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Mucopolysaccharidosis Type II

Synonyms: Hunter Syndrome, I2S Deficiency, Iduronate 2-Sulfatase Deficiency, MPS II
, MD, PhD
Center For Rare Diseases
Department of Pediatric and Adolescent Medicine
Horst Schmidt Klinik
Wiesbaden, Germany

Initial Posting: ; Last Update: March 26, 2015.

Summary

Clinical 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 heterozygous females manifest findings. Age of onset, disease severity, and rate of progression vary significantly among affected males. In those with early progressive 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 slowly progressive disease, the CNS is not (or is minimally) affected, although the effect of GAG accumulation on other organ systems may be early progressive to the same degree as in those who have progressive cognitive decline. Survival into the early adult years with normal intelligence is common in the slowly progressing 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; hepato-splenomegaly; dysostosis multiplex; 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 2-sulfatase (I2S) enzyme activity in white cells, fibroblasts, or plasma in the presence of normal activity of at least one other sulfatase. Detection of a hemizygous pathogenic variant in IDS confirms 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; and hip replacement.

Prevention of primary manifestations: Enzyme replacement therapy (ERT) with idursulfase (Elaprase®), a recombinant form of human iduronate 2-sulfatase, was approved in 2006 in the United States and the European Union in individuals with the slowly progressing form of the disease. More recently studies on the outcome of ERT in children younger than age five years or individuals with early progressive pulmonary compromise or early progressive CNS disease showed that although Elaprase® does not cross the blood-brain barrier (and, thus, no effect on CNS disease is anticipated), early treatment may improve somatic manifestations. Treatment of boys younger than age five years was as safe and as well tolerated as for older males. 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.

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; head/neck MRI to document ventricular size and cervicomedullary narrowing; and orthopedic evaluation to monitor hip disease.

Evaluation of relatives at risk: While 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, it is unclear at present whether the potential benefits of early initiation of ERT justify early diagnosis by either newborn screening or testing of at-risk male relatives.

Genetic counseling.

MPS II is inherited in an X-linked manner. The risk to sibs depends on the genetic status of the mother. If the mother of the proband has the pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers. Germline mosaicism has been observed. Affected males pass the pathogenic variant 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 pathogenic variant in the family is known.

Diagnosis

The diagnosis of mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) cannot be made on clinical findings alone. The specific combination of signs and symptoms and their physical manifestation vary widely, depending on disease severity, and the evolution of individual manifestations over time is often a better indicator of a diagnosis of MPS II.

Recommendations for the diagnosis and management of MPS II have been developed by the Hunter Syndrome European Expert Council (HSEEC) using an evidence-based approach [Scarpa et al 2011].

Suggestive Findings

MPS II is often suspected in a male proband with the following clinical findings at age 18 months to four years: 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.

Presence of sleep disturbance, increased activity, behavior difficulties, seizure-like behavior, perseverative chewing behavior, and inability to achieve bowel and bladder training may be strongly correlated with subsequent cognitive dysfunction [Holt et al 2011].

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.

Urine glycosaminoglycans (GAG) analysis shows large concentrations of the GAGs dermatan sulfate and heparan sulfate; however, these findings are not specific to MPS II as the profile is similar to that seen in MPS I.

Establishing the Diagnosis

Establishing the diagnosis of MPS II in a male proband requires documentation of absent or reduced iduronate 2-sulfatase (I2S) enzyme activity or identification of a hemizygous IDS pathogenic variant.

Iduronate 2-sulfatase (I2S) enzyme activity. The gold standard for diagnosis of MPS II in a male proband is absence or reduced levels of I2S enzyme activity in white cells, fibroblasts, or plasma. Most affected males have no detectable activity using the artificial substrate. Detailed analytic protocols for measurement of I2S enzyme activity have been published [Johnson et al 2013].

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.

Molecular genetic testing. Detection of a pathogenic variant in IDS confirms the diagnosis of MPS II in a male proband and may be useful in persons with an unusual phenotype or a phenotype that does not match the results of GAG analysis.

