Pediatric Summary Report

Secondary Findings in Pediatric Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Released 1.1.4
• Status (Adult): Incomplete (Consensus scoring is Incomplete)
• GENE/GENE PANEL: IDS
• Condition: Mucopolysaccharidosis Type II
• Mode(s) of Inheritance: X-linked

Actionability Assertion

• IDS ⇔ 0010674 (mucopolysaccharidosis type 2): Assertion Pending

Actionability Rationale

This topic was initially scored prior to development of the process for making actionability assertions. The Pediatric AWG decided to defer making an assertion until after the topic could be reviewed through the update process.

Final Consensus Scores

Gene Condition Pairs: IDS ⇔ 0010674 (OMIM:309900)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Somatic manifestations (as defined by quantitative measures of pulmonary function, 6 minute walk, and hepatosplenomegaly) / Enzyme replacement therapy (ERT) with idursulfase	2	3C	2B	2	9CB
Early Mortality / Enzyme replacement therapy (ERT) with idursulfase	2	3C	2N	2	9CN

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

Depending on sub-population evaluated, population incidence of mucopolysaccharidosis type II (MPS II) is typically cited to be between 0.3 and 1.4 per 100,000 live born males. However, in Israel, incidence is quoted as high as 1 in 34,000 live male births. [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15]

Clinical Features

The lysosomal storage disease MPS II, also called Hunter syndrome, is a progressive multisystem disorder due to the buildup of undegradable enzyme substrate. The degree, number, age of onset, rate of progression, and severity of symptoms varies significantly among affected individuals. MPS II is often divided into two clinical phenotypes, though is more recently being considered a continuum between two extremes: an early progressive (also called “severe”) form (60-80% of cases) which involve cognitive decline and a slowly progressive (also called “attenuated”) form, with normal or near-normal cognition. 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. In those with cognitive involvement, progressive cognitive deterioration, progressive airway disease, and cardiac disease/cardiomyopathy are serious early manifestations. In those with slowly progressive disease, the CNS is less affected (patients can have no learning deficit or mild to moderate learning difficulties), although the impact on other organs may be early progressive to the same degree as in those with the severe cognitive symptoms. Additional clinical findings of MPS II include many other multisystem manifestations. [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 13, 15, 16]

Natural History

Because MPS II is X-linked, the vast majority of affected individuals are male; on rare occasion, heterozygous females manifest symptoms of this disease due to skewed X-inactivation. MPS II patients appear healthy at birth, with first symptom onset typically between 18 months and 4 years of age. In both forms of the disease, growth begins to lag around age 5. Retinopathy is most common in individuals with the early progressive form but may be present in the slowly progressive form as well. Airway obstruction is progressive. Behavioral problems occur in both forms of the disease but are more common in the early progressive form. Though cognitive deterioration is uncommon in the slowly progressive form, chronic communicating hydrocephalus may still occur. In the early progressive form, cognitive decline onsets around 18 months-6 years of age, with the first manifestations being hyperactivity, aggression, and a reduced sense of danger. Developmental regression usually results between 6 and 8 years. In these individuals, death typically occurs in the first to third decade from progressive cognitive deterioration, progressive airway disease, and/or cardiac disease. For individuals with the slowly progressive form, symptoms are typically recognizable between 4 and 8 years of age. For these individuals, survival into the early adult years with normal intelligence is common, and survival into the seventh to ninth decade has been rarely reported. The rate of progression and the overall prognosis in these milder phenotypes is highly variable. Hip dysplasia is the most common long-term orthopedic problem and can become a significant disability. Upper airway obstruction is a significant cause of morbidity and mortality in patients with MPS II. [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 16]

2. How effective are interventions for preventing harm?

Patient Management

Upon diagnosis of MPS II, multisystem evaluation is required to establish extent of disease. Multisystem evaluations should include detailed clinical examination, and examination for ophthalmological, cardiologic, musculoskeletal, ear, nose and throat, airway, dermatologic, gastrointestinal, and psychological complications, as well as neurodevelopmental assessment. A multidisciplinary care team should include specialists as appropriate to meet each individual patient’s needs, as well as social workers. Evaluations should be carried out in a center with expertise in rare disorders. (Tier 2) [1, 3, 4, 5, 6, 16]

Enzyme replacement therapy (ERT) with idursulfase is recommended to treat somatic manifestations of disease, but guidelines note that the enzyme cannot cross the blood-brain barrier and neurocognitive improvements have not been seen. Guidelines differ on appropriate age for initiation, with some guidelines suggesting ERT be initiated as early as possible. Most guidelines agree that ERT should be initiated in all patients if death is not imminent from MPS II or another complication. However, for patients with neurocognitive decline, it is suggested that ERT be offered for a trial period of 6-18 months and be discontinued if benefits are not seen. (Tier 2) [3, 4, 5, 6, 16]

