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Mucopolysaccharidosis Type II

Synonyms: Hunter Syndrome, I2S Deficiency, Iduronate 2-Sulfatase Deficiency, MPS II
, MD, PhD
Department of Pediatrics
University of Padova
Padua, Italy

Initial Posting: ; Last Update: February 22, 2011.

Summary

Disease characteristics. Mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) is an X-linked multisystem disorder characterized by glycosaminoglycans (GAG) accumulation. The vast majority of affected individuals are male; on rare occasion carrier females manifest findings. Age of onset, disease severity, and rate of progression vary significantly. In those with severe disease, CNS involvement (manifest primarily by progressive cognitive deterioration), progressive airway disease, and cardiac disease usually result in death in the first or second decade of life. In those with attenuated disease, the CNS is not (or is minimally) affected, although the effect of GAG accumulation on other organ systems may be just as severe as in those who have progressive cognitive decline. Survival into the early adult years with normal intelligence is common in the attenuated form of the disease. Additional findings in both forms of MPS II include: short stature; macrocephaly with or without communicating hydrocephalus; macroglossia; hoarse voice; conductive and sensorineural hearing loss; hepatomegaly and/or splenomegaly; dysostosis multiplex and joint contractures including ankylosis of the temporomandibular joint; spinal stenosis; and carpal tunnel syndrome.

Diagnosis/testing. Urine GAGs and skeletal survey can establish the presence of an MPS condition but are not specific to MPS II. The gold standard for diagnosis of MPS II in a male proband is deficient iduronate sulfatase (I2S) enzyme activity in white cells, fibroblasts or plasma in the presence of normal activity of at least one other sulfatase. Molecular genetic testing of IDS, the only gene in which mutation is known to be associated with MPS II, is used to confirm the diagnosis in a male proband with an unusual phenotype or a phenotype that does not match the results of GAG testing.

Management. Treatment of manifestations: Interventions commonly include: developmental, occupational, and physical therapy; shunting for hydrocephalus; tonsillectomy and adenoidectomy; positive pressure ventilation (CPAP or tracheostomy); carpal tunnel release; cardiac valve replacement; inguinal hernia repair.

Prevention of primary manifestations: Enzyme replacement therapy (ERT) with idursulfase (Elaprase®), a recombinant form of human iduronate 2-sulfatase called idursulfase, has recently been approved in the United States and the European Union. Because only individuals with the attenuated form of the disease were studied, no information is yet available on the outcome of ERT in children younger than age five years or individuals with severe pulmonary compromise or severe CNS disease. Elaprase® does not cross the blood-brain barrier; thus, no effect on CNS disease is anticipated.

Prevention of secondary complications: Attention to risks associated with general anesthesia.

Surveillance: Depends on organ system and disease severity and usually includes annual: cardiac evaluation and echocardiogram; pulmonary evaluation including pulmonary function testing; audiogram; eye examination; developmental assessment; neurologic examination. Additional studies may include: sleep study for obstructive apnea; nerve conduction velocity (NCV) to assess for carpal tunnel syndrome; evaluation for hydrocephalus; orthopedic evaluation to monitor hip disease.

Evaluation of relatives at risk: Whether the potential benefits of early initiation of ERT justify early diagnosis either by newborn screening or by testing of at-risk male relatives is at present unclear. Clinical experience suggests that early diagnosis of at-risk males allows initiation of ERT before the onset of irreversible changes and often before significant disease progression.

Other: Although hematopoietic stem cell transplantation (HSCT) (using umbilical cord blood or bone marrow) could provide sufficient enzyme activity to slow or stop the progression of the disease, no controlled clinical studies have been conducted in MPSII.

Genetic counseling. MPS II is inherited in an X-linked manner. The risk to sibs depends on the carrier status of the mother. If the mother of the proband has the disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Males who inherit the mutation will be affected; females who inherit the mutation will be carriers. Germline mosaicism has been observed. Affected males pass the disease-causing mutation to all of their daughters and none of their sons. Carrier testing for at-risk female relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutation in the family is known.

Diagnosis

Clinical Diagnosis

The diagnosis of mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) cannot be made on clinical findings alone. The physical findings vary widely, depending on disease severity.

  • The diagnosis is often suspected in males age 18 months to four years with short stature, hepatosplenomegaly, joint contractures, and coarse facies; subtle early signs and symptoms such as frequent ear/sinus infections and umbilical hernia are often present.
  • A skeletal survey may show skeletal anomalies known collectively as dysostosis multiplex; however, these findings may not be present in early life and are not specific to MPS II.