Three general types of IDS pathogenic variants are observed in persons with MPS II:

  • Pathogenic variants within the gene (82%),
  • Deletions of exon(s) or the whole gene (9%), and
  • Complex rearrangements primarily the result of recombination with the pseudogene, IDSP1, located 25 kb telomeric to IDS (9%).

Table 1.

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

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
IDSSequence analysis 3, 482% 5, 6
Gene-targeted deletion/duplication analysis 79%
Complex rearrangements 89%
1.

See Table A. Genes and Databases for chromosome locus and protein name.

2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Lack of amplification by PCR prior to sequence analysis can suggest a putative exon(s) or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis

5.

Single-nucleotide changes and splicing mutations account for 65% of all pathogenic variants; small (i.e., intra-exonic) deletions and insertions account for 17% of all pathogenic variants [Froissart et al 2007].

6.

Sequence analysis may not detect complex rearrangements in males or females that result from a common pathogenic inversion between IDS and IDSP1.

7.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

8.

Complex rearrangements result from recombination with the IDSP1 pseudogene or from other type of processes. Testing may require multiple molecular methods (e.g., sequencing, SNP analysis, gene-targeted deletion/duplication analysis, chromosomal microarray [CMA]) to confirm and map rearrangement breakpoints [Lualdi et al 2005, Froissart et al 2007, Oshima et al 2011].

Clinical Characteristics

Clinical Description

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 "early progressive" 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 slowly progressive form of the disease, the CNS is minimally affected, if at all, yet the effect of glycosaminoglycans (GAG) accumulation on other organ systems may be early progressive to the same degree as in those who have progressive cognitive decline. Survival into the early adult years with normal intelligence is common in this group.

The early progressive CNS phenotype may be more than twice as prevalent as the slowly progressive form of the disease; however, accurate prevalence rates are not available. Some form of neurologic involvement is seen in 84% of affected males. 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 early progressively 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 early progressive form and about two years later for those with the slowly progressive form. Some develop ivory-colored skin lesions on the upper back and sides of the upper arms, pathognomonic of Hunter syndrome [Tylki-Szymańska 2014].

Growth. 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.

Although no statistical difference is observed between height in the slowly progressive and early progressive phenotypes, the growth pattern can help in monitoring disease progression and assessing therapeutic efficacy [Patel et al 2014].

Eye. In contrast to MPS I, corneal clouding occurs occasionally and 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 approximately 20% of affected individuals and optic atrophy in approximately 11% [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 affected by early progression than cone-mediated responses [Caruso et al 1986]. Progressive reduction in ERG amplitude suggests 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 retinal pigment epithelium 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. Dentigenous 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, occurs 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 and 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; 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. Cardiomyopathy, hypertension, rhythm disorder, and peripheral vascular disease are seen occasionally (<10%) [Wraith et al 2008].

Gastrointestinal. Hepatomegaly and/or splenomegaly occur in most affected individuals. Umbilical/inguinal hernia is also a frequent finding. In persons with early progressive 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 indication 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. Behavioral problems occur in both the early progressive and slowly progressive forms of the disease [Young & Harper 1981, Wraith et al 2008] but are more common in the early progressive 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 early progressive 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 slowly progressive 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.

  • The pathogenic variant c.1122C>T (which creates a new donor splice site at exon 8 with the loss of 20 amino acids) is primarily associated with the slowly progressive phenotype [Muenzer et al 2009].
  • Males with complete absence of functional enzyme as a result of gene deletion or complex gene rearrangements (~17% of affected individuals) invariably manifest the early progressive CNS presentation of the disease [Wraith et al 2008].

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] (see Molecular Genetics).

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/attenuated" and "severe" were often used in the past to describe the phenotypic variability of the condition but it is clear (as for all MPS disorders) that the range of severity is wide. It is now considered inappropriate to use these terms since the disease significantly alters the quality of life. Thus, the terms “slowly progressive” (to describe the former “attenuated” form of the disease) and “early progressive” (to describe the form of the disease previously designated “severe”) are currently being considered to better reflect the continuum of disease severity.

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).

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.

