Hurler Syndrome, Hurler-Scheie Syndrome, and Scheie Syndrome (Mucopolysaccharidosis Type I) 

Updated: Sep 28, 2018
Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Maria Descartes, MD 

Overview

Background

The mucopolysaccharidoses (MPSs) are a family of metabolic disorders caused by deficiency of lysosomal enzymes needed to degrade glycosaminoglycans (GAGs), or mucopolysaccharides.[1] GAG is an important constituent of the extracellular matrix, joint fluid, and connective tissue throughout the body. Progressive accumulation of GAG within the cells of various organs ultimately compromises their function. The major sites of disease differ depending on the specific enzyme deficiency; therefore, clinical presentation and approaches to therapy differ for the various disease types.

Mucopolysaccharidosis type I (MPS I) is the most common type of MPS. MPS I is heterogeneous, and symptom severity varies widely. Historically, the most-to-least severe subtypes of MPS I were as follows: Hurler syndrome (MPS IH, OMIM #607014), Hurler-Scheie syndrome (MPS I-HS, OMIM #607015), and Scheie syndrome (MPS IS, OMIM #6076016). Currently, since no biochemical differences between these subtypes have been identified and their clinical findings overlap, MPS I is now divided into two subtypes: severe MPS I and attenuated MPS I. Patients with severe MPS I typically have an earlier onset of symptoms, a decline in intellectual function, and a shorter lifespan.

Pathophysiology

Mucopolysaccharidosis type I (MPS I) is a rare, inherited lysosomal storage disorder caused by a deficiency of the lysosomal enzyme, alpha-L-iduronidase. The disease is inherited in an autosomal recessive manner. Alpha-L-iduronidase deficiency results in an inability of the lysosome to break down GAGs, namely dermatan sulfate (DS) and heparan sulfate (HS). This process is essential for normal growth and homeostasis of tissues. In this disease, GAGs progressively accumulate in the lysosomes, ultimately causing cell, tissue, and organ dysfunction by largely unknown pathophysiological mechanisms. Biochemically, alpha-L-iduronidase deficiency, as seen in patients with MPS I, causes an increase in the urinary excretion of dermatan sulfate (DS) and heparan sulfate (HS).

Hurler syndrome is caused by mutation in the gene (IDUA) that encodes alpha-L-iduronidase on chromosome 4.[15] Many different mutations have been found at this locus, including mutations that cause MPS IH (Hurler syndrome), MPS IS (Scheie syndrome), and MPS I-HS (Hurler-Scheie syndrome), among others. MPS I and all subtypes are discussed in detail below.

Epidemiology

Frequency

United States

The estimated incidence of severe mucopolysaccharidosis type I (MPS I) is about 1 in 100,000 newborns. Attenuated MPS I is less common and occurs in about 1 in 500,000 newborns.

International

The birth prevalence of mucopolysaccharidosis type I (MPS I) in England and Wales from 1981-2003 was 1.07 cases per 100,000 births.[2]

Mortality/Morbidity

Lifespan in mucopolysaccharidosis type I (MPS I) encompasses a wide range. Death in early childhood can occur in the more severe form and can range to an adulthood lifespan in the attenuated form.

Race

Mucopolysaccharidosis type I (MPS I) is inherited as autosomal recessive and equally affects both sexes.

Prognosis

MPS I-HS and MPS IS are considered attenuated forms. Symptoms tend to develop later in life, starting in the teenaged years and into the early third decade of life. Symptoms are milder than those observed in MPS IH (Hurler syndrome).

Patient Education

Genetic counseling should be provided to families to explain autosomal recessive inheritance. Organizations and support groups for patients and families affected by MPS disorders include the following:

 

Presentation

History

Historically, the most-to-least severe subtypes of MPS I were as follows: Hurler syndrome (MPS IH, OMIM #607014), Hurler-Scheie syndrome (MPS I-HS, OMIM #607015), and Scheie syndrome (MPS IS, OMIM #6076016). These classifications are arbitrary categorizations of points on a spectrum of patient phenotypes and represent clinical phenotypes ranging from most severe to least severe.

Currently, no biochemical differences between these subtypes have been identified, and their clinical findings overlap. MPS I is now divided into two subtypes; (1) severe MPS I (Hurler syndrome) and (2) attenuated MPS I (Hurler-Scheie syndrome and Scheie syndrome).

Physical

Clinical manifestations of mucopolysaccharidosis type I (MPS I) show a chronic multisystemic and progressive course.[3] The disease is highly heterogeneous, spanning a spectrum of severity.

Individuals with Hurler syndrome, considered the severe end of the syndrome spectrum, appear normal at birth and develop the characteristic phenotype over the first years of life.

