AUTHOR INFORMATION

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Authored by Paul Richard Harmatz, MD, Consulting Staff, Department of Gastroenterology and Nutrition, Children’s Hospital Oakland

Coauthored by Donald Nash, PhD †, Former Professor, Department of Biology, Colorado State University; Surendra Varma, MD, Vice-Chairman and Program Director, University Distinguished Professor, Department of Pediatrics, Texas Tech University School of Medicine

Paul Richard Harmatz, MD, is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, American Society of Human Genetics, North American Society for Pediatric Gastroenterology and Nutrition, and Society for Pediatric Research

Edited by Karl S Roth, MD, Chair, Professor, Department of Pediatrics, Creighton University School of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Margaret McGovern, MD, PhD, Vice Chair, Professor, Department of Human Genetics, Mount Sinai School of Medicine; Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Paul Richard Harmatz, MD
Editor's Email:	Karl S Roth, MD

eMedicine Journal, June 19 2003, VOLUME 4, Number 6

INTRODUCTION

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Background: The mucopolysaccharidoses (MPSs) are a group of 7 inherited lysosomal storage disorders caused by the deficiency of specific lysosomal enzymes required for the degradation of glycosaminoglycans (GAGs), which are complex macromolecules. The inability to degrade GAGs leads to their lysosomal accumulation and the subsequent clinical features of the disorders, which can include facial coarsening, corneal clouding, valvular heart disease, hepatosplenomegaly, and dysostosis multiplex accompanied by short stature. Mental retardation is also a feature of some of the MPS disorders, including MPS IH, or Hurler syndrome; MPS type II, or Hunter syndrome; and the type III MPS disorders, which are also known as the Sanfilippo syndromes.

MPS type I, which results from the deficiency of a-L-iduronidase activity, can manifest as one of 3 different clinical phenotypes. These include Hurler syndrome (ie, Mucopolysaccharidosis Type IH), Scheie syndrome (ie, mucopolysaccharidosis type IS), and Hurler-Scheie syndrome (ie, Mucopolysaccharidosis Type I H/S). Of these, Scheie syndrome is the mildest form of the metabolic defect.

The diagnosis of the MPS disorders is by the determination of the specific enzymatic activity in cultured fibroblasts, leukocytes, or serum. Prenatal diagnosis is possible by amniocentesis and chorionic villi biopsy.

Pathophysiology: Physical manifestations of Scheie syndrome rarely appear in children younger than 5 or 6 years; affected children appear to have normal development before this age. Coarse facial features begin to appear but never become as pronounced as in Hurler syndrome. Both syndromes may exhibit corneal clouding, which often leads to glaucoma or retinal degeneration. Deafness may occur in some patients. Joint stiffness and contractures may often lead to carpal tunnel syndrome and severe disability. Growth usually occurs at a normal rate, and intelligence usually is normal.

As with other type I MPSs, the underlying defect in Scheie syndrome is the deficiency in the a-L-iduronidase enzyme. The different enzymes involved in the MPSs are lysosomal enzymes that are involved in the breakdown of mucopolysaccharides. The deficient activity of the enzymes leads to abnormal cellular function as the partially degraded GAGs accumulate in the cells. As GAGs accumulate in connective tissue cells, the clinical features gradually appear.

Frequency:

• In the US: Precise figures for Scheie syndrome incidence are lacking, but estimated incidence is 1 case in 500,000 persons. The overall incidence of MPSs is approximately 1 case in 25,000 persons.

Mortality/Morbidity: Type IS MPS is the mildest form of the type I MPSs, and life expectancy is normal. Problems may arise from aortic valve disease.

Sex: Males and females are affected equally.

Age: Children appear normal at birth, and symptoms typically do not appear until about age 5 years. Age of onset and types of symptoms vary.

CLINICAL

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History:

• Patients with type IS MPS have normal intelligence and life span, and they develop less severe symptoms than people with either Hurler or Hurler-Scheie syndromes.



• At approximately age 5 years, dermatan sulfate accumulates in the tissues and facial features begin to show a mild coarsening. Prognathism may be particularly pronounced. A large mouth with thick lips may develop.