Testing

Urine glycosaminoglycans (GAGs). GAG quantitative and qualitative analysis is useful as a preliminary test to help establish that the person has an MPS condition. In MPS II, GAG analysis shows large concentrations of the GAGs dermatan sulfate and heparan sulfate. The profile is similar to that seen in MPS I.

Recently, a method based on the use of electrospray ionization–tandem mass spectrometry, has been proposed for the diagnosis of MPSII [Nielsen et al 2010].

Iduronate 2-sulfatase (I2S) enzyme activity. Confirmation of the diagnosis of MPS II is made by demonstrating deficient I2S enzyme activity in leukocytes, fibroblasts, or plasma. Most affected males have no detectable activity using the artificial substrate.

Absence or reduced levels of I2S enzyme activity decreases the amount of the sulfate moiety released from the glycosaminoglycans (GAGs) dermatan sulfate and heparan sulfate during their degradation.

Note: Documentation of normal enzymatic activity of at least one other sulfatase is critical, as low levels of I2S enzyme activity are present in multiple sulfatase deficiency, which can share some common clinical features with MPS II.

Carrier testing. Measurement of I2S enzyme activity is not reliable for detection of carrier females as a carrier may have normal I2S enzyme activity resulting from X-chromosome inactivation that may be non-random.

Molecular Genetic Testing

Gene. IDS is the only gene in which mutations are known to cause MPS II. A pseudogene (IDS2) is located 90 kb telomeric to IDS.

Clinical testing. Three general types of IDS mutations are observed in persons with MPS II: mutations within the gene, exonic and whole-gene deletions, and gross alterations resulting from recombination with the nearby IDS pseudogene, IDS2.

  • Sequence analysis of the entire IDS coding region detects 82% of mutations in both males and females [Froissart et al 2007]. Single nucleotide changes and splicing mutations account for 65% of all mutations. Small (i.e., intra-exonic) deletions and insertions account for 17% of all mutations
    Note: (1) Sequence analysis may be reported as normal in individuals (males or females) who have the most common pseudogene recombination. Therefore, Southern blot analysis should also be performed; however, this analysis could be preceded by a PCR-based method developed by Lualdi et al [2005] that can verify the presence of the most common types of recombination by analyzing the genomic exchange regions involved in the rearrangements. (2) Lack of amplification by PCR prior to sequence analysis can suggest a putative exonic or whole-gene deletion in males (but not females); confirmation may require additional testing of a male by deletion/duplication analysis. (3) Sequence analysis of cDNA allows the study of the effect of promoter mutations and intronic mutations affecting splicing that would be missed by other methods. This analysis is accurate in males, but may not be accurate in females.
  • Deletion/duplication analysis. A variety of methods may be used to detect the large (exonic or whole-gene) deletions in males and females that account for 9% of mutations [Froissart et al 2007] (Table 1).
  • Southern blot analysis is used to detect complex rearrangements resulting from recombination with the pseudogene or from other types of processes and accounting for 9% of all mutations [Froissart et al 2007]. These rearrangements could also be detected by deletion/duplication analysis if they are associated with a partial deletion or duplication of IDS. Different single nucleotide polymorphism (SNP) patterns of IDS and its pseudogene, IDS2 could help in the rearrangement characterization. Prior to performing Southern blot analysis, preliminary analysis with the PCR-based method of Lualdi et al [2005] could be performed to exclude the most common types of recombination

Table 1. Summary of Molecular Genetic Testing Used in MPS II (Hunter Syndrome)

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
MalesHeterozygous Females
IDSSequence analysisSequence variants 291% 3, 482% 5
Deletion/duplication analysis 6Deletion/duplication of one or more exons or the whole gene 9%9%

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Lack of amplification by PCRs prior to sequence analysis can suggest a putative deletion of one or more exons or the entire X-linked gene in a male; confirmation may require additional testing by deletion/duplication analysis.

4. Includes the mutation detection frequency using deletion/duplication analysis

5. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband

  • Urine GAGs and skeletal survey are useful in establishing the presence ofan MPS condition, but are not specific to MPS II.
  • The gold standard for diagnosis of MPS II in a male proband is assay of iduronate sulfatase (I2S) enzyme activity in white cells, fibroblasts, or plasma.
  • Molecular genetic testing of IDS to confirm the diagnosis in a male proband may be useful in persons with an unusual phenotype or a phenotype that does not match the results of GAG testing.

