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 - Under Revision 1.1.3
• Status (Adult): Incomplete (Consensus scoring is Incomplete)
• GENE/GENE PANEL: IDUA
• Condition: Mucopolysaccharidosis type I
• Mode(s) of Inheritance: Autosomal Recessive

Actionability Assertion

• IDUA ⇔ 0001586 (mucopolysaccharidosis type 1): Moderate Actionability

Actionability Rationale

The assertion of moderate is for Mucopolysaccharidosis type I, given the potential for clinically significant outcomes for which there are available interventions. However, we recognize that there are mild/attenuated forms where interventions may not be appropriate and for which there is limited evidence for actionability.

Final Consensus Scores

Gene Condition Pairs: IDUA ⇔ 0001586 (OMIM:607014) IDUA ⇔ 0001586 (OMIM:607015) IDUA ⇔ 0001586 (OMIM:607016)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Severe neurocognitive delay / Enzyme replacement therapy	2	3A	0A	2	7AA
Severe neurocognitive delay / Hematopoietic stem cell transplantation before age 2.5 years	2	3A	2B	1	8AB
Death due to cardiorespiratory failure / Enzyme replacement therapy	2	3C	1B 1	2	8CB
Death due to cardiorespiratory failure / Hematopoietic stem cell transplantation before age 2.5 years	2	3C	2B	1	8CB

1. The level of evidence was downgraded to a B on the basis of extrapolation from pulmonary function and 6 minute walk test results.

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

Prevalence of the Genetic Condition

The worldwide prevalence of mucopolysaccharidosis type I (MPS I) has been estimated at 0.69-3.8:100,000; however, recent neonatal screening data yield incidence rates from 1:7,353 to 1:14,567 in the United States. The prevalence of the Hurler, Hurler-Scheie, and Scheie subtypes has been estimated at 1:200,000, 1:115,000-435,000, and 1:500,000, respectively. [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13]

Clinical Features

The lysosomal storage disease MPS I is a progressive multisystem disorder caused by a deficiency of α-L-iduronidase, the enzyme encoded by IDUA, resulting in the buildup of undegradable enzyme substrate. This results in coarse facial features, early frequent upper respiratory infections including otitis media, inguinal or umbilical hernia, hepatosplenomegaly, characteristic skeletal and joint findings (gibbus deformity; limitation of joint range of motion), hearing loss, cardiovascular involvement (the leading cause of death), airway compromise, and ocular findings (e.g., corneal clouding potentially leading to vision impairment). The degree, number, age of onset, and severity of these symptoms varies. As such, MPS I has historically been divided into three MPS I subtypes based on severity of symptoms and age of onset: Hurler syndrome (severe), Hurler-Scheie syndrome (intermediate/moderate), and Scheie syndrome (attenuated/mild). Enzymatic activity alone is unreliable for phenotypic prediction. Because the clinical findings for these subtypes overlap, the disease has more recently been understood as a continuous spectrum and classified as one of two types: severe or attenuated MPS I, a distinction which impacts therapy options. Attenuated MPS I individuals have the greatest variability in clinical findings. [1, 2, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18]

Natural History

Severe MPS1 (Hurler syndrome) is characterized by chronic and progressive disease involving multiple organs and tissues. While infants appear normal at birth, they may have inguinal or umbilical hernias. Mean age of diagnosis of severe disease is nine months, with most affected patients diagnosed before age 18 months. Facial coarsening becomes apparent within the first two years. Children have early bone involvement, with some findings apparent on radiograph at birth and gibbus deformity being reported as early as age 6 months (typically apparent within the first 14 months). Cardiac disease can present as early as less than one year of age. Developmental delay is usually obvious by age 18 months, with a maximum function age of 2-4 years followed by deterioration. By age three, linear growth decreases. Death by cardiorespiratory failure typically occurs within the first two decades of life if left untreated, by which time children are severely intellectually disabled. A small subset of individuals with severe MPS I have an early-onset fatal thickening of the endocardium.
Children with attenuated MPS I (Hurler-Scheie or Scheie) are developmentally normal at age 24 months. Onset of disease with attenuated MPS I usually occurs between age three and ten years. Rate of disease progression in attenuated phenotypes is variable, from serious life-threatening complications leading to death in the second and third decades to a normal lifespan albeit with significant disease morbidity. Although intellectually normal in early childhood, some affected children may develop detectable learning disabilities. The manifestation of other symptoms in attenuated MPS I is variable, with the most significant source of disability deriving from skeletal/joint manifestations. The mildest forms of the disease may go unrecognized until adulthood. [1, 2, 4, 5, 6, 7, 8, 10, 13, 14, 15, 16]

