Hunters Syndrome

1 What is Hunters Syndrome?

Hunter syndrome, also known as mucopolysaccharidosis II, is a rare inborn error of metabolism characterized by inadequate production of an enzyme known as iduronate sulfatase, which is needed to break down complex sugars produced in the body.

Symptoms include growth delay, joint stiffness, and coarsening of facial features. In severe cases, patients experience respiratory and cardiac problems, enlargement of the liver and spleen, and neurological deficits. The disorder can lead to premature death in severe cases.

Hunter syndrome is one of a group of hereditary metabolic diseases known as the mucopolysaccharidoses (MPS), which in turn are part of a group known as lysosomal storage disorders. Lysosomes function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular nutrients, such as certain carbohydrates and fats.

In individuals with MPS disorders, including Hunter syndrome, deficiency or improper functioning of lysosomal enzymes leads to an abnormal accumulation of certain complex carbohydrates in cells within various tissues, such as the skeleton, joints, brain, spinal cord, heart, spleen, or liver.

Initial symptoms and findings associated with Hunter syndrome usually become apparent in children from two to four years of age. Such abnormalities may include progressive growth delays, resulting in short stature; joint stiffness, with associated restriction of movements; and coarsening of facial features, including thickening of the lips, tongue, and nostrils.

Affected children may also have an abnormally large head (macrocephaly), a short neck and broad chest, delayed tooth eruption, progressive hearing loss, and enlargement of the liver and spleen (hepatosplenomegaly).

Two relatively distinct clinical forms of Hunter syndrome have been recognized. In the late-onset, mild form of the disease (MPS IIB), intelligence may be normal or only slightly impaired. However, in the early-onset, more severe form (MPS IIA), profound mental retardation may be apparent by late childhood. In addition, slower disease progression tends to occur in those with the mild form of the disorder.

Hunter syndrome is inherited as an X-linked recessive trait. Mild and severe forms of the disorder result from changes (mutations) of a gene (i.e., IDS gene) that regulates production of the iduronate sulfatase enzyme. The IDS gene is located on the long arm (q) of chromosome X (Xq28).

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2 Symptoms

The symptoms of Hunter syndrome (MPS II) are generally not apparent at birth, but usually start to become noticeable after the first year of life.

The age of onset and severity of Mucopolysaccharidosis type II (MPS II) differ depending on the form. Signs of severe MPS II usually begin between ages two and four.

As the buildup of GAG continues throughout the cells of the body, signs of Hunter syndrome become more visible.

Early symptoms of Hunter syndrome:

  • Inguinal hernia
  • Ear infections
  • Runny nose
  • Difficulty breathing
  • Heart murmur

MPS II has a wide range of symptoms that vary in severity.

They have:

  • A distinctive coarse (puffy) facial features (full lips, large rounded cheeks, broad nose, enlarged tongue)
  • Large head (macrocephaly)
  • Enlarged/Swollen abdomen (due to enlarged liver and spleen)
  • Soft out-pouching around belly-button (umbilical hernia) or lower abdomen (inguinal hernia)
  • Breathing problems while sleeping
  • Limited lung capacity
  • Short pauses in breathing during sleep (sleep apnea)
  • Frequent upper respiratory infections
  • Frequent ear infections
  • Enlargement of vocal cords causing deep, hoarse voice
  • Cardiac/vascular heart disease
  • Hearing loss
  • Speech loss
  • Poor vision
  • Short stature
  • Joint stiffness (contractures) limited range of motion
  • Carpel Tunnel Syndrome
  • Severe intellectual disability
  • Developmental delays
  • Loss of basic skills, functions, and intelligence (developmental regression)
  • Seizures

3 Causes

Hunters syndrome is caused by a lack of the enzyme iduronate sulfatase. Without this enzyme, chains of sugar molecules build up in various body tissues, causing damage.

Hunter syndrome is an inherited condition, which means it is passed down through families. The affected gene is on the X chromosome. Therefore, boys are most often affected. Their mothers do not have symptoms of the disease, but they carry a non-working copy of the gene.

The early-onset, severe form of the disease begins shortly after age 2. A late-onset, mild form causes less severe symptoms to appear later in life.

The I2S enzyme that is deficient in Hunter syndrome is required for the break down and recycling of specific mucopolysaccharides called glycosaminoglycans or GAGs. A deficiency in this enzyme leads to a buildup of GAGs in cells throughout the body, which eventually interferes with the function of various tissues and organs.

