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Mucopolysaccharidosis Type I - Initial Diagnosis
Presentations
Infants with severe MPS I (Hurler syndrome) frequently appear normal at birth, though they may have inguinal or umbilical hernias. Coarsening of facial features and enlargement of the liver and spleen occurs 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. Individuals with the attenuated forms of MPS I are typically diagnosed in early childhood or adolescence and have a slower progression of disease.Because long-term clinical outcomes are enhanced with early treatment and treatment options become more limited with increasing age and clinical severity, early diagnosis is critical. The benefits, limitations, and risks of each therapeutic options should be thoroughly discussed with the family and various healthcare providers as soon as possible after diagnosis.
Diagnostic Criteria
The 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, can be used for confirmatory diagnostic testing.
Pearls And Alerts
Urinary glycosaminoglycans (GAGs) are used to screen for MPS disorders but their elevation is not specific to MPS I. Definitive diagnosis of MPS I requires demonstration of deficient activity of the lysosomal enzyme α-L-iduronidase in peripheral blood leukocytes or cultured fibroblasts.
Practice Guidelines
Muenzer J, Wraith JE, Clarke LA.
Mucopolysaccharidosis I: management and treatment guidelines.
Pediatrics.
2009;123(1):19-29.
PubMed abstract
Differential Diagnosis
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 will distinguish the conditions. Beckwith-Wiedemann syndrome presents with macroglossia and umbilical hernia, which can be in the differential diagnosis.History And Examination
Family History
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? (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)?
Medical History
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
- 6 mos. - 12 yrs.
- 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
Developmental and Educational History
Achievement of developmental milestones should be closely monitored, especially in children with severe MPS I, as this will help determine which treatment option(s) the child may benefit from, and qualify for.Children with severe MPS I may have normal early developmental; however, if untreated, all will eventually have severe global developmental delays with regression and mental retardation.
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 to mild learning disabilities. Baseline cognition and mental status should be carefully assessed; acute changes may represent increased intracranial pressure due to hydrocephalus that is not easily determined by imaging because the GAG accumulation prevents ventriculomegaly.
Social and Family History
Ask about the child's social abilities and interactions with other children, and about family functioning, including the availability of resources and supports from community groups and extended family.Physical Exam
Growth Parameters
Children with severe MPS I may have above-normal growth and head circumference in the first 6 months of life. Assess weight and length/height.Vital Signs
Pursue any respiratory distress, with concern about aspiration, cardiac failure, or respiratory muscle compromise.General
Coarsening of facial features results in a remarkably consistent appearance that involves: a short nose, flat face, thick lips and gums and large head (relatively elongated front to back with a prominent forehead). The eye sockets are shallow, the eyes protrude slightly, and the tongue is large. Body hair is coarse and abundant. Patients have protruding bellies and joint contractures, which cause them to stand and walk with a bent-over stance. Patients with milder forms of MPS I have normal facial features but a stocky build, a trunk that is shorter than the limbs, and a shortened, stiff neck.HEENT
Chronic and recurrent ear infections are common. Assess basic auditory skills. Look for upper airway obstruction, since the trachea becomes narrowed and may be floppy or softer than usual, due to abnormal cartilage rings. Assess swallowing.Document the presence of corneal clouding, which occurs in all individuals with MPS I. Examine optic nerve for compression and atrophy.
Examine the mouth for signs of infection and tooth decay. Gum cysts can lead to dental crowding.
Heart
Stenotic or regurgitant murmurs are common, secondary to GAG accumulation in cardiac valves, primarily aortic and mitral valves.Abdomen
Protruding abdomen and inguinal or umbilical hernias may be present. Hepatosplenomegaly is common in children and adolescents.Extremities
Assess for joint stiffness (elbows with lack of supination/pronation range of motion, shoulders with inability to fully extend arms over the head, hands) and contractures (initially present in the fingers resulting in the characteristic "claw-hand"); limited hip abduction and genu valgum. Assess grip strength and thenar muscle atrophy, related to carpal tunnel syndrome. (see MPS I: Orthopedic Manifestations)Neurologic Exam
Progressive compression of the spinal cord with resulting cervical myelopathy is relatively common in older individuals. Communicating hydrocephalus may occur without ventriculomegaly, due to the thickened arachnoid membrane. Presence of acute behavioral changes, headaches, and vomiting should trigger an evaluation of hydrocephalus.Testing
Sensory Testing
Hearing evaluation is indicated if there is suspicion of hearing loss or with a history of multiple or difficult to manage middle ear infections. Assess visual acuity, if possible at the child's age, and peripheral vision.Laboratory Testing
Baseline measurement of urinary GAGs can be useful for assessing response to enzyme replacement therapy and/or hematopoietic stem cell transplantation.Imaging and EEG
Brain and spine imaging with MRI provides a baseline for ongoing evaluation for hydrocephalus and spine stability. Nerve conduction studies are helpful to assess carpal tunnel syndrome (tendon entrapment). Skeletal survey should be performed at the time of diagnosis to assess for signs of dysostosis multiplex.Genetic Testing
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%. Testing can be done by your preferred genetics subspecialists or see Testing laboratories for MPS I (GeneTests).Subspecialist Collaborations and Other Resources
The role of subspecialists in the care of children with MPS I is crucial given the breadth of organ system involvement in these children. Communication between the primary care provider, subspecialists, and family are essential in improving quality of care.
