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Case Report/Case Series
October 2014

Mucocutaneous Granulomatous Disease in a Patient With Hermansky-Pudlak Syndrome

Author Affiliations
  • 1Bassett Healthcare Network, Oneonta, New York
  • 2Penn State College of Medicine, Hershey, Pennsylvania
  • 3Dermatology Unit, Myriad Genetics Inc, Salt Lake City, Utah
  • 4Department of Dermatology, Northwestern University, Chicago, Illinois
  • 5Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois
  • 6Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York
  • 7Penn State Hershey Medical Center, Hershey, Pennsylvania
 

Copyright 2014 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.

JAMA Dermatol. 2014;150(10):1083-1087. doi:10.1001/jamadermatol.2014.147
Abstract

Importance  Hermansky-Pudlak syndrome (HPS) is a rare genodermatosis characterized by oculocutaneous albinism, platelet dysfunction, and in some patients, pulmonary fibrosis and granulomatous colitis. The granulomatous inflammation in the bowel of patients with HPS can be indistinguishable clinically and histologically from that of Crohn disease (CD); however, mucocutaneous granulomatous lesions have not been considered among the typical skin findings of HPS.

Observations  We report a case of an albino woman in her 40s with a history of CD and pulmonary fibrosis who presented with ulcers, plaques, and nodules in the vulva, perineum, inguinal creases, and left axilla. These cutaneous findings had the typical clinical and histologic findings of metastatic cutaneous CD. However, she also had a genetically confirmed diagnosis of HPS.

Conclusions and Relevance  It is unclear whether our patient’s cutaneous findings were due to CD or secondary to HPS. This report reviews the features of HPS and CD, 2 entities characterized by a granulomatous inflammatory reaction pattern but with unique genetic and clinical features, and discusses the possible overlap between the 2 diagnoses.

Report of a Case

An albino woman in her mid-40s with a 30-year history of Crohn disease (CD) was referred for evaluation and treatment of recurrent, exquisitely tender, persistent ulcerations involving the vulvar, perianal, inguinal, and left axillary skin. She noted that her ulcers had partially responded to prednisone, infliximab, and azathioprine administered for her CD several years ago. Her gastrointestinal CD was quiescent, but she continued to have skin manifestations that had been diagnosed as hidradenitis suppurativa. On multiple occasions, exudate cultures from the ulcers grew mixed flora. She had been treated with long-term antibiotics, including cephalexin monohydrate, trimethoprim-sulfamethoxazole, doxycycline hyclate, metronidazole hydrochloride, and rifampin without improvement. A left axillary ulcer had been excised 1 year prior, but it recurred soon after surgery.

In addition to CD, the patient’s medical history included oculocutaneous albinism with horizontal nystagmus, episodic iritis, emphysema, and interstitial lung disease. Her surgical history included a proctocolectomy and end-ileostomy and perianal fistula repair for CD. She had required a blood transfusion following her gastrointestinal surgery but had had no other problems with excessive bleeding.

Her family history was significant for 2 sisters with albinism; her only child, a son, does not have albinism. There was no family history of gastrointestinal diseases.

Physical examination revealed an afebrile and mildly dyspneic woman with pale skin, white hair, light blue eyes, and horizontal nystagmus (Figure 1). Examination of her groin revealed well-demarcated, deep, tender, linear, inguinal and vulvar ulcers with surrounding erythematous, indurated, pink plaques and scaly patches extending to the medial thighs (Figure 2A). The vulva was diffusely swollen, and indurated firm nodules were present on the labia majora and labia minora. Erythematous indurated plaques with central ulceration extended along the bilateral gluteal folds. Examination of her left axilla revealed a deep, crusted ulcer overlying a surgical scar. All ulcers exuded serosanguineous or thick yellow discharge. There were no sinus tracts, comedones, or fistulas in any of the affected sites.

Figure 1.
Woman With Hermansky-Pudlak Syndrome (HPS)
Woman With Hermansky-Pudlak Syndrome (HPS)

Typical cutaneous findings of HPS include hypopigmented skin and hair, as shown here. Blue eyes and horizontal nystagmus are also common features.