See Mucopolysaccaridoses: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to SimulConsult®, 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 and needs 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 early progressive form, there is an increased risk of compromising the upper airway. See Prevention of Secondary Complications.
  • Eye examination
  • Developmental assessment
  • Medical genetics consultation

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

Patient management guidelines have been published [Scarpa et al 2011].

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 Clinical Description). 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) has shown encouraging results in possibly modifying/correcting the non-CNS manifestations; as confirmed in a long-term study [Lampe et al 2014b].

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]. When compared to the placebo group after one year of treatment, persons in the weekly idursulfase group demonstrated statistically significant improvement of the primary endpoint (a composite of distance walked and lung function). Based on the better clinical response in the group in which medication was administered weekly compared to group in which it was administered every other week, idursulfase was approved in both the US and EU for the treatment of MPS II at a weekly dose of 0.5 mg/kg. Because this trial only studied individuals with the slowly progressive form of the disease, it yielded little information on outcomes in individuals younger than age five years or with early progressive CNS disease.

Results of a study on ERT in children younger than age five years or individuals with severe pulmonary compromise or severe CNS disease have been published [Muenzer et al 2012].

More recently, in a 3.5 year independent follow-up of 27 individuals with MPS II, Tomanin et al [2014] determined that:

  • Long-term use of ERT was safe;
  • ERT efficacy was similar in both a younger age group (age 1.6-12 years at the start of ERT) and an older age group (age 12-27 years at the start of ERT); and
  • Improvement/stabilization of findings such as GAG level, hepatomegaly, splenomegaly, otologic disorders, adenotonsillar hypertrophy, and cardiac valve regurgitation (except mitral valve) was greater in individuals with the early progressive form compared to those with the slowly progressive form.

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. The young age is not adding any safety concerns, and patients have significant amelioration of somatic symptoms [Lampe et al 2014a].

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.

Because of the limitation of the design of the clinical trial, 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.

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 [Guffon et al 2009, Annibali et al 2013]; 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], and anecdotal case reports published to date have been disappointing, quite unlike the reports of bone marrow transplantation (BMT) in Hurler syndrome (MPS I). Overall, 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 undergoes transplantation, along with documentation of long-term follow up [Tanaka et al 2012]. Although this study needs to be validated, the use of HSCT is difficult to justify since HSCT and ERT have equal efficacy in restoring growth in children with MPS II [Patel et al 2014].

Prevention of Secondary Complications

Given the risks associated with sedation with/without 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, which has been 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

Guidelines for surveillance have been developed [Scarpa et al 2011].

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

Although 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 [Muenzer 2014], it is unclear at present whether early diagnosis (either by newborn screening or testing of at-risk male relatives) is beneficial as 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 Trials). Preliminary results showed no toxicity of the protein injected intrathetically at the dosage used (10 mg and 30 mg). The GAG concentration in the CSF was significantly reduced but clinical efficacy needed further evaluation [Muenzer et al 2014].

Another ongoing multicenter study is evaluating the effect of a one-year course of monthly intrathecal administration of 10 mg of idursulfase on neurodevelopmental status in children with MPS II and cognitive impairment who have previously received and tolerated a minimum of four months of Elaprase® therapy.

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]. Tissue uptake (including the brain and spinal cord) via the transferrin receptor of a fusion protein between iduronate 2-sulfatase (I2S) and a monoclonal antibody against the mouse transferrin receptor is being studied [Zhou et al 2012].

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

  • The father of an affected male will not have the disease nor will he be a carrier of the pathogenic variant.
  • In a family with more than one affected individual, the mother of an affected male may be an obligate carrier.
  • If a woman has more than one affected son and the IDS pathogenic variant cannot be detected in DNA extracted from her leukocytes, she has germline mosaicism.
  • If pedigree analysis reveals that the proband is the only affected family member, the mother may be a carrier or the pathogenic variant in the affected male may be de novo, in which case the mother is not a carrier.
  • When an affected male is the only affected individual in the family, several possibilities regarding his mother's carrier status need to be considered:
    • He has a de novo IDS pathogenic variant and his mother is not a carrier.
    • His mother has a de novo IDS pathogenic variant either (a) as a "germline mutation" (i.e., present at the time of her conception and therefore in every cell of her body); or (b) as "germline mosaicism" (i.e., present in some of her germ cells only) [Froissart et al 1997].
    • His mother has an IDS pathogenic variant that she inherited from a maternal female ancestor.
  • On rare occasion, heterozygous females manifest findings of MPS II. This is thought to result from skewed inactivation of the normal paternally inherited X chromosome and expression of the maternally inherited mutated IDS allele [Jurecka et al 2012, Guillén-Navarro et al 2013].

