AUTHOR INFORMATION

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Authored by Cydney L Fenton, MD, FAAP, Consulting Staff, Department of Pediatric Endocrinology, Children's Hospital Medical Center of Akron

Coauthored by William Rogers, MD, Chief, Pediatric Endocrinology and Pediatric Clinic, Wilford Hall Medical Center

Cydney L Fenton, MD, FAAP, is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, Endocrine Society, and Lawson-Wilkins Pediatric Endocrine Society

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:	Cydney L Fenton, MD, FAAP
Editor's Email:	Karl S Roth, MD

eMedicine Journal, August 7 2006, VOLUME 7, Number 8

INTRODUCTION

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Background: The mucopolysaccharidoses are inherited lysosomal storage diseases that result from the deficiency of specific enzymatic activities and the accumulation of partially degraded acid mucopolysaccharides. The mucopolysaccharides, also known as glycosaminoglycans, are macromolecules that are made up of repeating sulfated hexosamine and hexuronate disaccharide units attached to a core protein. Mucopolysaccharidosis II (MPS II) was first described by Charles Hunter in 1917. This X-linked disorder, which also has the eponym Hunter syndrome, results from the deficiency of iduronate 2-sulfatase.

Pathophysiology: The deficiency of iduronate sulfatase activity results in the lysosomal accumulation of heparan and dermatan sulfate. Because the mucopolysaccharides make up a large portion of the intercellular substance of connective tissue, multiple organ systems are involved, including the musculoskeletal, integumentary, cardiovascular, pulmonary, and ocular systems.

Frequency:

• In the US: Reports of the incidence of MPS II vary. MPS II occurs as frequently as 1 case in 65,000 births in some reports to as rarely as 1 case in 132,000 births in other reports.

• Internationally: Incidence may be increased among the Jewish population in Israel.

Mortality/Morbidity: Two forms of Hunter syndrome exist, a severe form designated as type A and a milder form designated as type B. In the more severe form, clinical manifestations become evident late in infancy, with the subsequent slow and systematic somatic and neurologic progression that ultimately leads to death by adolescence. The cause of death frequently is cardiorespiratory failure secondary to upper airway obstruction and cardiovascular involvement. Incidence of unexpected sudden death is about 11%.

• Type A MPS II is the more severe form and has clinical features very similar to those observed with Hurler syndrome. Clinical features are usually first observed in children aged 1-2 years. Clinical features do not progress as quickly as they do in Hurler syndrome. These children frequently are deaf and may survive into the second and third decades of life.

• Additional disease complications in older patients include carpal tunnel syndrome with entrapment of the medial nerve and a degenerative disease of the hips.

• Type B MPS II is milder than type A MPS II. Children with type B MPS II resemble children with Scheie syndrome (MPS I-S). These children are usually of normal intelligence but may have airway obstruction secondary to accumulation of mucopolysaccharide in the trachea and bronchi. They survive well into adulthood and may live into the seventh decade of life.

Race: Hunter syndrome is rare, but a slight increase in frequency has been noted in the Jewish population living in Israel.

Sex: Because of the X-linked recessive pattern of inheritance, this almost exclusively is a male dominant disorder. Females may be affected as well.

• Most females who inherit the iduronate-2-sulfatase gene inherit it from the maternal gene with preferential inactivation of the nonmutant paternal allele. Females tend to express the severe phenotype.

Age:

• The severe form of Hunter syndrome is typically diagnosed in children aged 18-36 months.

• The mild form of Hunter syndrome may not be diagnosed until well into adulthood.

CLINICAL

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History:

• Patients with Hunter syndrome almost always have neurocognitive degeneration with progressive and profound mental retardation. With type A MPS II, the diagnosis is made in children younger than 3 years. Organomegaly and a progressively severe decline in intellectual function occur. Patients with type A MPS II typically have the skeletal changes referred to as dysostosis multiplex (defects in ossification). Corneal clouding is not observed in Hunter syndrome. Patients occasionally report diarrhea.



• Type B MPS II may not be diagnosed until later in life. These patients typically have relatively normal intellectual function but may have abnormal verbal and reading skills.

Physical:

• The classic form of Hunter syndrome is type A MPS II. These children have progressive coarsening of facial features, short stature, joint stiffness, hepatosplenomegaly, and hernias as common presenting signs and symptoms. Children with type A MPS II may have papular skin lesions that are ivory in color and located on the upper back and on the lateral upper arms and thighs. These children tend to have severe mental retardation and deafness. Other presentations include cerebral ventricular dilation and mild dysostosis multiplex of bone. Other skin lesions include hypertrichosis and thickened skin. Extensive Mongolian spots associated with Hunter syndrome have also been reported.


