Mucopolysaccharidosis Type VII (Sly Syndrome) Presenting as Neonatal Cholestasis With Hepatosplenomegaly

Mucopolysaccharidosis type VII (Sly syndrome), a rare lysosomal storage disorder caused by deficiency of the enzyme β-glucuronidase, was first reported in 1973 in a two year old boy with hepatosplenomegaly, skeletal abnormalities and moderate mental retardation (1). MPS type VII is unusual amongst the MPS syndromes in that it can manifest clinically in the newborn period often in association with hydrops fetalis, however transient functional liver abnormalities have also been described. We report a neonate with MPS type VII who presented with significant cholestatic jaundice and hepatosplenomegaly and provide a review of the literature. CASE REPORT A male infant was born at 38 weeks' gestation by spontaneous vaginal delivery to a 19-year-old primigravid mother after an uneventful pregnancy. The parents were nonconsanguineous and there was no pertinent family history related to childhood disease. The boy's birth weight was 3.2 kg (50th percentile). The initial examination revealed a jaundiced infant with coarse facial features, a wide mouth, and edema of the hands and feet. He had a grade 2/6 soft systolic murmur. The liver was palpable at 5 cm; the spleen at 4 cm, below the costal margins respectively. There was no ascites. He had a left-sided “dislocatable” hip and metatarsus varus. Initial laboratory investigations revealed a hemoglobin concentration of 189 g/L (range, 149–229 g/L), a white blood cell count of 8.9 × 109/L (range, 5.0–20.0 × 109/L) and a platelet count of 70 × 109/L (range, 140–350 × 109/L). The total bilirubin concentration was 166 μmol/L (range, 2–17 μmol/L), conjugated bilirubin was 25 μmol/L (range, 0–2 μmoI/L), albumin was 23 g/L (range, 34–42 g/L), alanine aminotransferase (ALT) was 98 U/L (range, 6–50 U/L), aspartate aminotransferase (AST) was 236 U/L (range, 20–60 U/L), γ-glutamyl-transpeptidase (GGT) was 556 U/L (range, 34–263 U/L) and alkaline phosphatase was 330 U/L (range, 110–320 U/L). The chest radiogram was normal. Abdominal ultrasound confirmed the diffusely enlarged liver and spleen. Intravenous ampicillin and gentamicin therapy was started for presumed sepsis. The patient was breast-fed and gained weight appropriately. Peripheral edema had resolved, but hepatosplenomegaly and jaundice persisted. Total bilirubin concentration was 257 μmol/L and conjugated bilirubin was 134 μmol/L on day 18 of life. Blood and urine cultures and toxoplasmosis, rubella, cytomegalovirus, and herpes simplex (TORCH) screening results were negative. Cardiac ultrasound revealed a small patent foramen ovale. Results of acid–base status and serum amino acids, thyroid stimulating hormone (TSH), karyotype, and α1-antitrypsin levels were normal. An ophthalmology examination was unremarkable. The patient was referred to our center. He had coarse features with a flattened nasal bridge, a wide mouth with thin lips, and a long philtrum and mild macroglossia. The abdomen was slightly distended and the liver and spleen were 4 cm and 2 cm below the costal margins, respectively. He had normal male genitalia and bilateral small hydroceles. The stools were pigmented. A percutaneous liver biopsy showed expansion of sinusoids by markedly distended Kupffer cells with large clear cytoplasmic vacuoles (Fig. 1). Hepatocytes were normal, with small cytoplasmic vacuoles giving some cells a foamy appearance. The vacuoles did not stain with periodic acid-Schiff (PAS), iron, or Alcian blue. Some hepatocytes showed cholestasis or pseudoacinar transformation. The biliary epithelium appeared normal. Ultrastructural examination (Fig. 2) showed distended lysosomes, especially in Kupffer cells and cells of Ito, which were mostly empty or contained only scant fibrillary–granular material. Analysis of the blood smear demonstrated Alder–Reilly granules within the granulocytes, compatible with a mucopolysaccharidosis (Fig. 3). Analysis of urinary glycosaminoglycans revealed a highly elevated level of 180.7 μg uronic acid/mg creatinine (normal < 30 μg uronic acid/mg creatinine). Analysis of leukocyte enzyme activity showed that β-glucuronidase activity was not detectable (n = 4.2–13.3 nmol · min−1 · mg protein−1), thus confirming the diagnosis of mucopolysaccharidosis (MPS) type VII (2).FIG. 1.: Liver histology showing hepatocytes with intracytoplasmic bile (small arrows). Kupffer cells with pale cytoplasm (large arrow) markedly distend a sinusoid. Masson-Trichrome stain (×400)FIG. 2.: Electron photomicrograph of the liver showing distended lysosomes (large arrow) in a Kupffer cell and dark stained material (small arrow) in the hepatocyte representing bile. (×4,175)FIG. 3.: Peripheral blood smear demonstrating metachromatic (Alder–Reilly) granules within a granulocyte.DISCUSSION Mucopolysaccharidosis type VII (MPS VII), first reported by Sly et al. (1) is inherited as an autosomal recessive condition, with the gene locus for β-glucuronidase on the long arm of chromosome 7 (7q21.1 -q22) (3,4). Multiple mutations have been described that presumably give rise to the heterogeneity in phenotypes. Thirty-five cases of MPS type VII reported in the literature have confirmed the phenotypic and biochemical abnormalities in a broad range of age groups (1,5–29) (Table 1).TABLE 1: Summary of 36 reported cases in the literatureFour potential subgroups have been characterized, but not all cases fit this classification precisely (9,10). The most severe form manifests with hydrops fetalis in utero or in the early neonatal period. The second group presents with hepatosplenomegaly, inguinal and umbilical hernias, growth retardation, and radiologic abnormalities and portends a relatively poor prognosis. In common with other forms of MPS, recurrent otitis media and respiratory infections are seen, more