MPS II is an ultra-rare condition, with an estimated prevalence of approximately 1 in 100,000 to 170,000 male live births. It primarily affects males, as it is inherited in an X-linked recessive manner (see RareShare Guide on Genetic Inheritance). Female carriers may show mild symptoms but are typically less severely affected.

MPS II is caused by mutations in the IDS gene located on the X chromosome (Xq28). This gene encodes the enzyme iduronate-2-sulfatase (I2S), which is necessary for the degradation of large carbohydrate GAGs such as dermatan sulfate and heparan sulfate. Mutations can lead to a complete or partial loss of enzyme function, resulting in the accumulation of GAGs in lysosomes and causing cellular and tissue damage. For more information about how X-linked diseases are inherited in children born genetically male, visit the  RareShare Guide on Genetic Inheritance. 

Over 300 mutations have been identified, and the majority of the mutations are missense mutations, with one building block (nucleotide) change in the DNA molecule. IDS is located on the sex-determining chromosome, the X chromosome. Because male babies have only one X chromosome, a single altered copy of the IDS gene is enough to cause disease in boys. Thus Hunter syndrome primarily affects boys. Women who carry one normal X chromosome and one X chromosome with the disease mutations are “carriers”.

IDS provides instructions for synthesizing the enzyme iduronate 2-sulfatase (I2S). I2S is located in cellular compartments called lysosomes and is responsible for breaking down large sugar molecules known as glycosaminoglycans (GAGs). In particular, I2S removes a sulfate chemical group from two GAGs, heparan sulfate, and dermatan sulfate. The pathogenic mutations in the IDS gene partially or completely reduce the enzyme activity of I2S, which leads to GAG accumulation in lysosomes, disrupting normal cellular function and ultimately causing multiple organ injury in the affected individuals.

Symptoms for the severe form of MPS II typically appear between the ages of 2 and 4 years, while for milder forms, symptoms may not become apparent until late childhood or adolescence. Newborns with MPS II generally appear healthy at birth. Children with MPS II grow at a normal rate for the first 5 years and then growth slows, resulting in a shorter stature.  Common symptoms include:

• Coarse facial features such as a prominent forehead, macrocephaly (enlarged head), broad nose and thick lips.

• Short stature– reduced height as compared to peers.

• Skeletal abnormalities (dysostosis multiplex), including joint stiffness and abnormal bone development.

• Joint stiffness and limited mobility.

• Hepatosplenomegaly– enlargement of the liver and spleen.

• Respiratory Issues such as obstructive sleep apnea and recurrent respiratory infections (may result in deep, hoarse voice).

• Cardiac problems such as valve abnormalities and other heart-related issues.

• Skin lesions (pebbly, ivory-colored lesions).

• Hearing loss, including progressive hearing impairment due to middle ear infections.

• Cognitive impairment– possible developmental delays and learning difficulties, particularly in more severe forms.

• Behavioral Issues such as hyperactivity, aggression and other behavioral changes.

The diagnosis of MPS II is based on clinical evaluation and laboratory tests. Key steps include:

• Clinical assessment of symptoms and physical examination.

• Urine GAG analysis testing for elevated levels of glycosaminoglycans.

• Enzyme activity assay to measure iduronate-2-sulfatase activity in blood or tissue samples.

• Genetic testing to identify mutations in the IDS gene to confirm the diagnosis.

• Imaging studies using X-rays or MRI’s to evaluate skeletal deformities and organ size.

• Prenatal genetic testing can be used to detect the defective gene in the unborn.

The disease progresses slowly and signs can overlap with many other disorders. The journey to a definitve diagnosis can take a long time.

Currently, there is no cure for Hunter Syndrome. Treatment focuses on managing symptoms and improving quality of life. Treatment approaches include:

• Enzyme Replacement Therapy (ERT): Idursulfase (Elaprase), a recombinant human I2S enzyme, is administered intravenously to replace the deficient enzyme.

• Hematopoietic Stem Cell Transplantation (HSCT): May be considered for some patients, particularly those diagnosed early with the severe form.

• Surgical interventions for severe skeletal abnormalities or cardiac issues.

• Supportive Care: Management of specific symptoms, including:

  • Physical and occupational therapy.

  • Respiratory support for sleep apnea and other issues.

  • Cardiac monitoring and treatment for heart abnormalities.

  • Orthopedic care for skeletal deformities.

  • Hearing aids and audiology services for hearing impairment.

  • Emerging Therapies: Research is ongoing for potential treatments such as gene therapy and intrathecal enzyme replacement therapy.

The FDA-approved enzyme replacement therapy (ERT) uses artificially engineered I2S enzymes to replace patients’ missing or defective enzymes through intravenous injection once a week to ease disease symptoms. When given early, ERT may delay or alleviate some of the symptoms of Hunter syndrome. However, it is unclear whether the improvement associated with ERT treatment can significantly improve patients’ quality of life. ERT cannot cross the blood-brain barrier, a semipermeable border between the blood and the brain that controls material exchange between the blood network and the central nervous system. Therefore, the benefits in cognition and behaviors have not been seen with ERT.

The prognosis for individuals with MPS II varies significantly depending on disease severity. Those with severe forms often have a shortened lifespan, frequently not surviving beyond the second or third decade of life. In contrast, patients with milder forms may have a normal or near-normal life expectancy. Early diagnosis and management can improve quality of life and potentially slow disease progression.

1. Wraith, J.E., Scarpa, M., Beck, M., Bodamer, O.A., De Meirleir, L., Guffon, N., Lund, A.M., Maim, G., Van der Ploeg, A.T. & Zeman, J. (2007). “Mucopolysaccharidosis Type II (Hunder Syndrome): A Clinical Review and Recommendations for Treatment in the Era of Enzyme Replacement Therapy.” E. J. Pediatr., 167(3), 267-277.

2. Hampe, C.S. et al. (2023). “Diagnosis and Management of Mucopolysaccharidosis Type II (Hunter Syndrome): A Review.” JAMA Pediatr. 177(8), 829-838.

3. Stapleton, M., Kubaski, F., Mason, R.W., Yabe, H., Suzuki, Y., Orii, K.E., Orii, T. & Tomatsu, S. (2017). “Presentation and Treatments for Mucopolysaccharidosis Type II (Hunter Syndrome.” Expert Opin Orphan Drugs, 5(4), 295-307.

4. Orphanet: Mucopolysaccharidosis Type 2.

5. NORD (National Organization for Rare Disorders): Mucopolysaccharidosis Type II.

6. Medline Plus:  Mucopolysaccharidosis Type II.

7. MPS Society:  https://mpssociety.org.