INTRODUCTION	Section 2 of 9
Author Information Introduction Clinical Differentials Workup Treatment Follow-up Miscellaneous Bibliography

Background: The mucopolysaccharidoses (MPSs) are a group of inherited lysosomal storage disorders that are caused by a deficiency of specific lysosomal enzymes required for the degradation of glycosaminoglycans (GAGs) (mucopolysaccharides). MPSs show extensive genetic heterogeneity, both among and within loci. Seven types of MPS exist. MPS VII, or Sly disease, results from the deficiency of b-glucuronidase. Sly et al characterized a patient with skeletal features similar to those observed in other patients with MPS. Historically, MPS VII is of interest because it was the first MPS (excluding the sex-linked gene for Hunter syndrome) for which the mutant gene was localized to a specific chromosome, chromosome 7.

Pathophysiology: The severity of symptoms in patients with MPS VII varies widely. The most severe phenotype is evident at birth, which is unusual for MPSs. In severe cases, the condition presents as hydrops fetalis. Neonatal jaundice may be present at birth. More typically, the clinical features of the disorder become evident in the first few years of life. These early symptoms include dysostosis multiplex with dislocated hips, joint contractures, and thoracolumbar kyphoscoliosis. In many patients, a J-shaped turcica and odontoid hypoplasia also may occur. Radiographs demonstrate a flattening of the vertebral bodies termed platyspondyly.

Coarse facial features may be present, producing a facial appearance somewhat similar to that seen in children with MPS IH (Hurler syndrome). Hepatosplenomegaly may be present, and umbilical and inguinal hernias are common. Other features that may be present are macrocephaly, short neck, valvular heart disease, and hearing loss. Mental retardation also occurs but is not progressive. Developmental delays in the acquisition of speech and language may be evident. Corneal clouding also is a feature, but it varies considerably in age at onset. Milder forms of MPS VII typically appear several years after birth, usually in patients older than 4 years. Clinical forms have been delineated into 3 subtypes. Subtypes 1 and 2 have early onset, at birth or during the patient's first 4 years of life. Both produce severe clinical features. Subtype 3 has late onset, frequently in patients older than 4 years, and patients develop milder symptoms.

The underlying defect in the disorder is a molecular defect that leads to a deficiency in the enzyme b-glucuronidase. b-Glucuronidase is required for the breakdown of dermatan sulfate (DS), heparan sulfate (HS), and chondroitin sulfate (CS). Accumulation of DS, HS, and CS takes place in many systems and tissues, including the central nervous system. An increase in the urinary excretion of HS, DS, and/or CS occurs. The exact pattern may vary considerably based on the subtype of MPS VII involved.

Frequency:

• In the US: MPS VII is extremely rare, and few cases have been described.

• Internationally: In his extensive study of MPSs in Northern Ireland in 1997, Nelson reported that no living cases of MPS VII were observed from 1958-1985. Three cases of nonimmune hydrops fetalis were believed to be MPS VII on the basis of placental histology and enzyme studies in the parents.

Mortality/Morbidity: Only a small sample of cases is available from which to extrapolate mortality figures for MPS VII. Fetal deaths have been noted several times. In mild cases, survival to age 19-20 years has been reported. Upper respiratory tract infections, neurodegenerative complications, and gastrointestinal tract conditions may contribute to reduced survival rates.

Sex: Males and females are affected in equal numbers.

Age: In severe forms, defects may appear prenatally, and in other forms, defects may be present at birth or during the first 2 of years of life. In the milder forms, clinical features may not be evident until age 4 years or later. As a point of emphasis, Sly syndrome is one of the few MPSs and lysosomal storage diseases that may be clinically evident at birth.

	CLINICAL	Section 3 of 9
Author Information Introduction Clinical Differentials Workup Treatment Follow-up Miscellaneous Bibliography

History:

• Hydrops fetalis and dysostosis multiplex are associated with the severe form of Sly syndrome that is present in neonates.

• Some symptoms observed in patients with other severe forms of MPS, such as MPS IH (Hurler syndrome), also may be evident in patients with severe cases of Sly syndrome.

• Coarse facial features with macrocephaly, hepatomegaly, hepatosplenomegaly, inguinal and umbilical hernias, repeated upper respiratory infections, and severe growth retardation may be prominent during the first 2 years of life in patients with severe disease.

• In the milder forms of Sly syndrome, development of some of the same symptoms is likely; usually, however, patients are aged 4 years or older before symptoms become a problem. Corneal opacities may develop at any time in patients older than 1 year.

• Mental retardation is a common feature of Sly syndrome, but it usually is moderate and nonprogressive.

• Finding a deficiency of b-glucuronidase activity in skin fibroblasts or leukocytes can help confirm a diagnosis of either severe or mild Sly syndrome.

Physical:

• Severe MPS VII may be present at birth as hydrops fetalis. These patients may have neonatal jaundice. Coarse facial features, similar to those characterizing Hurler syndrome, may be present.

• Hepatosplenomegaly is a characteristic feature. Inguinal and umbilical hernias are common.

• Variable levels of corneal clouding may exist and begin in patients at approximately age 8 years.

• Patients have short stature because of postnatal growth deficiency. The head is macrocephalic, the neck is short, and valvular heart disease may be present. Hearing loss may be associated with MPS VII. Other symptoms include dysostosis, dislocated hips, spinal malformations, and aortic regurgitation.

• Mental retardation is moderate, nonprogressive, and begins in patients older than 3 years.

• Milder forms of Sly syndrome are manifested in patients older than 4 years.

• Recurrent respiratory infections are a problem.

• Patients may show signs of hirsutism.

• Inclusions of the polymorphonuclear leukocytes are a feature.

Causes:

• Deficiency of the lysosomal enzyme b-glucuronidase

• Accumulation of the undegraded mucopolysaccharides HS, DS, and CS in tissues and organs

• Storage of excess mucopolysaccharides, contributing to numerous morphologic abnormalities

• Genetic causes

• The metabolic defect in patients with MPS VII has an autosomal recessive mode of inheritance (as is true of the other MPSs, except for MPS II or Hunter syndrome, which is transmitted as a sex-linked recessive trait).

• Various mutations lead to a wide variety of phenotypes in patients with MPS VII.

• The b-glucuronidase gene has been mapped to chromosome bands 7q21.11-q22.1.