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).
Two types of Hunter syndrome (MPS II) have been recognized, mild and severe, both with the same enzymatic deficiency, iduronate sulfatase. The severe form of Hunter syndrome has features similar to Hurler syndrome except for the lack of corneal clouding and slower progression of physical involvement and mental retardation.
In the severe form of this disorder, physical and mental development reach a peak at 2-4 years of age with subsequent deterioration. Recurrent urinary and upper respiratory infections, a chronic runny nose, liver enlargement, joint stiffness and growth failure commonly occur with the severe from of Hunter syndrome. Coarsening of the facial features with thickening of the nostrils, lips and tongue usually occur between 2 and 4 years of age. Hydrocephalus is commonly found in this form of Hunter syndrome after 4 years of age. (For more information, choose “hydrocephalus” as your search term in the Rare Disease Database.) Thick skin, short neck, widely spaced teeth, and hearing loss of varying degree are also commonly present. Nodular skin lesions on the arm or the posterior chest wall, extra- high arched feet (pes cavus) and diarrhea also may occur.
In the mild form of Hunter syndrome, mental function is usually normal and physical deterioration is greatly reduced compared to the severe form. Complications of the mild form of the disorder may include heart, coronary and valvular disease, hearing impairment, reduced circulation in the hands due to compression of veins in the wrist (carpal tunnel syndrome), and joint stiffness which can result in loss of hand function.
Hunter syndrome is transmitted as an X-linked recessive trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes for that condition, one received from the father and one from the mother.
X-linked recessive disorders are conditions that are coded on the X chromosome. Females have two X chromosomes, but males have one X chromosome and one Y chromosome. Therefore, in females, disease traits on the X chromosome may be “masked” by the normal gene on the other X chromosome (random X chromosome inactivation). Since males only have one X chromosome, if they inherit a gene for a disease present on the X, it will be expressed. Men with X-linked disorders transmit the gene to all their daughters, who are carriers, but not to their sons. Women who are carriers of an X-linked disorder have a 50 percent risk of transmitting the carrier condition to their daughters and a 50 percent risk of transmitting the disease to their sons. Thus, in summary, because Hunter syndrome is inherited as an X-linked recessive trait, the disorder is usually fully expressed in males only.
The gene responsible for Hunter syndrome, known as the iduronate sulfatase (IDS) gene, has been located on the long arm of chromosome X (Xq28). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q”. Chromosomes are further subdivided into bands that are numbered.
In many individuals with Hunter syndrome, the disorder results from relatively small changes (e.g., certain missense or nonsense mutations) within the IDS gene or abnormal loss (deletion) or insertion of genetic material (e.g., single-base deletions or insertions) affecting its normal functioning. Less commonly, Hunter syndrome may result from complete absence or major structural changes of the IDS gene. According to researchers, different mutations or structural changes of the gene account for the wide variability of symptoms and findings associated with the disorder (i.e., mild versus severe disease).
The IDS gene regulates (encodes for) the production of the lysosomal enzyme iduronate sulfatase. In individuals with the mild or severe form of Hunter syndrome, deficiency of the enzyme results in an abnormal accumulation of certain complex carbohydrates (glycosaminoglycans [mucopolysaccharides]) within the cells of various tissues of the body.
Hunter Syndrome affects only males, with symptoms becoming apparent at approximately 2-4 years of age. The disorder occurs in 1 out of 100,000 live births.
An enzyme replacement therapy, idursulfase (Elaprase), has been approved (July 2006) by the U.S. Food and Drug Administration (FDA) as a treatment for Hunter syndrome. This drug is sponsored by Shire Human Genetic Therapies Inc., a British company that acquired the original developer of the drug, TKT Therapeutics, in 2005. For information on Elaprase, contact Shire at (800) 536-7878 or firstname.lastname@example.org.
Other treatment of Hunter syndrome is symptomatic and supportive. Hernias and joint contractures may be corrected by surgery. Surgical implantation of a ventricular shunt may be used to treat possible hydrocephalus. Hearing devices may be prescribed to treat hearing loss. Physical therapy, medical and genetic counseling services may be helpful to patients and families. Prenatal diagnosis is now possible for this disorder.
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Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number 309900; 7/23/99. Available at: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?309900.
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