MPS I is a rare condition that is seen in all populations; there are no known ethnic predilections. The incidence of severe MPS I is estimated to be approximately 1:100,000, and the attenuated MPS I is even rarer. [Moore: 2008]

MPS I is an autosomal recessive condition caused by inactivating mutations in the IDUA gene. This gene encodes the enzyme α-L-iduronidase. Mutation analysis is clinically available and will detect mutations in ~95% of individuals with MPS I. A genotype-phenotype correlation may identify those at risk for the more severe clinical manifestations. Parents of children with MPS I are obligate carriers of the condition and have a 25% chance of having other children with MPS I with a similar phenotype. Carriers do not have any known symptoms of MPS I. For further details about heterozygous carriers and genotype/phenotype correlations, see Missing link with id: 88d3be56.xml.

If untreated, individuals with a severe form of MPS I will experience progressive manifestations that begin early in life and often result in death by age 10. Individuals with attenuated MPS I usually experience onset of symptoms in childhood or adolescence and survival to adulthood is common. Individuals with an attenuated form still require stringent clinical management, particularly related to their cardio-pulmonary and skeletal manifestations.

The medical home clinician may be the first to suspect this disorder and to approach the family about testing to confirm the diagnosis and the level of severity. The clinician can discuss potential therapeutic and treatment options for MPS I in a time-sensitive manner and help families weigh the benefits and risks related to enzyme replacement therapy (ERT), hematopoietic stem cell transplants (HSCT), and the many surgical interventions that may be recommended. Eventually, gene therapy may become available, which would require more extended consultation.
Once a diagnosis is established, coordination of selected MPS I therapies should be initiated by the medical home. In those with severe MPS I, establishing a collaboration with the transplant team is imperative for long-term care. For those with attenuated MPS I who elect to have ERT, initial infusions should be carried out in a hospital-based unit familiar with potential adverse events of enzyme replacement therapy. After at least 8 infusions and the placement of an indwelling catheter, the medical home can establish a relationship with the pharmaceutical company that supplies the recombinant enzyme and develop a plan with the metabolic genetics team and home health nursing to provide infusions in the home.
Given the rapid progression of the disease, assessments several times a year are indicated for children with severe MPS I. Those with the attenuated forms may also benefit from frequent visits, though the need will depend upon their clinical status. Because of the extensive and widespread organ system involvement, every child with MPS I should receive multidisciplinary and subspecialty care from a center with expertise in lysosomal storage disorders.

Children with MPS I have progressive multisystem organ involvement, as well as growth and developmental delays, making initial diagnosis somewhat complicated and necessitating a thorough approach with consideration of age-dependent onset of symptoms and signs. See Table 1 (page 3 of the pdf) in Mucopolysaccharidosis I: Management and Treatment Guidelines (AAP) ( 344 KB) for a recommended schedule of assessments.

The clinical manifestations of MPS I may not become evident until the child is a few months to a few years of age; therefore, screening in early childhood is not indicated unless a family member is affected. When there is suspicion of MPS I, measurement of urinary excretion of glycosaminoglycans (GAGs) is a non-invasive way to evaluate the condition. An elevation of urinary GAGs is a strong indication of an underlying mucopolysaccharide disorder. The pattern of GAG excretion should be compared to the patterns seen in each of the MPS disorders. If consistent with an MPS, confirmatory enzyme testing should be performed. Genotype confirmation after enzyme analysis is preferred.
Newborn screening has been implemented in a number of states, including Utah in 2019, and is under consideration in other states where it will likely be added to the Newborn Screen Panel.

Any sibling of an individual with confirmed MPS I should have an enzyme screening and/or genetic testing (if the mutations in the family have already been identified) at birth so that treatment may be discussed and initiated as early as possible. Those with severe MPS I should be offered hematopoietic stem cell transplant, whereas those with the attenuated form should begin enzyme replacement therapy (ERT) as soon as possible.
Carrier screening of parents and other family members via enzyme analysis is not recommended since there can be significant overlap in enzyme levels between carriers and non-carriers. Carrier screening via molecular genetic testing is indicated in family members if the mutations within the family are known.

