Hermansky‐Pudlak Syndrome: Severe Colitis and Good Response to Infliximab

Abstract

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disease with a relatively higher prevalence of 1:8000 in people of Puerto Rican descent, which was first described in 1959. HPS consists of tyrosine-positive oculocutaneous albinism with nystagmus, variable skin hypopigmentation, a platelet storage pool deficiency resulting in a bleeding diathesis due to decreased or absent platelet dense bodies, and ceroid deposition within the reticuloendothelial system. Seven genotypes have been described in HPS. HPS 1 and HPS 4 genotypes have been implicated in patients with severe pulmonary fibrosis, which usually presents in the third decade of life, and granulomatous colitis (1). Case reports of HPS in adults with gastrointestinal complications related to chronic granulomatous colitis, including fistulization and perineal disease, have been described (2). The majority of the cases failed to respond to conventional treatment of Crohn disease and required surgery. We report the first pediatric patient with HPS and severe granulomatous colitis who responded to infliximab. CASE REPORT A 17-year-old Puerto Rican boy presented to our institution with bloody diarrhea. The patient was evaluated 2 years before this visit at an outside institution, with complaints of abdominal pain and 4 to 5 bloody stools per day. Initial colonoscopy showed severe active colitis. Biopsies showed crypt architectural distortion and granulomas consistent with Crohn disease. He was given sulfasalazine and rowasa enemas, with no improvement in his symptoms. Two months later he presented with severe rectal bleeding and increased abdominal pain. He required multiple transfusions for hemoglobin of 7 g/dL. Corticosteroids 20 mg twice daily and 6-mercaptopurine 75 mg daily were added to his regimen, again with poor response. One month later, his hemoglobin dropped to 7 g/dL, requiring another blood transfusion. Emergency colonoscopy showed patchy areas of melanosis from transverse colon to cecum (Fig. 1A and B). There were multiple areas of deep ulcerations in the rectum extending to the cecum in a patchy distribution. The colonoscopy was consistent with Crohn disease, but no biopsies were obtained because of active bleeding. At this time the patient was transferred to our care.FIGURE 1: A, Endoscopic view of cecum at the time of diagnosis. Severe inflammatory changes with deep ulcerations and multiple pseudopolyps are evident. B, Endoscopic view of transverse colon at the time of diagnosis. Multiple areas of melanosis and ulcerations are visible.His physical examination was significant for horizontal nystagmus, strabismus, pupils equally reactive to light, ocular albinism, fair eyelashes and hair, and fair skin (Fig. 2A and B).FIGURE 2: A, Eye examination with findings of ocular albinism and fair eyelashes. B, Ophthalmologic examination with findings of albinotic fundi.Laboratory evaluations showed normal erythrocyte sedimentation rate and C-reactive protein, hemoglobin 10.2 g/dL after blood transfusion, platelets 350 k/μL, albumin 3.5 g/dL, 6-methylmercaptopurine 3859 (<5700), and 6-thioguanine 300 pmol/8 × 108 red blood cells. Serology for inflammatory bowel disease showed anti-Saccharomyces cerevisiae antibodies IgA 67.8 EU/mL (<20 EU/mL), anti-S cerevisiae antibodies IgG 22.1 EU/mL (<40 EU/mL), AntiOmpC 99.8 EU/mL (<16.5 EU/mL), antiCBr1 13.9 EU/mL (<21 EU/mL), and protoplasmic-staining anti-neutrophil cytoplasmic antibodies 33 EU/mL (<12.1 EU/mL). Because of poor response to conventional treatment for presumed Crohn disease, infliximab 5 mg/kg was given. He had marked improvement 72 hours after the first dose, with resolution of his complaints of abdominal pain and bloody diarrhea. He did not require additional blood transfusions. 6-Mercaptopurine was discontinued after 6 months of clinical remission because of the increased risk of hepatosplenic T-cell lymphoma. The patient presented 1 year later with painful skin lesions in the right inguinal area and bilateral axillary areas, which prompted a dermatologic evaluation. A biopsy of the lesions was consistent with pyogenic granuloma most likely because of a ruptured follicular cyst, consistent with a diagnosis of hidradenitis suppurativa. Rectal magnetic resonance imaging was performed because of the inguinal lesion, which showed a small intramural ulceration of the rectum posteriorly with fluid collection that extended onto the perineum bilaterally, with fistulae about 56 × 7 mm on the right and 40 × 10 mm on the left side (Fig. 3). The patient was treated with intravenous antibiotics for 2 weeks, with significant improvement of the inguinal lesion. The patient's colitis and perianal disease continue to be quiescent on scheduled infliximab treatments.FIGURE 3: Rectal magnetic resonance imaging demonstrating coronal T2-weighted fat-suppressed fast-spin echo image of fistulae about 56 × 7 mm on the right and 40 × 10 mm on the left side.Because of the features of albinism and nystagmus, which were suspicious for HPS, additional evaluation for platelet