanthoma elasticum: similar autosomal recessive subtype in Belgian and Afrikaner families. Am J Med Genet 1991;38:16-20. 6. Neldner KH. Pseudoxanthoma elasticum. Clin Dermatol 1988;6:1. 7. Struk B, Neldner K, Rao V, St. Jean P, Lindpaintner K.

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8.

9.

10. 11. 12.

13.

14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.

27.

Mapping of both autosomal recessive and dominant variants of pseudoxanthoma elasticum to chromosome 16p13.1. Hum Mol Genet 1997;6:1823-8. van Soest S, Swart S, Tijmes N, Sandkuijl L, Rommers R, Bergen AAB. A locus for autosomal recessive pseudoxanthoma elasticum, with penetrance of vascular symptoms in carriers, maps to chromosome 16p13.1. Genome Res 1997;7:830-4. Lebwohl MG, Phelps RG, Yannuzzi L, Chang S, Schwartz I, Fuchs W. Diagnosis of pseudoxanthoma elasticum by scar biopsy in patients without characteristic skin lesions. N Eng J Med 1987;317:347-50. Yannuzzi LA. Angioid streaks. In: Yannuzzi LA, Guyer DR, Green WR, editors. The retina atlas. St Louis: Mosby; 1995. p. 332-40. Kundrotas L, Novak J, Kremzier J, Meenaghan M, Hassett J. Gastric bleeding in pseudo-xanthoma elasticum. Am J Gastroenterol 1988;8:868-72. Lebwohl MG, Distefano D, Prioleau PG, Uram M, Yannuzzi LA, Fleischmajer R. Pseudoxanthoma elasticum and mitral valve prolapse. N Eng J Med 1982; 307:228-31. Smith EW, Malak JA, Goodman RM, McKusick VA. Reactive perforating elastosis: a feature of certain genetic disorders. Bull Johns Hopkins Hosp Med J 1962;111:235-51. Schutt DA. Pseudoxanthoma elasticum and elastosis perforans serpiginosa. Arch Dermatol 1965;91:151-2. Caro I, Sher MA, Rippey JJ. Pseudoxanthoma elasticum and elastosis perforans serpiginosa. Dermatologica 1975;150:36-42. Funabashi T, Tsuyuki S. A case of elastosis perforans with pseudoxanthoma elasticum. Jpn J Dermatol 1966; 75:649. Pai SH, Zak FG. Concurrence of pseudoxanthoma elasticum, elastosis perforans serpiginosa and systemic sclerosis. Dermatologica 1970;140:54-9. Lund HZ, Gilbert CF. Perforating pseudoxanthoma elasticum: its distinction from elastosis perforans serpiginosa. Arch Pathol Lab Med 1976;100:544-6. Hicks J, Carpenter CL, Reed RJ. Periumbilical perforating pseudoxanthoma elasticum. Arch Dermatol 1979; 115:300-3. Pruzan D, Rabbin PE, Heilman E. Periumbilical perforating pseudoxanthoma elasticum. J Am Acad Dermatol 1992;26:642-4. Neldner KH, Martinez-Hernandez A. Localized acquired cutaneous pseudoxanthoma elasticum. J Am Acad Dermatol 1979;1:523-30. Schwartz RA, Richfield DF. Pseudoxanthoma elasticum with transepidermal elimination. Arch Dermatol 1978;114:279-80. Lebwohl M, Halpern J, Phelps RG. Occult pseudoxanthoma elasticum in patients with premature cardiovascular disease. New Engl J Med 1993;329:1237-9. Paton D. The relation of angioid streaks to systemic disease. Chicago: Charles C. Thomas; 1972. p. 6-8. Premalatha S, Yesudian P, Thambiah AS. Periumbilical pseudoxanthoma elasticum with transepidermal elimination. Int J Dermatol 1982;10:604-5. Nickoloff BJ, Noodleman FR, Abel EA. Perforating pseudoxanthoma elasticum associated with chronic renal failure and hemodialysis. Arch Dermatol 1985;121: 1321-2. Somasundaram V, Premalatha S, Rao NR, Razack EM, Zahra A. Periumbilical perforating pseudoxanthoma elasticum. Int J Dermatol 1987;26:536-7.

344 Sapadin et al. 28. Kazakis AM, Parish WR. Periumbilical pseudoxanthoma elasticum. J Am Acad Dermatol 1988;19:384-8. 29. Toporcer MB, Kantor GR. Periumbilical hyperpigmented plaque. Arch Dermatol 1990;126:1639-42. 30. Goldstein BG, Lesher JL. Periumbilical pseudoxanthoma elasticum with systemic manifestations. South Med J 1991;84:788-9. 31. Pruzan D, Rabbin PE, Heilman ER. Periumbilical perforating pseudoxanthoma elasticum. J Am Acad Dermatol 1992;26:642-4. 32. Karp DL, O’Neill MS, Haberman AL, Taylor RM. A yellow plaque with keratotic papules on the abdomen. Arch Dermatol 1996;132:224-7. 33. Lee HW, Park MA, Lee SC, Won YH, Chun IK. A case of actinic granuloma associated with periumbilical perforating pseudoxanthoma elasticum. Acta Derm Venereol 1996;76:133-5. 34. Clarkson JG, Altman RD. Angioid streaks. Surv Ophthalmol 1982;26:235-46.

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35. Lever WF, Schaumburg-Lever G. Histopathology of the skin. 7th ed. Philadelphia: JB Lippincott; 1989. 36. Jurzyk RS, Ditre CM, Kantor GR, Spielvogel RL. Plaque-type intertriginous cutaneous calcification. Cutis 1992;49:289-91. 37. Laurent R, Thiery F, Saint-Hillier Y, Blanc D, Agache P. Calcifying panniculitis associated with renal insufficiency: a tissue calciphylaxis syndrome. Ann Dermatol Venereol 1987;114:1073-81. 38. Rapini RP, Herbert AA, Drucker CR. Acquired perforating dermatosis. Arch Dermatol 1989;125:1074-8. 39. Farrell AM. Acquired perforating dermatosis in renal and diabetic patients. Lancet 1997;349:895-6. 40. Martinex-Hernandez A, Huffer WE, Neldner K, Gordon S, Reeve EB. Resolution and repair of elastic tissue calcification in pseudoxanthoma elasticum. Arch Pathol Lab Med 1978;102:303-5.