Carrier testing of at-risk relatives requires prior identification of the disease-causing mutation in the family.

Identification of female carriers requires one of the following:

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) has multisystem involvement with significant variability in both age of onset and rate of progression.

CNS involvement, the most significant feature in the group of children often labeled with "severe" disease, manifests primarily by progressive cognitive deterioration. Such cognitive decline, combined with the progressive airway and cardiac disease, usually results in death in the first or second decade of life.

In individuals with the attenuated form of the disease, the CNS is minimally affected, if at all, yet the effect of GAG accumulation on other organ systems may be just as severe as in those who have progressive cognitive decline. Survival into the early adult years with normal intelligence is common in this group.

The severe CNS phenotype may be more than twice as prevalent as the attenuated form of the disease; however, accurate prevalence rates are not available. Eighty-four percent of affected males have some form of neurologic involvement. Cardiovascular involvement was reported in 82% of affected individuals [Wraith et al 2008].

GAG accumulation in virtually all organs occurs in MPS II, but specific body systems are more affected than others.

The clinical presentations of the organ systems most severely affected in are the following:

General. The appearance of newborns with MPS II is normal. Coarsening of facial features — the result of macroglossia, prominent supraorbital ridges, a broad nose, a broad nasal bridge, and deposition of GAG in the soft tissues of the face resulting in large rounded cheeks and thick lips — generally manifests between ages 18 months and four years in the severe form and about two years later for those with the attenuated form.

Growth in the first five years of life is above average for most boys with MPS II; after that growth lags and short stature is the norm. Macrocephaly is universal.

Eye. In contrast to MPS I, corneal clouding is not a typical feature of MPS II. However, discrete corneal lesions that do not affect vision may be discovered by slit-lamp examination. Optic nerve head swelling is present in about 20% of affected individuals and optic atrophy was found in approximately 11% of affected individuals [Collins et al 1990, Ashworth et al 2006]. Retinopathy has been reported; electroretinography (ERG) may reveal retinal dysfunction, and visual field loss can occur. Initially, rod-mediated responses are more severely affected than cone-mediated responses [Caruso et al 1986]. Progressive reduction in ERG amplitude suggests a deterioration in retinal function [Leung et al 1971].

However, signs and symptoms do not necessarily correlate with ERG change, as often only minimal changes are observed in the RPE despite significant ERG changes [Ashworth et al 2006].

Ear, nose, throat. Common oral findings in boys with MPS II include macroglossia, hypertrophic adenoids and tonsils, and ankylosis of the temporomandibular joint, which limits opening of the mouth. These changes may be responsible for progressive swallowing impairment. GAG deposition in the larynx typically results in a characteristic hoarse voice.

Teeth are often irregularly shaped and gingival tissue is overgrown. Dentigerous cysts can occur, often causing pain and discomfort. They can be difficult to diagnose particularly in males with CNS involvement.

Conductive and sensorineural hearing loss, complicated by recurrent ear infections, occur in most affected individuals. Otosclerosis can contribute to the conductive hearing loss. Neurosensory hearing loss can be attributed to compression of the cochlear nerve resulting from arachnoid hyperplasia, reduction in the number of spiral ganglion cells, and degeneration of hair cells.

Joints/skeletal. Joint contractures, particularly of the phalangeal joints, are universal. The contractures cause significant loss of joint mobility and are one of the earliest noteworthy diagnostic clues.

The skeletal abnormalities in MPS II are comparable regardless of the severity of the cognitive phenotype but are not specific to MPS II. Termed dysostosis multiplex, these radiographic findings are found in all MPS disorders and manifest as a generalized thickening of most long bones, particularly the ribs, with irregular epiphyseal ossification centers in many areas. Notching of the vertebral bodies is common.

Hip dysplasia is the most common long-term orthopedic problem and can become a significant disability with early-onset arthritis if not treated.

Respiratory. Frequent upper respiratory infections are one of the earliest findings in MPS II. The airway progressively narrows as GAGs accumulate in the tongue, soft tissue of the oropharynx, and the trachea, eventually leading to airway obstruction. Complicating this obstruction are thickening of respiratory secretions, stiffness of the chest wall, and hepatosplenomegaly, which can reduce thoracic volume. The progression of airway obstruction is relentless and usually results in sleep apnea, the need for positive pressure assistance, and eventually tracheostomy.