• • The skin lesions, which develop in a reticular pattern and appear pebbly, are considered a marker for the disease. The papules and nodules are ivory-white and are distributed symmetrically between the angles of the scapulae and posterior axillary lines. They also develop in the pectoral region and on the lateral aspects of the upper arms and legs. The skin lesions typically develop before age 10 years and are seen in both types of Hunter syndrome. The Mongolian spots in Hunter syndrome tend to develop in the lumbosacral region and are large, extending to both buttocks and onto the back.
  
  
  
  • The hypertrichosis may result in synophrys.
  
  
  
  • Respiratory obstruction is secondary to the accumulation of glycosaminoglycans in the cells of the trachea.
  
  
  
  • Patients frequently have macrocephaly. The facial features of Hunter syndrome are coarse, but the children still have faces that resemble other family members.
  
  
  
  • Patients with Hunter syndrome tend to have short necks, broad chests, and a protuberant abdomen with an umbilical hernia accompanied by hepatosplenomegaly. These patients tend to have a thoracolumbar kyphosis, and their trunk is relatively short when compared with their extremities. Joint mobility is decreased, and the fingers may have clawlike deformities. Patients tend to walk with a stiff gait. Short stature is not usually detected until after the child is aged 3 years.
  
  
  
  • The hearing loss observed with MPS II often is of mixed type but may be either conductive or sensorineural and is progressive in nature.
  
  
  
  • These patients may exhibit some oral manifestations of the disease with widely spaced teeth and an enlarged tongue. The enlarged tongue is more pronounced in children older than 5 years.
  
  
  
  • Despite the absence of corneal opacities that are observed in other mucopolysaccharidoses, MPS II has ocular findings. These findings include an atypical retinitis pigmentosa and a chronic form of papilledema that leads to visual impairment.
  
  
  
• Children with type B are not usually mentally retarded but have physical features that are similar to those with type A. Skeletal manifestations in adults with type B may be restricted to small carpal bones or mild dysplasia of the pelvis or femoral heads with premature arthritis.

Causes: Hunter syndrome differs from the other mucopolysaccharidoses in that it is transmitted in an X-linked recessive fashion. A rare subtype exists that is autosomal recessive in nature.

The gene for Hunter syndrome has been localized on the X chromosome to the q27-28 region. No one specific mutation exists that leads to the syndrome, rather a number of different molecular abnormalities including deletions and translocations have been found.

DIFFERENTIALS

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Mucopolysaccharidosis Type IH
Mucopolysaccharidosis Type IS

Other Problems to be Considered:

Multiple sulfatase deficiency

WORKUP

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Lab Studies:

• Measurement of mucopolysaccharides in the urine



• Enzyme analysis: The definitive diagnosis is made by enzyme analysis for iduronate sulfatase in white blood cells or cultured skin fibroblasts. If the enzyme activity is decreased, this confirms the diagnosis of Hunter syndrome. Of note, multiple sulfatase deficiency can be confused with Hunter syndrome.

Imaging Studies:

• Radiologic imaging of the skeleton reveals characteristic bone changes (dysostosis multiplex).


• • Skull radiographs frequently show a large dolichocephalic shape with a thickened calvarium. An enlarged sella with anterior excavation of the sella may also be observed.
  
  
  
  • Long bone radiographs may reveal a precocious osteoarthritis, most notable in the femoral head.
  
  
  

TREATMENT

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Medical Care: No medical cure exists for Hunter syndrome, and care for these patients is symptomatic in nature. Researchers are exploring gene therapy to provide iduronate 2-sulfatase enzyme activity as a potential therapeutic option for the treatment of Hunter syndrome.

Surgical Care: Many children with Hunter syndrome come to medical attention because of chronic hydrocephalus or nerve entrapment. Both nerve entrapment and the chronic hydrocephalus can be treated by the appropriate surgical procedures. The risk of postobstructive pulmonary edema during anesthesia in children with Hunter syndrome appears to have increased.

• Researchers have tried bone marrow transplantation for the treatment of lysosomal storage diseases. In 16 children with Hunter syndrome who have undergone bone marrow transplantation, marked deterioration in mental retardation continued in 15. All 15 children had intelligence quotients that fell below 50. Some of these children did have improvement in their somatic symptoms, with a decrease in the coarsening of their face and hair and an increase in the range of motion in their joints. The hearing deficits also may not improve after bone marrow transplantation.