Infants with severe MPS I (Hurler syndrome) frequently appear normal at birth, though they may have inguinal or umbilical hernias. Coarsening of facial features with increased body hair, thoracolumbar gibbus, and enlargement of the liver and spleen occur over the first few months leading to diagnosis usually by 18 months. Within the first year, skeletal deformities, joint stiffness, and developmental delay may become apparent. Chronic otitis media is common, and if anesthesia is required for surgical intervention for ear tubes or hernia repair, an alert anesthesiologist can identify those with increased GAG accumulation of the airway. Individuals with the attenuated forms of MPS I are typically diagnosed in early childhood or adolescence and have a slower progression of disease. Often, joint contractures of the hands are initially noted. If a combination of these features is suspected, measurement of urinary excretion of glycosaminoglycans (GAGs) is a noninvasive way to rule out the condition.
Manifestations observed include:

• Frequent upper airway infections with otitis media
• Hepatosplenomegaly
• Corneal clouding
• Cardiac involvement, valve disease
• Skeletal dysplasia (dysostosis multiplex)
• Growth delay
• Profound neurological involvement (in the severe form only)
• Macrocephaly

Orthopedic manifestations cause significant morbidity and discomfort to individuals with mucopolysaccharidosis type I (MPS I). Orthopedic concerns include:

• Progressive arthropathy leading to severe joint deformity (occurs in all patients)
• Early bone involvement, with diminution of linear growth by age 3 in children with severe MPS I
• Carpal tunnel syndrome is common, but early symptoms (pain, tingling, and numbness) often go unreported. More commonly, parents notice increased difficulty with fine motor skills (a late symptom) or gnawing on fingertips.

Individuals with attenuated MPS I may have severe progressive bone involvement despite absence of cognitive impairment. Joint stiffness and contractures may present initially in the fingers resulting in the characteristic "claw hand." Progressive skeletal dysplasia, or dysostosis multiplex, is seen in all individuals with severe MPS I. Dysostosis multiplex congenita is a radiologic finding with a number of related features, including:

• Dolichocephaly
• Spatulate ribs (oar-like)
• Wide diaphyses and narrow epiphyses
• Wide metacarpals, phalanges, metatarsals (bullet-like)
• Hypoplastic acetabulae
• Kyphoscoliosis (gibbus deformity)
• Anterior beaking of vertebrae
• Platyspondyly
• Ossification defects of the lower vertebral bodies

Complications may include:

• Spinal nerve entrapment, including sciatica
• Acute spinal injury
• Atlanto-occipital instability
• Knees that are prone to valgus and varus deformities
• Pelvic abnormalities
• Carpal tunnel syndrome
• Progressive and debilitating hip deformity leading to early hip replacement
• Resultant joint pain

Diagnosis of MPS I is established by:

• Confirming deficiency of α-L-iduronidase in peripheral blood leukocytes or cultured fibroblasts
• Molecular genetic testing for mutations in IDUA, the gene that encodes α-L-iduronidase

Traditional classifications of MPS I, Hurler, Hurler-Scheie, and Scheie syndromes do not reflect the wide variation in clinical findings. Manifestations often overlap between categories. The disease is best characterized as either severe or attenuated MPS I.
Severe MPS I (formerly Hurler syndrome): Infants may appear normal at birth. Coarsening of facial features and enlargement of the liver and spleen occurs over the first few months. If untreated, death occurs in the first decade. The following features are usually present at an early age:

• Skeletal deformities including gibbus and distinctive radiographic findings
• Obstructive airway disease
• Progressive and severe physical problems
• Communicating hydrocephalus
• Limited language ability and progressive mental deterioration
• Hepatosplenomegaly
• Recurrent ear/nose infections
• Multiple hernias; umbilical and inguinal
• Coarse facial features with increased body hair for family background

