AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

The mucopolysaccharidoses (MPSs) are a group of inherited lysosomal storage disorders caused by the deficiency of specific enzymes that are required for the degradation of glycosaminoglycans (GAGs), or mucopolysaccharides. The inability to degrade these macromolecules, which are ubiquitous, results in their storage in a variety of tissues, including liver, spleen, heart, connective tissue, and others. The precise clinical features of each MPS depend upon the specific enzymatic deficiency and the pattern of storage of the particular MPS. Thus, these disorders display extensive genetic heterogeneity. In addition to somatic features, which may be severe, mental retardation also occurs in MPS-IH, MPS-II and MPSIII. Although the MPSs are rare individually, the overall incidence is approximately 1 in 25,000 people.

The diagnosis of a MPS is by determination of the specific enzymatic activity in cultured fibroblasts, leukocytes, or serum. Prenatal diagnosis by measurement of the particular enzyme in cultured amniocytes or chorionic villi is also possible.

Hurler-Scheie syndrome, also known as type I H/S MPS, is 1 of the 3 major subgroups of type I MPS. Many different mutations have been found at this locus. The other 2 major subgroups are Mucopolysaccharidosis Type IH (Hurler Syndrome) and Mucopolysaccharidosis Type IS (Scheie Syndrome).

Pathophysiology

Although MPS type IH is commonly regarded as the classic form of MPS, characteristics common to all of the subgroups include unusual and sometimes coarse facial features, some degree of dysostosis multiplex, and varied and progressive symptoms.

MPS type I H/S produces clinical features that are intermediate between types IH and IS. Type I H/S is milder than type IH and progresses more slowly. Children with this syndrome are usually healthy at birth, with onset of symptoms when aged 3-8 years. Survival to adulthood is common. Patients with type I H/S characteristically have corneal clouding, joint stiffness, dysotosis multiplex, and heart disease—characteristics shared with subgroups IH and IS, although the severity of type I H/S symptoms lies midway between the latter subgroups. Deaths from these disorders are usually caused by upper airway obstruction and pulmonary complications.

As in types IH and IS, the underlying defect in MPS type I H/S is the deficiency in the a-L-iduronidase enzyme and the lysosomal accumulation of mucopolysaccharides. In particular, a-L-iduronidase is necessary for the degradation of dermatan sulfate (DS) and heparin sulfate (HS). As a result of the deficiency, patients with type I H/S accumulate GAGs throughout their systems and urinary excretion of DS and HS is also increased.

Frequency

United States

The incidence of MPS type I H/S is quite low, ie, 1 case in 115,000 people. Overall incidence of the 3 type I subgroups and the 6 other types of MPS is approximately 1 case in 25,000 people.

International

In 1997, Nelson reported the incidence in Northern Ireland at 1 case in 280,000 people.

Mortality/Morbidity

Most patients survive into adulthood, although respiratory problems and lung complications may arise earlier.

Race

MPS I H/S affects people of all races.

Sex

With the exception of Hunter syndrome (MPS II), the MPSs are inherited as autosomal recessive traits and affect males and females equally.

Age

Children with type I H/S usually are healthy at birth. Clinical features typically appear in children aged 3-8 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

As the name Hurler-Scheie syndrome suggests, the clinical features of type I H/S lie somewhat between those of Hurler syndrome and Scheie syndrome. Until a patient's specific molecular defect is determined, assignment to types IH, IS, or I H/S is based on the severity of the symptoms. Progressive involvement of the various organs and tissues of the body occurs in all 3 subgroups of type I MPS.

In general, type I H/S symptom onset occurs in patients older than those typically affected by type IH. Symptom onset, however, varies considerably both within and among the 3 subgroups. Diagnoses based solely on the onset of clinical symptoms may be proven incorrect by subsequent precise determination of the mutant alleles involved. In each of the 3 major groups of MPS I, children are usually born without distinguishing clinical features. In patients with type IH, craniofacial abnormalities usually develop by age 1-2 years; in type I H/S, by age 3-8 years; and in type IS, at age 5 or by age 10-20 years.

Patients with type I H/S usually have normal intelligence, although, in 1976, Winters et al described an interesting case of type I MPS that differed from types IH and IS. The patient, who might have had type I H/S, was aged 10 years before problems were noted in school. She did not develop coarse facial features until age 20 years, and she died at age 25 years.

Features observed in type IH, such as joint stiffness, corneal clouding, and valvular heart disease, may also occur in patients with type I H/S but usually not until they become teenagers.

Physical

MPS type I H/S is intermediate in severity compared to type IS and type IH.

Intelligence is normal, with physical symptoms that are not as severe as those observed in Hurlers syndrome.

All symptoms develop in the early-to-late teens and include valvular heart disease, corneal clouding, deafness, and joint stiffness.

Causes

• A deficiency of the lysosomal enzyme, a-L-iduronidase
• Accumulation of the undegraded mucopolysaccharides DS and HS in tissues and organs
• Storage of excess mucopolysaccharides, leading to numerous morphological abnormalities
• • The metabolic defect in type I H/S has an autosomal recessive mode of inheritance. This mode is shared by all other MPS types except type II, which is transmitted as a sex-linked recessive defect.
  • Both types IS and IH involve deficiencies of the a-L-iduronidase enzyme, which results from mutations at the same genetic locus. Because both occur at the same locus, genetic compounds of the 2 alleles are possible, and the compound produces type I H/S.
  • The a-L-iduronidase gene has been mapped to chromosome band 4p16.3.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Mucolipidoses

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Urinary levels of DS and HS mucopolysaccharides are increased.
• Levels of the enzyme a-L-iduronidase may be assayed in cultured fibroblasts and in leukocytes. Prenatal diagnosis is also possible by measuring the enzyme levels in amniotic cells and chorionic villi cells.