• Affected individuals may experience an early onset of stiffness of the joints and deformed hands and feet.



• Corneal clouding is common, appearing early in the development of symptoms, and may lead to loss of vision and glaucoma.



• Aortic valve disease often appears as a result of the buildup of dermatan sulfate deposits in the valve leaflets.

Physical: Type IS MPS is a mild form of the type I MPSs. Patients usually have normal intelligence, stature, and life span. In addition to corneal clouding, patients may have pigmented retinopathy. Aortic valve disease may be present. Skeletal defects include joint stiffness, claw hands, deformed feet, genu valgum, and carpal tunnel syndrome. Deafness may be evident in the fourth decade of life.

Causes: All type I MPSs are caused by a deficiency of the lysosomal enzyme, a-L-iduronidase. This deficiency leads to accumulation of undegraded mucopolysaccharides, especially dermatan sulfate, in tissues and organs. The buildup of excess dermatan sulfate leads to the gradual development of numerous morphological abnormalities.

• The metabolic defect in Scheie syndrome has an autosomal recessive mode of inheritance. Other MPSs also have autosomal recessive inheritance, except for type II MPS (ie, Hunter syndrome), which is transmitted in a sex-linked recessive mode.



• The gene responsible for a-L-iduronidase has been mapped to chromosome band 4p16.3.

DIFFERENTIALS

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Mucopolysaccharidosis Type I H/S
Mucopolysaccharidosis Type IH
Mucopolysaccharidosis Type II
Mucopolysaccharidosis Type III
Mucopolysaccharidosis Type IS
Mucopolysaccharidosis Type IV
Mucopolysaccharidosis Type VI
Mucopolysaccharidosis Type VII

Other Problems to be Considered:

Mucolipidoses

WORKUP

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Lab Studies:

• Thin layer chromatographic analysis of urine shows increased levels of dermatan sulfate.



• Levels of the enzyme a-L-iduronidase may be assayed in cultured fibroblasts and in leukocytes. The enzyme level can also be ascertained prenatally in amniotic cells and chorionic villi cells.

Imaging Studies:

• A characteristic mild dysostosis multiplex can often be demonstrated radiologically.

TREATMENT

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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 needed for patients with joint contractures and/or foot and hand deformities.



• Corneal transplants may be required if vision problems become severe.

Consultations: Because of the varied symptoms observed in Scheie syndrome, a multidisciplinary approach to care may require involvement with the following specialists:

• Neurologist

• Cardiologist

• Orthopedist

• Ophthalmologist

• Audiologist

In addition, patients should be referred to a medical geneticist for genetic diagnosis and genetic counseling.

MEDICATION

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Drug Category: Enzymes -- Replacing the deficient enzyme may improve symptoms and delay disease-induced complications.

Drug Name	Laronidase (Aldurazyme) -- Indicated to treat mucopolysaccharidosis I (MPS I) forms Hurler and Hurler-Scheie. Used to increase catabolism of glycosaminoglycans (GAG), which accumulates with MPS I. Treatment has shown to improve walking capacity and pulmonary function. Laronidase is a polymorphic variant of the human enzyme alpha-L-iduronidase produced by recombinant DNA technology.
Adult Dose	0.58 mg/kg IV qwk administered over 4 h; initiate at IV infusion rate of 10 mcg/kg/h and increase incrementally q15min as tolerated within first h; not to exceed 200 mcg/kg/h
Pediatric Dose	<5 years: Not established >5 years: Administer as in adults
Contraindications	Documented hypersensitivity (consider risks and benefits of readministering drug following severe hypersensitivity reaction; exercise extreme care with appropriate resuscitation measures if decision is made to readminister product)
Interactions	None reported
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Antibodies to laronidase develop by 12 wk; infusion-related hypersensitivity reactions (eg, flushing, headache, rash, fever) may occur (decreasing infusion rate or administering antihistamines may diminish symptoms)

FOLLOW-UP

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Further Outpatient Care:

• Organizations and support groups include the following:


• • Genetic Alliance
  
  
  
  • March of Dimes
  
  
  
  • National Organization for Rare Disorders
  
  
  
  • National MPS Society
  
  
  

Prognosis:

• Patients with type IS MPS have normal intelligence and life span.