Attenuated (formerly Hurler-Scheie syndrome): If development is normal at 24 months of age and moderate somatic involvement is evident (mild coarsening, little skeletal involvement), individuals are classified as having intermediate severity. The onset of symptoms tends to occur between 3–8 years of age. Cognitive impairment may be present to a lesser extent; however, rapid and progressive cognitive decline is not characteristic of the attenuated forms. If intellectual decline is present, it tends to follow a more gradual course occurring at a later age and over a longer period of time. Cardiac involvement and upper respiratory tract obstruction contribute to mortality (often in teens or early twenties). Individuals with attenuated MPS I have progressive somatic involvement, including:

• Dysostosis multiplex
• Arthropathy
• Corneal clouding
• Joint stiffness
• Hearing loss
• Cardiac involvement, including valvular heart disease
• Spinal cord compression
• Obstructive airway disease

Attenuated (formerly Scheie syndrome): Often diagnosed in adolescence or young adulthood, individuals generally have normal intellect and a longer lifespan. Major clinical manifestations are:

• Corneal clouding
• Sleep apnea
• Arthropathy and joint stiffness
• Carpal tunnel syndrome and other nerve entrapment (such as cervical cord compression)
• Valvular heart disease
• Visual impairment
• Mild facial coarseness
• Spinal cord compression

The overlap of attenuated forms of MPS I makes it difficult to separate Scheie syndrome from Hurler-Scheie syndrome. It may be easier to reflect the continuum and simply state either more- or less-attenuated, primarily based on age of clinical presentation.

Individuals with other lysosomal storage disorders, such as Hunter syndrome, multiple sulfatase deficiency, and I-cell disease, can have features similar to those found in individuals with MPS I. Clinical and biochemical enzyme assays distinguish these conditions. Beckwith-Wiedemann syndrome presents with macroglossia and umbilical hernia, which can be in the differential diagnosis.

In the patient’s history, it is important to note the age and presentation of the first symptoms. Typical clinical findings at various ages include:

• 0 - 6 months
  • Chronic rhinitis
  • Recurrent otitis media or "glue ear" with thick cerumen
  • Umbilical or inguinal hernia
  • Above normal growth and head size
  • Gibbus of the thoracolumbar spine
• 6 months -12 years
  • Distinctive facial gestalt, with coarsening over time
  • Hepatosplenomegaly
  • Skeletal deformities
  • Joint stiffness - especially distal interphalangeal and elbow joints
  • Developmental delay
  • Corneal clouding
  • Chronic rhinitis
  • Recurrent otitis media or "glue ear"
• 12+ years
  • Corneal clouding
  • Joint stiffness
  • Valvular heart disease
  • Cardiopulmonary disease with easy fatigue

Assess caloric intake, feeding problems, and time required for feeding.

A detailed family history should be obtained. Questions that may help elucidate the presence of other affected individuals include:

• Are there any individuals with developmental delays, regression, or learning problems?
• Any children who died at a young age?
• Any individuals with joint problems? Pain, tingling, or numbness in the hands or difficulty with fine motor skills? (It may signify carpal tunnel syndrome.)
• Any individuals with heart problems? Recurrent ear infections or chronic rhinitis?
• Which ethnicities exist in the family?
• Are the parents related to each other (consanguinity)?

Monitor developmental milestones closely, especially in children with severe MPS I, as this will help determine a recommended treatment option. Individuals with the attenuated forms of MPS I may have normal to mildly delayed development. Intelligence in individuals with attenuated MPS I can range from normal cognition to mild learning disabilities. Baseline cognition and mental status should be carefully assessed; acute changes in cognition or mental status should be promptly evaluated because this may represent increased intracranial pressure due to hydrocephalus that is not easily determined by imaging because GAG accumulation in the intracranial membranes attenuates ventriculomegaly.

Ask about the child's social abilities, interactions with other children, and about family functioning (including the availability of resources and supports from community groups and extended family).

Assess on a regular basis:

• Hearing and speech discrimination
• Visual acuity, including peripheral vision
• Fingertip touch

Baseline and serial measurement of urinary GAGs are useful for assessing response to ERT and/or HSCT.

