*Department of Pediatrics, University of Würzburg, Germany; and †Pediatric Oncology Branch, National Institutes of Health, Bethesda, Maryland, U.S.A.
Received April 10, 1998; revised June 24, 1998; accepted September 3, 1998.
Address correspondence and reprint requests to Thomas Lehrnbecher, M.D., Pediatric Oncology Branch, National Institutes of Health, Building 10, Room 13N240, Bethesda, MD 20892, U.S.A.
Crohn's disease, a chronic relapsing inflammatory bowel disorder, is often associated with cutaneous manifestations. These manifestations may occur as nonspecific lesions, which include erythema nodosum, erythema multiforme, and pyoderma gangrenosum. The non-specific skin lesions must be distinguished from skin lesions with the characteristic histologic pattern of Crohn's disease. In this group, two types of lesions can be distinguished. First, and by far the more common, is direct extension from the involved bowel. The skin lesions are contiguous with the gastrointestinal tract and are perianal, peristomal, or perifistular. Second, metastatic involvement occurs, in which the granulomas are separated from affected areas of the gastrointestinal tract by normal skin. This cutaneous manifestation of Crohn's disease, termed metastatic Crohn's disease (MCD), is extremely rare (1,2).
We report a case of a 9-year-old boy whose initial symptom of Crohn's disease was granulomatous skin lesions of his genitalia. Treatment and long-term follow-up are presented to underline the importance of including low-dose metronidazole in the treatment regimen.
A previously healthy 9-year-old boy had a 2-month history of a nontender, erythematous plaque on his penis. Histopathologic examination of a biopsy of the lesion showed granulomas with giant cells, macrophages, lymphocytes, and plasma cells characteristic of granulomatous inflammation of the sarcoid type. No definitive diagnosis could be made at that time. The genital skin lesions progressed, and the boy was admitted to our hospital. The patient's medical history and family history for dermatologic or inflammatory bowel disease was unremarkable except for eczema. The patient's height and weight percentiles were normal for age. Penile and scrotal skin were erythematous and indurated. A 1-mm diameter fistula, which was not seen in previous examinations, was found in the perianal area. The fistula was clearly separated from the scrotum by normal skin. The inguinal lymph nodes were increased up to 2.5 cm in diameter bilaterally. The laboratory findings showed a normal complete blood count, an erythrocyte sedimentation rate of 24 mm/hr, serum immunoglobulin (Ig) G 1630 mg/dl (normal range, 608-1572 mg/dl), and IgA 281 mg/dl (normal range, 33-236 mg/dl). There was no indication of abnormalities in cell-mediated immunity; a PPD was negative. No infectious process was detected. Colonoscopy was performed. Macroscopic inspection showed no major inflammatory disease. Microscopic examination of biopsy specimens taken during colonoscopy revealed ulcerations and an inflammatory reaction with lymphocytes, plasma cells, and granulomas consisting of giant cells and epithelioid cells. These histopathologic findings were identical to the re-evaluated specimens from skin biopsies of the scrotum. The diagnosis of Crohn's disease was made, and his penile and scrotal skin lesions were classified as MCD.
The patient's treatment course and response is diagramatically displayed in Figure 1. The patient was initially treated with prednisone (2 mg/kg per day) and metronidazole (20 mg/kg per day). His skin lesions improved markedly with this regimen, and the fistula began to heal. The metronidazole was discontinued after 2 weeks, and the prednisone was slowly tapered to 1 mg/kg per day. Almost two years later, the patient had exacerbation of the skin lesions and pus draining from the perianal fistula. Oral metronidazole (20 mg/kg per day) was initiated with prompt clinical response. Shortly thereafter, the dose of prednisone was tapered to 0.3 mg/kg per day secondary to behavior changes, and azathioprine (1.5 mg/kg per day) was added. On two occasions, attempts were made to discontinue metronidazole without success. Over the years, the dose of metronidazole was reduced to 5 mg/kg per day. With this treatment regimen of daily low-dose metronidazole, azathioprine, and every-other-day doses of prednisone, the patient's disease has remained in remission. No adverse effects of the medications have been noted.
We report a case of a 9-year-old boy whose initial symptoms of Crohn's disease were penile and scrotal skin lesions. To the best of our knowledge, only five cases of children with MCD have been reported in the English literature (3-7), and only one of them is described in a pediatric journal (7). Three of the five patients had lesions in the genital area. The other patients had lesions on an extremity. In adults and children, MCD can affect any area of the body and may appear as an ulcer, a papule, a nodule, an indurated plaque, vitiligo or a hyperpigmented lesion (8). The diagnosis of MCD may be extremely difficult, and the number of reported cases may reflect an underestimation of the true incidence. Of the 69 patients with MCD reported in the literature, only 5 had skin lesions that occurred simultaneously with or preceded the bowel symptoms (7-11). An association between the appearance of the metastatic lesions and the activity of the bowel disease has been described in some patients but has not been seen in others.