2. How effective are interventions for preventing harm?

Patient Management

At diagnosis, all patients with MPS I should have a detailed multidisciplinary evaluation for phenotype prediction and to guide treatment, including evaluations from ophthalmology, otolaryngology, cardiology, orthopedic surgery, pulmonology, neurodevelopmental specialists, and pediatric neurosurgery as necessary. Patients should also undergo radiography, audiometry, polysomnography, echo- and electro-cardiography, abdominal ultrasound, respiratory studies, imaging of the brain and spine, vital sign assessment, and assessment of functional ability and quality of life. (Tier 2) [2, 3, 8, 17]

Decisions on selection of disease-modifying treatment for a patient with MPS I should be made within a team of specialists with expertise in MPS I. (Tier 2) [3]

For patients diagnosed early with severe MPS I (Hurler syndrome) and/or a genotype exclusively associated with a severe phenotype, the preferred treatment strategy is hematopoietic stem cell transplantation (HSCT) performed before age 2 or 2.5, depending on guideline and as soon as the somatic condition allows and before developmental deterioration (DQ ≥ 70). Some guidelines caution that it should only be undertaken in carefully selected children for whom long-term monitoring is possible. The decision to transplant in patients with advanced CNS disease should be made by a team, as these patients are less likely to benefit. Case data suggest that HSCT performed before 24 months of age and onset of significant developmental delay has better engraftment rates and the highest probability of rescuing neurocognitive outcome, though survivors may still experience speech delay and learning disability. Based on numerous case reports and case series, successful HSCT eliminates hepatosplenomegaly, improves joint mobility, improves respiratory and cardiovascular function, and reduces frequencies of otitis media. (Tier 2) HSCT does not significantly improve musculoskeletal outcomes as demonstrated by systematic review of these outcomes in case data from patients treated with HSCT. (Tier 2) [2, 3, 8]

HSCT does not significantly improve musculoskeletal outcomes as demonstrated by systematic review of these outcomes in case data from patients treated with HSCT. (Tier 1) [9]

Guidelines differ regarding the role of HSCT in moderate disease and/or disease of unknown phenotype. Some guidelines cite a potential role for HSCT in moderate (Hurler-Scheie) phenotype, although there is no effectiveness data to support this. Others state that patients should be monitored and HSCT considered if cognition declines or make no specific recommendation. HSCT should not be unnecessarily administered in mild disease (no cognitive impairment likely) due to associated morbidity and mortality. (Tier 2) [2, 3, 8]

Guidelines differ regarding the use of enzyme replacement therapy (ERT) with laronidase, the FDA approved drug for treatment of MPS I. Some guidelines state that all patients, regardless of disease severity or HSCT treatment plan, should receive ERT starting at diagnosis. Other guidelines suggest individualized management with the use of clinical judgement for pursuing either HSCT or ERT based on patient phenotype and clinical condition and age at diagnosis. (Tier 2) [2, 3, 8]

Systematic reviews and meta-analyses of the small studies and clinical trials resulting in approval have concluded long-term ERT effectively treats several somatic signs and symptoms. However, these findings have been mainly limited to one RCT of 45 patients which found an improvement in lung functioning and 6-minute walk time as well as reductions in urinary excretion of glycosaminoglycans (GAGs) and sleep disorder breathing in those on ERT compared to placebo. Further, effects on cognition have not been examined in clinical trials. Reviews incorporating non-RCTs confirm improvements in urinary excretion of GAGs, hypertrophy, and hepatomegaly. (Tier 1) [10, 11, 12, 13]

All patients affected with MPS I should undergo general anesthesia and dental anesthesia in centers staffed by anesthesiologists with experience in managing individuals with MPS. Radiography should be performed on all patients to evaluate individual risks. Individuals with MPS I present major anesthetic risks, including fatality due to difficulty with intubation. (Tier 2) [8]

A case series of retrospective chart review of 39 patients documented the outcomes from 114 general anesthetics for 141 procedures. In the severe MPS patients treated by HSCT, 39% (7/18) had an airway problem at least once, with an overall incidence of airway problems in 14% (10/71) of anesthesia events; in attenuated MPS ERT-treated patients, 60% (12/20) experienced airway problem with an overall incidence of 57% (24/52 anesthesia events). (Tier 5) [19]

