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; Robert Konop, PharmD, Director, Clinical Account Management, Ancillary Care Management, 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, December 16 2003, VOLUME 4, Number 12

INTRODUCTION

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Background: Mucopolysaccharidoses (MPSs) are a group of 7 inherited lysosomal storage diseases caused by a deficiency in the lysosomal enzymes that degrade glycosaminoglycans (GAGs), also known as mucopolysaccharides. The deficiency in lysosomal enzymes leaves undegraded GAGs that are either stored in the lysosome or excreted in the urine. The MPSs show extensive genetic heterogeneity among and within loci.

Multiple enzymes are involved in the degradation of GAGs; a deficiency in just one of these enzymes causes the symptoms of MPS. Many clinical features are common to the different MPS disorders, and the features may be of different intensity. Excess of one or more of the GAGs results in numerous physical and mental features that may involve virtually all organ systems. Disorders may include hearing and visual defects, cardiovascular functional impairments, hepatosplenomegaly, and dysostosis multiplex. Severe mental retardation usually is associated with MPS type IH (MPS-IH), MPS type II, and MPS type III. Symptoms vary in type and severity, depending on which MPS is involved. Although, individually, the MPSs are rare, the overall incidence is approximately 1 per 25,000 population.

Diagnosis is made by enzyme assays in fibroblasts, leukocytes, or serum, and it is possible to have prenatal diagnosis by amniocentesis or chorionic villi biopsy. Measurement of enzyme activity is becoming more definitive for determining heterozygotes. Supportive treatment is used for the management of hearing loss, hydrocephaly, and pulmonary and cardiovascular complications. Treatments using exogenously supplied genes have been encouraging.

Of the MPSs, type IH is, by far, the most common. Many different mutations have been found at the locus. In addition to MPS-IH (Hurler syndrome), the locus includes type IS (Scheie syndrome) and type I H/S (Hurler-Scheie syndrome), among others. These 2 syndromes are discussed in more detail in the eMedicine articles, Mucopolysaccharidosis Type IS and Mucopolysaccharidosis Type I H/S.

Pathophysiology: MPS-IH is regarded as the classic MPS, and the features of this syndrome typically come to mind when practitioners think of MPS. Although children born with this disease usually appear healthy at birth, during the first year of life the features become course, and the face assumes an abnormal appearance; in early times, individuals with this condition were often referred to as gargoylelike. The head becomes enlarged, and the patient has a prominent forehead, enlarged eyes, and a flattened nasal bridge. The lips are thick, and the tongue becomes enlarged. MPS-IH affects multiple organ systems and produces its characteristic dysmorphic syndrome.

The underlying defect in the disorder is molecular and leads to a 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. Deficient activity of the enzymes leads to abnormal cellular function as the partially degraded GAGs accumulate in the cells. As GAGs accumulate in cells of the connective tissue, the gradual appearance of the clinical features unfolds.

a-L-iduronidase is responsible specifically for the breakdown of dermatan sulfate (DS) and heparan sulfate (HS). As a result of the deficiency, an increase in the urinary excretion of DS and HS occurs in patients with MPS-IH.

Frequency:

• In the US: MPS-IH has an overall frequency of 1 per 100,000 population.

• Internationally: In 1997, Nelson published a comprehensive study, which yielded a frequency of 1 per 76,000 population in Northern Ireland; in 1999, Poorthius et al reported a frequency of 1.19 per 100,000 population in the Netherlands.

Mortality/Morbidity: A progressive physical and mental deterioration occurs after the onset of MPS-IH symptoms, usually around age 1 year. Maximum functional development of the child usually is reached when the child is aged 2-4 years. Orthopedic complications are common, leading to pain and immobility. Death usually occurs by age 14 years and usually is caused by obstructed airway diseases, cardiac complication, or respiratory infections.

Sex: No sex predilection exists.

Age: Children with MPS-IH usually are born without the abnormal features that typically appear before age 1 year and almost always by age 2 years. At birth, inguinal and umbilical hernias may be present. Physical and mental development delays appear about the time of the appearance of craniofacial abnormalities.

CLINICAL

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History: MPS-IH is the most clinically severe type of the MPS.

• In addition to the inguinal and umbilical hernias that may be present early in life, chronic rhinitis also may be common.



• Growth is normal or even higher than normal in infancy; however, usually by age 12-14 months, patients experience a declining growth rate resulting in short stature.



• The language skills of the child do not develop because of hearing loss, enlarged tongue, and impaired vision.



