DOI: 10.17235/reed.2015.3948/2015

CASE REPORTS

 

Metastatic Crohn's disease in pediatrics

Enfermedad de Crohn metastásica en pediatría

 

 

Javier Blasco-Alonso^1,4, Francisco Girón-Fernández-Crehuet², Miguel Ángel Lendinez-Ramírez³, Silvia Gallego-Gutiérrez³, Silvia Luque Pérez³, Juliana Serrano-Nieto¹, Víctor M. Navas-López^1,4 and Carlos Sierra-Salinas^1,4

¹Department of Gastroenterology, Hepatology and Infant Nutrition. Hospital Regional Universitario de Málaga. Málaga, Spain.
²Department of Infant Gastroenterology. Hospital Universitario San Cecilio. Granada, Spain.
³Pediatrics Department. Hospital Regional Universitario de Málaga. Málaga, Spain.
⁴Multidisciplinary Pediatric IBIMA Group. Universidad de Málaga. Málaga, Spain

Correspondence

 

 

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ABSTRACT

Introduction: Metastatic Crohn's disease (MCD) is an extraintestinal manifestation of Crohn's disease, with biopsy as fundamental diagnostic tool. There are few References to MCD in children, with a 0.5-1% estimated incidence in adults. There is no consensus about its therapeutic approach. We describe our diagnostic and therapeutic experience in MCD.
Case Reports: Four cases of MCD are described in our Pediatric Gastroenterology Unit in a tertiary care hospital. The age at diagnosis was between 7 and 13 years. Lesions appeared before the diagnosis of Crohn's disease in three of them, and during the course of the disease in another one, with genital location in three patients and bilateral pretibial region in the other. All four cases demonstrated non-caseificant granulomas on biopsy. Only two patients used exclusive enteral nutrition therapy with complete resolution, while other two cases received a combination of therapies (corticosteroids, azathioprine, tacrolimus, infliximab and adalimumab) because of recurrence. Only one case required surgery after poor clinical control.
Discussion: The MCD is infrequent but must always be included in the differential diagnosis of cutaneous lesions in Crohn's disease, considering it could be the debut of the disease. We will rely on biopsy anyway for definitive diagnosis. In this series the genital region is verified as the most commonly affected in children. The therapeutic approach does not differ from the management of intestinal involvement.

Key words: Crohn's disease. Metastatic Crohn's disease. Pediatrics. Cutaneous lesions. Biologic therapy.

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RESUMEN

Introducción: la enfermedad de Crohn metastásica (ECM) constituye una manifestación extraintestinal de la enfermedad de Crohn, siendo fundamental la biopsia para su diagnóstico. Existen referencias escasas a ECM en la edad pediátrica, y en adultos se estima una incidencia del 0,5-1%. No hay consenso sobre su abordaje terapéutico. Nuestro objetivo es describir nuestra experiencia diagnóstica y terapéutica en ECM.
Caso clínico: se describen 4 casos de ECM en seguimiento en una Unidad de Gastroenterología Infantil en un hospital pediátrico de tercer nivel. Edades al diagnóstico entre 7 y 13 años. Las lesiones aparecieron antes del diagnóstico de enfermedad de Crohn (EC) en tres de ellos y durante la evolución de la enfermedad en otro. Localización genital en tres pacientes y en región pretibial bilateral en el otro. Todos demostraron granulomas no caseificantes en la biopsia. Dos pacientes precisaron únicamente nutrición enteral exclusiva, observándose resolución completa, mientras que otros dos recibieron terapias combinadas (corticoides, azatioprina, tacrolimus, infliximab y adalimumab) por recurrencia. Solo un caso requirió cirugía por mal control clínico.
Discusión: la ECM es una entidad rara aunque siempre debemos incluirla en el diagnóstico diferencial de las lesiones cutáneas en enfermedad de Crohn, teniendo en cuenta que puede ser el debut de la enfermedad. Nos basaremos en la biopsia en cualquier caso para el diagnóstico definitivo. En esta serie se verifica la región genital como la más habitual en niños. El abordaje terapéutico no difiere del manejo de la afectación intestinal.

