Granulomatous Dermatitis with Pseudoxanthoma Elasticum–Like Changes Report of a Case in a Patient with Cystic Fibrosis

OBSERVATION Granulomatous Dermatitis With Pseudoxanthoma Elasticum–Like Changes Report of a Case in a Patient With Cystic Fibrosis

Jeffrey B. Tiger, BA; Jill McKenzie, MD; Don T. Tran, MD; John E. Olerud, MD; Evan George, MD

Background: There is scant literature that documents of PXE. The rash gradually resolved itself over the next pseudoxanthoma elasticum (PXE)–like histologic changes several months. in the setting of inflammatory skin diseases. This article documents granulomatous dermatitis with PXE-like Conclusions: There are few publications that docu- changes in a patient with cystic fibrosis. This is the first ment PXE-like changes in association with various in- report of its kind, to our knowledge. flammatory skin conditions. Thus, the clinical significance of this finding remains uncertain. This case and Observations: A 33-year-old woman with cystic fibro- previous reports are discussed in the context of current sis developed a papular eruption on the flexural sur- molecular and genetic knowledge. It is hoped that greater faces of the upper and lower extremities, which was ini- awareness of this phenomenon will promote further in- tially treated with prednisone. A punch biopsy showed vestigation and elucidation of the clinical and biologic granulomatous inflammation and associated PXE-like significance of PXE-like changes observed in biopsies of changes. The combined histologic and clinical findings inflammatory skin disorders. were most consistent with granuloma annulare. There was no family history of PXE or clinical manifestations Arch Dermatol. 2009;145(11):1292-1295

SEUDOXANTHOMA ELASTICUM REPORT OF A CASE (PXE) is a genetic disorder that primarily affects the skin, A 33-year-old white woman with ad- eyes, and cardiovascular sys- vanced cystic fibrosis (homozygous 1 tem. It is caused by a homo- ⌬F508) was seen by her primary care phy- zygousP or compound heterozygous muta- sician for a nonpruritic erythematous papu- tion in the adenosine triphosphate– lar eruption that involved the flexural sur- binding cassette, subfamily C, member 6 faces of the knees, elbows, axillae, and gene (ABCC6). Recent research has shown groin. The lesions had developed while she that heterozygote carriers of the ABCC6 gene was being treated intravenously with me- also sometimes manifest the characteristic ropenem and ceftazidime for a pulmo- histologic and clinical phenotypic abnor- nary infection. She reported no fever, ar- malities of PXE.2 thralgias, or constitutional symptoms This article documents an intriguing associated with the eruption. example of PXE-like histologic changes The history of the patient was remark- that accompany granulomatous dermati- able for a vasculitic syndrome associated tis in a patient with cystic fibrosis. Al- with antibiotic administration, for which though Bowen and colleagues3 have re- she had received prophylactic predni- Author Affiliations: cently documented PXE-like changes that sone concurrently with antibiotics. How- Departments of Dermatology accompany various inflammatory derma- ever, with this most recent course of an- (Drs McKenzie and Olerud) and toses in the biopsies of 13 patients, there tibiotics, corticosteroids had not been Anatomic Pathology are only a few reports that document administered. After she reported the erup- (Dr George) and School of these changes in the setting of granuloma- tion to her primary care physician, she re- Medicine (Mr Tiger), University 3 of Washington, Medical Center, tous dermatitis. Moreover, to our knowl- ceived oral prednisone. Although some im- Seattle; and Cellnetix Pathology edge, this is the first reported example of provement was noted, the lesions persisted. and Laboratories, Seattle PXE-like changes in a patient with cystic She was referred to the Dermatology de- (Dr Tran). fibrosis. partment for evaluation approximately