Pediatric Genetics (see Services below for relevant providers)
Referral to a Genetics specialist is indicated when the diagnosis of MPS I is suspected and/or confirmed. A geneticist will help coordinate referral to other subspecialists for optimal management of individuals with this condition.
Pediatric Genetic Counseling (see Services below for relevant providers)
Genetic counselors can be very helpful to families in understanding the condition and its inheritance, impact on other family members and future childbearing. Genetic counselors are often very knowledgeable about community resources and family support.
Pediatric Ophthalmology (see Services below for relevant providers)
Corneal clouding is a hallmark feature and can aid in the diagnosis of MPS I. Assessment at diagnosis should include measurement of visual acuity and intraocular pressure, slit lamp examination of the cornea, and electroretinography (ERG). Assess the optic nerve for signs of intracranial pressure.
Pediatric Orthopedics (see Services below for relevant providers)
Dysostosis multiplex, a combination of skeletal abnormalities on x-ray imaging, is highly concerning for a mucopolysaccharidosis. Contractures of small and large joints and gibbus deformity of the spine are very common in the early stages of MPS I.
Pediatric Cardiology (see Services below for relevant providers)
Referral to cardiology is indicated at diagnosis and every two years for evaluation, echocardiogram, and an ECG to monitor valvular involvement and cardiac function.
Resources
Information & Support
For Professionals
Mucopolysaccharidosis Type I (GeneReviews)
An excellent review of MPS I includes genetics, clinical description, management, resources and references from the GeneReviews
Web site funded by the National Institutes of Health.
Hurler syndrome (OMIM)
A very detailed description of Hurler syndrome, its genetics, clinical features, diagnosis, and treatment; from Online Mendelian
Inheritance in Man (OMIM), from the National Center for Biotechnology Information.
For Parents and Patients
Support
National MPS Society
Provides information about the disorder, research, support for families, fund raising, and efforts to increase public awareness
about MPS and related disorders. Allows users to contact and communicate directly with other parents/patients.
Hide & Seek Foundation
"Hide & Seek is a community of people dedicated to finding treatments and cures for a devastating genetic condition called
Lysosomal Disease."
LysoLife Community
"The LysoLife Community connects families, friends and caregivers for support and inspiration. The LysoLife Community is sponsored
by the Hide & Seek Foundation in partnership with Inspire."
Mucopolysaccharidosis syndromes resources (KUMC)
A list of international resources for patients/families; from the University of Kansas Medical Center, Medical Genetics -
Genetics and Rare Conditions Site.
General
Mucopolysaccharidosis Type I (Genetics Home Reference)
Excellent overview of MPS I for families/patients, from Genetics Home Reference, a service of the National Library of Medicine.
Includes links for more consumer-level information and support.
Mucopolysaccharidoses Fact Sheet
The National Institute of Neurological Disorders and Strokes (NINDS) provides a fact sheet addresing signs and symptoms, risks,
types, treatments, research and resources.
Hurler syndrome (MedlinePlus Encyclopedia)
Brief overview and links, from the National Library of Medicine and National Institutes of Health.
Practice Guidelines
Muenzer J, Wraith JE, Clarke LA.
Mucopolysaccharidosis I: management and treatment guidelines.
Pediatrics.
2009;123(1):19-29.
PubMed abstract
Patient Education
National MPS Society Booklets
More than 10 booklets (large files) about mucopolysaccharidoses and related diseases for patients, families, and providers;
includes information about MPS I, II, III, IV, VI, VII; ML II/III; daily living; anesthesia; resources, and more.
National MPS Society Fact Sheets
More than 25 fact sheets about mucopolysaccharidoses and related diseases for patients, families, and providers; topics include
cardiac problems, caregiver support, family coping strategies, melatonin, transplants, pamidronate, tube feedings, stem cell
transplants, and more.
Services
Pediatric Genetic Counseling
See all Pediatric Genetic Counseling services providers (4) in our database.
For other services related to this condition, browse our Services categories or search our database.
Studies
Current studies of MPS I (ClinicalTrials.gov)
A list of ongoing clinical studies for which patients may be eligible. The list includes registered studies that are closed
and may have links to their published outcomes.
MPS I Registry
An ongoing, observational database that tracks natural history and outcomes of patients with MPS I. The Registry was initiated
worldwide in April 2003 as an international observational program sponsored by BioMarin/Genzyme LLC and administered by Genzyme
Corporation. Registration is voluntary, free, and confidential.