An Unusual Case of Diarrhea in Schimke Immuno-Osseous Dysplasia

INTRODUCTION Schimke immuno-osseous dysplasia (SIOD) is an osteochondrodysplasia that results in short stature and abnormal body proportions. Prominent features of this rare multi-system disorder (Table 1) include progressive nephropathy leading to renal failure, defective cellular immunity with lymphopenia, facial dysmorphism, and cerebral ischemic episodes. Additional features include hypothyroidism, bone marrow hypoplasia, hyperpigmented skin macules, and ocular abnormalities (1). There is significant morbidity and mortality associated with the condition; of the 39 patients reported by Boerkoel et al.(1), 18 had died by age 15. It was recently determined that mutations in SMARCAL1 (SWI/SNF2-related matrix-associated actin-dependent regulator of chromatin, subfamily a-like1), a gene involved in chromatin remodeling, are responsible for this disorder (2).TABLE 1: Clinical features of Schimke immuno-osseous dysplasiaThere is only one previous report on gastrointestinal manifestations in SIOD, in a four-year-old with prolonged diarrhea diagnosed with autoimmune enteropathy (3). We now report a case of prolonged diarrhea in a nine-year-old girl with SIOD proven to be due to atypical mycobacterial infection. We suggest that opportunistic infections are one of the potential causes of gastrointestinal symptoms in patients with Schimke immuno-osseous dysplasia. Clinical Report The patient was a nine-year-old girl with SIOD, the eldest child of non-consanguineous parents. She had been previously diagnosed with focal glomerulosclerosis, severe immunodeficiency (cell mediated and humoral) with lymphopenia, bronchiectasis due to recurrent lower respiratory tract infections, and a previous cerebral ischemic episode. She exhibited the phenotypic features of SIOD with extreme short stature, hyperpigmented macules on the trunk, and dysmorphic facies. In addition, flattening of the vertebrae was noted with abnormalities of the end plates and loss of height of the vertebral bodies in keeping with spondyloepiphyseal dysplasia. These changes were noted throughout the entire spine with more prominent changes found in the lumbar vertebrae. Immune function testing confirmed a T-cell immunodeficiency (Table 2) with low CD3+, CD4+, and CD8+ counts. Mitogen-induced proliferation of peripheral lymphocytes was abnormal in this patient with no response to phytohemagglutinin, concanavalin A, and to pokeweed mitogen. A minimal response was demonstrated with Staphylococcus protein A.TABLE 2: Flow cytometry for lymphocyte markersOne month before admission she developed diarrhea, passing 20 stools daily in the week preceding admission. The stools were loose to watery with mucus but no blood. Vomiting occurred occasionally in the early stages of her illness, and she complained of intermittent abdominal pain. There was no history of fever. Clinical examination on admission revealed an unwell, dehydrated child with the phenotypic features of SIOD. Her weight was 11.1 kg (well below the third percentile) and 1.6 kg less than previously documented 12 months before. Her height was 89 cm, also well below the third percentile. She had oral thrush. Her abdomen was distended, soft, and not tender. There was no organomegaly. Bowel sounds were normal. Initial laboratory tests included: potassium 1.9 mmol/L (3.5–5.2 mmol/L), magnesium 0.34 mmol/L (0.7–0.95 mmol/L), serum albumin 21 g/L (33–58 g/L). Total white cell count was 1.5 x 109 (4–10 x109), neutrophils 1.2 (1.5–8 x 109) and lymphocytes 0.15 (1.5–4 x 109). Hemoglobin was 86 g/L (120–160 g/L). Inflammatory markers were markedly elevated, erythrocyte sedimentation rate (ESR) 128 mm/h (1–10 mm/hr) and C-reactive protein (CRP) 113 mg/L (0–8 mg/L). Initial management involved fluid resuscitation, electrolyte correction, and commencement of parenteral nutrition. Her diarrhea improved while nil per os but she continued to have four or five loose stools daily. Stool analysis for parasites, viruses, and bacterial pathogens (including Clostridium difficile toxin) was negative. Serum immunoglobulins were normal, antigliadin antibodies were IgA positive and IgG negative, while anti-endomysial antibodies were negative. Anti-enterocyte antibodies were negative (testing performed by Dr P. Russo at Ste. Justine Hospital for Children, Montreal, Quebec, Canada). Stool α-1 antitrypsin clearance was normal. The cause of the low serum albumin was thought to be of renal origin after finding an extremely high urinary protein: creatinine ratio. An abdominal ultrasound showed marked abdominal lymphadenopathy and thickening of the small bowel wall. Upper and lower gastrointestinal endoscopies and biopsies were performed. Macroscopically the esophagus, stomach and duodenum, and the colon up to the sigmoid, appeared normal. Histopathologic examination of endoscopic biopsies of duodenum and gastric antrum revealed focal granulomatous inflammation forming noncaseating granulomas in loose aggregates (Fig. 1) Special stain for acid fast bacilli (Ziehl-Neelsen) showed numerous rod shaped organisms within the cytoplasm of histiocytes forming the granulomas (Figure 1, insert). In addition, the duodenal biopsy showed mild villous atrophy but without features indicative of autoimmune enteropathy (4). The biopsies from other sites (esophagus, body of stomach and colon) showed no significant abnormalities.FIG. 1: Photomicrograph of duodenal biopsy with noncaseating granuloma (arrow) partially displacing crypts. (Hematoxylin