• Upper respiratory infections, ear infections, loud breathing, and continuous nasal discharge are common.



• Endocardial fibroelastosis with acute cardiomyopathy may be a problem, usually in infancy. Diffuse coronary artery disease may set in early stages. Cardiac diseases and complications are major features late in the course of the disorder and are major causes of death.



• Onset of developmental delay is usually by age 1-2 years. Functional age is achieved by 2-4 years with progressive deceleration. Poor head control and an inability to walk progress rapidly. A rapid decline of muscle tone results in breathing problems.

Physical:

• The head may appear somewhat enlarged before some of the other typical facial features develop.



• A gibbus deformity of the lower spine and hepatosplenomegaly are good early indications of the syndrome. If a diagnosis of MPS-IH is suspected from either of these nonspecific features (including possible skeletal abnormalities), a biochemical assay for urinary excretion of DS and HS is helpful for confirmation.



• The most physically visible symptoms are the skeletal abnormalities known as dysostosis multiplex. Major features include an enlarged skull, enlarged but shortened bones, malformed pelvis, and other skeletal defects.



• Corneal clouding is variable, but the progressive clouding is a common feature of the syndrome and may lead to blindness.



• Hydrocephalus also may be a complication for children older than 2 years.



• Diagnosis of the disease usually is made by age 24 months, as indicated by an enlarged liver, enlarged spleen, enlarged tongue, course facial features, prominent forehead, joint stiffness, and skeletal deformities.

Causes:

• A deficiency of the lysosomal enzyme, a-L-iduronidase


• • Accumulation of the undegraded mucopolysaccharides, DS and HS, occurs in tissues and organs.
  
  
  
  • Storage of excess mucopolysaccharides leads to numerous morphological abnormalities.
  
  
  
• Genetic causes


• • The metabolic defect in MPS-IH has an autosomal recessive mode of inheritance (as is true of the other MPSs, except for MPS-IH, Hunter syndrome, which is transmitted as a sex-linked recessive disorder).
  
  
  
  • The a-L-iduronidase gene has been mapped to band 4p16.3.
  
  
  

DIFFERENTIALS

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Mucopolysaccharidosis Type II
Mucopolysaccharidosis Type III
Mucopolysaccharidosis Type IV
Mucopolysaccharidosis Type VI
Mucopolysaccharidosis Type VII

WORKUP

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Lab Studies:

• Lymphocytes in the blood smears may be examined for abnormal cytoplasmic inclusions.



• Urinary levels of the mucopolysaccharides, DS and HS, are increased.



• Levels of a-L-iduronidase enzyme may be assayed in cultured fibroblasts and in leukocytes. Prenatal diagnosis of the enzyme level also may be made in amniotic cells and chorionic villi cells.

Imaging Studies:

• X-rays of the skeleton and especially the spine may be useful for detecting a gibbus deformity of the lower spine.



• Echocardiograms are useful for determining the nature of cardiac complications.

TREATMENT

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Medical Care: Enzyme replacement therapy with laronidase may provide clinically important benefits (eg, improved pulmonary function and walking ability, reduction of excess carbohydrates stored in organs).

Consultations:

• Referral of patients to specialists depends on the nature and progression of different symptoms in specific patients and may include audiologists, ophthalmologists, neurologists, orthopedic specialists, and pulmonary/infectious disease specialists.



• Corrective surgery may be necessary in patients with severe joint contractures and other skeletal deformities.

• Corneal transplants may be required.



• Refer patients to medical geneticists for genetic diagnosis and genetic counseling. The numerous mutations at this genetic locus call for identification of the specific allele or alleles involved.



• Support groups


• • Alliance of Genetic Support Groups (www.medhelp.org)
  
  
  
  • National Foundation-March of Dimes (www.modimes.org)

  • National Organization for Rare Disorders (www.rarediseases.org)

  • National MPS Society (www.mpssociety.org)
  
  
  

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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Complications:

• Orthopedic complications leading to pain and immobility



• Obstructed airway disease



• Cardiac complications



• Respiratory infections

Prognosis:

• Death usually occurs by age 14 years.

Patient Education:

• See Support groups.

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Patients with MPS have unusual sensitivity to anesthesia and special consideration should be undertaken before any surgery.

Special Concerns:

• Because MPSs are caused by different genetic causes and share some features in common, determining the precise genetic cause is essential. Distinguishing MPS-IH from MPS-II, Hunter syndrome (sex-linked recessive), and the other MPSs (autosomal recessives) is especially critical.