Cardiovascular. The heart is abnormal in the majority of boys with MPS II and is a major cause of morbidity and mortality (see Table 2); 82% of individuals have cardiovascular signs/symptoms, 62% have a murmur which can be related to valvular disease, including in order of frequency the mitral, aortic, tricuspid, and pulmonary valves.

Table 2. Cardiovascular Involvement in MPSII

Cardiovascular Involvement Prevalence
Cardiac valve involvement57%
Cardiomyopathy8%
Tachycardia7%
Hypertension6%
Arrhythmia and congestive heart failure 4%
Peripheral vascular disease2%

Wraith et al [2008]

Reported "baseline" organ involvement in 202 individuals enrolled in the Hunter Outcome Survey (HOS) as of May 15, 2007. Note: "Baseline" is defined as a finding present at the time data were initially entered into the HOS database.

Gastrointestinal. Hepatomegaly and/or splenomegaly occur in most affected individuals. Umbilical/inguinal hernia is also a frequent finding. In persons with severe MPS II, chronic diarrhea is a common complaint.

Nervous system. Infants with MPS II appear normal at birth; early developmental milestones may also be within the normal range. Delay in global developmental milestones is typically the first clue of brain involvement in children with the CNS form of MPS II.

As is the case for the other organ systems, progression of the CNS manifestations is inexorable, usually resulting in developmental regression between ages six and eight years.

The most common neurologic signs are behavioral and cognitive problems, which Wraith et al [2008] found in 36% and 37% of affected individuals, respectively. Behavior problems occur in both the severe and attenuated forms of the disease [Young & Harper 1981, Wraith et al 2008] but are more common in the severe form.

Chronic communicating hydrocephalus may complicate the clinical picture, especially on the background of deteriorating cognitive ability. Seizures may also occur.

The decline of cognitive function, combined with progression of severe pulmonary and cardiac disease, generally heralds the terminal phase of the disease, with death in the first or second decade of life.

Males who do not have the progressive CNS form of the disease have normal or nearly normal intelligence. However, while deteriorating cognitive abilities and seizures are not common in males with the attenuated form of MPS II, chronic communicating hydrocephalus may still occur.

Carpal tunnel syndrome (CTS) is often an overlooked complication of MPS II. Unlike adults with CTS, most children with MPS II do not complain of the typical symptoms. Nonetheless, nerve conduction studies are abnormal; hand function improves after surgical correction.

Another nervous system complication that must be monitored is narrowing of the spinal canal (spinal stenosis), particularly in the cervical region, with spinal cord compression.

Endocrine. Infants with MPS II appear normal at birth; in the first years of life the height of most children with MPS II is above the 50th percentile and in some it is over the 97th percentile. However, growth velocity decreases with age: by age eight years height is below the third percentile, and nearly all children exhibit growth retardation before puberty [Schulze-Frenking et al 2011]. The cause of short stature is unknown; it may be related to osseous growth-plate disturbances.

Genotype-Phenotype Correlations

Outside of the following two groups neither the amount of I2S protein nor its enzyme activity can be correlated with phenotypic severity.

Genotype-phenotype correlations for point mutations, most of which are unique to a particular family, are not reliable for MPS II [Vafiadaki et al 1998, Li et al 1999, Moreira da Silva et al 2001].

  • At least two sibships have been reported in which one brother has the severe phenotype while another brother has an attenuated phenotype [Yatziv et al 1977].
  • Several missense mutations have been associated with the severe phenotype (p.Arg468Gln, p.Arg468Trp, and p.Ser333Leu), as well as in individuals with an intermediate or attenuated phenotype.

Penetrance

Penetrance of MPS II in males is complete; however, it is anticipated that if newborn screening becomes available for MPS II, much milder presentations would be documented.

Nomenclature

The modifier terms "mild" and "severe" are often used to describe the phenotypic variability of the condition but it is clear (as for all MPS disorders) that the range of severity is wide. The term "attenuated" MPS II (Hunter syndrome) has been suggested as a replacement for the word "mild" to describe those individuals with the non-CNS form of the disease since this group often has somatic presentations just as debilitating as those found in the "severe" CNS group.

Prevalence

Several surveys suggest an incidence between 1:100,000 and 1:170,000 male births [Nelson et al 2003, Baehner et al 2005].

Differential Diagnosis

The differential diagnosis for mucopolysaccharidosis type II (MPS II, or Hunter syndrome) essentially includes all of the other MPS disorders, given the significant overlap of clinical presentation and radiologic findings (see MPS I, MPS IVA).

