Hunter syndrome (MPS II)

Overview

Hunter syndrome, also known as Mucopolysaccharidosis Type II (MPS II), is a rare genetic condition where the body cannot properly break down certain long chains of sugar molecules called glycosaminoglycans (GAGs), sometimes referred to as mucopolysaccharides [PMID:33604085]. These GAGs are essential building blocks found in many parts of the body, including connective tissues. In Hunter syndrome, a specific enzyme called iduronate 2-sulfatase (IDS) is deficient or absent. This deficiency means GAGs cannot be broken down and recycled effectively, causing them to accumulate inside cells throughout the body.

The build-up of GAGs leads to progressive damage in various tissues and organs over time. Hunter syndrome is classified as a lysosomal storage disorder because the accumulation happens within cellular compartments called lysosomes, which are responsible for waste breakdown and recycling. The condition typically presents in early childhood and primarily affects males.

Symptoms & clinical features

The symptoms of Hunter syndrome can vary significantly between individuals, ranging from milder to more severe forms. Common features often include distinct facial characteristics, such as a prominent forehead, thickened lips, and an enlarged tongue. Many individuals experience skeletal abnormalities, which can lead to joint stiffness and problems with mobility [PMID:20301662].

Other symptoms may involve an enlarged liver and spleen (hepatosplenomegaly), frequent ear infections, and respiratory issues due to narrowed airways. Some individuals may also experience heart valve problems and carpal tunnel syndrome. In more severe forms, there can be developmental delay and progressive cognitive impairment. Hearing loss and vision problems can also occur.

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Affected organs

Hunter syndrome can affect multiple organ systems due to the widespread accumulation of GAGs. The skeletal system is commonly affected, leading to joint stiffness, short stature, and skeletal deformities. The liver and spleen often become enlarged, and the heart can be impacted, particularly the heart valves.

Respiratory issues can arise from narrowed airways and increased secretions, affecting the lungs. Neurological involvement, including developmental delay and cognitive decline, is seen in the more severe forms. The eyes and ears can also be affected, potentially leading to vision and hearing problems.

Multiple body systems

Systemic involvement

Cellular impact

Mechanism at cellular level

Risks & severity

Hunter syndrome can present with a wide spectrum of severity. More severe forms typically involve significant developmental delay and a shorter life expectancy, often with onset in early childhood. Milder forms may have a later onset of symptoms and slower disease progression, with some individuals experiencing normal cognitive development and a longer life expectancy [PMID:20301662].

Complications such as airway obstruction, cardiac disease, and neurological decline can contribute to disease severity. The exact prevalence of Hunter syndrome is estimated to be around 1 in 100,000 to 170,000 males. As the condition primarily affects males, females are typically carriers and usually do not display symptoms.

Genetic causes

Hunter syndrome is caused by pathogenic variants in the IDS gene, which provides instructions for making the iduronate 2-sulfatase enzyme [PMID:20301662]. This enzyme is crucial for breaking down specific GAGs, dermatan sulphate and heparan sulphate, within lysosomes. When the IDS gene contains a pathogenic variant, the enzyme is either not produced correctly or is non-functional.

As a result, dermatan sulphate and heparan sulphate accumulate within cells, particularly in the lysosomes. This build-up disrupts normal cellular function and leads to the progressive damage observed in various tissues and organs throughout the body.

• IDS
  iduronate 2-sulfatase

Inheritance pattern

Hunter syndrome has an X-linked recessive (XLR) inheritance pattern. This means the IDS gene is located on the X chromosome, one of the two sex chromosomes. Females have two X chromosomes, while males have one X and one Y chromosome.

In X-linked recessive conditions, males are typically affected because they only have one X chromosome. If their single X chromosome carries a pathogenic variant in the IDS gene, they will develop the condition. Females with one affected X chromosome and one unaffected X chromosome are generally carriers; they usually do not show symptoms but can pass the pathogenic variant to their children. If a female carrier has a son, there is a 50% chance he will inherit the affected X chromosome and develop Hunter syndrome. If she has a daughter, there is a 50% chance the daughter will be a carrier.

Diagnosis & testing

The diagnosis of Hunter syndrome typically begins with a clinical suspicion based on the characteristic physical features and symptoms. Initial laboratory tests may involve urine screening for elevated levels of GAGs. However, elevated GAG levels can be found in other conditions, so further specific testing is required.

Confirmation of Hunter syndrome usually involves an enzyme assay, which measures the activity of the iduronate 2-sulfatase (IDS) enzyme in blood cells or skin fibroblasts. A significantly reduced or absent IDS enzyme activity level confirms the biochemical diagnosis. Genetic testing of the IDS gene is then performed to identify the specific pathogenic variant, confirming the diagnosis and allowing for family studies. This genetic testing falls under the NHS Genomic Medicine Service (GMS) pathways, with relevant R-codes for rare disease testing.

Management & lifestyle

While there is no cure for Hunter syndrome, management focuses on enzyme replacement therapy (ERT) and supportive care to alleviate symptoms and improve quality of life. ERT involves regular intravenous infusions of a manufactured version of the IDS enzyme, which helps to break down accumulated GAGs [PMID:33604085]. ERT can help manage many systemic symptoms but has limited ability to cross the blood-brain barrier, meaning neurological symptoms may not be significantly impacted.

Supportive care involves a multidisciplinary team of specialists, including paediatricians, geneticists, orthopaedic surgeons, cardiologists, and ear, nose, and throat (ENT) specialists. Treatments may include addressing skeletal problems, managing respiratory and cardiac issues, and providing developmental support. Regular monitoring of organ function is important to anticipate and manage complications. Genetic counselling is also a crucial part of the care pathway, offering information and support to families.

UK care pathway

In the UK, individuals suspected of having Hunter syndrome can be referred through their GP or other clinicians to a specialist for assessment. If a genetic condition is suspected, they may be referred to an NHS Clinical Genetics service. Genetic testing for rare diseases, including Hunter syndrome, is part of the NHS Genomic Medicine Service (GMS) national testing directory. A clinical geneticist or a genetic counsellor will discuss the testing options and implications with the family. The relevant NHS R-code for testing the IDS gene would be used by clinicians when requesting genomic testing.

Related conditions

Hunter syndrome is part of a larger group of conditions called mucopolysaccharidoses (MPS), all of which involve the accumulation of GAGs due to different enzyme deficiencies. Other MPS conditions, such as Hurler syndrome (MPS I) or Sanfilippo syndrome (MPS III), can share some similar physical features and symptoms but are caused by pathogenic variants in different genes and affect different enzymes. Differentiating between these conditions often requires specific enzyme assays and genetic testing.

Frequently asked questions