Hunter's syndrome

Hunter syndrome is a genetic defect in intracellular carbohydrate (glycosaminoglycan) catabolism that is transmitted to males by X-linked recessive inheritance and causes skeletal and organ abnormalities and mental retardation.

This syndrome is also called mucopolysaccharidosis type II and is classified as a lysosomal storage disease. According to ICD-10, this congenital enzymopathy is classified as a metabolic disorder and has the code E76.1.

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Epidemiology

According to foreign experts, there are only about two thousand living patients suffering from Hunter syndrome worldwide. 500 of them live in the USA, 70 in Korea, 20 in the Philippines, 6 in Ireland. One living patient was counted in Chile, Pakistan, India, Palestine, Saudi Arabia, Iran and New Zealand.

A study of the incidence among British men found that the rate was approximately one case in 130,000 live-born boys.

According to other sources, in European countries Hunter syndrome is detected in one boy out of every 140-156 thousand live-born male children.

In female children, sporadic cases of this disease are extremely rare.

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Causes Hunter's syndrome

Geneticists have established that the causes of Hunter syndrome are mutations in the IDS gene (located on the X chromosome, locus Xq28), which encodes the I2S enzyme.

Mucopolysaccharides, also known as glycosaminoglycans (GAGs), are the carbohydrate component of macromolecules of complex proteins called proteoglycans, which fill the spaces between cells and form the matrix. The matrix surrounds the cells and is essentially the “framework” of tissues. But like many other biochemical components of the body, proteoglycans are subject to metabolism. In particular, two types of GAG molecules, dermatan sulfate and heparan sulfate, must be metabolized by the enzyme I2S, which is present in their composition as sulfated alpha-L-iduronic acid.

Deficiency of this enzyme in Hunter syndrome leads to incomplete hydrolysis of dermatan and heparan sulfate, and they accumulate in the lysosomes of cells of almost all tissues (skin, cartilage, tendons, intervertebral discs, bones, vessel walls, etc.). Such a violation of glycosaminoglycan catabolism entails pathological changes in the structure of tissues, and this, in turn, causes the formation of anatomical defects and functional disorders of various systems and organs.

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Risk factors

Obvious risk factors for inheritance of mucopolysaccharidosis type II by a male child: the presence of a defective gene on the X chromosome of the mother, who is healthy (she has a second X chromosome that compensates for the gene mutation), but is a carrier of the altered IDS gene.

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Pathogenesis

While studying the pathogenesis of Hunter syndrome, endocrinologists have identified in patients with this disease a deficiency of one of the intracellular enzymes of the lysosomal hydrolase class – iduronate sulfatase (I2S), which ensures the process of breaking down mucopolysaccharides.

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Symptoms Hunter's syndrome

The rate at which the disease progresses from the initial stage to clinically severe form varies widely, and the symptoms of Hunter syndrome – that is, their presence and degree of manifestation – differ in each specific case.

This congenital disease is a progressive pathology, even when the diagnosis is formulated as a weakened or mild form. It is obvious that the form of manifestation of mucopolysaccharidosis type II depends on the nature of genetic mutations and determines both the age of manifestation of the disease and the severity of the pathology. Signs of a severe form of Hunter syndrome (type A) are noted on average at the age of two and a half years and intensify very quickly. In patients with a weakened form (type B), symptoms may appear at five to eight years (on average, according to statistics, at 4.5 years) or even in adolescence.

It should be borne in mind that the first signs of Hunter syndrome do not manifest themselves at the birth of the child, but begin to become noticeable after the first year of life. These symptoms are non-specific - frequent upper respiratory tract infections, ear inflammation, inguinal or umbilical hernias, so it is difficult to make a diagnosis right away.

As the accumulation of glycosaminoglycans in cells of various tissues continues, clinical symptoms of Hunter syndrome appear, such as:

• enlargement and coarsening of facial features due to multiple dysostoses (full lips, large round cheeks, wide nose with a flattened bridge, thickened tongue);
• large head (macrocephaly);
• shortening of the cervical spine;
• increased abdominal size;
• low, hoarse voice (due to expansion of the vocal cords);
• stridor (wheezing) breathing;
• apnea (stopping breathing during sleep);
• incorrect formation of the dental row (large interdental spaces, thickened gums);
• thickening and decreased elasticity of the skin;
• ivory-colored papular skin lesions in a mesh-like pattern between the shoulder blades on the back, on the sides of the chest, on the arms and legs (these signs are almost pathognomonic for Hunter syndrome);
• progressive hearing loss;
• enlargement of the liver and spleen (hepatosplenomegaly);
• growth retardation (especially noticeable after three years);
• limitation of joint mobility leading to ataxia (flexion contractures due to desostoses of the multiplex and stresses in the structure of cartilage and tendons);
• mental retardation;
• mental disorders in the form of attention deficit, attacks of aggression and anxiety, sleep disorders, compulsive disorders, etc.