TEST QUESTIONS

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CME Question 1: Which of the following conditions is most likely to appear early in the life of patients with mucopolysaccharidosis type IH (MPS-IH)?

A: Hydrocephalus
B: Corneal clouding
C: Growth retardation
D: Hepatomegaly
E: Inguinal hernia

The correct answer is E: Inguinal hernia is one of the first conditions to be present in patients with MPS-IH. All the other symptoms are associated with MPS-IH, but they usually manifest after the first year.

CME Question 2: Death of patients with mucopolysaccharidosis type IH (MPS-IH) is likely to be caused by all but which of the following?

A: Cardiac complications
B: Obstructed airways
C: Respiratory infections
D: Renal disease
E: None of the above

The correct answer is D: A progressive physical and mental deterioration occurs after the onset of MPS-IH, usually around age 1 year. Maximum functional development of the child usually is reached by age 2-4 years. Orthopedic complications are common, leading to pain and immobility. Death usually occurs by age 14 years and usually is caused by obstructed airway diseases, cardiac complication, or respiratory infections (not renal disease).

Pearl Question 1 (T/F): The coarse facial features characteristic of mucopolysaccharidosis type IH (MPS-IH) are useful to diagnose the syndrome at birth.

The correct answer is False: Typically, the coarse facial features do not develop until the child is older than 1-2 years.

Pearl Question 2 (T/F): The chance that parents of a child with mucopolysaccharidosis type IH (MPS-IH) may give birth to another child with the condition is 100%.

The correct answer is False: MPS-IH is inherited as an autosomal recessive condition; thus, because the parents presumably are each a carrier for the gene, the risk for the second child is 25%.

Pearl Question 3 (T/F): The underlying mechanism for the dysmorphic features of mucopolysaccharidosis type IH (MPS-IH) involves deficiency of one enzyme.

The correct answer is True: In all variants of MPS-IH, patients appear to have deficiency of the a-L-iduronidase enzyme.

Pearl Question 4 (T/F): No causal therapy is available for mucopolysaccharidosis type IH (MPS-IH).

The correct answer is True: Although some success has been achieved after bone marrow transplantation, results have not been uniformly successful.

BIBLIOGRAPHY

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• Belmont PJ, Polly DW: Early diagnosis of Hurler's syndrome with the aid of the identification of the characteristic gibbus deformity. Mil Med 1998 Oct; 163(10): 711-4[Medline].
• Connor J M, Emery A E, Rimoin D L, Pyeritz RE, eds: Emery and Rimoin's Principles and Practice of Medical Genetics. 3rd ed. Churchill Livingstone; 1996.
• Fensom AH, Benson PF: Recent advances in the prenatal diagnosis of the mucopolysaccharidoses. Prenat Diagn 1994 Jan; 14(1): 1-12[Medline].
• GeneTests: Mucopolysaccharidosis Type I (Hurler Syndrome). 2000; Available at: http://genetests.org[Full Text].
• Jablonski S: Jablonski's Dictionary of Syndromes and Eponymic Diseases. 2nd ed. Melbourne, 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].
• National Center for Biotechnology Information: Mucopolysaccharidosis Type I-H (Hurler Syndrome). Availablet at: http://www3.ncbi.nlm.nih.gov/Omim/[Full Text].
• Nelson J: Incidence of the mucopolysaccharidoses in Northern Ireland. Hum Genet 1997 Dec; 101(3): 355-8[Medline].
• Nelson J, Crowhurst J, Carey B, Greed L: Incidence of the mucopolysaccharidoses in Western Australia. Am J Med Genet 2003 Dec 15; 123A(3): 310-3[Medline].
• Poorthuis BJ, Wevers RA, Kleijer WJ, et al: The frequency of lysosomal storage diseases in The Netherlands. Hum Genet 1999 Jul-Aug; 105(1-2): 151-6[Medline].
• 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].
• Scriver CR, Beaudet AL, Sly WL, et al: The Metabolic Basis of Inherited Disease. 7th ed. McGraw-Hill; 1995.
• Spitz JL: Genodermatoses: A Full-Color Clinical Guide to Genetic Skin Disorders. Lippincott Williams & Wilkins; 1996.
• Thoene JG, ed: Physicians' Guide to Rare Diseases: 1995 Edition. 2nd ed. Montvale, NJ: Dowden Publishing Co; 1995.

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