Sly syndrome is an autosomal recessive disease that belongs to a family of disorders identified as lysosomal storage diseases, and historically as the mucopolysaccharidoses. This disorder is characterized by the lysosomal accumulation of glucuronic acid-containing glycosaminoglycans (dermatan, heparan, and chondroitin 4-, and 6-sulfates) as a consequence of deficiencies in the lysosomal hydrolase, β-glucuronidase.
The β-glucuronidase gene (GUSB) resides on chromosome 7q21.11 spanning 21 kb and comprising 12 exons that generate four alternatively spliced mRNAs. The longest isoform (isoform 1) derived from the GUSB gene is a 651 amino acid precursor protein. Active β-glucuronidase functions as a homotetrameric complex. More than 30 different mutations have been identified in the GUSB gene resulting in Sly syndrome. Identified mutations include missense, nonsense, frameshift, and splice site mutations. Complicating the diagnosis of the inheritance of mutant alleles of GUSB is the presence of several pseudogenes on chromosomes 5, 6, 7, 20, 22 and Y. These pseudogenes can be detected with probes from exons 2, 3,4, 6, 7, and 11 of the wild-type GUSB gene.
Like many other lysosomal storage diseases, Sly syndrome patients exhibit a wide spectrum of clinical manifestations ranging from mild disease in adults to nonimmune hydrops fetalis (resulting in death in utero). The disease was first recognized in a patients exhibiting symptoms similar to those seen in Hurler syndrome patients (another mucopolysaccharidotic disease). The severe neonatal form of Sly syndrome is the most commonly encountered form and can range from death in utero to mild or no hydrops at birth. Neonatal Sly syndrome is one of the few lysosomal storage diseases that manifests in utero or at birth.
Sly syndrome is characterized by coarse facial features, hepatosplenomegaly, protruding sternum and dystosis multiplex. Dystosis multiplex refers to a constellation of skeletal abnormalities and is characterized by an enlarged skull, thickened calvarium, premature closure of lamboid and sagittal sutures, shallow orbits, enlarged J-shaped sella turcica (a saddle-shaped skull structure into which sits the bottom of the pituitary gland), and abnormal spacing of the teeth with dentigerous cysts. There is anterior hypoplasia of the lumbar vertebrae, the long bone diaphyses are enlarged and an irregular appearance of the metaphyses. The epiphyseal centers not well developed, the pelvis is poorly formed with small femoral heads and coxa valga. The clavicles are short, thick and irregular and the ribs are oar shaped. Phalanges are shortened and trapezoidal in shape.