Multiple sulfatase deficiency and mucolipidosis types II and III) may also present with findings similar to MPS II. See: Mucolipidosis II, Mucolipidosis III Alpha/Beta, and Mucolipidosis III Gamma.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome), the following evaluations are recommended:

  • Echocardiogram
  • Pulmonary function testing
  • Sleep study if sleep apnea is a potential concern
  • Hearing test
  • Nerve conduction velocity (NCV) study to assess for carpal tunnel syndrome
  • Head-cervical MRI and/or opening pressure on lumbar puncture to assess for hydrocephalus and spinal cord compression. Because MRI needs to be performed under sedation and/or intubation in individuals with the severe form, there is an increased risk of compromising the upper airway. See Prevention of Secondary Complications.
  • Eye examination
  • Developmental assessment

Note: Many of these assessments are age dependent. For example, pulmonary function and sleep studies would not be appropriate in a two year old.

Treatment of Manifestations

At this time, treatment of complications in MPS II is symptomatic.

The involvement of specialists for each affected organ system is required to monitor and treat specific problems (see Natural History). Commonly required interventions include the following:

  • Shunting for hydrocephalus
  • Tonsillectomy and adenoidectomy
  • Positive pressure ventilation (CPAP or tracheostomy)
  • Carpal tunnel release
  • Cardiac valve replacement
  • Inguinal hernia repair
  • Hip replacement

Developmental, occupational, and physical therapy are often necessary.

Enzyme replacement therapy (ERT) (see Prevention of Primary Manifestations) is now available for MPS II. ERT has shown encouraging results in possibly modifying/correcting the non-CNS manifestations; however, no data are yet available as to any long-term benefits of such treatment.

Prevention of Primary Manifestations

Enzyme replacement therapy (ERT). Idursulfase (Elaprase®) is a recombinant form of human iduronate 2-sulfatase that has been approved in the United States and the European Union for the treatment of MPS II [US Food and Drug Administration 2006a, US Food and Drug Administration 2006b].

Clinical efficacy of ERT was shown in a double-blind placebo-controlled study of 96 patients [Muenzer et al 2006]. After one year of treatment, persons in the weekly idursulfase group compared to the placebo group demonstrated statistically significant improvement of the primary endpoint, a composite consisting of distance walked in six minutes and the percentage of predicted forced vital capacity based on the sum of ranks of change from baseline. Based on the larger clinical response in the weekly compared to the every other week group, idursulfase was approved for the treatment of MPS II in both the US and European Union at a dose of 0.5 mg/kg weekly.

Patients with relatively attenuated forms of Hunter syndrome were studied in the clinical trial leading to FDA approval of Elaprase®; thus, it is not known at this time whether the incidence or severity of infusion-related reactions is different for patients younger than age five years with severe respiratory compromise or with severe CNS disease.

Because of the trial design, the study only included individuals with the attenuated form of the disease. Despite Elaprase ® being approved for treatment of MPS II, no information is yet available on the outcome of using the drug for individuals who are younger than age five years or have severe CNS disease. Since Elaprase® does not cross the blood-brain barrier, no effect on CNS disease is anticipated. However, there is reason to believe that somatic manifestations of those with severe CNS involvement would benefit from ERT.

Infusion-related reactions that may occur with use of Elaprase® ERT are comparable to similar reactions seen with other ERT products used in treatment of lysosomal storage disease and with other infused proteins such as monoclonal antibodies (e.g., infliximab). The etiology of the more severe forms of these non-allergic reactions, referred to as anaphylactoid, is unknown. Current evidence suggests that anaphylactoid (as opposed to anaphylactic) reactions are not immune mediated [Mayer & Young 2006].

Infusion reactions are generally mild and include brief, insignificant decreases or increases in heart rate, blood pressure, or respiratory rate; itching; rash; flushing; and headache. Mild reactions can usually be managed by slowing the infusion rate for several treatments and then slowly returning to the prior rate.

Pretreatment with anti-inflammatory drugs or antihistamines, as is often done for ERT in other conditions, is not suggested on the label for Elaprase®; however, if mild or moderate infusion reactions (e.g., dyspnea, urticaria, or systolic blood pressure changes of ≤20 mm Hg) cannot be ameliorated by slowing the infusion rate, the addition of treatment one hour before infusion with diphenhydramine and acetaminophen (or ibuprofen) to the regimen usually resolves the problem. Pretreatment can typically be discontinued after six to ten weeks.