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Patients with MPS may have unusual mechanical difficulties with anesthesia. Because of the bony abnormalities, the atlantoaxial joint may be unstable so cervical hyperextension should be avoided. The airway may also be difficult to visualize and/or of smaller caliber than normal, making endotracheal intubation difficult. Take precautions prior to surgery for patients who have even the mild form of type I MPS (Scheie syndrome).

Special Concerns:

• Because the MPS syndromes have different genetic causes yet share some common features, determination of the precise genetic cause is essential. Differentiation is especially critical between type II MPS (ie, Hunter syndrome), which has sex-linked recessive inheritance, and other autosomal recessive MPSs.

TEST QUESTIONS

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CME Question 1: Which of the following conditions is a specific diagnostic clue for Scheie syndrome at birth?

A: Corneal clouding
B: Coarse facial features
C: Inguinal hernia
D: Aortic valve disease
E: None of the above

The correct answer is E: Patients with Scheie syndrome usually appear normal at birth. All of the above symptoms may appear later in children with Scheie syndrome, but they may also appear in other mucopolysaccharidosis syndromes.

CME Question 2: Symptom onset in Scheie syndrome usually occurs around which of the following ages?

A: Age 1-2 years
B: Age 4-6 years
C: In the early teenage years
D: In early adulthood
E: In middle age

The correct answer is B: Most patients appear normal at birth, and the syndrome usually is not suspected until age 4-6 years. Some features may have mild expression at birth, but they tend to be progressive and lead to complications in children older than 6 years.

Pearl Question 1 (T/F): If a couple's first child has Scheie syndrome, the chances their next child will have the condition is 25%.

The correct answer is True: Scheie syndrome is inherited as an autosomal recessive trait, and, because each parent presumably is a carrier for the gene, the risk for the second child developing Scheie syndrome is 25%.

Pearl Question 2 (T/F): Unlike Hurler syndrome, caused by a deficiency of the a-L-iduronidase enzyme, patients with Scheie syndrome have an excess of this enzyme.

The correct answer is False: All type I mucopolysaccharidosis syndromes involve a lack or deficiency of the enzyme.

Pearl Question 3 (T/F): All of the type I mucopolysaccharidosis (MPS) syndromes have identical clinical features.

The correct answer is False: Although the 3 major subgroups of type I MPS have many common features, Hurler syndrome, Scheie syndrome, and Hurler-Scheie syndrome are differentiated by the severity of the symptoms.

Pearl Question 4 (T/F): Corneal clouding may be a useful symptom for distinguishing Scheie syndrome from Hunter syndrome (type II mucopolysaccharidoses).

The correct answer is True: Corneal clouding typically appears in Scheie syndrome but not in Hunter syndrome. Corneal clouding, however, is not unique to Scheie syndrome.

BIBLIOGRAPHY

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• Fensom AH, Benson PF: Recent advances in the prenatal diagnosis of the mucopolysaccharidoses. Prenat Diagn 1994 Jan; 14(1): 1-12[Medline].
• Fortuin JJ, Kleijer WJ: Hybridization studies of fibroblasts from Hurler, Scheie, and Hurler/Scheie compound patients: support for the hypothesis of allelic mutants. Hum Genet 1980 Feb; 53(2): 155-9[Medline].
• GeneTests: GeneTests Home Page. 2001; 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.
• Man TT, Tsai PS, Rau RH, et al: Children with mucopolysaccharidoses--three cases report. Acta Anaesthesiol Sin 1999 Jun; 37(2): 93-6[Medline].
• McKusick VA: Online Mendelian Inheritance in Man (OMIM) Home Page. Available at: http://www.ncbi.nlm.nih.gov/Omim[Full Text].
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• Roubicek M, Gehler J, Spranger J: The clinical spectrum of alpha-L-iduronidase deficiency. Am J Med Genet 1985 Mar; 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 1990 Nov; 47(5): 802-7[Medline].
• Scott HS, Bunge S, Gal A, et al: Molecular genetics of mucopolysaccharidosis type I: diagnostic, clinical, and biological implications. Hum Mutat 1995; 6(4): 288-302[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.
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