In patients with severe phenotypes, dental care should be carried out by a dentist based at a children's hospital with pediatric dentistry experience. (Tier 2) [8]

Resources such as social services, family therapy, and MPS resource groups should be made available to assist patients and families. (Tier 2) [8]

For orthopedic manifestations, physical therapy and early evaluation and treatment of carpal tunnel are recommended. (Tier 3) [1]

Aggressive evaluation of progressive compression of the spinal cord with resulting cervical myelopathy is recommended because early surgical intervention may prevent complications (Tier 4) [1]

Cardiac valve replacement should be considered early. (Tier 4) [1]

Surveillance

All MPS I patients should be evaluated at least annually; these evaluations may be facilitated by a short hospital stay or coordinate clinic visits for efficient multispecialty review. Schedule of follow-up assessments should be tailored to individual parameters. (Tier 2) [2, 8]

Patients with moderate or severe skeletal disease and/or severe MPS I should be monitored by an orthopedic surgeon familiar with MPS disorders. (Tier 2) [8, 17]

Patients with attenuated disease should be monitored by a metabolic specialist every three months. (Tier 2) [2]

Infants with severe disease should have regular neurodevelopmental assessments performed to follow the developmental trajectory during and after the HSCT treatment process. (Tier 2) [2]

Patients with an unknown phenotype should have a neurodevelopmental assessment every three months and be followed regularly by a metabolic specialist and other specialists. (Tier 2)

Circumstances to Avoid

When possible, procedures requiring general anesthesia should be avoided, to minimize risk. (Tier 2) [8]

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

Mode of Inheritance

Autosomal Recessive

Prevalence of Genetic Variants

No genetic variant prevalence information has been provided for the Pediatric context.

Penetrance

From systematic review of untreated natural history case reports meeting inclusion criteria, the following manifestations were reported, as delineated by Hurler, Hurler-Scheie, and Scheie phenotype classifications (age not always reported; studies not included if not stratified by phenotype):
Severe MPS I (Hurler):
-hepatomegaly: 30/32 (94%)
-splenomegaly: 3/10 (30%)
-inguinal hernia: 29/41 (71%)
-kyphosis: 22/22 (100%)
-restricted joint extension: 22/22 (100%)
-mental delay: 6/10 (60%)
-cardiac symptoms: 8/10 (80%)
-corneal clouding: 49/49 (100%)
-cardiac hypertrophy: 22/43 (51%)
-airway obstruction: 7/13 (54%)
-obstructive sleep apnea: 8/8 (100%)
-optic atrophy: 2/14 eyes (14%)
Moderate MPS 1 (Hurler-Scheie):
-hepatomegaly: 1/3 (33%)
-splenomegaly: 0/3 (33%)
-mental delay: 2/3 (67%)
-obstructive sleep apnea: 2/2 (100%)
-optic atrophy: 4/21 eyes (19%)
-mental delay: 2/3 (66%)
-cardiac hypertrophy: not reported
Mild MPS 1 (Scheie):
-mitral valve involvement: 7/8 (88%)
-aortic valve involvement: 7/8 (88%)
-cardiac hypertrophy: not reported (Tier 1) [10]

International registry data (N = 891) show that 57% of individuals were classified as having Hurler syndrome, 23.5% as Hurler-Scheie syndrome, and 10% as Sheie syndrome; 8.6% were classified as unknown or indeterminant phenotype, though this data may be subject to ascertainment bias. Death, typically caused by cardiorespiratory failure, usually occurs within the first ten years of life in patients with severe MPS I (Hurler syndrome). (Tier 3)

Relative Risk

Information on relative risk was not available for the Pediatric context.

Expressivity

There are some mutations without clear genotype-phenotype correlations, and additional polymorphisms may modulate phenotype expression. Some alleles have resulted in a range of phenotypes encompassing the entire disease spectrum. Clinical heterogeneity is found even within subtypes. (Tier 3) [1, 2, 3, 8, 10, 12]

4. What is the Nature of the Intervention?

Nature of Intervention

The major drawback to HSCT is its high morbidity and mortality. Recent advances in chemotherapeutic conditioning and donor selection have improved the outcome of this procedure. Yet, a recent retrospective analysis (n = 146) found a reported mortality rate of 15%, with a survival engraftment of 56%. [3]

ERT with laronidase requires weekly administration by infusion. The most common adverse events in a RCT and open-label extension (45 patients) included infusion-related reactions (which also occurred in placebo infusion), such as flushing, fever, headache and rash, which can be managed by adjusting rate of infusion or antihistamines/antipyretics. One patient experienced two severe laronidase-related adverse events resulting in a severe hypersensitivity and dyspnea requiring emergency tracheostomy. [10, 11]