Severe non-allergic anaphylactoid reactions such as major changes in blood pressure, wheezing, stridor, rigors, or drop in oxygen saturations should be immediately addressed by stopping the infusion and giving appropriate doses of subcutaneous (SQ) epinephrine, intravenous (IV) diphenhydramine, and hydrocortisone or methylpredinsolone. Subsequent infusions should then be given at a significantly reduced rate with pretreatment with prednisone 24 hours and eight hours before the infusion, diphenhydramine and acetaminophen or ibuprofen orally one hour before the infusion, and IV methylpredinsolone just before beginning the infusion.

Hematopoietic stem cell transplantation (HSCT) using umbilical cord blood or bone marrow is a potential way of providing sufficient enzyme activity to slow or stop the progression of the disease; however, the use of HSCT is controversial because of the associated high risk of morbidity and mortality. Furthermore, it remains unclear if treatment early in life significantly reduces the progression of neurologic disease [Mullen et al 2000].

Anecdotal case reports published to date have been disappointing, quite unlike the reports of bone marrow transplantation (BMT) in Hurler syndrome (MPS I), in which early treatment (age ≤2 years) has met with good success [Tolar et al 2011]. For example, a six-year-old boy who underwent cord blood stem cell transplantation (CBSCT) from an unrelated donor had reduction of hepatomegaly and normal growth; however, he died ten months post-therapy due to a laryngeal post-transplantation lymphoproliferative disorder. Autopsy showed that donor-derived IDS-positive cells were predominantly localized in perivascular brain spaces with some present in the brain parenchyma. However,his hyperactivity, estimated mental age, and brain MR findings had not improved. The efficacy of CBSCT was judged to be insufficient ten months post-therapy [Araya et al 2009].

The efficacy of BMT for MPS II cannot be determined until a number of children with MPS II younger than age two years with known or probable severe CNS disease undergo transplantation, along with documentation of long-term follow up.

Prevention of Secondary Complications

Because of risks associated with sedation with/out intubation, anesthesia is best administered in centers familiar with the potential complications in persons with MPS II. Risks associated with general anesthesia include the following:

  • Ankylosis of the temporomandibular (TM) joint can restrict oral access to the airway.
  • Visualization of the vocal cords is compromised by the large tongue, GAG-infiltrated soft tissues, and large tonsils and adenoids.
  • Care must be taken to avoid hyperextension of the neck secondary to atlantoaxial instability and cervicomedullary compression which may be present.

Nasopharyngeal intubation is often necessary. When endotracheal intubation is difficult or when sedation is required for brief procedures, laryngeal mask airway may be indicated.

The risk of airway complications may continue following successful surgery. Extubation may be difficult because laryngeal edema, reported up to 27 hours post surgery, may prevent maintenance of a proper airway [Hopkins et al 1973]. Breathing a helium-oxygen mixture during extubation has been reported to relieve obstruction and improve outcome [Grosz et al 2001].

Surveillance

Modes of surveillance for complications over time depend, like treatment, on organ system and disease severity. Because all persons with MPS II face the same organ failure issues, with the time of failure being dependent on severity, when and how often to monitor for change cannot be generalized. However, the following studies/evaluations are likely indicated on at least a yearly basis beginning in early to mid-childhood:

  • Cardiology visit with echocardiogram
  • Pulmonary clinic visit with pulmonary function testing
  • Audiogram
  • Eye examination, including examination through a dilated pupil to view the optic disc
  • Developmental assessment
  • Neurologic examination

The following are appropriate at baseline and/or when symptoms/age dictates:

  • Sleep study for obstructive sleep apnea
  • NCV study for evidence of carpal tunnel syndrome
  • Head/neck MRI to document ventricular size and cervicomedullary narrowing
  • Opening pressure on lumbar puncture
  • Orthopedic evaluation to monitor hip disease

Evaluation of Relatives at Risk

Clinical experience suggests that early diagnosis of at-risk relatives allows initiation of ERT before the onset of irreversible changes and often before significant disease progression. It is unclear at present whether early diagnosis, either by newborn screening or testing of at-risk male relatives, is beneficial from the standpoint of early initiation of ERT. No data are available on whether early ERT improves the outcome of the somatic disease in MPS II. ERT is not expected to benefit children with the CNS form of the disease.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

A number of interventions are being evaluated for potential use in MPS II.

Recently, a phase I intrathecal delivery of iduronate-2-sulfatase was initiated. See Clinical Trial).