Figure 2.
Mucocutaneous Disease Before and After Treatment
Mucocutaneous Disease Before and After Treatment

A, The patient had deep, linear, “knifelike” flexural ulceration and vegetative papillomatous vulvar nodules that are typical of genital metastatic cutaneous Crohn disease. B, Nearly complete healing of the vulvar ulcers and reduction in edema and erythema after 12 months of therapy with infliximab and prednisone.

Biopsy samples from the vulvar ulcer and axilla demonstrated deep dermal and subcutaneous lymphoplasmacytic infiltrates with noncaseating granulomas including numerous multinucleated giant cells (Figure 3). Tissue cultures from the vulvar ulcers were negative for atypical mycobacteria and fungi. Mixed flora were cultured from ulcer exudate, including Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. Tuberculin skin test and serologic analysis for lymphogranuloma venereum had negative results. Routine laboratory studies, including complete blood cell count with differential and a comprehensive metabolic panel, had unremarkable results.

Figure 3.
Cutaneous Granulomatous Inflammation From the Vulva
Cutaneous Granulomatous Inflammation From the Vulva

A, Histopathologic evaluation of stained sections of vulvar (shown) and axillary (not shown) biopsy samples revealed deep dermal and subcutaneous granulomatous inflammation (hematoxylin-eosin [H&E], original magnification ×100). B, High-power magnification of the lymphoplasmacytic infiltrate with noncaseating granulomas including numerous multinucleated giant cells (H&E, original magnification, ×400).

Because of her constellation of cutaneous and systemic findings, the patient was evaluated for Hermansky-Pudlak syndrome (HPS). Electron microscopic examination of her platelets revealed an absence of dense bodies, a finding considered pathognomonic for HPS. Genetic testing identified a homozygous mutation of the HPS1 gene (c.1189 del C), thus confirming the diagnosis of HPS.

The patient was treated with prednisone, azathioprine, and nabumetone and initially experienced improvement of pain and swelling in the vulvar area, although the ulcers remained unchanged in size. Several months later, however, she developed increased vulvar pain and edema. A combined medical and surgical approach was commenced, including infliximab infusions at a dose of 10 mg/kg monthly, prednisone 30 mg daily, and surgical debridement of granulation tissue in the vulvar ulcers followed by the use of a negative-pressure wound therapy system. No bleeding complications arose as a result of the surgical debridement. She continued to improve 12 months after starting this regimen, with nearly complete healing of the vulvar ulcers, pain relief, and reduction in edema and erythema (Figure 2B). The prednisone dosage was decreased to 10 mg daily, and she continues to receive infliximab 10 mg/kg infusions every 4 weeks; attempts to reduce the dosages of these medications have been unsuccessful because of cutaneous disease flares.

Discussion

Hermansky-Pudlak syndrome is a rare autosomal-recessive genodermatosis. All patients have oculocutaneous albinism and variably severe platelet dysfunction. Some patients have pulmonary fibrosis and granulomatous colitis. It is unclear whether our patient’s skin findings were due to cutaneous CD or rather were a manifestation of HPS. Her skin findings were clinically and histologically indistinguishable from those of metastatic cutaneous CD, just as the colitis of HPS is indistinguishable from that of CD. There has been only 1 other report of a patient with HPS with cutaneous granulomatous disease; a 9-year-old Puerto Rican girl with HPS developed granulomatous colitis and subsequently an erosive genital and peristomal eruption, which on biopsy showed nonnecrotizing granulomas.1 An infectious workup was unrevealing. These 2 cases support the possibility of metastatic cutaneous involvement of granulomatous colitis in HPS. Herein we review the features of cutaneous CD and HPS, genetically distinct diseases that share a common granulomatous inflammatory reaction pattern.

Hermansky-Pudlak syndrome (OMIM 203300) is a rare, autosomally recessive, multisystem disorder resulting from mutations in genes that encode proteins involved in the biogenesis and function of intracellular organelles found in melanocytes, platelets, T cells, neutrophils, and lung epithelial cells.2 To date, 8 HPS genes have been identified; these genes encode subunits of the adaptor protein complex 3 and biogenesis of lysosome-related organelles complexes. Defects in these distinct genes result in 1 of 8 subtypes of HPS2 (Table). An inability to form melanosomes in melanocytes and dense bodies in platelets causes the oculocutaneous albinism and bleeding diathesis that occur to variable extents in all affected patients. The mechanisms through which mutations in the HPS genes cause the pulmonary, intestinal, immunologic, or, rarely, renal and cardiac manifestations of HPS have yet to be fully elucidated. Defects in the production or transport of lysosomes appear to be central to the pathogenesis.