Imaging Studies

• Radiography may help in the diagnosis of skeletal abnormalities.
• Echocardiography should be obtained to search for valvular heart disease.

Other Tests

• Other tests for problems in vision, hearing, and heart disease become necessary as symptoms appear.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Enzyme replacement therapy with laronidase may provide clinically important benefits, such as improved pulmonary function and walking ability and reduction of excess carbohydrates stored in organs.

Surgical Care

Corrective surgery may be necessary for patients with joint contractures or foot and hand deformities. Corneal transplants may be required if vision problems become severe.

Consultations

• Because of the varied symptoms, a multidisciplinary approach to care may be needed. In addition to surgical care, these patients may require the services of specialists in neurology, cardiology, orthopedics, ophthalmology, and audiology.
• Given the numerous mutations at this genetic locus, identification of which allele(s) are involved requires referral to medical geneticists for diagnosis and genetic counseling.

Activity

The skeletal complications of the disorder may result in some restrictions on activity.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drug Category: Enzymes

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

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prognosis

• Type I H/S is an intermediate form of the MPSs. Symptoms tend to develop during the late teens to early twenties and are milder than the symptoms in 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:
• • Genetic Alliance
  • March of Dimes
  • National Organization for Rare Disorders
  • National MPS Society

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Patients with MPS may have unusual sensitivity to anesthesia. Take precautions prior to any surgery with patients who have even a mild form of type I MPS such as type IS.

Special Concerns

• Because MPS disorders have different genetic causes yet share some common features, determination of the precise genetic cause is essential. This distinction is especially critical between type II MPS, which is sex-linked, and other MPS disorders, which are autosomal recessive.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Connor JM, Emery AE, Rimoin DL, Pyeritz RE. Emery and Rimoin's Principles and Practice of Medical Genetics. 3rd ed. New York, NY:. Churchill Livingstone;1996.
• Fensom AH, Benson PF. Recent advances in the prenatal diagnosis of the mucopolysaccharidoses. Prenat Diagn. Jan 1994;14(1):1-12. [Medline].
• GeneTests. GeneTests Home Page. Available at http://genetests.org. [Full Text].
• Jablonski S. Jablonski's Dictionary of Syndromes and Eponymic Diseases. 2nd ed. Malabar, Fla:. Krieger Publishing Co;1991.
• Jensen OA, Pedersen C, Schwartz M, et al. Hurler/Scheie phenotype. Report of an inbred sibship with tapeto-retinal degeneration and electron-microscopie examination of the conjuctiva. Ophthalmologica. 1978;176(4):194-204. [Medline].
• Kaibara N, Eguchi M, Shibata K, Takagishi K. Hurler-Scheie phenotype: a report of two pairs of inbred sibs. Hum Genet. 1979;53(1):37-41. [Medline].
• Kajii T, Matsuda I, Osawa T, et al. Hurler/Scheie genetic compound (mucopolysaccharidosis IH/IS) in Japanese brothers. Clin Genet. 1974;6(5):394-400. [Medline].
• Man TT, Tsai PS, Rau RH, et al. Children with mucopolysaccharidoses--three cases report. Acta Anaesthesiol Sin. Jun 1999;37(2):93-6. [Medline].
• McKusick VA. Online Mendelian Inheritance in Man. Available at: www.ncbi.nlm.nih.gov/omim. [Full Text].
• Mueller OT, Shows TB, Opitz JM. Apparent allelism of the Hurler, Scheie, and Hurler/Scheie syndromes. Am J Med Genet. Jul 1984;18(3):547-56. [Medline].
• Nelson J. Incidence of the mucopolysaccharidoses in Northern Ireland. Hum Genet. Dec 1997;101(3):355-8. [Medline].
• Poorthuis BJ, Wevers RA, Kleijer WJ, et al. The frequency of lysosomal storage diseases in The Netherlands. Hum Genet. Jul-Aug 1999;105(1-2):151-6. [Medline].
• Roubicek M, Gehler J, Spranger J. The clinical spectrum of alpha-L-iduronidase deficiency. Am J Med Genet. Mar 1985;20(3):471-81. [Medline].
• Scott HS, Ashton LJ, Eyre HJ, et al. Chromosomal localization of the human alpha-L-iduronidase gene (IDUA) to 4p16.3. Am J Hum Genet. Nov 1990;47(5):802-7. [Medline].
• Scriver CR, Beaudet AL, Sly WS, Valle DL, eds. The Metabolic Basis of Inherited Disease. 7th ed. New York, NY:. McGraw-Hill;1993.
• Spitz JL, ed. Genodermatoses: A Full-Color Clinical Guide to Genetic Skin Disorders. Baltimore, Md:. Lippincott Williams & Wilkins;1996.
• Thoene JG, ed. Physicians' Guide to Rare Diseases. 2nd ed. Montvale, NJ: Dowden Publishing Co;1995.
• Winters PR, Harrod MJ, Molenich-Heetred SA. alpha-L-iduronidase deficiency and possible Hurler-Scheie genetic compound. Clinical, pathologic, and biochemical findings. Neurology. Nov 1976;26(11):1003-7. [Medline].

Article Last Updated: Jun 19, 2003