Sibs of a proband

  • The risk to sibs depends on the carrier status of the mother.
  • If the mother of the proband has the IDS pathogenic variant identified in her son, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the IDS pathogenic variant will be affected; female sibs who inherit the IDS pathogenic variant will be carriers.
  • Germline mosaicism for an IDS pathogenic variant has been observed in MPS II [Froissart et al 1997, Froissart et al 2007]. Thus, even if the pathogenic variant has not been identified in leukocyte DNA from the mother, sibs of the proband are still at increased risk of inheriting the pathogenic variant.

Offspring of a proband. Affected males will pass the pathogenic variant 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

Molecular genetic testing. Carrier testing for at-risk female relatives requires one of the following:

Biochemical genetic 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.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on testing 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, allelic variants, 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 I2S enzyme activity is more difficult.

Molecular genetic testing. If the IDS pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

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 families in which the IDS pathogenic variant 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)

300823IDURONATE 2-SULFATASE; IDS
309900MUCOPOLYSACCHARIDOSIS, TYPE II; MPS2

Molecular Genetic Pathogenesis

Mutation of IDS results in minimal to absent lysosomal I2S (iduronate 2-sulfatase) enzyme activity, depending on the pathogenic variant. Lack of enzyme activity causes accumulation of heparan and dermatan sulfate (two forms of glysosaminoglycans, or GAGs) in lysosomes, disrupting cellular function and causing disease.

Gene structure. IDS consists of nine exons and spans about 24 kb of genomic DNA. An IDS pseudogene, IDSP1, is located about 25 kb telomeric to IDS. Homologous regions shared by IDS and IDSP1 predispose to unequal recombination events, leading to complex rearrangements and sometimes large deletions. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. More than 300 IDS pathogenic variants have been described, the majority being point mutations or small deletions [Froissart et al 2007]. Novel mutations being identified continuously [Brusius-Facchin et al 2014]. Up to 18% of MPS II results from deletion of exon(s) or the whole gene, and/or complex rearrangements, typically associated with the early progressive phenotype.

Lack of genotype/phenotype correlation is demonstrated by identification of several missense pathogenic variants (p.Arg468Gln, p.Arg468Trp, and p.Ser333Leu) in individuals with the early progressive phenotype and others with the intermediate or slowly progressive phenotype. At least two sibships have been reported in which one brother has the early progressive phenotype and another brother has a slowly progressive phenotype [Yatziv et al 1977].

A 178-bp deletion in the promoter region was identified in two affected individuals with low enzyme activity [Brusius-Facchin et al 2013]. Alteration of the promoter region may explain low enzyme activity in some affected individuals in whom no IDS pathogenic variant in the coding region or deletion of exon(s) or the whole gene were detected.

Table 2.

Selected IDS Pathogenic Allelic Variants

DNA Nucleotide Change Protein 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. 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 2015].

Abnormal gene product. 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.

  • Missense mutations make up the majority of IDS mutations, 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 early progressive phenotype (see Genotype Phenotype Correlations).

References

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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;33 Suppl 3:S67–72. [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 May 28;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 a 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 Notes

Dr. Maurizio Scarpa is the Director of the Rare Disease Center at the Horst Schmidt Klinik in Wiesbaden Germany (www.hsk-wiesbaden.de/abteilungen/zentrum-fuer-seltene-erkrankungen.html). He is also the President of the Brains for Brain Foundation (B4B). B4B aims to develop new and innovative therapeutic strategies to cross the blood-brain barrier and supports the following activities in the field of rare neurological disorders: scientific research, knowledge dissemination, social and socio-medical assistance, and health assistance.

Author History

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

Revision History

  • 26 March 2015 (me) Comprehensive update posted live
  • 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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