Table.  
Features of Hermansky-Pudlak Syndrome (HPS) Subtypes
Features of Hermansky-Pudlak Syndrome (HPS) Subtypes

Patients with mutations in the HPS1 gene tend to have more severe disease and a greater likelihood of pulmonary fibrosis and granulomatous colitis.2 A granulomatous reaction to intracellular ceroid lipofuscin, a compound believed to be derived from lipid peroxidation of polyunsaturated lipids of subcellular membranes in the lungs and gastrointestinal tract of patients with HPS, may lead to the pulmonary and gastrointestinal manifestations of HPS.3 Patients with HPS may be unable to eliminate this compound as a result of the aberrant genesis or function of lysosomes.3 On histopathological examination, however, granulomas are not always formed in proximity to ceroid deposits.3 In some cases, however, no ceroid deposits are observed,4 and the clinical and histopathologic features of the enterocolitis of HPS can be identical to those of CD. This has prompted speculation that there may be a genetic linkage between HPS and CD.3

The pulmonary fibrosis and the enterocolitis associated with HPS are often recalcitrant to medical therapy. Several recent reports have documented successful treatment of some patients with agents used to treat intestinal CD including the tumor necrosis factor inhibitor infliximab.4

Crohn disease is a multisystem granulomatous inflammatory disease that typically begins in the gastrointestinal tract. The disease may involve any portion of the gastrointestinal tract. Dermatologic findings are the most common extraintestinal manifestations of intestinal CD, occurring in 10% to 75% of patients.5-7 Other extraintestinal manifestations of CD include inflammatory arthropathies, hepatobiliary disease, ocular disease (episcleritis, scleritis, and uveitis), osteoporosis, anemia, nephrolithiasis, urinary tract fistulas, and renal amyloidosis.8

The cutaneous manifestations of CD can be generally classified into nutritional deficiency–associated dermatoses (acrodermatitis enteropathica and pellagra resulting from zinc and niacin deficiency, respectively, among patients with CD8), reactive dermatoses (pyoderma gangrenosum, erythema nodosum, palmar plantar pustulosis, Sweet syndrome, oral aphthae, epidermolysis bullosa acquisita, necrotic or granulomatous vasculitis, hidradenitis suppurativa, finger clubbing, palmar erythema, pyoderma faciale, and pathergy reactions8), and cutaneous granulomatous disease.

Cutaneous granulomatous disease is the most common cutaneous manifestation of CD. It may be contiguous or noncontiguous with the gastrointestinal tract. Contiguous disease affects 36% to 80% of patients with CD and is the most common form of all CD-related skin diseases.5 Noncontiguous or “metastatic” granulomatous disease, conversely, is the rarest skin manifestation of CD and is defined as the presence of noncaseating granulomas arising in the skin at a site distant to and separate from the intestine.5 Patients with granulomatous skin disease are more likely to have extensive gastrointestinal disease.5

Clinical features of metastatic cutaneous CD vary by patient age and anatomic site. The genital skin is the most common site of metastatic cutaneous CD in both adults (59%) and children (75%).5 In children, genital swelling with or without erythema is the most common presentation, but ulceration is uncommon.5 In contrast, adult metastatic cutaneous CD is ulcerative in the majority of cases.5 Deep “knifelike,” linear ulcerations are characteristic, and these preferentially affect the vulva and intertriginous areas. Vegetative, papillomatous nodules mimicking condyloma have been described.6,9 Genital infiltration and edema with or without erythema have also been reported in adults.5,9 Nongenital metastatic CD more commonly presents with erythematous or violaceous nodules and plaques.10 Up to 20% of adults and 86% of children present with cutaneous disease prior to the diagnosis of intestinal disease, which makes diagnosis more challenging.11,12

Emanuel and Phelps13 recently reviewed the histopathologic characteristics of 12 cases of metastatic cutaneous CD. All cases were characterized by a superficial and/or deep granulomatous dermatitis. Granulomas consisting of epithelioid histiocytes were present in 8 cases. Granulomas with Langhans-type giant cells were also common. Five of 12 cases showed ulceration. Granulomatous vasculitis was present in 2 cases, and in 2 others, massive papillary dermal edema was noted.