Brain and spine imaging with MRI provides a baseline for ongoing evaluation that is performed every 2-3 years to evaluate hydrocephalus and spine stability. Nerve conduction studies may be helpful to assess carpal tunnel syndrome. Skeletal survey should be performed at diagnosis to assess for signs of dysostosis multiplex, a combination of skeletal abnormalities on X-ray imaging, which is highly concerning for MPS 1.

Molecular genetic testing for mutations in IDUA, the gene that encodes α-L-iduronidase, can be used for confirmatory diagnostic testing, carrier testing, prenatal diagnosis, and genotype-phenotype correlations with certain types of mutations. Mutation detection rate in affected individuals is approximately 95%. Mucopolysaccharidosis Type I (MPS 1) Genetics has information about obtaining tests. Testing can be done by your preferred genetics subspecialists or see Testing Laboratories for MPS I (Genetic Testing Registry).

• Annual ophthalmology assessments should include measurement of visual acuity and intraocular pressure, slit lamp examination of the cornea, and electroretinography. Assessment of optic nerve for signs of intracranial pressure
• Regular sleep assessments, with sleep studies as needed, to identify the presence of sleep apnea, both obstructive and central
• Pulmonary function tests when of age with regular assessments
• Dental exam every 6-12 months
• Annual audiology exam to determine the degree and cause of hearing impairment

Early treatment is critical to better long-term clinical outcomes. Treatment options become more limited with increasing age and clinical severity:

• Hematopoietic stem cell transplantation (HSCT) for severe MPS I increases survival, reduces facial coarseness and hepatosplenomegaly, improves hearing, and preserves normal heart function. If HSCT is accomplished before significant developmental delay (usually before 2 years old), the degree and rate of cognitive decline will likely be reduced; however, individuals may still have mild intellectual disability. Cardiac valvular disease, skeletal manifestations, and corneal clouding may continue to progress. [Kunin-Batson: 2016]
• Enzyme replacement therapy (ERT) can significantly reduce liver size, improve the distance traveled in a 6-minute walk test, decrease joint restriction, lessen sleep apnea, and improve breathing in individuals with attenuated MPS I. The benefit of ERT in those with severe disease has not been assessed; 1 patient with severe MPS who had been treated for 3 years with ERT continued to experience a decline in respiratory status, musculoskeletal and spinal involvement, and developmental skills. [Thomas: 2006] Because the recombinant enzyme is not thought to cross the blood-brain barrier, the best option to reduce the risk of cognitive impairment remains early HSCT.
• Combined HSCT and ERT is another option for individuals with severe MPS I. Providing ERT before and into the peri-HSCT period may improve the child's existing respiratory and cardiac manifestations to an extent that may reduce the risk of transplant-related complications. [Tolar: 2008] See Mucopolysaccharidosis Type I (MPS 1) Hematopoietic Stem Cell Transplantation & Enzyme Replacement Therapy for details about therapy and dosing regimen.
• Under investigation for the treatment of cognitive decline in severe MPS I is intrathecal ERT (injecting the enzyme into the spinal fluid). Some long-term benefits to the heart from successful bone marrow transplantation have been documented. [Braunlin: 2003]

The benefits, limitations, and risks of each therapeutic option should be thoroughly discussed with the family and other health care providers as soon as possible after diagnosis. Management of the multiple organ system involvement in MPS I requires a multispecialty and multidisciplinary approach, ideally guided in part by the medical home.

There are no growth curves specific to MPS I, so growth and weight should be followed on standardized growth curves based on age and gender. Children with severe MPS I may have above-normal growth and head circumference in the first 6 months of life, but their growth usually slows down between 6 and 18 months of age and may plateau between 3-6 years of age.

Chronic ear infections are common. Physicians should have a low threshold for placing pressure equalization (PE) tubes since most individuals will have recurrent and frequent ear infections. Heavy-duty grommets are preferred due to recurrent infections and buildup of cerumen.

Instruct parents to avoid over-the-counter drugs commonly used to treat colds and congestion (antihistamines that make mucus thicker and harder, decongestants that contain stimulants that raise blood pressure and narrow blood vessels, cough suppressants that may contribute to sleep apnea).