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Complications and consequences

The consequences and complications of further accumulation of GAG in lysosomes of cells affect:

• cardiac functions (due to thickening of the valves and myocardium, cardiomyopathy and valvular anomalies develop);
• respiratory tract (development of obstruction due to accumulation of heparan and dermatan sulfate in the tissues of the trachea);
• hearing (complete deafness);
• musculoskeletal system (spinal deformity, dysplasia of the pelvis or femoral head, wrist bones, early osteoarthritis, problems with movement);
• intelligence and cognitive functions (with irreversible regression of mental development);
• Central nervous system and psyche (behavioral problems).

In Hunter syndrome type B, one organ may be pathologically altered, while intellectual abilities are almost unaffected: most often, verbal skills and learning to read may be impaired. The average age of death in mild cases of the disease is 20-22 years, but life expectancy can be about 40 years or more.

The severe form of the syndrome leads to earlier mortality (12-15 years) as a result of cardiorespiratory complications.

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Diagnostics Hunter's syndrome

Today, the diagnosis of Hunter syndrome includes:

• examination and identification of visible signs of disease;
• tests: urine for the level of glycosaminoglycans and blood for the activity of the I2S enzyme;
• Skin biopsy for the presence of iduronate sulfatase in fibroblasts and determination of its functional adequacy.

Genetic analysis (prenatal diagnostics) is performed in cases of family history of this syndrome, for which a puncture of the amniotic sac is performed and the enzymatic activity of I2S in the amniotic fluid is examined. There are also methods for determining the activity of this enzyme in the umbilical cord blood of the fetus or in the tissue of the chorionic villi (by cordocentesis and biopsy).

Instrumental diagnostics are carried out:

• X-ray of all bones (to determine ossification anomalies and bone deformities);
• Ultrasound of abdominal organs;
• spirometry;
• ECG (to detect cardiac abnormalities);
• EEG, CT and MRI of the brain (to detect cerebral changes).

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Differential diagnosis

Differential diagnostics aims to distinguish Hunter syndrome from other types of mucopolysaccharidoses (Hurler, Scheie, Hurler syndromes, etc.), lipochondrodystrophy (gargoylism), multiple sulfatase deficiency (mucosulfatidosis), etc.

Treatment Hunter's syndrome

Because of the congenital nature of the pathology, treatment of Hunter syndrome focuses on palliative care - to reduce the effects of deterioration of many body functions. That is, supportive and symptomatic treatment often focuses on cardiovascular complications and problems with the respiratory tract. For example, surgical treatment in the form of removal of tonsils and adenoids can open the child's airways and help relieve respiratory complications. However, as the disease progresses, the tissues do not return to normal, so the problems can return.

For a long time, the most effective approach was a bone marrow transplant or hematopoietic stem cell transplant as a new source of the missing I2S enzyme. Bone marrow transplant can improve or stop the progression of some physical symptoms in the early stages of the disease, but it is useless for progressive cognitive dysfunction. Therefore, such operations are rarely performed in Hunter syndrome.

The current focus is on enzyme replacement therapy, i.e. long-term (and in this case lifelong) administration of the exogenous enzyme I2S. The main drug for this syndrome is Elaprase, which contains the recombinant lysosomal enzyme idursulfase, similar to the endogenous one. This drug passed clinical trials in 2006 and was approved by the FDA.

For pediatric and adolescent patients, Elaprazu should be administered intravenously by infusion once a week at a rate of 0.5 mg per kilogram of body weight. Possible side effects include skin reactions, headaches and dizziness, tremors, hot flashes to the head, blood pressure surges, heart rate disturbances, shortness of breath, bronchial spasms, joint and abdominal pain, soft tissue swelling, etc.

An important part of Hunter syndrome treatment is physiotherapy: a properly selected set of exercise therapy helps maintain joint mobility in the early stages of the disease, and electrophoresis and magnetic therapy help reduce the intensity of joint pain. Symptomatic agents and vitamins are also prescribed to support the functioning of the cardiovascular system, lungs, liver, intestines, etc.

Prevention

Prevention of congenital syndromes, which include mucopolysaccharidoses, is possible only through prenatal diagnostics, as well as genetic testing of future parents when planning a pregnancy and counseling families that already have a sick child.

For some children with Hunter syndrome, early diagnosis may prevent or delay the development of serious consequences of the pathology, although even enzyme replacement therapy cannot cure the genetic defect.

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Forecast

Although treatment can increase the life expectancy and improve the quality of life of children with this pathology, patients with severe Hunter syndrome die before reaching the age of 15. And in the absence of mental symptoms, such patients with severe disabilities can live twice as long.