Continuing Education Activity

Mucopolysaccharidosis Type II (Hunter syndrome) is a rare X-linked recessive disorder. It has an early age of onset with clinical symptoms involving multiple organ systems. The severity of the disease depends on the phenotype. The severe phenotype has high morbidity and mortality. Early diagnostic evaluation should be carried out in suspected patients. This activity reviews the clinical picture, evaluation, and treatment of Hunter syndrome and highlights the role of the interprofessional team in evaluating and treating the patients.

Objectives:

• Identify the etiology of Hunter syndrome.
• Summarize the evaluation of Hunter syndrome.
• Describe the management options available for Hunter syndrome.

Introduction

Hunter syndrome is a genetically associated lysosomal storage disorder due to the deficiency of the iduronate 2-sulfatase enzyme (IDS). It is an X-linked recessive disorder and occurs predominantly in males. Iduronate 2-sulfatase (IDS) is responsible for the breakdown of large sugar molecules called glycosaminoglycans. Decreased activity of IDS results in intracellular and extracellular accumulation of heparan sulfate (HS) and dermatan sulfate (DS) in multiple organs of the body. Hunter syndrome presents during childhood.

Etiology

Mucopolysaccharidosis 2 (MPS II) results due to decreased activity of IDS. The enzyme is encoded by the IDS gene located on the long arm of chromosome X. The IDS gene consists of 9 exons, and over 600 different types of mutations have been reported to cause MPS II. The main mutations include point, frameshift, insertion, mutation at splice site, and minor and complete deletion of the IDS gene.[1] The genetic variations result in different phenotypes of the disease. The two main phenotypes are severe and attenuated.

Severe Phenotype

• Occurs in 60% of the affected individuals.[2] 
• Presents initially as hydrocephalus followed by behavioral changes and central nervous system (CNS) involvement.
• The child develops normally until 3 or 4 years of age when he develops behavioral changes, attention difficulties, speech delay, cognitive decline, and poor performance in school.
• The child also has hearing loss due to deformities in the middle ear, inner ear, and frequent ear infections.
• May be associated with episodes of epileptic seizures.[3][4]

Attenuated Phenotype

• Patients have less severe clinical symptoms without CNS involvement.
• Patients have normal cognitive and intellectual development.
• A few patients may report retinal degeneration and neurological symptoms at an advanced stage.[4]

Epidemiology

Hunter syndrome is a rare congenital metabolic disease. It was first reported in 1917 by a Canadian physician Charles Hunter in two brothers in a family. Both the brothers had short stature, inguinal hernia, macroglossia, enlarged skull, decreased hearing, coarse facial features, protruded abdomen with hepatosplenomegaly, umbilical hernia, and skeletal deformities. The younger brother had CNS symptoms, while the older brother did not have CNS involvement.[5] 

The estimated incidence is 1 in 162,000 live male births.[6] It is a sex-linked genetic disorder inherited in an X-linked recessive pattern. This disease manifests exclusively in males. A few sporadic cases have been reported in carrier females due to the chromosomal rearrangement or inactivation of the normal gene expressing the X-chromosome.

Pathophysiology

Mucopolysaccharides are long-chain sugar molecules consisting of repeating disaccharide units. They are the main component of the extracellular matrix of connective tissue throughout the body, including the skin, joints, heart valves, eyes, and tendons. The breakdown of mucopolysaccharides starts in lysosomes.

Iduronate 2-sulfatase in the first enzyme involved in the catabolism of heparan and dermatan sulfate. It cleaves the O-linked sulfate moiety from the mucopolysaccharides. Absent or decreased activity of this enzyme results in excessive abnormal accumulation of glycosaminoglycans, dermatan, and heparan sulfate in lysosomes. This causes hypertrophy and increases the number of lysosomes in the cells throughout the body. The increased accumulation of dermatan and heparan sulfate causes impaired cellular functions like cell adhesion, endocytosis, intracellular trafficking of different molecules, and intracellular ionic balance. It also promotes nitric oxide synthesis and inflammatory cascade, which have deleterious effects.[7][8]

There is a secondary accumulation of gangliosides (GM2 and GM3) in the brain. It causes mitochondrial dysfunction and storage of impaired proteins in neurons resulting in activation of microglia and neuronal death. It involves generalized grey and white matter in the brain.