and Eosin stain, Mag. x 150) Insert: Numerous acid-fast bacilli (arrowhead) within the cytoplasm of histiocyte in a granuloma.Subsequent stool and gastric washings identified acid-fast bacilli on microscopy. Culture of blood, stool, and gastric washings were subsequently negative for both Mycobacterium tuberculosis and Mycobacterium avium intracellulare. Polymerase chain reaction (PCR) testing on gastric aspirates for Mycobacterium tuberculosis was negative. This suggested a diagnosis of nontuberculous mycobacterial infection, although an organism was not isolated. PCR amplification of the small bowel biopsy specimen was positive for Mycobacterium species, but we were unable to distinguish between MAI and Mycobacterium genavense. Treatment was commenced with ethambutol, rifampicin, and clarithromycin. Despite therapy her diarrhea continued, and she remained dependent on parental nutrition. Six months after the diagnosis of the atypical mycobacterial infection her condition deteriorated due to progression of her renal and neurologic dysfunction and she required intensive care support. She died shortly after from multi-organ failure. Autopsy was not performed. DISCUSSION This report highlights an uncommon cause of chronic diarrhea in Schimke immuno-osseous dysplasia. To our knowledge there is only one previous report of gastrointestinal complications of SIOD (3). Given the common occurrence of profound immunodeficiency in SIOD, it is surprising that there are not other reports detailing unusual gastrointestinal infections in this condition. After finding acid fast bacilli and then excluding Mycobacterium tuberculosis by PCR and culture, Mycobacterium avium complex was, epidemiologically, the most likely bacterium to cause this clinical scenario (5), though typically this organism would be expected to grow in culture. Other nontuberculous mycobacteria were considered, including M. kansasii, M. xenopi and M. malmoense, but while recognized as causing clinical disease, they tend to result in disseminated infection (6). PCR findings on small bowel biopsy suggest that Mycobacterium genavense may be the most likely organism, as it usually is hard to grow and has been reported in HIV patients with disseminated infections (7,8). Infection with a nontuberculous mycobacteria such as Mycobacterium Avium Complex (MAC) almost always occurs in immune-suppressed individuals, particularly those with the Acquired Immune Deficiency Syndrome (AIDS) (9). MAC is widely distributed in the environment, particularly soil and water, and exposure to the organisms is common. Disease can be acquired by either inhalation or ingestion of organisms, leading to pulmonary and/or gastrointestinal disease. In healthy hosts, infection is not usually clinically apparent, though children can develop cervical lymphadenopathy and adults may develop clinical pulmonary disease (9). In several studies of adult patients with AIDS, the gastrointestinal (GI) tract is the portal of entry in >90% cases, and GI involvement is twice as common as pulmonary involvement (9). Initially, organisms adhere to the gut wall and then rapidly penetrate the intestinal mucosa, entering the lamina propria. Once MAC enters the lamina propria, phagocytosis by macrophages occurs (9). In patients with an immune defect, intracellular killing does not occur, and organisms multiply within macrophages. Granuloma formation, a mechanism for control of mycobacteria in tissues, is impaired in patients with AIDS (9). However, in our patient there was extensive granulomatous inflammation with noncaseating granulomas present in loose aggregates. Continued unimpeded replication of organisms leads to massive thickening of the gut wall while spreading via lymphatics leads to marked lymphadenopathy (9). The clinical presentation of our patient is similar to reports of MAC infection of the gastrointestinal tract in pediatric patients with AIDS, particularly the presence of persistent diarrhea, failure to gain weight, anorexia, and anemia (10,11). The only previous report on gastrointestinal manifestations of SIOD suggested autoimmune enteropathy as the etiology of prolonged diarrhea in a four-year-old patient with this disease (3). This diagnosis was based on increased serum immunoglobulin A anti-gliadin antibody, varying grades of jejunal villous atrophy with normal density of intraepithelial lymphocytes, plus a symptomatic response to oral corticosteroids. However, autoantibodies (anti-enterocyte, anti-epithelial cell) were not found. Our experience suggests that protracted diarrhea in a child with SIOD is more likely to be due to an infectious etiology than an autoimmune enteropathy. Furthermore, unusual organisms such as nontuberculous Mycobacterium should be sought in these patients, since these patients are immunodeficient. The overall prognosis for patients with Schimke immuno-osseous dysplasia is poor. The mortality rate is high, with death occurring due to infections, renal failure, or cerebral infarcts. Our patient eventually died due to multi-organ failure as a result of renal and neurologic disease, not directly related to gastrointestinal infection. However, her poor nutritional status was likely contributory to the fatal outcome. In general the disease process in SIOD is refractory to medical therapy, though combined renal and bone marrow transplantation have been recently reported to successfully treat the renal failure, bone marrow failure, and immunodeficiency (12).

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