• In addition to the study of bone marrow transplantation, the use of umbilical cord blood transplantation from unrelated donors has been attempted at least once following the failure of a bone marrow transplant.



• Surgeons are also frequently involved in the surgical correction of hernias and joint contractures.



• Because of the risk of severe pulmonary edema during anesthesia, children with Hunter syndrome should undergo anesthesia at a center with experienced personnel.

Consultations: The supportive therapy for Hunter syndrome involves a multidisciplinary approach. Subspecialists who should be involved in the care of a child with MPS II include pediatricians, neurologists, orthopedists, otolaryngologists, ophthalmologists, occupational and physical therapists, as well as geneticists. The need for genetic counseling cannot be overstated.

MEDICATION

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Idursulfase, a purified form of human iduronate-2 sulfatase was approved by the US Food and Drug Administration (FDA) as an orphan drug in July 2006.

Drug Category: Enzymes -- Enzyme replacement therapy with idursulfase delays disease progression and premature death. An improved capacity to walk was observed in those receiving idursulfase in a randomized, double-blind, placebo-controlled study of 96 patients.

Drug Name	Idursulfase (Elaprase) -- Purified form of human iduronate-2-sulfatase, a lysosomal enzyme. Hydrolyzes 2-sulfate esters of terminal iduronate sulfate residues from the glycosaminoglycans (GAGs) dermatan sulfate and heparan sulfate in the lysosomes of various cell types. Indicated for mucopolysaccharidosis type II (Hunter syndrome) because it replaces insufficient levels of the lysosomal enzyme iduronate-2-sulfatase.
Adult Dose	0.5 mg/kg IV qwk; total volume typically infused over 1-3 h; initiate at rate of 8 mL/h for first 14 min, if tolerated may increase by 8-mL/h increments q15min; not to exceed 100 mL/h
Pediatric Dose	<5 years: Not established >5 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Anaphylactoid reactions have occurred (additional monitoring required, especially for individuals with respiratory compromise); appropriate medical support should be available during infusion, and premedication with antihistamines and/or corticosteroids recommended prior to infusion; common adverse effects include infusion-related reactions (eg, pyrexia, headache, arthralgia, pruritus, malaise, visual disturbance, musculoskeletal pain, urticaria)

FOLLOW-UP

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Complications:

• Various complications may arise in the severe form of MPS II.



• Thickening of the tracheal walls may lead to obstructive airway disease.



• As the hepatosplenomegaly progresses, the abdominal wall becomes markedly distended and hernias become more prominent.



• All of the major joints, including the hips, knees, wrists, elbows, shoulders, and finger joints, become involved. This results in a decreased ability to pick up small objects, and, over time, walking becomes more difficult. The wrist is prone to carpal tunnel syndrome, which can further decrease hand function.



• Boney involvement occurs in MPS II, which may lead to short stature.

Prognosis:

• The life expectancy for patients with the severe form (MPS IIA) is only about 10-15 years; however, those with the milder form (MPS-IIB) may live well into the seventh or eighth decades of life.



• After hematopoietic stem cell transplant, the characteristic cutaneous papules tend to regress and most are gone by 3 months after the transplant.

Patient Education:

• Genetic counseling is strongly encouraged for families with a history of Hunter syndrome.



• Support groups can be a good source of information for families, some of which are listed below.



• National Organization for Rare Disorders, Inc (NORD)
  55 Kenosia Ave
  PO Box 1968
  Danbury, CT 06813-1968
  Phone: (203) 744-0100
  Toll-free: (800) 999-6673
  Fax: (203) 798-2291



• The Society for Mucopolysaccharide Diseases
  46 Woodside Road
  Amersham Buckinghamshire, HP6 6AJ
  United Kingdom
  Phone: 0845 389 9901
  Fax: 0845 389 9902



• The National MPS Society
  102 Aspen Drive
  Dowington, PA 19335
  Phone:(610) 942-0100
  Fax: (610) 942-7188



• Children Living with Inherited Metabolic Diseases (CLIMB)
  The Quadrangle, Crewe Hall
  Weston Road
  Crewe
  Cheshire, CW1-6UR
  England, United Kingdom
  (127) 0 2 50221



• Mucopolysaccharide & Related Diseases Society Australia Ltd.
  PO Box 623 Hornsby, NSW 2077 Australia
  Phone: 612.9476.8411
  Fax: 612.9476.8422
  E-mail: info@mpssociety.org.au



• The Canadian Society for Mucopolysaccharide and Related Diseases Inc.
  PO Box 30034
  RPO Parkgate
  North Vancouver BC, V7H 2YB
  Phone: (604) 924-5130
  Toll-free: (800) 667-1846
  Fax: (604) 924-5131
  Email: kirsten@mpssociety.ca

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Mucopolysaccharidoses represent a wide clinical spectrum of phenotypes that range from very mild to severe forms. The very mild forms of MPS I, II, and VI frequently cannot be differentiated based on clinical experience. Pitfalls in the early diagnosis of mucopolysaccharidoses can be minimized if the appropriate laboratory studies are obtained and if the physician understands that these diseases are dynamic in nature.