History and Physical

Hunter syndrome has a wide clinical spectrum with the involvement of multiple organs.

Central Nervous System

The Hunter syndrome initially presents as hydrocephalus. Hydrocephalus results in an increased diameter of skull manifesting clinically as macrocephaly. It is followed by behavioral symptoms, attention difficulties, hyperactivity, and seizures. The decreased attention span is attributed to reduced volumes of the corpus callosum. Patients also have cognitive decline is school years with below-average school performance.[3] The language skills are delayed due to both hearing impairment and cognitive decline.

Oral Cavity

Patients have an abnormal number of teeth, enamel defects (in both milk and permanent teeth), morphological problems, malocclusion, and jaw defects. There is an increased incidence of dental caries, cysts, and abscesses. Patients should have an early follow-up with the dental surgeon prior to the development of the symptoms.[9]

Respiratory System

There is an increased amount of deposition of GAG in the respiratory tract, lymphoid organs, and tongue. It manifests as macroglossia, hypertrophied tonsils, adenoids, thickened vocal cords, and constriction of the trachea.[9] There is also excessive production of thick respiratory secretions and an exacerbated immune response in the respiratory tract. Patients present with recurrent sinusitis, middle ear infections, loud and noisy breathing. The enlarged tonsils, adenoids, and thick tracheal wall narrow the respiratory passage, resulting in breathing difficulties, obstructive sleep apnea, and frequent respiratory tract infections.[9] The structural deformities in the ribcage and vertebral column result in a restrictive pattern of breathing.

Cardiovascular System

Dermatan and heparan sulfate is an important and primary constituent of heart valves. In Hunter syndrome, an abnormal accumulation of these substances results in a thick valve. This results in valvular heart disease, mitral and aortic regurgitation, left ventricular hypertrophy, and hypertension. There is an overall decrease in cardiac efficiency. A survey in Hunter syndrome patients showed that 63% of patients have valvular heart disease.[10]

Gastrointestinal System

The progressive accumulation of GAG in the abdominal viscera causes hepatosplenomegaly. One of the first clinical signs of Hunter syndrome is protruded abdomen. Hepatosplenomegaly elevates intra-abdominal pressure, causing increased tension on the abdominal wall. This may result in an inguinal and umbilical hernia. Patients complain of chronic diarrhea with voluminous, mucoid stools.

Musculoskeletal System

Patients present with coarse facial features, short stature, joint contractures, joint stiffness, and myopathy. The skeletal manifestations in Hunter syndrome cause a rare congenital condition known as dysostosis multiplex. The failure of endochondral ossification due to GAG accumulation in the growth plate results in short stature. It also results in kyphosis, scoliosis, and structural deformities in the rib cage.[10] 

The structural deformities in the vertebral column compress spinal cord and nerve roots, which can cause muscle weakness, paralysis, urinary bladder, and bowel incontinence. Progressive accumulation of dermatan and heparan sulfate damages articular and hyaline cartilage at a joint. It causes joint pain, stiffness, decreased range of motion, and contractures.[11]

GAGs also accumulate in muscles and tendons, resulting in myopathy and death of muscle spindle cells. Both these factors produce stiffness and contractures at the hip, knee, ankle, shoulder, and wrist joints. It decreases the range of movement, grip, and muscle power of hand muscles. The contractures produce claw hand deformity. The accumulation of GAGs around tendons can compress the median nerve at the wrist joint, producing carpal tunnel syndrome.

Evaluation

The tests carried out for the diagnosis of Hunter syndrome are as follows:

• Urine and plasma GAG levels:

The screening test for mucopolysaccharidosis II is the measurement of the urinary and plasma GAG levels. The plasma levels of DM and HS are elevated in newborns with lysosomal storage diseases, including MPS I, II, III, and IV.[12] The urinary level of GAG has less clinical significance. It can be falsely negative in patients with less severe disease and attenuated phenotypes. The urine level of GAGs does not correlate with the severity of the disease. The level remains constant with the progression of the disease, and it can vary according to the status of renal function.[13]

• Iduronate sulfatase (IDS) levels:

The gold standard test for the diagnosis of Hunter syndrome is the IDS level. IDS levels are assessed in the culture of a number of cells, including leukocytes, fibroblasts, and dried blood cells. IDS levels can also be measured in free plasma or serum samples. In high-risk pregnancies, prenatal tests for MPS II can be done by checking IDS levels in chorionic villus samples. Most patients with a clinically severe form of the disease have a very low or undetectable level of the enzyme.[13] 

Levels of other lysosomal enzymes involved in the breakdown of mucopolysaccharides should be measured as well to rule out other lysosomal storage diseases.