Systematic review of efficacy data from a randomized controlled trial (RCT) with 96 participants (age: 4.9-30.9 years) indicate that ERT significantly improves 6 minute walk test results compared to placebo; absolute forced vital capacity, but not predicted forced vital capacity, was significantly increased from baseline compared to placebo; further, hepatosplenomegaly (HSM) improved with ERT compared to placebo; finally urinary glycosaminoglycan (GAGs) secretion was reduced with ERT compared to placebo. Trial inclusion criteria were limited to patients who could reproducibly perform these evaluations. Additionally, systematic review and meta-analysis of available quantitative data from RCTs, case studies, open-label trials, and clinical case series, found similar support for a reduction in urinary GAGs secretion, HSM, improvements in 6 minute walk test, though it was noted that many patients were not tested at a longer interval of 36 months, possibly biasing the effects. The meta-analysis noted an uncertain effect on forced vital capacity, but did note that declines in growth may be less steep in treated patients, and found small improvements in physical disability in patients with both early and slowly progressive forms. (Tier 1) [7, 8]

Recommendations for starting ERT at age <5 years are on the basis of a phase IV, open-label, multicenter single-arm study (N = 28, age = 1.4-7.5 years, with 4 patients > 5 years) and multiple observational studies. In these studies, liver size and urinary GAG levels decreased in treated patients; some studies have indicated positive benefits on growth from earlier initiation of ERT. (Tier 2) [5, 6]

In terms of survival, in the Hunter Outcome Survey, 124/800 (15.5%) patients treated with ERT had died versus 28/95 untreated patients (29.5%) and median survival was 33.0 years (95% CI: 30.4-38.4 years) in treated patients versus 21.2 years (95% CI: 16.1-31.5 years) in untreated patients. Cox models adjusted for other factors such as disease severity and age of diagnosis indicated a 54% lower risk of death in treated compared to untreated patients (HR = 0.46; 95% CI: 0.29-0.72). (Tier 5) [17]

Beyond ERT, manifestations are managed symptomatically according to existing care regiments and are beyond the scope of this report. Such management may include pharmacotherapy, physical therapy, surgery, and behavioral therapy, depending on symptoms. Some manifestations, such as airway compromise or spinal cord compression, may require aggressive and early intervention to preserve function. (Tier 2) [1, 3, 5, 6]

Some guidelines recommend prophylactic antibiotics for endocarditis prior to surgery or major dental procedures, or as appropriate. (Tier 2) [1, 6]

It is recommended that patients with MPS II should only undergo surgery, general anesthesia, or sedation at centers with experience in perioperative management of individuals with MPS II and with on-site intensive care facilities, with especial expertise required for general anesthesia, which is considered high risk in these patients. (Tier 2) [1, 3, 5, 6]

Surveillance

Detailed multisystem surveillance is recommended every 6-12 months for patients with MPS II to identify and mitigate or prevent complications through early intervention via symptomatic management. For instance, without early intervention, spinal compression can be associated with irreversible neurological dysfunction and patients typically do not experience symptoms of carpal tunnel until irreversible dysfunction occurs. Multisystem surveillance evaluations should include detailed clinical examination, and examination for ophthalmological, cardiologic, musculoskeletal, ear, nose and throat, airway, dermatologic, gastrointestinal, and psychological complications; patients should also have neurodevelopmental workup to assess severity. Patients should regularly undergo the following: radiography, audiologic examination, polysomnography, echo- and electro-cardiography, abdominal ultrasound, respiratory studies, 6 minute walk test, fundoscopy, applanation tonometry, visual field testing, retinoscopy/refractrometry, slit lamp biomicroscopy, nerve conduction studies for carpal tunnel syndrome, imaging of the brain and spine, EEG, neurodevelopmental assessment, and assessment of functional ability and quality of life. Where possible, monitoring should take place at a center with experience of treating lysosomal storage disorders. (Tier 2) [1, 3, 4, 5, 6]

Circumstances to Avoid

Avoid the use of neuromuscular blocking agents during anesthesia until after endotracheal intubation has been achieved and the airway is secured. (Tier 4) [15]

3. What is the chance that this threat will materialize?

Mode of Inheritance

X-linked [1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16]

Prevalence of Genetic Variants

No information on population prevalence of pathogenic variants was provided. However, because penetrance is presumed to be near 100% in males with one copy, it’s probable that the incidence of pathogenic variants is similar to the incidence of the disorder in male live births cited above.

