Mucopolysaccharidosis Type VII

Mucopolysaccharidosis type VII (Sly syndrome) is a rare autosomal recessive lysosomal storage disorder due to biallelic variants in GUSB, with deficiency of beta glucuronidase and storage of chondroitin, dermatan and heparan sulphates. It varies from hydrops foetalis to an attenuated form compatible with adult life. Enzyme replacement therapy is available.

Pathophysiology. Beta glucuronidase removes terminal glucuronic acid from glycosaminoglycans. Deficiency causes storage in lysosomes of many tissues, including the skeleton, heart, liver, spleen, brain and cornea.

Severity relates to residual activity.

Early treatment reduces visceral and some skeletal disease.

• Non-immune hydrops foetalis in severe cases
• Coarse facial features, macrocephaly and short stature
• Hepatosplenomegaly and inguinal or umbilical hernias
• Dysostosis multiplex, kyphosis and joint contractures
• Recurrent respiratory infections, airway obstruction and sleep apnoea
• Cardiac valve disease
• Developmental delay and intellectual disability (variable)
• Corneal clouding and hearing loss
• Granulocyte inclusions (Alder-Reilly bodies) on blood film
• Attenuated forms: milder skeletal disease with normal intelligence

• Urine glycosaminoglycans: raised chondroitin, dermatan and heparan sulphate. Results may be normal in attenuated forms.
• Beta glucuronidase activity in leukocytes, plasma or fibroblasts: markedly reduced.
• GUSB sequencing with deletion and duplication analysis.
• Skeletal survey, echocardiography and abdominal ultrasound.
• Brain MRI, ophthalmology and audiology assessment.
• Blood film for inclusions in neutrophils.
• Prenatal ultrasound for hydrops, with enzyme or genetic testing of the foetus.

Differential diagnosis.

• Other causes of non-immune hydrops (lysosomal storage disorders, infections, cardiac disease)
• Hurler syndrome and Hunter syndrome
• GM1 gangliosidosis and mucolipidosis II and III
• Sialidosis and galactosialidosis

• Enzyme replacement therapy: vestronidase alfa 4 mg/kg intravenously every 2 weeks as a lifelong infusion. Premedicate with an antihistamine (cetirizine 10 mg orally; children 1 to 5 years 2.5 mg twice daily, 6 to 11 years 5 mg twice daily) 30 to 60 minutes before each infusion. Observe for anaphylaxis, with adrenaline 0.5 mg intramuscularly (children 0.01 mg/kg, maximum 0.5 mg) and resuscitation equipment available.
• Haematopoietic stem cell transplantation: an option in early disease at specialist centres.
• Respiratory care: sleep study, continuous positive airway pressure, adenotonsillectomy, and vaccination.
• Cardiac care: echocardiography yearly, and valve surgery for severe disease.
• Orthopaedic and spinal care: cervical spine imaging before anaesthesia, hip and spine surgery as needed, and physiotherapy.
• Hernia repair for symptomatic hernias.
• Eye and hearing care: correction of refractive error, corneal transplant for severe clouding, and hearing aids.
• Development and education: early intervention, speech therapy and special education.
• Genetic counselling: a 25% recurrence risk in each pregnancy, with prenatal diagnosis available.

Special groups.

• Pregnancy with hydrops and negative infection screen: send amniotic fluid or foetal blood for lysosomal enzyme analysis.

Monitoring. Growth, respiratory status and infusion tolerance at each visit. Echocardiography yearly, cervical spine and skeletal imaging yearly, and eye and hearing review yearly.

Referral and escalation. Refer to clinical genetics, metabolic medicine and orthopaedics. Emergency for anaphylaxis during infusion, airway obstruction or spinal cord compression.