• Genetic testing:

Molecular genetic testing is the confirmatory test for Hunter syndrome. It can provide a definitive diagnosis in patients with atypical clinical presentation or patients with the usual clinical presentation but equivocal lab tests. This disease is sporadically reported in a few girls. The molecular genetic test is performed in females with a clinical phenotype suggestive of MPS II.[14]

• Imaging:

A skeletal survey is performed in patients with a clinical picture suggestive of MPS II. Radiographic X-ray with characteristic findings in the skull, joints, the axial skeleton, and limbs are known as dysostosis multiplex. A few of these findings include a characteristic J shaped deformity in sella turcica, oar shaped ribs with scoliosis and kyphosis of the vertebral column, notching of the vertebral bodies, shortening of the diaphysis of the long bones, multiple epiphyseal ossification centers in long bones, hypoplastic and thickened tarsal, and carpal bones.[14]

Treatment / Management

The management of MPS II patients involves a multi-disciplinary team. A definite cure has not been established for Hunter syndrome yet. The aims of treatment are to replenish the deficient enzyme and treat the associated symptoms.

The two approved treatments for MPS II are enzyme replacement therapy and hematopoietic stem cell transplantation.

• Enzyme replacement therapy:

Recombinant IDS is administered to Hunter syndrome patients to normalize the levels of IDS enzyme in the body. The schedule of recombinant IDS administration to MPS II patients is once weekly via the intravenous route. The enzyme replacement therapy should be initiated before six years of age for maximum benefit with the treatment.[15]

Intravenous administration of recombinant IDS improves somatic symptoms. The ERT has been documented to result in significant improvement in one of the following somatic symptoms, including coarse facial features, joint contractures, joint mobility, and high frequency of respiratory tract infections.[16] Intravenous ERT has little or no beneficial effect on CNS symptoms. Recombinant IDS cannot cross the blood-brain barrier when administered intravenously. Currently, clinical trials are being carried out to assess the efficacy of recombinant IDS administered via the intrathecal route for the treatment of neurological symptoms. It has shown improvement in neurocognitive symptoms in patients who were administered ERT intrathecally as compared to controls. Though intrathecal ERT has shown promising improvement in neurocognitive symptoms in MPS II patients, there is also a risk of serious adverse effects with the administration of the drug with an indwelling intrathecal drug delivery device (IDDD).[17]

• Hematopoietic stem cell transplantation (HSCT):

Hematopoietic stem cell transplantation is considered a superior therapy compared to ERT. It is more cost-effective, as it is a one-time procedure. The stem cells cross the blood-brain barrier.[18] It has shown improvement in neurocognitive functions and decreases the rate of neurodegeneration seen by brain imaging. Ideally, HSCT should be done before the emergence of neurological symptoms. Many research studies have shown significant improvement in somatic symptoms with HSCT. These include improvement of hepatosplenomegaly back to normal and reduction in aortic and mitral valve thickening. The cardiac function, speech, elasticity, and mobility of joints are also improved.

• NSAIDs:

The accumulation of GAGs at articular cartilage, extracellular matrix, and tendons at joints initiate inflammatory cascade, which causes erosive dysplasia and degenerative changes at the articular cartilage. This results in osteoarthritis with structural deformation and a decreased range of movement at joints. The claw hand deformity in hands and osteoarthritic changes at hip and knee-joint decreases mobility and independence in performing tasks of patients. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the production of inflammatory mediators and prevent the associated degenerative joint changes.

• Gene therapy:

The emerging treatment for MPS II is gene therapy. It will be superior to both ERT and HSCT as it will be a one-time procedure with better safety and efficacy profile. Hunter syndrome is a genetic disease caused by a defect in a single gene on the X chromosome. Normal IDS gene can be delivered to patients through specific vectors via intravenous, intracisternal, or intrathecal routes.