Penetrance

Unselected penetrance data for MPS II were not available. However, the penetrance of any feature in males is presumed to be near 100%, though it is anticipated that if newborn screening becomes available for MPS II, much milder presentations would be documented. (Tier 4) [2, 14]

It is estimated that 67-75% of males will have the early progressive form. In severe cases, death occurs in the first to second decade of life usually as a result of respiratory or cardiac failure. (Tier 3) [1, 2, 5, 6, 7, 10, 13, 16]

In individuals with MPS II, the prevalence of the following has been cited:
-Coarse facial features: 95-98%
-Otitis media: 72-73%
-Hearing loss: 67%
-Nasal obstruction: 34%
-Enlarged tonsils/adenoids: 68%
-Optic nerve swelling: 20%
-Optic atrophy: 11%
-Hernia: 69-78%
-HSM: 88-89%
-Joint stiffness and/or limited function/contracture: 84-87%
-Kyphosis/scoliosis: 39%
Any cardiovascular signs or symptoms:72- 82%
-Heart murmur: 52-62%
-Arrythmia: 4%
-Cardiomyopathy: 8-9%
-Congestive heart disease: 4%
-Valve disease: 53-57%
-Myocardial infarction: 0.5%
Any neurological involvement: 84%
-Cognitive problems: 37%
-Behavior problems: 36%
-Hydrocephalus: 17%
-Seizures: 18%
-Carpal tunnel syndrome: 25% (Tier 3) [1, 2, 6, 13]

For individuals undergoing surgery, difficulty with airway management was surveyed in a review of case series in the literature. It was found that there was difficulty with masking in 21 of 68 patients (31%) requiring masking and difficulty with intubation in 23 of 65 patients (35%) requiring intubation. Failed incubation occurred in 1 patient. (Tier 5) [18]

A study of 34 Taiwanese MPS II patients who died between 1995 and 2012 found that the mean age of death for patients with a severe form of the disease (n = 31) was 13.2 ± 3.2 years, compared to 22.6 ± 4.3 years in the three patients with mild form; respiratory was the leading causes of death (56%), followed by cardiac failure (18%). Similarly, in the Hunter Outcome Survey, for 129 patients entered into the database following death (death between 1951 and 2007), patients with cognitive involvement died at a median age of 11.7 years (n = 33; range 6.3-22.9 years) versus a median age of 14.1 years for those who did not have cognitive involvement (n = 63; range 5.4-45.3 years). Airway impairment was the primary cause of death (46%); cardiac involvement caused 16% of deaths. (Tier 5) [19, 20]

Relative Risk

No information on relative risk was available.

Expressivity

Genotype-phenotype correlations are difficult to make consistently due to the lack of recurrent variants. Further, phenotypic prediction is not possible on the basis of enzyme activity. However early progressive form has been consistently associated with deletions and complex rearrangements, and there are a few known variants consistently associated with either the early or slowly progressive forms. However, some variants are variably expressed as early or slowly progressive forms, depending on the patient. (Tier 3) [1, 2, 4, 5, 7, 10, 13, 16]

In slowly progressive forms, there is great variability in rate of progression, even when siblings carry an identical pathogenic variant. (Tier 4) [11]

4. What is the Nature of the Intervention?

Nature of Intervention

ERT with idursulfase is given by weekly intravenous infusion over three hours; patients may require premedication to control infusion reaction. ERT should be initially administered in hospitals or expert care centers. In most situations, idursulfase is a therapy that can be administered safely in the patients home after 3-6 months of infusions in a hospital or expert care center. Adverse reactions occurs in approximately 30% of patients, with most being mild to moderate. Non-allergic anaphylactoid reactions, which can be life-threatening in severe circumstances, have occurred. Other infusion related reactions include classic reactions during infusion, which manifest with fever, chills, and urticaria, and late reactions occurring 12 hours or more following infusion, which include rash and mild wheezing. [1, 2, 3, 4, 5, 6, 7, 8, 13, 16]

For some types of surveillance, sedation or anesthesia may be required; other types of surveillance may not be possible in very young children or patients with the early progressive form.

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Because the initial signs and symptoms of MPS II can be nonspecific, identification of patients at a young age can be difficult. Clinical recognition may not occur until facial features or other physical features become evident, between 18 months and 4 years of age in early progressive cases, and about two years later in slowly progressive cases. This may result in a substantial delay between disease onset and diagnosis. Early ascertainment is currently only possible through family-based testing; there are no newborn screening programs for MPS II. (Tier 4) [3, 4, 5]

Date of Search: 04.17.2019

Reference List

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