so in persons with significant and early disease. A third group, including the original patient described by Sly et al. (1) have hepatosplenomegaly, moderate radiologic changes, and mild developmental delay. A less severe presentation has also been described in adolescence, with predominantly radiologic abnormalities often in the absence of hepatosplenomegaly, hernias, developmental delay, and corneal clouding (11). As is seen in other MPS syndromes, the phenotypic features of MPS VII are variable in their frequency, severity, and progression (1–3). Macrocephaly, a flattened J-shaped sella turcica, and odontoid hypoplasia are described. Rib widening and spinal kyphosis and scoliosis are seen. A thoracolumbar gibbus may form secondary to irregularity and flattening of the inferior and superior surfaces of the vertebral bodies and is usually most prominent in the thoracic spine. Dysplasia of the acetabulum of the hip, forefoot varus deformities, metacarpal abnormalities, and delayed facial sinus formation are also described. This constellation of features is referred to as dysostosis multiplex. Cholestasis is an unusual manifestation of MPS VII, not previously considered in the differential diagnosis of neonatal cholestasis in standard textbooks or reviews (30). The clinical jaundice described in only five of the reported cases of MPS type VII is not well defined. A marked elevation of the conjugated fraction was confirmed in only one patient with peripheral edema, hepatosplenomegaly, thrombocytopenia, and elevated liver function test results (2). Another patient had hydrops fetalis; however, the conjugated fraction of bilirubin was only 14% of the total concentration (5). Hyperbilirubinemia was seen in three other patients, but the conjugated fraction was not specified in two patients (15,23), and a combined picture without exact values was described in the third (22). The current patient had clinical, biochemical, and histologic features of cholestasis. The pathogenesis of cholestasis in MPS VII is not known; however, the accumulation of intact and partially degraded glycosaminoglycan material in the lysosomes may cause distension of the hepatocytes and Kupffer cells, resulting in compression of the sinusoids and lobular distortion, with altered trafficking through the Golgi and lysosomes. Alternatively, enzymes and proteins involved in bile acid transport may be directly inhibited by β-glucuronidase substrates—a plausible mechanism given the lack of cholestasis in other MPS syndromes. The factors contributing to subsequent fibrosis and cirrhosis also are unclear (31). The diagnosis of MPS VII relies on the measurement of urinary mucopolysaccharides, which usually show elevation of chondroitin-4 and -6 sulfates, with variable presence of dermatan and heparan sulfate. Some patients may not excrete elevated levels of MPS and, in some patients, levels may vary with time (1). Metachromatic cytoplasmic (Alder–Reilly) granules seen in neutrophils on a blood smear stained with toluidine blue can be useful clues to the diagnosis. In cases of fetal hydrops, placental examination may demonstrate foamy changes in the Hofbauer cells (placental macrophages) (12,13). A liver biopsy, although not essential for the diagnosis of MPS VII, was helpful in this case to exclude other conditions causing neonatal cholestasis. Typically, the liver histology demonstrates a storage pattern with distension of Kupffer cells, especially in the early stages when hepatocytes are less affected. Electron microscopy shows distended lysosomes, which are mostly empty because the glycosaminoglycans are dissolved during processing, in contrast to other lysosomal storage diseases. The definitive diagnosis, however, can only be confirmed by finding markedly reduced or absent β-glucuronidase activity in granulocyte or cultured skin fibroblast lysosomes. Amniotic fluid and chorionic villi both express β-glucuronidase activity and can be used for antenatal screening (2,12,14,26,29). Within a family group, carrier detection can be determined using enzyme analysis in leukocytes, but there is overlap with the normal population. DNA testing is more reliable but may require identification of the mutant allele within a family before screening. Novel treatment strategies for MPS VII are being developed. A single report of bone marrow transplantation for MPS VII described dramatic improvement in motor function and respiratory symptoms; however, the IQ did not change (15). In a murine model, direct enzyme replacement initiated at birth followed by bone marrow transplantation at 5 weeks of age resulted in improvement of skeletal and central nervous system manifestations (32). Again, in mice, direct enzyme replacement has demonstrated that early treatment, from birth onward, may significantly alter the pathology of somatic tissues, including skeletal and central nervous system disease (2,33). Gene transfer using neonatal administration of an adenoassociated virus expressing human β-glucuronidase resulted in impressive enzyme concentrations within all tissues, including the brain (33,36). Further development of gene-based therapeutics in the early treatment of this disorder will likely prove effective in alleviating effects of the disease. In summary, MPS VII is a rare heritable disorder of glycosaminoglycan degradation caused by a deficiency of the lysosomal enzyme β-glucuronidase. Patients with this condition can have markedly diverse clinical presentations at varying ages. Mucopolysaccharidosis type VII should be included as part of the differential diagnosis of hepatosplenomegaly and neonatal cholestasis. The treatment is generally supportive. Experience with early bone marrow transplantation is limited and should still be considered experimental.

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