Phenotypic features seen in both MPS I and attenuated MPS I include facial dysmorphism, corneal clouding, hepatomegaly, valvular heart disease, obstructive airway disease,[4] developmental delay, hearing loss, skeletal deformities,[5] and joint stiffness.

In individuals with severe disease, symptoms arise early in life. These include multisystemic progressive debilitating symptoms and include neurological impairment. They have a shortened lifespan to less than 10 years. Individuals with less-severe attenuated disease have similar phenotypic features but generally have normal intellect and stature and a normal lifespan.

The Hurler syndrome (MPS IH) clinical spectrum is outlined below. These characteristic features in children with the severe form of MPS I are less obvious in children diagnosed with attenuated MPS I.

Facial dysmorphism or coarsened facial features

Coarse facial features become apparent at age 3-6 months and may progress with age.

The individual’s head is large (macrocephalic) with frontal bossing. The skull shape is often scaphocephalic owing to premature closure of the metopic and sagittal sutures. The individual’s eyes may be wide-spaced (hypertelorism) with shallow eye sockets, causing the eyes to protrude slightly. Depressed nasal bridge with broad nasal tip and anteverted nostrils is seen. Chronic nasal discharge is present. Lips are enlarged. Oropharyngeal features include a high-arched palate with macroglossia. Mandibular prognathism is present.

The clinical presentation of attenuated MPS I may be limited to mildly coarse facial features and mandibular prognathism.

Corneal clouding

As a result of glycosaminoglycan (GAG) storage and accumulation, progressive corneal clouding is common in MPS I and can begin within the first year of life. Corneal clouding has a ground-glass appearance and can lead to blindness. Retinal degeneration is also common in MPS I.

Visceral involvement

Progressive hepatosplenomegaly is common in MPS I. GAG storage in the liver and spleen does not lead to organ dysfunction; however, organ size may be markedly enlarged. Loose stools and diarrhea are episodic problems for some patients. Inguinal and umbilical hernias are common. They are occasionally present at birth or develop within the first several months of life and are often one of the first clinical signs noted.

Skeletal involvement

Patients with severe disease demonstrate skeletal manifestations of MPS I early in life, by about age 6 months. At that time, widening of the ribs and mild bone abnormalities (detected by radiological methods) are common, particularly within the hip and ovoid vertebrae. At the clinical level, skeletal involvement does not become obvious until age 10-14 months, when a gibbus deformity of the back, or dorsolumbar kyphosis, is observed in patients with severe disease.

Eventually, progressive skeletal dysplasia involving all bones is seen in all types of MPS. The vertebrae may become progressively flattened and beaked, often leading to spinal deformity. Typically, the pelvis is poorly formed, with small femoral heads and coxa valga. Involvement of the femoral head leads to progressive and debilitating hip deformity. Clavicles may be short, thickened, and irregular (“oar-shaped”).

Height progresses normally until about age 2 years; subsequently, linear growth stops. By age 3 years, height is less than the third percentile. Patients may not reach an overall height of greater than 4 feet.

Joint stiffness

The joints may become stiffened by age 2 years, and progressive arthropathy affects all joints. The hands take on a characteristic "claw" deformity, resulting from both phalangeal dysostosis and synovial thickening.

Carpal tunnel syndrome, a common complication in the MPSs, probably results from a combination of excessive lysosomal storage in the connective tissue of the flexor retinaculum and a deformity secondary to the underlying skeletal dysplasia.

Cardiopulmonary

Valvular disease, specifically aortic valve disease, may be seen in these patients. Frequent upper and lower respiratory tract infections are common. Respiratory obstruction results from enlargement of tonsils, adenoids, and tongue.

Development

In severe forms of MPS I, developmental delay is often apparent by age 12-24 months, reaching a maximum functional age of 2-4 years, followed by progressive deterioration. Language skills are often limited and can be related to hearing impairment due to chronic hearing loss/deafness. In mild forms, intellect may be within a normal range.

Others

The neck is short, and odontoid hypoplasia is noted. Vertebral subluxation with cord compression can occur. Hirsutism is present, and body hair may be coarser than usual.

Causes

Mucopolysaccharidosis type I (MPS I) is caused by a deficiency of the lysosomal enzyme, alpha-L-iduronidase.[6] This deficiency leads to accumulation of undegraded mucopolysaccharides, especially dermatan sulfate (DS), in tissues and organs. The buildup of excess dermatan sulfate leads to the gradual development of numerous morphological abnormalities in tissues and organs. The alpha-L-iduronidase gene has been mapped to the short arm of chromosome 4, band 16.3 (4p16.3). MPS I is inherited as autosomal recessive.