Classically, MCD has been histologically characterized by a granulomatous inflammation of the sarcoid type identical to the primary bowel lesion, consisting of noncaseating giant cell granulomas, histiocytes, plasma cells, and lymphocytes (12). These changes are considered to be primary (4). Other granulomatous cutaneous lesions, as seen in sarcoidosis, tuberculosis, foreign body reactions, fungal infections, lymphogranuloma venereum, and filariasis must be differentiated from MCD.
Treatment of MCD with different chemotherapeutic agents including steroids, cyclosporin A, 6-mercaptopurine, azathioprine, sulfasalazine, antibiotics, surgery, and hyperbaric oxygen have been tried with variable success (8). In our patient, the response to treatment clearly seemed to be linked to metronidazole. On three occasions, the introduction of metronidazole resulted in the disappearance of the skin lesions, and twice, discontinuation of metronidazole was promptly followed by relapse (Fig. 1). The role of metronidazole in the treatment of MCD has also been demonstrated by other investigators (6,7,13). Brand et al. (14) suggest a daily dose of 20 mg/kg for patients with perineal Crohn's disease. Of note, this group described that attempts at dose reduction of metronidazole in their patients resulted in exacerbation of the Crohn's disease within 3 months, with or without the addition of steroids. In contrast, our patient has had a sustained remission of disease for more than 4 years with a regimen of 5 mg/kg per day metronidazole. We recognize that this might be caused, at least in part, by the additional therapeutic effect of prednisone and/or azathioprine. That the introduction of metronidazole was associated with the resolution of the skin lesions on three occasions, and that discontinuation of the medicine was twice promptly followed by relapse underlines the key role of metronidazole in the treatment of our patient. With the dosage of 5 mg/kg per day, the more serious central nervous system side effects of metronidazole, such as encephalopathy, seizures, and peripheral neuropathy, which appear to be related to the dosage of the drug rather than the duration of therapy, were not observed in our patient (14).
In summary, children with Crohn's disease may have a wide variety of cutaneous lesions associated with MCD. The skin lesions may precede gastrointestinal symptoms. The long-term follow-up of our patient demonstrates the importance of including metronidazole in the treatment of MCD. The use of the fairly benign drug metronidazole, even in low doses, may allow for the reduction of immunosuppressive agents and thus avoid their side effects.
1. Mountain JC. Cutaneous ulcerations in Crohn's disease. Gut 1970;11:18-26.
2. Levine N, Bangert J. Cutaneous granulomatosis in Crohn's disease. Arch Dermatol 1982;118:1006-9.
3. Tuffnell D, Buchan PC. Crohn's disease of the vulva in childhood. Br J Clin Pract 1991;45:159-60.
4. Tatnall FM, Dodd HJ, Sarkany I. Crohn's disease with metastatic cutaneous involvement and granulomatous cheilitis. J R Soc Med 1987;80:49-51.
5. Atherton DJ, Massam M, Wells RS, Harries JT, Pincott JR. Genital Crohn's disease in a 6-year-old boy. BMJ 1978;4:552.
6. Sutphen JL, Cooper PM, Mackel SE, Nelson DL. Metastatic cutaneous Crohn's disease. Gastroenterology 1984;86:941-4.
7. Lally MR, Orenstein SR, Cohen BA. Crohn's disease of the vulva in an 8-year-old girl. Pediatr Dermatol 1988;5:103-6.
8. Marotta PJ, Reynolds RPE. Metastatic Crohn's disease. Am J Gastroenterol 1996;91:373-5.
9. Slater DN, Waller PC, Reilly G. Cutaneous granulomatous vasculitis: Presenting feature of Crohn's disease. J R Soc Med 1985;78:589-90.
10. Phillips RKS, Glazer G. Metastatic Crohn's disease of the umbilicus. BMJ 1981;283:887.
11. Baker VV, Walton LA. Crohn's disease of the vulva. South Med J 1988;81:285-6.
12. Hackzell-Bradley M, Hedblad MA, Stepahnsson EA. Metastatic Crohn's disease: Report of 3 cases with special reference to histopathologic findings. Arch Dermatol 1996;132:928-32.
13. Boerr LA, Bai JC, Olivares L, Moran CE, Kowalczuk A. Cutaneous metastatic Crohn's disease: Treatment with metronidazole. Am J Gastroenterol 1987;82:1326-7.
14. Brand LJ, Bernstein LH, Boley SJ, Frank MS. Metronidazole therapy for perineal Crohn's disease: A follow-up study. Gastroenterology 1982;83:383-7.
© 1999 Lippincott Williams & Wilkins, Inc.