Palabras clave: Enfermedad de Crohn. Enfermedad de Crohn cutánea metastásica. Pediatría. Lesiones cutáneas. Terapia biológica.

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Introduction

Inflammatory bowel disease (IBD) should be considered as a multisystemic disease, since it may affect practically any organ in the body. Extraintestinal manifestations (EIM) may appear at the time of diagnosis, before or after it (Table I), with a lower prevalence in pediatric patients than in adults, about 24-28% along the evolution (1,2). Mucocutaneous involvement is the second most common one after bone and joint, with a prevalence of approximately 20% (2), regardless of the perianal disease. Metastatic cutaneous Crohn's disease (MCD) is a rare form of skin involvement. It is defined by the presence of skin lesions without contiguity with the gastrointestinal tract (i.e., separated by healthy skin) and pathological study which highlights non-caseificant granulomas (3).

 

 

We present 4 cases of metastatic cutaneous Crohn's disease diagnosed in our unit over the last 13 years.

 

Case Reports

Case 1

A 13-year-old girl, suffering from asthenia, anorexia, pale skin, mucous and bloody diarrhea and weight loss (2 kg) for two months, was diagnosed with severe (PCDAI 60) A1bL3L4aB1G0p Crohn's disease (CD). On physical examination the right labia majora was clearly swollen without phlogosis, and perianal abscess was noticed. Histological examination of the vulvar lesion confirmed the presence of MCD (Fig. 1). She started exclusive enteral nutrition therapy with polymeric formula for 8 weeks, mesalazine, metronidazole and azathioprine after two weeks' time, with good performance and complete disappearance of the genital injury.

 

 

Case 2

Male diagnosed at the age of 6 with Crohn's disease (A1aL3B1G0p) (4,5). Initially he was treated with prednisone for several months and mesalazine was maintained in order to control gastrointestinal symptoms. Two years after establishing the diagnosis, 6-mercaptopurine was associated to prednisone due to the exacerbation of perianal lesions (severe erythema with fissures and perianal abscess, without clinical or radiological evidence of fistula) with marked improvement. After being with this triple therapy for 1 year, he developed edema and skin redness in penis and scrotal sacs. The patient continued topical treatment with steroids and antibiotics, without improvement. He denied fever, anorexia, abdominal pain or diarrhea, and perianal lesions remained stable. On physical examination important scrotal and penis edema, with erythema, nodules with no ulcer, slightly tender to palpation, was observed (Fig. 2). Testicular ultrasonography showed thickening of the scrotum, with significant increase in blood flow. The testes were normal with adequate intratesticular flow. Scrotal skin biopsy resulted in noncaseating granulomatous inflammation. Cultures and special staining techniques (Zielh and PAS) were negative. The basic treatment was modified, increasing the dose of prednisone and associating metronidazole. There was a marked improvement of genital lesions, but several months after reducing the dose of systemic steroid the genital skin lesion worsened and it was decided to start infliximab (only induction under the scheme 0, 2, 6 months), obtaining partial response but failing to remove the corticosteroid treatment. The patient, after 6 months, developed fever, bloody diarrhea, abdominal pain and worsening of genital injury, so tacrolimus was associated (dose of 0.12 mg/kg/day, adjusted for 5-10 ng/mL blood levels). Two months later, prednisone could be retired with good clinical response but genital injury persisted without full resolution after several months. Ileocolic resection surgery was carried out with ileostomy discharge, thereby achieving very good development of genital injury, with complete disappearance.

 

 

Case 3

Thirteen-year-old female patient was referred from the Endocrinology consultation because of stunting and abdominal pain for 3 years. She suffered from low intensity recurrent abdominal pain and mucous and bloody inconsistent stools in the previous two weeks. The examination revealed tenderness in the right lower quadrant, painful swelling with inflammatory signs in vulvar and anal fissure as well as increased CRP, ESR and fecal calprotectin. Entero-magnetic resonance was performed, discarding the presence of any contiguity or fistulous lesion between vulvar lesion and the gastrointestinal tract. Endoscopy showed moderate ileocolonic involvement. With the diagnosis of CD (A1bL3B1G0) she started exclusive nutritional treatment for 8 weeks, mesalazine and metronidazole with good clinical response and progressive decrease in vulvar lesion, achieving complete resolution.