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 4 weeks after the onset of the rash. At that time, erythematous papules were observed on the flexural surfaces of A her knees and right groin, along with mild erythema over her antecubital fossae and right axilla (Figure 1). According to the patient, the papular nature and flexural distribution of the new eruption differed from her previous vasculitic reaction. The absence of associated arthralgia and constitutional symptoms further argued against a recurrent vasculitic drug reaction. Because of the complex medical condition of the patient and her im- pending lung transplantation procedure, a 4-mm punch biopsy from a right inguinal papule was obtained to rule out an infectious or neoplastic process and further ad- dress concern for a drug-related cause. The cutaneous lesions gradually resolved during the next few months without any additional treatments. Microscopic examination revealed histiocytic dermal inflammation associated with destruction of colla- gen and elastic tissue, variable numbers of neutrophils and eosinophils, and focal deposition of stromal mucin. B Less-inflamed portions of the dermis showed frayed and thickened elastic fibers associated with calcium deposition, which recapitulated the characteristic histologic findings of PXE (Figure 2). A von Kossa stain highlighted the calcified elastic tissue. There was no evidence of vas- culitis, and no acid-fast microorganisms or fungal ele- ments were identified via Ziehl-Neelson or Gomori meth- enamine silver stains, respectively. Together, the histologic and clinical findings were most consistent with granuloma annulare, accompanied by sec- ondary PXE-like changes. The histologic differential diagnosis included a granulomatous drug eruption, but this diagnosis was not favored clinically. Granulomatous inflammation is not a histologic feature of PXE; thus, PXE- like histologic changes were unexpected and motivated Figure 1. Clinical presentation of erythematous papules distributed across us to report this case. Although there is limited infor- flexural surfaces. A, Papules across the backs of both knees, and B, on right mation in the medical literature with regard to the clini- groin. cal significance of PXE-like histologic changes in biopsies of inflammatory skin disorders, Bowen and colleagues3 embedded tissue was performed on tissue from 6 of these documented heterozygous mutations in the ABCC6 gene patients. Heterozygous PXE-associated ABCC6 muta- in tissue from 2 of 6 patients with apparently incidental tions were identified in 2 of the 6 specimens.3 PXE-like histologic changes.3 Pseudoxanthoma elasticum is traditionally diagnosed by a set of major and minor clinical-pathologic criteria that were developed by a consensus conference in COMMENT the early 1990s. The major criteria include: (1) characteristic skin involvement (yellow cobblestone-shaped le- There is limited literature with regard to PXE-like changes sions in flexural locations), (2) characteristic histopatho- associated with inflammatory skin diseases. A recent pub- logic features of lesional skin (altered and calcified elastic lication documented 13 patients without the clinical phe- fibers, confirmed with a histochemical stain for cal- notype of PXE who manifested PXE-like histologic al- cium), and (3) characteristic ocular disease (angioid terations in the lesional skin of various inflammatory skin streaks, peau d’orange, or maculopathy) in adults more diseases.3 The patients were elderly women with a range than 20 years of age. The minor criteria include: (1) char- of histologic diagnoses. Of the 13 biopsies, 12 had been acteristic histopathologic features of nonlesional skin (al- obtained from the lower extremities. In 1 patient, the bi- tered and calcified elastic fibers, confirmed with a his- opsy was obtained from the palm with a histologic diag- tochemical stain for calcium), and (2) family history of nosis of granuloma annulare. The other diagnoses men- PXE in first-degree relatives.4 Our patient meets only 1 tioned in that report were lipodermatosclerosis, lichen of these criteria: characteristic histopathologic features sclerosus, morphea profunda, erythema nodosum, sep- of PXE of lesional skin. Even though the flexural distri- tal panniculitis, basal cell carcinoma, and fibrosing der- bution of her eruption paralleled the distribution ob- matitis not otherwise specified. The polymerase chain reserved in patients with PXE, her lesions did not have the action was used for DNA amplification, and sequencing characteristic yellow cobblestonelike appearance. Fur- of exons 24 and 28 of the ABCC6 gene from paraffin- thermore, other than this recent transitory skin erup-

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Figure 2. Skin biopsy. A, Scanning magnification that shows nodular and interstitial dermal inflammation (hematoxylin-eosin, original magnification ϫ20). B, Histiocytic infiltrate with necrobiosis (arrows) and thickened, hypereosinophilic elastic fibers (arrowhead) (hematoxylin-eosin, original magnification ϫ400). C, Calcified elastic fibers (arrows) (von Kossa, original magnification ϫ40).