Other side effects of laronidase are vomiting, nausea, arthralgia, diarrhea, tachycardia, abdominal pain, hypertension, erythema, and cyanosis. [11]

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

Chance to Escape Clinical Detection

Early ascertainment is currently only accomplished through family-based testing. (Tier 2) [2]

Newborn screening for MPS I and other lysosomal storage diseases is being piloted and may improve early identification. (Tier 3) [1]

Date of Search: 08.08.2018

Reference List

1. LA Clarke. Mucopolysaccharidosis Type I. 2002 Oct 31 [Updated 2016 Feb 11]. In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1162

2. de Ru MH, Boelens JJ, Das AM, Jones SA, van der Lee JH, Mahlaoui N, Mengel E, Offringa M, O'Meara A, Parini R, Rovelli A, Sykora KW, Valayannopoulos V, Vellodi A, Wynn RF, Wijburg FA. Enzyme replacement therapy and/or hematopoietic stem cell transplantation at diagnosis in patients with mucopolysaccharidosis type I: results of a European consensus procedure. Orphanet J Rare Dis. (2011) 6:55.

3. Mucopolysaccharidosis type 1. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=579

4. Hurler syndrome. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=93473

5. Hurler-Scheie syndrome. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=93476

6. Scheie syndrome. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=93474

7. Muenzer J, Wraith JE, Clarke LA. Mucopolysaccharidosis I: management and treatment guidelines. Pediatrics. (2009) 123(1):19-29.

8. van der Linden MH, Kruyt MC, Sakkers RJ, de Koning TJ, Oner FC, Castelein RM. Orthopaedic management of Hurler's disease after hematopoietic stem cell transplantation: a systematic review. J Inherit Metab Dis. (2011) 34(3):657-69.

9. Connock M, Juarez-Garcia A, Frew E, Mans A, Dretzke J, Fry-Smith A, Moore D. A systematic review of the clinical effectiveness and cost-effectiveness of enzyme replacement therapies for Fabry's disease and mucopolysaccharidosis type 1. Health Technol Assess. (2006) 10(20):iii-iv, ix-113.

10. Jameson E, Jones S, Remmington T. Enzyme replacement therapy with laronidase (Aldurazyme((R))) for treating mucopolysaccharidosis type I. Cochrane Database Syst Rev. (2016) 4:CD009354.

11. Dornelles AD, Artigalas O, da Silva AA, Ardila DLV, Alegra T, Pereira TV, Vairo FPE, Schwartz IVD. Efficacy and safety of intravenous laronidase for mucopolysaccharidosis type I: A systematic review and meta-analysis. PLoS One. (2017) 12(8):e0184065.

12. El Dib RP, Pastores GM. Laronidase for treating mucopolysaccharidosis type I. Genet Mol Res. (2007) 6(3):667-74.

13. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. HURLER SYNDROME. MIM: 607014: 2018 May 30. World Wide Web URL: http://omim.org.

14. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. HURLER-SCHEIE SYNDROME. MIM: 607015: 2016 Jul 09. World Wide Web URL: http://omim.org.

15. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. SCHEIE SYNDROME. MIM: 607016: 2016 Jul 09. World Wide Web URL: http://omim.org.

16. Langereis EJ, Borgo A, Crushell E, Harmatz PR, van Hasselt PM, Jones SA, Kelly PM, Lampe C, van der Lee JH, Odent T, Sakkers R, Scarpa M, Schafroth MU, Struijs PA, Valayannopoulos V, White KK, Wijburg FA. Treatment of hip dysplasia in patients with mucopolysaccharidosis type I after hematopoietic stem cell transplantation: results of an international consensus procedure. Orphanet J Rare Dis. (2013) 8:155.

17. Stelzner J, Terboven T, Osthaus A, Beck M. Anaesthesia recommendations for patients suffering from Hurler syndrome. Orphan Anesthesia. (2014) Accessed: 2018-08-08. Website: https://www.orpha.net/data/patho/Pro/en/Hurler_EN.pdf

18. Kirkpatrick K, Ellwood J, Walker RW. Mucopolysaccharidosis type I (Hurler syndrome) and anesthesia: the impact of bone marrow transplantation, enzyme replacement therapy, and fiberoptic intubation on airway management. Paediatr Anaesth. (2012) 22(8):745-51.