Other therapies under preclinical investigation include more direct delivery of enzyme into the CNS, higher peripheral dosing regimens, small molecule therapies such as chaperone and substrate reduction, and gene therapy [Beck 2010].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) is inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

Offspring of a proband. Affected males will pass the disease-causing mutation to all of their daughters and none of their sons.

Other family members of a proband. The proband's maternal aunts may be at risk of being carriers and the aunt's offspring, depending on their gender, may be at risk of being carriers or of being affected.

Carrier Detection

Carrier testing of at-risk female relatives is possible if the IDS mutation has been identified in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

In families in which the molecular basis of MPS II is known, prenatal diagnosis should be performed by molecular genetic testing, as assay of enzyme activity is more difficult.

Molecular genetic testing. Prenatal testing using molecular testing is the preferred method of diagnosis for pregnancies of women who are carriers of an IDS mutation previously identified in a family member. The usual procedure is to determine fetal sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or by amniocentesis usually performed at approximately 15 to 18 weeks' gestation. If the karyotype is 46,XY, DNA from fetal cells can be analyzed for the known disease-causing mutation.

Biochemical genetic testing. Prenatal testing is technically feasible for pregnancies at increased risk for MPS II by measuring I2S enzyme activity in cultured cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. However, such testing is not readily available.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Canadian Society for Mucopolysaccharide and Related Diseases, Inc.
    PO Box 30034
    North Vancouver British Columbia V7H 2Y8
    Canada
    Phone: 800-667-1846 (toll free); 604-924-5130
    Fax: 604-924-5131
    Email: info@mpssociety.ca
  • Hunter Disease eClinic
    A multimedia virtual clinic applied specifically to mucopolysaccharidosis type II (MPS II, Hunter disease). Educational software designed to meet the needs of clinicians, biologists, geneticists, biochemists, and other healthcare professionals who are interested in independent learning about mucopolysaccharidosis type II. Note: Flash Player is required for use.
  • Medline Plus
  • National MPS Society
    PO Box 14686
    Durham NC 27709-4686
    Phone: 877-677-1001 (toll-free); 919-806-0101
    Fax: 919-806-2055
    Email: info@mpssociety.org
  • Society for Mucopolysaccharide Diseases (MPS)
    MPS House Repton Place
    White Lion Road
    Amersham Buckinghamshire HP7 9LP
    United Kingdom
    Phone: +44 0845 389 9901
    Email: mps@mpssociety.co.uk

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Mucopolysaccharidosis Type II: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
IDSXq28Iduronate 2-sulfataseIDS @ LOVDIDS

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Mucopolysaccharidosis Type II (View All in OMIM)

309900MUCOPOLYSACCHARIDOSIS, TYPE II; MPS2

Molecular Genetic Pathogenesis

Mutations in IDS result in minimal to absent lysosomal I2S (iduronate 2-sulfatase) enzyme activity, depending on the mutation. Lack of enzyme activity causes heparan and dermatan sulfate (two forms of glysosaminoglycans, or GAGs) to accumulate in the lysosomes of the cell, disrupting their function and causing disease.

Normal allelic variants. IDS spans 24 kb with nine exons. An IDS pseudogene, IDS2, is approximately 20 kb away in the telomeric direction.

Pathologic allelic variants. Over 300 mutations have been described, the majority being point mutations or small deletions [Froissart et al 2007]. However, up to 10% of MPS II is the result of large intragenic deletions and/or chromosomal rearrangements, typically associated with the severe phenotype. The presence of homologous regions in the nearby IDS2 pseudogene predisposes to unequal recombination events, leading to complex rearrangements and sometimes to large deletions.

Table 3. Selected IDS Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
c.998C>Tp.Ser333LeuNM_000202​.5
NP_000193​.1
c.1403G>Ap.Arg468Gln
c.1402C>Tp.Arg468Tryp
c.1122C>TSplice variant

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. Iduronate 2-sulfatase (I2S), a 550-amino acid protein, catalyzes the release of sulfate from the iduronate sulfate residues of heparan sulfate and dermatan sulfate [Neufeld & Muenzer 2002].

Abnormal gene product. Missense mutations make up the majority of gene mutations in IDS, resulting in reduced expression of I2S enzyme activity and variable disease severity. Genotype-phenotype predictions are not reliable in these cases. In males with large deletions and intragenic rearrangements, no enzyme is produced and these individuals typically have the severe phenotype.