Case 4

A 7 year-old boy was referred to our Gastroenterology unit because of recurrent abdominal pain and purple skin lesions in the front face of both tibias (Fig. 3), suggestive of erythema nodosum. Analytical data evidenced systemic inflammation (CRP 20 mg/L, ESR 40 mm/1sth, fecal calprotectin 400 mcg/g) and he was diagnosed of CD (A1aL3B1G0), with presence of deep ulcers and granulomas in endoscopy. After diagnosis, he started with exclusive enteral nutrition for 8 weeks and azathioprine, with obvious improvement in clinical and skin lesions. After nutritional therapy ended, painful bilateral pretibial edema reappeared, with suspicion of erythema nodosum, starting systemic steroids at doses of 1 mg/kg/day and achieving complete resolution, but with reappearance when attempting to decrease prednisone. Thereby, biopsy of the cutaneous lesions was performed, showing noncaseating granulomas compatible with MCD. Given the corticosteroid dependence, despite thiopurine therapy, and fecal calprotectin levels < 250 mcg/g, it was decided to start adalimumab (80/40/40), achieving good response with withdrawal of steroids and finally azathioprine after 12 months of combined therapy, remaining with no skin damage so far.

 

 

Discussion

Ten to twenty per cent of patients with IBD have skin EIM in the course of the disease which may be of several types (Table II). Metastatic skin lesions are one of the rarest forms of skin involvement in CD patients. The MCD was first described by Park et al. in 1965, in a 70-year-old patient who was suffering from CD for four years (3). Due to the unusual presentation (there are fewer than 200 cases reported in the literature, mostly in adults), there are isolated cases, with no large series, making it difficult to draw Conclusions on epidemiology (prevalence, predictors, etc.), pathogenesis, relationship with intestinal disease activity and location, and about which are the most effective treatments against it. Some revisions on this issue are Palamaras et al. (6), which include adult and pediatric patients; Keiler et al. (7), which include children aged less than 18, and Romero et al. (8), including only adults. The latter describes a prevalence of 0.66% over the course of the disease. During the period 1990-2014, 99 patients have been diagnosed with CD in our unit, with only 4 cases of MCD (4%). The age at diagnosis is 7 to 13 years with an equal gender distribution.

The pathogenesis remains unknown. For some authors it is the result of deposit of circulating immune complexes; others suggest a type IV mediated reaction between unknown antigens of the skin and T-lymphocytes. According to this hypothesis, Mycobacterium paratuberculosis antigen could be responsible for this condition, with some studies finding DNA fragments, using PCR, in intestinal samples from patients with CD. Our series has unsuccessfully sought the presence of mycobacteria. More recent theories speak of the role of beta-2 integrins and alterations in the MLH-1 gene, responsible for the repair mechanisms of DNA (6).

Clinically, the MCD can take many forms, such as ulcers, papules, nodules, indurated plaques or crusts, usually painless, and can be located at any level of the body surface. Lesions may be single or multiple, sometimes affecting different locations simultaneously (9,10). In children, the most common presentation is swelling/induration with or without associated erythema, localized in the genital area, mainly in vulva, penis and scrotum, in 85% of cases (7), while in adults they mainly affect lower extremities. In our series, the location was pretibial in one case and genital in three children (vulva, affecting labia majora; scrotum and penis).