Differential Diagnosis

• Mucopolysaccharidosis Type III (Sanfilippo syndrome)
• Mucopolysaccharidosis Type IS
• Mucopolysaccharidosis Type IH
• Mucopolysaccharidosis Type I H/S
• Mucopolysaccharidosis Type VII (Sly syndrome)

Prognosis

The prognosis of Hunter syndrome depends upon the phenotype of the disease. Patients with severe phenotype have high mortality. The majority of the patients die by the second decade of life due to pulmonary dysfunction, cardiac valvular abnormalities, or a combination of both. Patients with attenuated phenotype have a better life expectancy than the severe form. Patients have an average life expectancy until the fifth decade. The main cause of death in the attenuated phenotype is the same as the severe form.

Complications

Complications occur as sequelae of the progressive accumulation of GAG in different tissues and organs. The main complications are:

• Hydrocephalus
• Short stature
• Joint contractions at hip-joint causing the patient to be wheel-chair bound
• Airway obstruction due to thickened tracheal wall, hypertrophied tonsils, adenoids, and macroglossia
• Cardiac myopathy
• Mitral and aortic stenosis or regurgitation
• Hepatomegaly eventually causing deranged liver functions

Deterrence and Patient Education

Education should be given to patients regarding long-term monitoring. A regular follow-up should be done annually with the cardiologist to assess heart valves and cardiac function. Regular echocardiograms should be done to assess rhythm abnormalities, valvular stenosis, valvular regurgitation, and cardiomyopathy. The orthopedic surgeon will assess the joint function and severity of contractures. The patient may need physical therapy, intra-articular steroid injections, or surgery to relieve joint pain and immobility.

The patient’s cognitive learning and psychological status should be monitored closely. MPS II patients are at increased risk of suffering from depression and social withdrawal in the teenage years. Education and counseling about the psychological clinical symptoms and learning difficulties experienced by the MPS II patients should be given to the parents. Counseling, medication management, special educational classes, Individualized Education Program (IEP), classroom accommodations, and behavioral therapy should be offered to address hyperactivity, learning disability, and mood disorders. Psychologists should provide support to both patient and their families.

Pearls and Other Issues

Here are some important points to take note of:

• The first clinical symptoms to appear in MPS II are somatic symptoms. The parents of the patients first notice coarseness of facial features, delayed development of motor and cognitive milestones, short stature, and abdominal distention.
• The two approved treatment ERT and HSCT are both maximally effective in relieving somatic symptoms when administered to patients earlier in their clinical course. Both treatments are ineffective in improving musculoskeletal symptoms if they are given after the appearance of skeletal symptoms.
• HSCT is more effective than ERT for the treatment of neurological symptoms as it can cross the blood-brain barrier. The HSCT is minimally effective in the treatment of cognitive decline if the treatment is initiated after the onset of symptoms.
• It is important to initiate treatment early in the disease course, as both ERT and HSCT become less effective at later stages of the disease. There is a need to make more effort in the early diagnosis of the disease. There is a need to provide cost-effective and easily available diagnostic facilities for newborn screening of MPS II.

Enhancing Healthcare Team Outcomes

The management of MPS II patients requires a holistic approach. A team of specialists including pediatrician, neurologist, orthopedic surgeon, otolaryngologist, cardiologist, speech therapist, physiotherapist, pulmonologist, and child psychiatrist treats the wide spectrum of clinical symptoms of patient's with Hunter disease. Surgical treatment might be required for joint mobility and cardiac valves replacement. Patients should have a regular follow-up with an otolaryngologist. Recurrent middle ear infections may require placement of ear tubes. MPS II patients usually undergo adenoidectomy and tonsillectomy to relieve airway narrowing. Patients require oxygen supplementation and positive airway pressure for sleep apnea in severe cases.

Primary care physicians and specialists should have good communication to improve patient outcomes with this condition. Each specialist should follow up with the patient regularly for early diagnosis and correction of relevant complications. Geneticists should provide genetic counseling to the patient and their families. Interdisciplinary collaboration is pivotal to good patient outcomes in MPS II patients.