References

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  9. Grosz AH, Jacobs IN, Cho C, Schears GJ. Use of helium-oxygen mixtures to relieve upper airway obstruction in a pediatric population. Laryngoscope. 2001;111:1512–4. [PubMed: 11568598]
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  12. Li P, Bellows AB, Thompson JN. Molecular basis of iduronate-2-sulphatase gene mutations in patients with mucopolysaccharidosis type II (Hunter syndrome). J Med Genet. 1999;36:21–7. [PMC free article: PMC1762941] [PubMed: 9950361]
  13. Lualdi S, Regis S, Di Rocco M, Corsolini F, Stroppiano M, Antuzzi D, Filocamo M. Characterization of iduronate-2-sulfatase gene-pseudogene recombinations in eight patients with Mucopolysaccharidosis type II revealed by a rapid PCR-based method. Hum Mutat. 2005;25:491–7. [PubMed: 15832315]
  14. Mayer L, Young Y. Infusion reactions and their management. Gastroenterol Clin North Am. 2006;35:857–66. [PubMed: 17129817]
  15. Moreira da Silva I, Froissart R, Marques dos Santos H, Caseiro C, Maire I, Bozon D. Molecular basis of mucopolysaccharidosis type II in Portugal: identification of four novel mutations. Clin Genet. 2001;60:316–8. [PubMed: 11683780]
  16. Muenzer J, Beck M, Eng CM, Escolar ML, Giugliani R, Guffon NH, Harmatz P, Kamin W, Kampmann C, Koseoglu ST, Link B, Martin RA, Molter DW, Muñoz Rojas MV, Ogilvie JW, Parini R, Ramaswami U, Scarpa M, Schwartz IV, Wood RE, Wraith E. Multidisciplinary management of Hunter syndrome. Pediatrics. 2009;124:e1228–39. [PubMed: 19901005]
  17. Muenzer J, Wraith JE, Beck M, Giugliani R, Harmatz P, Eng CM, Vellodi A, Martin R, Ramaswami U, Gucsavas-Calikoglu M, Vijayaraghavan S, Wendt S, Puga AC, Ulbrich B, Shinawi M, Cleary M, Piper D, Conway AM, Kimura A. A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome). Genet Med. 2006;8:465–73. [PubMed: 16912578]
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Suggested Reading

  1. Manara R, Rampazzo A, Cananzi M, Salviati L, Mardari R, Drigo P, Tomanin R, Gasparotto N, Priante E, Scarpa M. Hunter syndrome in an 11-year old girl on enzyme replacement therapy with idursulfase: brain magnetic resonance imaging features and evolution. J Inherit Metab Dis. 2010 [PubMed: 20052546]
  2. Martin R, Beck M, Eng C, Giugliani R, Harmatz P, Muñoz V, Muenzer J. Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome). Pediatrics. 2008;121:e377–86. [PubMed: 18245410]
  3. Pinto LL, Vieira TA, Giugliani R, Schwartz IV. Expression of the disease on female carriers of X-linked lysosomal disorders: a brief review. Orphanet J Rare Dis. 2010;5:14. [PMC free article: PMC2889886] [PubMed: 20509947]
  4. Suzuki Y, Aoyama A, Kato T, Shimozawa N, Orii T. Retinitis pigmentosa and mucopolysaccharidosis type II: an extremely attenuated phenotype. J Inherit Metab Dis. 2009;32:582–3. [PubMed: 19588268]
  5. Whitley CB, Anderson RA, Aronovich EL, Crotty PL, Anyane-Yeboa K, Russo D, Warburton D. Caveat to genotype-phenotype correlation in mucopolysaccharidosis type II: discordant clinical severity of R468W and R468Q mutations of the iduronate-2- sulfatase gene. Hum Mutat. 1993;2:235–7. [PubMed: 8364592]
  6. Wraith JE, Scarpa M, Beck M, Bodamer OA, De Meirleir L, Guffon N, Meldgaard Lund A, Malm G, Van der Ploeg AT, Zeman J. Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy. Eur J Pediatr. 2008;167:267–77. [PMC free article: PMC2234442] [PubMed: 18038146]

Chapter Notes

Author History

Rick A Martin, MD; Saint Louis University (2007-2011)
Maurizio Scarpa, MD, PhD (2011-present)

Revision History

  • 22 February 2011 (me) Comprehensive update posted live
  • 6 November 2007 (me) Review posted to live Web site
  • 8 June 2007 (rm) Original submission
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