The clinical differential diagnosis of metastatic cutaneous CD may include infectious etiologies such as cellulitis, erysipelas, tuberculosis, deep fungal infection, tertiary syphilis, filariasis, actinomycosis, schistosomiasis, leishmaniasis, lymphogranuloma venereum, granuloma inguinale, and chronic herpes simplex virus infection. Appropriate cultures and serologic studies should be used to exclude infectious etiologies. Metastatic cutaneous CD may also be mistaken for dermatitis, foreign-body reactions, intertrigo, Behçet disease, Wegener granulomatosis, lichenoid eruptions, hidradenitis suppurativa, pyoderma gangrenosum, or sarcoidosis. Hidradenitis suppurativa can be ruled out clinically by the absence of interconnecting sinuses and comedones. Deep, linear ulcerations in flexural skin and vegetative papillomatous nodules in the vulva are characteristic findings of genital metastatic cutaneous CD.

The pathogenesis of metastatic cutaneous CD is unclear, but it has been postulated that T lymphocytes react with unknown antigens in the skin and lead to the granulomatous infiltrates of metastatic cutaneous CD.6,8,14

Metastatic cutaneous CD, particularly genital disease, often responds poorly to treatment. There are no randomized, controlled studies of therapy for this entity. Antibiotics, immunosuppressive medications, and anti-inflammatory agents have been used with limited success.

Conclusions

Our patient’s history of albinism, pulmonary fibrosis, and colitis were suggestive of HPS, which was then confirmed ultrastructurally and genetically. Her gastrointestinal biopsies revealed the histopathologic features typical of both metastatic CD and HPS. It is unclear whether the cutaneous findings in this case are manifestations of CD or, in fact, sequelae of HPS. Cutaneous granulomatous disease has been reported in only 1 other patient with HPS; this is likely due to the rarity of HPS in general. Clinicians should be aware of the possibility of skin manifestations in patients with HPS. Further observation of patients with this rare disease is required to determine whether such cutaneous findings are due to HPS or whether skin lesions originate from a separate disease process, such as CD, that may be in some way genetically linked with HPS.

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Article Information

Accepted for Publication: January 28, 2014.

Corresponding Author: Jennie T. Clarke, MD, Department of Dermatology, Penn State Hershey Medical Center, 500 University Dr, MC HU-14, Hershey, PA 17033 (jclarke1@psu.edu).

Published Online: July 2, 2014. doi:10.1001/jamadermatol.2014.147.

Author Contributions: Drs J.T. Clarke and Salvaggio had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Salvaggio, Graeber, J.T. Clarke.

Acquisition, analysis, or interpretation of data: Graeber, L.E. Clarke, Schlosser, Orlow, J.T. Clarke.

Drafting of the manuscript: Salvaggio, Graeber, J.T. Clarke.

Critical revision of the manuscript for important intellectual content: All authors.

Administrative, technical, or material support: L.E. Clarke, Schlosser, J.T. Clarke.

Study supervision: Salvaggio.

Conflict of Interest Disclosures: None reported.

Additional Contributions: Bryan E. Anderson, MD, Department of Dermatology, Penn State Hershey Medical Center, provided technical assistance in the production of the composite photographs. Dr Anderson was not provided with any compensation for his assistance.