tion, the patient did not manifest the other clinical fea- Thus, it is conceivable that our patient could have a tures of PXE. In particular, she denied a history of visual heterozygous mutation within the ABCC6 gene. This disturbances or symptoms of cardiovascular disease, and would be an intriguing finding because the CFTR gene she lacked a family history of PXE. responsible for cystic fibrosis is also classified in the ABC With the advent of molecular testing, direct genetic cassette transporter gene family and is designated as analysis for PXE is now possible. Currently available mo- ABCC7. An association between the two disorders can- lecular tests for PXE have moderate sensitivity: they de- not be explained on simple genetic grounds, however, tect mutations in approximately 80% of affected indi- because the genes reside on separate chromosomes: viduals.5 Pseudoxanthoma elasticum has traditionally been ABCC6 is on chromosome 16, whereas CFTR/ABCC7 is classified as an autosomal recessive disorder, which re- on chromosome 7.8-10 One could postulate a metabolic quires homozygous or compound heterozygous muta- disturbance common to both conditions; however, we tions in the ABCC6 gene. Recently, however, there have would expect to find additional reports of cystic fibrosis been reports of heterozygous individuals with single patients with PXE-like changes if this were the case. To ABCC6 mutations who fully manifest the characteristic the contrary, a search of English-language medical pub- clinical and histologic abnormalities of PXE. One of these lications between 1939 and 2008 (http://www.ncbi.nlm reports documents 4 such cases.2 Other studies have .nih.gov/pubmed) did not identify any reports of PXE in shown that parents of children diagnosed with PXE, who patients with cystic fibrosis. We discussed with the pa- themselves had not previously been diagnosed with the tient the possibility of genetic testing for PXE, including disease, can have mild ocular and/or cutaneous find- polymerase chain reaction analysis on the skin biopsy ings, such as the characteristic histopathology of PXE.6 specimen, but she declined further testing. Likewise, heterozygote carriers in families with a his- In summary, this report documents PXE–like changes tory of PXE have been shown to have dermal alterations in association with granulomatous dermatitis. To our very similar to, although less severe than, those of typi- knowledge, this is the first report of PXE-like histologic cal patients with PXE.7 changes in the setting of cystic fibrosis. The clinical sig-

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 nificance of PXE-like changes in biopsies of inflamma- REFERENCES tory dermatoses remains unclear owing to the small num- ber of published reports, most of which lack long-term 1. Neldner KH. Pseudoxanthoma elasticum. Clin Dermatol. 1988;6(1):1-159. clinical follow-up. It is hoped that greater awareness of 2. Martin L, Maıˆtre F, Bonicel P, et al. Heterozygosity for a single mutation in the this phenomenon will promote further investigation to ABCC6 gene may closely mimic PXE: consequences of this phenotype overlap elucidate its clinical and biological significance. for the definition of PXE. Arch Dermatol. 2008;144(3):301-306. 3. Bowen AR, Götting C, LeBoit PE, McCalmont TH. Pseudoxanthoma elasticum– like fibers in the inflamed skin of patients without pseudoxanthoma elasticum. Accepted for Publication: March 11, 2009. J Cutan Pathol. 2007;34(10):777-781. Correspondence: Evan George, MD, University of Wash- 4. Lebwohl M, Neldner K, Pope FM, et al. Classification of pseudoxanthoma elas- ington Medical Center, Department of Anatomic Pathol- ticum: report of a consensus conference. J Am Acad Dermatol. 1994;30(1): ogy, Box 356100, 1959 Northeast Pacific St, Seattle, WA 103-107. 98195 ([email protected]). 5. Pseudoxanthoma elasticum. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi ?book=gene&part=pxe. Accessed July 15, 2008. Author Contributions: Drs Olerud and George and Mr 6. Sherer DW, Bercovitch L, Lebwohl M. Pseudoxanthoma elasticum: significance Tiger had full access to all the data in the study and take of limited phenotypic expression in parents of affected offspring. J Am Acad responsibility for the integrity of the data and the accu- Dermatol. 2001;44(3):534-537. racy of the data analysis. Study conception and design: 7. Bacchelli B, Quaglino D, Gheduzzi D, et al. Identification of heterozygote carriers McKenzie and Tran. Acquisition of data: McKenzie, Tran, in families with a recessive form of pseudoxanthoma elasticum (PXE). Mod Pathol. 1999;12(12):1112-1123. Olerud, and George. Analysis and interpretation of data: 8. Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis Olerud and George. Drafting of the manuscript: Tiger, gene: cloning and characterization of complementary DNA. Science. 1989; McKenzie, Olerud, and George. Critical revision of the 245(4922):1066-1073. manuscript for important intellectual content: Tran, Olerud, 9. Rommens JM, Iannuzzi MC, Kerem B, et al. Identification of the cystic fibrosis and George. Administrative, technical, and material sup- gene: chromosome walking and jumping. Science. 1989;245(4922):1059- 1065. port: Tiger, McKenzie, Olerud, and George. Study super- 10. Struk B, Neldner KH, Rao VS, St Jean P, Lindpaintner K. Mapping of both auto- vision: McKenzie, Olerud, and George. somal recessive and dominant variants of pseudoxanthoma elasticum to chro- Financial Disclosure: None reported. mosome 16p13.1 Hum Mol Genet. 1997;6(11):1823-1828.

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