 

DDx

 

Workup

Laboratory Studies

Alpha-L-iduronidase activity is less than 1% in all forms of mucopolysaccharidosis type I (MPS I). The following studies are indicated in patients with suspected MPS I:

  • Lymphocytes in the blood smears may be examined for abnormal cytoplasmic inclusions.
  • Urinary testing to detect levels of the mucopolysaccharides dermatan sulfate (DS) and heparan sulfate (HS)
  • Levels of alpha-L-iduronidase, present in lysosomes, may be assayed in cultured fibroblasts and in leukocytes. [6]
  • Prenatal diagnosis to detect alpha-L-iduronidase can be performed on amniotic cells and chorionic villi cells.

Imaging Studies

Echocardiography is useful to diagnose cardiac abnormalities.

In severe MPS I, skeletal radiography (especially of the spine) can be used to detect a gibbus deformity of the lower spine.

Dysostosis multiplex (a specific pattern of radiographic changes observed in many lysosomal storage disorders) can be seen on radiographs. See the images below.

Hurler syndrome; lateral radiograph of thoracolumb Hurler syndrome; lateral radiograph of thoracolumbar vertebrae illustrates vertebral plana. Courtesy of Bruce M. Rothschild, MD.
Hurler syndrome; widened metaphyses and diaphyses Hurler syndrome; widened metaphyses and diaphyses with truncated distal portions forming a peg characterize this radiograph. Courtesy of Bruce M. Rothschild, MD.
Hurler syndrome; widened metaphyses and diaphyses Hurler syndrome; widened metaphyses and diaphyses with truncated distal portions forming a peg characterize this radiograph. Courtesy of Bruce M. Rothschild, MD.

Other Tests

Visual and auditory impairments require ocular and otic evaluations in patients with MPS I and attenuated MPS I.

Guidelines for hearing assessments in infants and children have been established by the American Academy of Pediatrics.[7]

 

Treatment

Medical Care

Because of multisystem involvement in patients with mucopolysaccharidosis type I (MPS I), treatment is multidisciplinary and encompasses both curative and palliative elements.[8] Continuity of care with ongoing evaluation at a hospital center with expertise in the management of MPS I is essential.

Enzyme replacement therapy (ERT) with laronidase may provide clinically important benefits such as improved pulmonary function, improved walking ability, and reduced excess carbohydrates stored in organs.[9, 10, 11, 12, 13] ERT can help visceral manifestations; however, since laronidase cannot cross the blood-brain barrier into the central nervous system, this treatment cannot help or stop neurodegeneration.

Treatment with hematopoietic stem cell transplantation may be an option if the patient is diagnosed at younger than age 24 months.

Surgical Care

Corrective surgery may be necessary for patients with mucopolysaccharidosis type I (MPS I) who have joint contractures and/or foot and hand deformities.[14] Corneal transplantation may be considered if visual impairment progresses and becomes markedly severe.

Consultations

Because of the varied clinical concerns and symptoms observed in patients with mucopolysaccharidosis type I (MPS I), a multidisciplinary approach to care is essential. Besides a general pediatrician’s well-child care, the following pediatric specialties are needed:

  • Neurologist
  • Cardiologist
  • Pulmonologist
  • Orthopedist/physical therapist
  • Ophthalmologist
  • Audiologist/speech therapist
  • Dentist/orthodontics
  • Developmental-behavioral specialist
  • Medical geneticist/genetic counselor: Given numerous mutations at 4p16.3, identification of which allele or alleles are involved in a patient's case requires referral to medical geneticists for diagnosis and genetic counseling.

Long-Term Monitoring

Because of the progressive disease process seen in MPS I, these patients should be regularly monitored. The focus of these evaluations should be to identify potential problems, to support early intervention, to decrease morbidity, to prevent premature mortality, and to enhance quality of life. Every patient with MPS I is unique. A general schedule of assessment and follow-up is available through the MPS I Registry to give guidance to medical providers and families. Support organizations, such as The National MPS Society, can also assist medical care personnel, caregivers, and patients.

 

Medication

Enzyme, Replacement Therapy

Class Summary

Replacing the deficient enzyme may improve symptoms and delay disease-induced complications.

Laronidase (Aldurazyme)

Indicated to treat MPS I (Hurler syndrome and Hurler-Scheie syndrome). Used to increase catabolism of GAG, which accumulates with MPS I. Treatment has been shown to improve walking capacity and pulmonary function. Laronidase is a polymorphic variant of the human enzyme a-L-iduronidase produced by recombinant DNA technology.