References
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Carmona-Rivera  C, Golas  G, Hess  RA,  et al.  Clinical, molecular, and cellular features of non-Puerto Rican Hermansky-Pudlak syndrome patients of Hispanic descent.  J Invest Dermatol. 2011;131(12):2394-2400.PubMedGoogle ScholarCrossref
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Grucela  AL, Patel  P, Goldstein  E, Palmon  R, Sachar  DB, Steinhagen  RM.  Granulomatous enterocolitis associated with Hermansky-Pudlak syndrome.  Am J Gastroenterol. 2006;101(9):2090-2095.PubMedGoogle ScholarCrossref
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Mora  AJ, Wolfsohn  DM.  The management of gastrointestinal disease in Hermansky-Pudlak syndrome.  J Clin Gastroenterol. 2011;45(8):700-702.PubMedGoogle ScholarCrossref
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Palamaras  I, El-Jabbour  J, Pietropaolo  N,  et al.  Metastatic Crohn’s disease: a review.  J Eur Acad Dermatol Venereol. 2008;22(9):1033-1043.PubMedGoogle ScholarCrossref
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Schrodt  BJ, Callen  JP.  Metastatic Crohn’s disease presenting as chronic perivulvar and perirectal ulcerations in an adolescent patient.  Pediatrics. 1999;103(2):500-502.PubMedGoogle ScholarCrossref
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    The Knife-Cut Sign: A Clinical Presentation Of Herpes Infection In Immunocompromised Patients
    Philip R. Cohen, MD | Division of Dermatology, University of California San Diego
    The Knife-Cut Sign: A Clinical Presentation Of Herpes Infection In Immunocompromised Patients Philip R. Cohen, MD Division of Dermatology, University of California San Diego, San Diego, California.Short Title: Knife-Cut Sign Total words: 233 (text) Correspondence to: Philip R. Cohen, MD 10991 Twinleaf Court San Diego, CA 92131-3643713-628-5143 (telephone) mitehead@gmail.com (email) Knife-Cut Sign-Letter to Editor 10-31-14 To-the-Editor: Salvaggio et al [1] described the clinical features of mucocutaneous granulomatous disease associated with Hermansky-Pudlak syndrome and emphasized that the ‘knifelike’ ulcerations in their patient’s inguinal regions were similar to those described in the genital skin of individuals with metastatic cutaneous Crohn disease. Recently an immunosuppressed 57-year-old man with multiple myeloma was described who had linear ulcers of disseminated herpes simplex virus (HSV) infection in the intertriginious areas of his inguinal folds (Figure 1) and the curved supra-auricular fold between his external ear and scalp that were morphologically similar in appearance to a ‘knife-cut’ [2]. Previously, linear erosive skin lesions of HSV infection that demonstrate the ‘knife-cut sign’ have also been reported in 4 immunocompromised patients [3,4]. The term ‘knife-cut’ has been associated with linear lesions of Crohn disease--originally referring to the fissures noted on colonoscopy and subsequently to the ulcerations observed on the vulva [3-5]. Lieb et al [3] used the phrase ‘knife-cut sign’ to describe the intertriginous linear erosive HSV infection lesions in immunocompromised patients; this distinctive presentation can provide a morphologic clue to the diagnosis of HSV infection in immunosuppressed individuals [2-4]. Hence, the clinical differential diagnosis for ‘knifelike’ ulcerations and the ‘knife-cut sign’ includes not only metastatic cutaneous Crohn disease of the genital region, but also ulcerative linear HSV infection of intertriginous and fissured areas in immunocompromised hosts and mucocutaneous granulomatous disease in patients with Hermansky-Pudlak syndrome. References1.Salvaggio HL, Graeber KE, Clarke LE, Schlosser BJ, Orlow SJ, Clarke JT: Mucocutaneous granulomatous disease in a patient with Hermansky-Pudlak syndrome. JAMA Dermatol 2014;150:1083-1087.2.Cohen PR: The ‘knife-cut sign’ revisited: a distinctive presentation of linear erosive herpes simplex virus infection in immunocompromised patients. J Clin Aesthet Dermatol, in press.3.Lieb JA, Brisman S, Herman S, MacGregor J, Grossman ME: Linear erosive herpes simplex virus infection in immunocompromised patients: the “knife-cut sign”. Clin Infect Dis 2008;47:1440-1441.4.LeBoeuf NR, Lieb J, Grossman ME: Linear erosive herpes simplex virus: the ‘knife-cut sign’ in a patient on high-dose corticosteroids. Clin Exp Dermatol 2010; 35:557-558.5. Vettraino IM, Meritt DF: Crohn’s disease of the vulva. Am J Dermatopathol 1995;17:410-413. Legend Figure 1. The ‘knife-cut sign’ associated with linear erosive HSV infection in an immunosuppressed man. The linear ulcer of the left inguinal groove has a ‘knife-cut’ appearance. The well-demarcated ulcers at the base of the penile shaft, on the scrotum and on the pubic area represent typical lesions of HSV infection in an immunocompromised host.

    CONFLICT OF INTEREST: None Reported
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