What is Hunter Disease?
Hunter syndrome also known as Mucopolysaccharidosis Type II (Online Mendelian Inheritance in Man number -309900) is a genetic disorder caused due to deficiency of enzyme iduronidase 2 sulfatase. This results in accumulation of glycosamnioglycans in the internal organs of body, leading to clinical symptoms like cognitive decline, hepatosplenomegaly, macrocephaly and physical disabilities like contracture of joints, spinal synostosis and carpal tunnel syndrome. This disease is inherited in an X linked recessive manner and usually affects males. Rarely females can also manifest the disease symptoms.
When do we suspect Hunter syndrome?
Usually symptoms are not apparent at birth. The child is brought to a pediatrician in view of delayed development, large head, loss of acquired milestones or a prominent distended abdomen with an umbilical hernia. Some children are also brought to a clinic in view of coarse facial features. In early progressive form, symptoms appear between 18 months and 4 years, where as in late slowly progressive form symptoms are seen 2 years later.
What are the clinical symptoms?
- Macroglossia (Large tongue)
- Large head size
- Delay in development
- Coarse face (prominent nose, broad nasal bridge, thick lips)
- Short stature
- Hoarse voice
- Joint contractures especially in small joints of hands
- Frequent upper respiratory illness
- Behavioral problems
- Cognitive decline (Males with slowly progressive form of the disease can have normal intelligence also)
How is Hunter syndrome diagnosed?
Hunter syndrome should be suspected clinically in any male child with coarse facies, hepatosplenomegaly with or without cognitive decline. Radiological changes in bones known as dysostosis multiplex support the clinical diagnosis of mucopolysaccharidosis / storage disease group of disorders. The gold standard of diagnosis in a male child is by demonstrating low levels of the deficient enzyme in WBC’s, plasma or fibroblasts in the presence of normal activity of any other sulfatase enzyme. Family history supporting X linked mode of inheritance, absence of corneal clouding and presence of subculaneous nodules on the back in some cases helps to differenciate from other types of mucopolysaccharidosis and mucolipidosis which have similar clinical presentations.
The diagnosis is confirmed by detection of a hemizygous disease causing variant (mutation) in IDS gene. This can be done by Sanger sequencing of all the nine exons of the gene which would identify 80 % of the disease causing variants. The rest of the 10% can be due to deletion / duplication of part of the gene. Mutation detection is important especially for providing carrier testing to female relatives and for preventing recurrence in the family by prenatal diagnosis.
What are the treatment modalities available?
Enzyme Replacement Therapy (ERT) in the form of recombinant iduronate sulfatase (Elaprase) is available for treatment and has been shown to decrease the progression of disease in children with slowly progressive disease with normal cognition. This enzyme is given as an injection every 2 weeks. Since this enzyme does not cross blood brain barrier, no effect on neurological manifestations is seen. Hematopoetic stem cell therapy (HSCT) or bone marrow transplantation with HLA matched sibling can provide sufficient enzyme to slow the disease progression, but efficacy has not been proved. Supportive therapy in form of physiotherapy, regular monitoring for possible complications etc may be provided.
Without definitive treatment like ERT, the disease course is progressive and respiratory, cardiological and neurological complications may lead to shortening of life span.
What are the implications for family?
- If mother is found to be a carrier of the disease causing variant, there the chance that her son will have the same disease is 50%.
- If a couple has a child with Hunter syndrome, molecular diagnosis should be done and prenatal diagnosis provided to the couple in next pregnancy by chorion villus sampling at 11- 12 weeks and targeted molecular analysis.
- The sisters of the individual with Hunter syndrome and sisters of his mother are likely to be carrier of the disease causing mutation and may be at a risk of giving birth to the child with Hunter syndrome. Hence, they should be offered carrier detection test by DNA based analysis and genetic counseling.
Correction of gene defect leading to complete and permanent cure of the disease is the dream for all genetic disorders. Research in the gene therapy for Hunter syndrome is in early stages and is showing early positive results in animal studies.
More to read
Uttarilli A, et al. Identification and Characterization of 20 Novel Pathogenic Variants in 60 unrelated Indian patients with copolysaccharidoses (MPS) type I and type II. Clin Genet. 2016 May 5. doi: 10.1111/cge.12795. [Epub ahead of print] PubMed PMID: 27146977.
Narayanan DL, et al. Hunter Syndromein Northern India: Clinical features and Mutation Spectrum. Indian Pediatr. 2016Feb;53(2):134-6.
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Dr Shubha Rao Phadke/p>
Sanjay Gandhi Postgraduate Institute of Medical Sciences