morphology was done. Electron microscopy showed absence of dense bodies in platelets, which was consistent with a diagnosis of HPS. Genetic testing showed homozygous c.1472_87 16 duplication mutation in chromosome 10q23, confirming the diagnosis of HPS type 1. The biopsy slides from the previously done colonoscopy at an outside institution were reviewed and found to have the brown pigment that is consistent with ceroid accumulation in intestinal macrophages (Fig. 4).FIGURE 4: Colonic mucosal biopsy with brown pigment consistent with ceroid accumulation in the intestinal macrophages.DISCUSSION Granulomatous colitis was first described by Schinella et al (3) in 2 Puerto Rican families with HPS, which included 5 people with severe colitis. The patients presented with severe bloody diarrhea and abdominal pain. Four of 5 patients did not respond to medical management and required either total or partial colectomy. In the present case series 1 of the patients was a 17-year-old boy who presented with a 3-month history of abdominal pain and malaise. He had an exploratory laparotomy for presumed ruptured appendix and required a colectomy. Following surgery he developed severe bleeding and shock, and died 10 days postoperatively. Histologic findings of the colon showed noncaseating granulomas, deep ulcerations, and a small amount of brown granular pigment (3). Mahadeo et al (4) described 2 pediatric cases with HPS and granulomatous colitis in 1990. The first patient was a 7-year-old Puerto Rican girl who was lost to follow-up and a 3-year-old boy with severe colitis that failed conventional therapy with corticosteroids and sulfasalazine. He required multiple blood transfusions along with 6-mercaptopurine and cyclosporine (4). The clinical presentation of patients with HPS and granulomatous colitis is similar to that of Crohn disease. Symptoms may include abdominal pain and bloody diarrhea with possible perineal involvement, with mild or no constitutional symptoms (2). The colonoscopic examination commonly reveals multiple scattered superficial or deep ulcers with pseudopolyps. Case reports of ileal involvement have been described, but with no isolated small bowel involvement (2). Pathological features include broad ulcers, which extend to the muscularis mucosa, brown granular pigmentation due to ceroid deposition, and nonnecrotizing granulomas (3,4). These pathological findings are also seen in Crohn disease with the exception of the ceroid depositions. HPS can be caused by 7 different genotypes, and multiple chromosomes have been involved, including 10q23.1, 5q14.1, 3q24, 22q11.2-q12.2, 11p15-p23, 10q24.32, and 6p22.3 (5). These genes cause abnormal vesicle formation, involving melanosomes, platelet-dense body, and a subset of lysosomes, which cause visual impairment, skin hypopigmentation, and increased risk of bleeding (6). Granulomatous colitis is more common in HPS type 1 and type 4, the cause of which is unknown. It has been suggested that the accumulation of ceroid pigment in intestinal macrophages eventually causes rupture of the macrophages, resulting in activation of the inflammatory cascade and the formation of granulomatous colitis (7). In the study by Hussain et al (6), 8 of 122 patients with HPS had evidence of colitis. This suggests that the prevalence of granulomatous colitis in HPS may be higher than the prevalence of inflammatory bowel disease in the general US population (0.48%). Seven of 8 patients were genotype HSP 1 and 1 was HSP 4. Additional studies are being conducted to evaluate the pathogenesis of granulomatous colitis in HPS 1 and HPS 4. Given the clinical similarity of HPS to Crohn disease, the therapeutic approach for HPS granulomatous colitis is similar to that for Crohn disease. A review of the literature reveals no consistent remission of disease with standard therapy including corticosteroids, sulfasalazine, and 6-mercaptopurine (2). Sulfasalazines inhibit platelet aggregation and may aggravate the platelet disorder, leading to an increase in bleeding (4). These findings were also seen in our patient. There were 13 patients in the English-language literature with HPS that required surgery because of lower gastrointestinal bleeding, intractable colitis, or perirectal disease. Inflixamib has been shown to be effective in HPS granulomatous colitis, as seen in the adult population (8,9). Our patient is the first pediatric patient who has shown significant improvement on infliximab. In conclusion, granulomatous colitis seen in HPS has many similarities with Crohn disease, but it is refractory to standard treatment regimens. Stronger immunomodulators may need to be started promptly if the patient does not respond to standard therapy, preventing serious complications such as colectomy. Additional studies and long-term follow-up are needed to explore the relation of HPS and Crohn disease because of their genetic, immunologic, and serologic similarities. Acknowledgments The authors gratefully acknowledge the skilled contributions of Dr John Hart for pathology assessment and of Dr Aytekin Oto for interpretation of the imaging procedures.