As the cellular GAG accumulation continues over time, the symptoms and complication associated with Hunter syndrome gradually worsen and become more noticeable.

4 Making a Diagnosis

A diagnosis of Hunter syndrome is usually suspected in young people who display signs and symptoms of the condition.

Characteristic changes in the facial features provide the main initial warning that a child may have Hunter syndrome. In most cases, the diagnosis is usually made at around 2 to 4 years of age. Once a diagnosis is suspected, further laboratory tests are arranged by the physician to confirm the diagnosis.

Hunter syndrome is a lysosomal storage disease that is inherited in an X-linked recessive manner. The condition therefore mainly affects male children.

The disease is caused by a deficiency in an enzyme called iduronate-2-sulfatase (I2S), which is normally required to break down and replace mucopolysaccharides or glycosaminoglycans (GAGs).

In particular, the I2S enzyme is responsible for the breakdown of dermatan sulfate and heparan sulphate. However, deficiency or absence of this enzyme in people with Hunter syndrome means GAGs accumulate in cells throughout the body, particularly in tissues where dermatan sulfate and heparan sulfate are abundant.

As increasing amounts of GAGs collect in cells, the function of organs and cells is increasingly compromised, leading to more severe symptoms as the disease progresses.

Further tests that are carried out to confirm the diagnosis include blood, urine or tissue samples.

First, a general screening test to check for the presence of a mucopolysaccharide (MPS) disorder is performed using a urine sample. A definitive diagnosis can then be made by checking the I2S enzyme level, which can be determined using blood, white blood cells or a skin biopsy. Analysis of the I2S gene may also be performed to determine the severity of the condition.

A diagnosis can also be made before a baby is born, using prenatal testing. Here, the fluid that surrounds the baby while it is in the womb called the amniotic fluid can be tested for levels of I2S activity using a process called amniocentesis.

Alternatively, the activity of the enzyme can be checked using a tissue sample taken from the placenta, which is referred to as chorionic villus sampling.

In some cases, a diagnosis of Hunter syndrome may come to light due to the presence of another health issue. A child may have pneumonia, for example, and a chest X-ray may happen to show ribs or vertebrae that are abnormally shaped, which is a symptom of the condition.

However, due to slow progression of the disease and the number of conditions the syndrome shares clinical features with, a definitive diagnosis can take some time to reach.

5 Treatment

There is no cure for the syndrome and treatment is aimed at managing the condition so as to ease symptoms and provide some relief for the sufferer. This is referred to as palliative treatment and the objective is to minimize negative effects on bodily functions as the condition worsens.

Some emerging treatments have also been shown to help slow disease progression and decrease the severity of the syndrome.

Some of these treatments include:

  • Bone marrow transplantation – In milder cases of Hunter syndrome, bone marrow transplantation may be performed to provide a new source of the deficient iduronate-2-sulfatase. Bone marrow is taken from the hip of a healthy donor who matches the patient’s blood and tissue type.

The bone marrow is transplanted through intravenous injection. This transplantation can help improve respiratory problems and the function of major organs such as the heart, liver and spleen. Mobility may also be improved and mental regression prevented.

However, the treatment does not improve problems associated with vision or the bones.

  • Enzyme therapy – This therapy involves the use of synthetic enzymes to restore levels of the deficient iduronate-2-sulfatase enzyme. The therapy is called idursulfase or Elaprase. The therapy is administered intravenously once a week and may delay or prevent some symptoms of this syndrome developing if administered early enough in the disease course.
  • Gene therapy – Researchers are currently investigating the possibility of replacing the chromosome responsible for iduronate-2-sulfatase, which technically could cure Hunter syndrome.

6 Prevention

As hunter syndrome is a genetic disorder it can't be prevented.

Preimplantation genetic diagnosis (PGD) enables the identification of affected embryos prior to implantation and is a reliable method to prevent pregnancy of children affected with Hunter syndrome.

7 Risks and Complications

There are several complications associated with hunters syndrome.

People with the early-onset (severe) form usually live for 10 to 20 years. People with the late-onset (mild) form usually live 20 to 60 years.

Possible Complications

These complications may occur:

  • Airway obstruction
  • Carpal tunnel syndrome
  • Hearing loss that gets worse over time
  • Loss of ability to complete daily living activities
  • Joint stiffness that leads to contractures
  • Mental function that gets worse over time