Clinical characteristics.

Mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) is an X-linked multisystem disorder characterized by glycosaminoglycan (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; hepatosplenomegaly; dysostosis multiplex; spinal stenosis; and carpal tunnel syndrome.

Diagnosis/testing.

The diagnosis of MPS II is established in a male proband by identification of 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. The diagnosis of MPS II is usually established in a female proband with suggestive clinical features by identification of a heterozygous IDS pathogenic variant on molecular genetic testing.

Management.

Targeted therapies: Weekly enzyme replacement therapy (ERT) with infusions of idursulfase (Elaprase^®), a recombinant form of human iduronate 2-sulfatase, is approved to treat somatic manifestations and prolong survival. Pre-treatment with anti-inflammatory drugs or antihistamines may be needed for mild or moderate infusion reactions.

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; however, no controlled clinical studies have been conducted in MPS II.

Supportive care: 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 secondary complications: Anesthesia is best administered in centers familiar with the potential complications in persons with MPS II.

Surveillance: Depends on organ system and disease severity and usually includes annual: cardiology evaluation and echocardiogram; pulmonary evaluation including pulmonary function testing; audiogram; ophthalmology examination; developmental assessment; neurologic examination. Additional studies may include: sleep study for obstructive apnea; nerve conduction velocity to assess for carpal tunnel syndrome; head/neck MRI to document ventricular size and cervicomedullary narrowing; opening pressure on lumbar puncture; 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.

Suggestive Findings

MPS II should be suspected in a male proband with the following clinical, radiographic, and laboratory findings.

Clinical features common at age 18 months to four years

• Short stature
• Hepatosplenomegaly
• Joint contractures
• Coarse facies
• Frequent ear/sinus infections
• Umbilical hernia

Radiographic findings. Skeletal survey reveals dysostosis multiplex (i.e., generalized thickening of long bones, particularly the ribs; irregular epiphyseal ossification centers in many areas; notching of the vertebral bodies).

Note: These findings may not be present in early life and are not specific to MPS II.

Laboratory findings. Urine glycosaminoglycan (GAG) analysis shows large concentrations of the GAGs dermatan sulfate and heparan sulfate.

Note: These findings are not specific to MPS II; the profile is similar to that seen in MPS I.

Establishing the Diagnosis

Male proband. The diagnosis of MPS II is established in a male proband by identification of absent or reduced iduronate 2-sulfatase (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 clinical features with MPS II.

Identification of a hemizygous IDS pathogenic (or likely pathogenic) variant by molecular genetic testing (see Table 1) 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.

Female proband. Although the disease is almost exclusively reported in males, rare sporadic cases in females do occur. The diagnosis of MPS II is usually established in a female proband presenting with suggestive clinical features by identification of a heterozygous IDS pathogenic (or likely pathogenic) variant on molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a hemizygous or heterozygous IDS variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of MPS II is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of MPS II has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

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 glycosaminoglycan (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].

In individuals with MPS II, GAG accumulation occurs in virtually all organs; however, specific body systems are more affected than others.

Following are the clinical presentations of the organ systems that are earliest and most progressively affected in individuals with MPS II.

Genotype-Phenotype Correlations

Limited information is available regarding genotype-phenotype correlations:

• 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].
• Recent data from a cohort study of Dutch individuals with MPS II suggest that very low or cell-type-specific IDS residual activity is sufficient to prevent the neuronal phenotype of MPS II. While the molecular effects of IDS pathogenic variants do not discriminate between MPS II phenotypes, the IDS genotype is indicated as a strong predictor [Vollebregt et al 2017].

Penetrance

Penetrance of MPS II in males is 100%; 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].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MPS II, the following evaluations are recommended if they have not already been completed:

• Echocardiogram
• Pulmonary function testing preferably in individuals age six years and older. Pulmonary function testing (e.g., spirometry) can be quite challenging in younger individuals and may be impossible for individuals with significant central nervous system (CNS) involvement since it requires their full cooperation and is effort dependent [Kamin 2008].
• Sleep study if sleep apnea is a potential concern or in case of sleep disturbances not related to upper airway obstruction or impairment of ventilatory control (e.g., difficulty initiating or maintaining sleep, awakening several times per night, decreased REM sleep, atypical sleep stage distribution, and restless legs), which might start to manifest at a median age of four to five years [Rapoport & Mitchell 2017]
• Audiologic evaluation
• Nerve conduction velocity (NCV) and nerve ultrasound examination 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.
• Ophthalmologic evaluation
• Developmental assessment
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

There is no cure for MPS II.

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 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 that 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 [McGarvey & Pollack 2008].

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
• Ophthalmology 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], a recent study showed that while early diagnosis and use of ERT improved outcomes, mortality and morbidity remained high [Franco et al 2017]. It is still unclear 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.

A Phase II/III study of intrathecal delivery of iduronate 2-sulfatase has been initiated (NCT02055118). Preliminary results showed no toxicity of the protein injected intrathecally 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 in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

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 hemizygous for the IDS pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the IDS pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism (germline mosaicism has been observed in MPS II) [Froissart et al 2007].
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a de novo IDS pathogenic variant, in which case the mother is not a carrier.
• 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 genetic 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%. Males who inherit the IDS pathogenic variant will be affected; females who inherit the IDS pathogenic variant will be carriers (on rare occasion, heterozygous females manifest findings of MPS II).
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the IDS pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population because of the possibility of maternal germline mosaicism (germline mosaicism for an IDS pathogenic variant has been observed in MPS I) [Froissart et al 2007].

Offspring of a proband. Affected males transmit the pathogenic variant to:

• All of their daughters, who will be (heterozygotes) carriers and will usually not be affected;
• None of their sons.

Other family members. The proband's maternal aunts may be at risk of being heterozygotes (carriers) for the IDS pathogenic variant, and the aunts' offspring, depending on their sex, may be at risk of being heterozygotes (carriers) for the pathogenic variant or of being affected.

Heterozygote (Carrier) Detection

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

• Testing for the family-specific IDS pathogenic variant identified in an affected male relative, OR
• If an affected male is not available for testing, molecular genetic testing:

  1.

  First by sequence analysis

  2.

  If no IDS pathogenic variant is identified, use of gene-targeted deletion/duplication analysis methods to detect intragenic and exon deletions

  3.

  If no IDS pathogenic variant is identified, use of appropriate molecular methods to detect complex rearrangements from recombination between IDS and the pseudogene, IDSP1, or other processes

Biochemical genetic testing. Measurement of iduronate 2-sulfatase enzyme activity is not reliable for detection of heterozygous 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/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the IDS pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. In families in which the causative IDS pathogenic variant has been identified, prenatal testing should be performed by molecular genetic testing, as assay of I2S enzyme activity is more difficult.

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.)

Author Notes

Dr Maurizio Scarpa is the Director of the Center for Rare Diseases at the Horst Schmidt Klinik in Wiesbaden, Germany. 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 neurologic 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

• 11 April 2024 (aa) Revision: targeted therapies linked as Key Section
• 4 October 2018 (sw) Comprehensive update posted live
• 26 March 2015 (me) Comprehensive update posted live
• 22 February 2011 (me) Comprehensive update posted live
• 6 November 2007 (me) Review posted live
• 8 June 2007 (rm) Original submission

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