Chronic Diarrhea in Mucopolysaccharidosis IIIB

Abstract

Mucopolysaccharidosis (MPS) IIIB (Sanfilippo syndrome, OMIM 252920) is a lysosomal storage disorder caused by the deficiency of α-N-acetylglucosaminidase (NAGLU), a lysosomal hydrolase involved in the degradation of heparan sulphate (HS) (1). MPS IIIB is characterized by multisystem involvement and a complex phenotype. The most debilitating manifestations of the disease are those related to central nervous system disease, with severe and progressive mental retardation, hyperactivity, and behavioral problems. Skeletal and visceral manifestations are less prominent, as compared with other MPS. Gastrointestinal manifestations, including diarrhea and constipation, have occasionally been described in patients with MPS IIIB, but they have been poorly characterized and their pathophysiology is not known. Although gastrointestinal symptoms are often overshadowed by the severe neurological phenotype, they may affect the quality of life of patients and of their families. We describe a case of MPS IIIB, referred to our hospital because of chronic diarrhea, in which abnormalities of intestinal endoscopy, histology, and scintigraphy with Tc-99m–labeled human serum albumin were found, partially overlapping with the features of intestinal lymphangiectasia. In this patient, a low-fat diet and supplementation of medium-chain triglycerides were started, leading to persisting improvement of diarrhea. These results add information on the pathophysiology of intestinal manifestations in MPS IIIB patients and possibly in other MPS patients with a history of chronic diarrhea. CASE REPORT We describe a case of MPS IIIB, an 11-year-old Italian boy, born to healthy consanguineous parents, referred to our hospital at the age of 9 years because of developmental delay and severe chronic diarrhea. Besides parental consanguinity, family history was noncontributory. The first years of life were uneventful. Developmental delay was initially noticed at the age of 3 years. Gastrointestinal manifestations started at the age of 8 years. At the time of admission to our hospital his parents reported that the boy had 14 to 15 movements per day of semiformed to watery large-volume stools, often associated with abdominal pain. The parents also reported that because the boy was not continent, frequent emission of large amounts of stools caused significant discomfort to them and to other attendants, both at home and at school. The patient was unsuccessfully treated with oral antibiotics and cholestyramine. On physical examination height was 137 cm (90th–95th percentile), weight 36.1 kg (90th–95th percentile), and body mass index 19.2 kg/m2. Facial coarsening, macrocephaly, confluence of eyebrows, hirsutism, and hepatosplenomegaly were present. The patient had severe developmental delay and hyperactivity; he was not able to collaborate in an IQ test. On the basis of the clinical history and presentation, the diagnosis of MPS IIIB was suspected. Urine glycosaminoglycan (GAG) excretion was increased: 40 mg/g GAG creatinine (normal value for age: 22 ± 13). Serum NAGLU deficiency was demonstrated and the molecular analysis of the NAGLU gene showed compound heterozygosity for the P115S and IVS3 + 1G > A mutations. A diagnostic work-up to investigate possible associated causes of diarrhea was started. His hemogram showed hemoglobin values of 12.1 g/dL, and a white blood cell count of 4.60 × 103/μL without lymphocytopenia (2.57 × 103/μL). Peripheral CD4 and CD8 cell counts were normal. Routine laboratory analyses were normal with erythrocyte sedimentation rate of 2 mm in the first hour, total serum protein 6.7 g/dL (normal range 6.0–8.0 g/dL) and serum albumin 4.3 g/dL (normal range: 3.7–5.5 g/dL), Na+ 139 mmol/L, K+ 4.4 mmol/L, Ca tot 9.7 mg/dL, serum iron 93 mg/dL and ferritin 53 ng/mL, and normal serum protein electrophoresis. Liver function, renal function, urinalysis, and kidney ultrasonography were also normal. Immunoglobulin (Ig) G was slightly reduced (6.63; normal range for age: 6.73–17.34 g/L). Serological markers for celiac disease (antitissue trans-glutaminase, antiendomysial and antigliadin IgG and IgA) were negative. Serologic markers for inflammatory bowel disease, including anti-Saccharomyces cerevisae IgG and IgA and anti-neutrophil cytoplasmic IgG, were negative. Fecal calprotectin concentration was within the normal range. Neither fecal occult blood loss nor steatorrhea was detected. Common gastrointestinal infections were excluded by repeated stool cultures and search for parasites. Fecal adenovirus and rotavirus antigens were also negative. Infection by Helicobacter pylori was excluded through invasive (histological examination) and noninvasive (serology and stool antigen assay) diagnostic tests. Stool testing for Clostridium difficile toxins A/B was negative. Lactose intolerance was excluded by a negative breath hydrogen test. Mucosal damage was excluded by cellobiose or mannitol tests (repeated on 2 different occasions), suggesting normal intestinal permeability. Possible enteric protein losses were investigated by fecal α-1-antitrypsin, showing normal results (0.07 mg/g wet feces; normal < 0.44 ± 0.06 mg/g wet feces). Ultrasound examination of the heart showed only the typical findings of MPS (thickening of mitral and aortic valves and aortic valve regurgitation) without significant hemodynamic consequences. An abdominal computed tomography was normal, with exception of moderate hepatosplenomegaly. Upper gastrointestinal tract endoscopy revealed scattered white spots in the proximal duodenum (Fig. 1); histological examination of ileum showed dilated lymphatic vessels in the lamina propria, without evidence of inflammation (Fig. 2). Colonoscopy revealed no apparent abnormalities.FIG. 1: Endoscopic examination revealed diffusely scattered white spots throughout the mucosa of the proximal duodenum.FIG. 2: Histological examination of ileum mucosa showing dilatation of the lymphatic vessels in the lamina propria.An abdominal scintigraphy with Tc-99m–labeled human serum albumin was performed, showing radioactivity in duodenum, proximal jejunum, and ileocecal valve (Fig. 3).FIG. 3: Tc-99m–human serum albumin scintigraphy showing abnormal uptake of tracer material (arrows) in duodenum, proximal jejunum and ileocecal valve.The histologic and endoscopic features, together with the findings of the scintigraphy, overlapped with those of intestinal lymphangiectasia (IL). Therefore, we decided to start a therapeutic trial with a low-fat diet supplemented with medium-chain triglyceride (MCT)–based formula (Portagen, Mead Johnson, Nijmegen, the Netherlands) (2,3). After 2 months on this treatment, the patient showed signs of a favorable response and diarrhea gradually improved (1–3 times/day). He remained stable for the following months. Two years after the start of treatment with MCT-rich diet, the patient's growth is still normal. His height is 152 cm (75th–90th percentile), his weight is 45 kg (75th–90th percentile), and his body mass index is 19.3 kg/m2. Laboratory tests show normal serum protein, albumin, and calcium levels; a mild decreased levels of IgG persists (6.23–normal range for age: 8.21–18.35); fecal clearance of α1-antitrypsin is also normal (0.01 mg/g wet feces). Compliance with a low-fat diet is reported as good. The improvement and the stabilization of gastrointestinal manifestation are judged by the parents as a substantial improvement of the patient's quality of life. DISCUSSION We report on a case of a patient affected by MPS IIIB with chronic and intractable diarrhea. Because of its severity (elevated stools' frequency) and its chronic course, diarrhea had a strong impact on the patient's quality of life and overall health. Chronic diarrhea has occasionally been observed in MPS IIIB, but there are no reports in the literature on the characterization of intestinal manifestations in these patients. Thus, this is the first description of intestinal findings in an MPS IIIB patient. In our patient a diagnostic work-up to investigate causes of chronic diarrhea resulted in findings that partially overlapped with those observed in IL. IL is an uncommon condition, characterized by dilated intestinal submucosal and subserosal lymphatics (4). Protein-losing enteropathy, resulting from blocked intestinal lymphatics and loss of lymphatic fluid within the gastrointestinal tract, is the most common manifestation of this disease. IL can be primary or associated with different conditions (secondary or syndromic). Typical features of the disease, presenting with variable severity, include general or peripheral edema, diarrhea, chylous ascites, chylous pleural effusion, and blindness due to macular edema (4). The findings observed in our patient, particularly the appearance of the intestinal mucosa at endoscopy, histology, showing dilated lymphatics and scintigraphy, were puzzling, as they were not associated with the typical clinical (eg, growth retardation, edema) and biochemical manifestations of IL (protein loss). However, Van der Meer et al (5) reported a case of a girl with IL without physical signs and laboratory evidence of enteric protein loss; also in this case, such as in our patient, the diagnosis of IL was made basis on the endoscopic and histological manifestations. Investigations to detect other conditions causing intractable and chronic diarrhea were negative. Causes of secondary IL (abdominal tumors, recurrent parasitic infection, hepatic cirrhosis, chronic pancreatitis, Crohn disease, Whipple disease, radiotherapy, constrictive pericarditis, and other cardiac conditions) were also excluded by a negative clinical history or by the results of specific investigations. Despite the absence of a complete clinical picture of IL, we started a treatment on the basis of low-fat normo-caloric diet, enriched with MCT (2,3). This dietary regimen was effective in reducing stool frequency (1–3 per day). The positive clinical response to MCT-based formula is difficult to explain. It may be speculated that the early start of a dietary treatment in our patient has been able to prevent the full expression of protein-losing enteropathy, including the biochemical profile charaterized by hypoproteinemia, hypoalbuminemia, lymphocytopenia, hypogammaglobulinemia, and hypocalcemia. The abnormalities of intestinal endoscopy, histology, and scintigraphy with Tc-99m–labeled human serum albumin, reported in IL, remain unexplained in our patient. This association may be casual. However, gastrointestinal findings with recurrent and occasionally severe diarrhea are described in MPSs, including MPS II and MPS IIIB (1). The pathogenesis of gastrointestinal involvement in MPSs is obscure. Wegrzyn et al (6), suggested a possible role of microbial infections of digestive tract in an MPS I patient. In our patient, we did not find evidence of bacterial, viral, and fungal infection, although we cannot exclude an infection by uncommon or atypical pathogens. Alternatively, a localized GAG storage may cause a mechanical obstruction of intestinal lymphatics that may lead to fluid loss and diarrhea. This is consistent with the finding in our patient of dilated lymphatic vessels in the ileal lamina propria and abnormal pattern on scintigraphy with Tc-99m–labeled human serum albumin. A possible role of HS, the substrate accumulated in MPS IIIB, in the occurrence of gastrointestinal manifestations may also be considered. HS is not only an important component of the extracellular matrix and cell surface but it is also associated with important cell functions (cell motility, interaction between the intra- and extracellular matrices) and with regulation of extracellular signalling pathways (eg, by modulating fibroblast growth factor cytokine activity). In addition, a role of HS proteoglycan has been recognized in protein-losing enteropathy, with correlations with protein leakage and modulation of cytokines, although the molecular mechanisms that mediate this effect are unknown (7,8). In conclusion, we suggest that MPS patients presenting with diarrhea should be investigated carefully to detect the signs, such as those found in our patient, with particular attention to histological findings of dilated intestinal lymphatics. A treatment with MCT-based formula may be considered to alleviate the clinical course of MPS disorders. A careful characterization of gastrointestinal manifestations may also add further information on the role of GAGs levels and localization in the function of intestine.