No relationship has been demonstrated between the MCD and the activity of the intestinal disease. Like the rest of skin lesions, the MCD is more frequently related to the location of the gastrointestinal diseasein case of ileocolonic or colonic involvement (6), as in our 4 cases. However, it appears to be related to the presence of other extraintestinal manifestations, unlike what happens with erythema nodosum and arthritis. An important aspect is whether or not the MCD precedes intestinal IBD. In this way, 70-80% of cases of MCD in adult patients often appear years after diagnosis of intestinal disease, while in children 85% of patients had not yet been diagnosed with IBD when metastatic skin lesions were already present, mainly noncaseating granulomas in the pathological study, guiding the clinician to a possible CD. In our series, lesions appeared before the diagnosis of IBD in 3 cases and during the course of the disease in the other one. Indeed, in most reports on MCD in children it is a skin lesion the one that initiates the study of probable IBD, with up to 74% of patients presenting unnoticed symptoms compatible with CD, especially unspecific symptoms such as recurrent abdominal pain, diarrhea, constipation or growth retardation. More striking is that up to 78% of patients suffered from concomitant perianal disease (anal fissures, fistulae, abscesses or perianal erythema) (6,7,11).

According to several publications, there is a delay time, 9 months to 4 years, from the onset of MCD lesions until the diagnosis is made. This time might be shortened if at the time of clinical suspicion all necessary complementary explorations currently available for the diagnosis of IBD could be performed (gastroscopy, ileocolonoscopy, intestinal MRI and/or video capsule endoscopy), since many of these CD cases are pauci-symptomatic. In the initial differential diagnosis, and depending on the type and location of the damage, there are various entities such as dermatitis, intertrigo, hidradenitis suppurativa, chronic cellulitis, erythema nodosum (as thought in our fourth case), seborrheic dermatitis, erysipelas, lichenoid eruptions and various sexually transmitted diseases, being forced, in some cases, to rule out sexual abuse. Regarding the granulomatous lesion, it obliges clinicians to rule out pathologies with the same pathology, such as sarcoidosis and tuberculosis (12,13). All cases in our series demonstrated the presence of noncaseating granulomas in biopsy, with all expanded etiology being negative.

There is no consensus document for the treatment of MCD. Treatment depends on the clinical condition of the patient, severity and extent of disease because many options have been tried (6,8): topical, intralesional or systemic steroids, metronidazole, dapsone, tetracycline, azathioprine, 6-mercaptopurine, sulfasalazine, tacrolimus (5), cyclosporine and infliximab (14,15). The two girls in our series were quite similar according to management and further development. Their disease was controlled with enteral nutrition and mesalazine with or without azathioprine, showing complete resolution of skin lesions as well as good control of bowel symptoms. The other two cases (with pretibial involvement and genital involvement) had a torpid evolution with relapsed after corticosteroids decrease, so it was decided to start biological therapy. In the case of genital involvement, 12 years ago, infliximab was started, but only induction was achieved with no maintenance, which might have been able to reverse the MCD, and he required further association with systemic tacrolimus because of persistent symptoms. In the case of the patient with the pretibial involvement, he responded after initiation of adalimumab, and steroids could be descended until complete withdrawal. Surgical treatment is reserved for situations of failure of medical treatment. In the evolution, surgery was performed only in one of our cases, with resection and ileostomy discharge because of endoscopically increased inflammatory activity in the intestinal tract, and the reduction of inflammatory activity was the one that cured the MCD skin lesion.

 

Conclusions

The MCD is a rare extraintestinal manifestation. It is usually located at the genital level in children and coincides with inflammatory bowel involvement in a high percentage of patients. The diagnosis is confirmed by demonstration of noncaseating granulomas in tissue biopsies. The therapeutic option will be chosen depending on the extent and severity of the disease, being nutritional therapy an option in milder cases of debut. Biological, used in the last 10 years, are a good way to control the MCD, but not always avoiding local surgery in severe cases. Erythema nodosum must be ruled out, as in case 4.

 

References

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Correspondence:
Javier Blasco-Alonso.
Department of Gastroenterology, Hepatology and Infant Nutrition.
Hospital Regional Universitario de Málaga.
Avda. Arroyo de los Ángeles, s/n.
29011 Málaga, Spain
e-mail: javierblascoalonso@yahoo.es

Received: 30/07/2015
Accepted: 01/08/2015