Special Concerns:

• The option of prenatal testing exists. Prenatal testing can be performed using chorionic villus sampling or using cells collected via amniocentesis.

TEST QUESTIONS

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CME Question 1: An 18-month-old boy is brought to the doctor's office for his routine well-child care. When the mother is asked if she has any concerns, she tells the physician that her son does not seem to be as smart as her daughter. He does not say mama or dada, and his belly button is pushed out from his body. On examination, the physician notes coarsened facial features with a prominent forehead and flattened nasal bridge. On abdominal examination, the physician is able to palpate an enlarged liver and spleen, and the patient has a small umbilical hernia. What is the most likely diagnosis?

A: Untreated congenital hypothyroidism
B: Normal for age
C: One of the mucopolysaccharidoses
D: Glycogen synthase deficiency
E: None of the above

The correct answer is C: This vignette is designed to raise the possibility of the diagnosis of a mucopolysaccharide disorder. Congenital hypothyroidism still is a distinct possibility, and thyroid function tests must be performed in this child; however, the facial features and hepatosplenomegaly make the diagnosis of congenital hypothyroidism less likely. Normal for age is not a likely diagnosis because these findings are not normal findings on history or physical examination for any 18-month-old child. In considering glycogen synthase deficiency as a diagnosis, the hallmark of this condition is fasting hypoglycemia, and it is not associated with the clinical phenotype presented in this case.

CME Question 2: A woman is considering having a second child. Her first son was recently diagnosed with Hunter syndrome, and she knows that she is a carrier. She wants to know what the chances are that her next child will have Hunter syndrome as well. What should the physician tell her?

A: Hunter syndrome is so rare that she is unlikely to have another affected child.
B: Because she is a carrier, a 50% chance exists that any male offspring will have the disorder. A 50% chance also exists that any female offspring will be a carrier as well.
C: Because she is a carrier, a 50% chance exists that any female offspring will have the disorder. A 50% chance also exists that any male offspring will be a carrier.
D: Because she is a carrier, any child that she has will have the disorder or be a carrier.
E: None of the above is correct.

The correct answer is B: Hunter syndrome is an X-linked recessive disorder; therefore, males are predominately affected. Knowing the mother’s carrier status is vital to providing appropriate genetic counseling. One half of her male offspring will get the mutated X chromosome, while the other half will be normal. The female offspring are at an increased risk of being a carrier for Hunter syndrome as well, with 50% of the females being carriers.

Pearl Question 1 (T/F): The most common cause of sudden unexplained death in a patient with Hunter syndrome is stroke.

The correct answer is False: While cardiovascular complications are common in patients with Hunter syndrome, the most common cause of death is cardiorespiratory failure. Unexplained sudden death occurs in patients with mucopolysaccharidosis (MPS) and is thought to be caused by an abnormality of the cardiac conduction system.

Pearl Question 2 (T/F): Males are more likely to be affected by Hunter syndrome than females.

The correct answer is True: Hunter syndrome is the only mucopolysaccharidosis (MPS) that is X-linked, so the vast majority of patients are male. Case reports exist in the literature of females affected as well.

Pearl Question 3 (T/F): Café au lait lesions and hypopigmented macules are the characteristic skin lesions observed in patients with mucopolysaccharidosis II (MPS II).

The correct answer is False: MPS II is associated with several skin findings, including hypertrichosis and pebbly-appearing ivory-white papules and nodules. Hypopigmented lesions and café au lait macules are not characteristic of Hunter syndrome.

Pearl Question 4 (T/F): Patients with Hunter syndrome do not have corneal clouding.

The correct answer is True: Mucopolysaccharidosis II (MPS II) is not associated with corneal clouding as is observed in other mucopolysaccharidoses. This can be helpful in making a clinical diagnosis.

BIBLIOGRAPHY

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• Bergstrom SK, Quinn JJ, Greenstein R, Ascensao J: Long-term follow-up of a patient transplanted for Hunter's disease type IIB: a case report and literature review. Bone Marrow Transplant 1994 Oct; 14(4): 653-8[Medline].
• Fenichel GM: Psychomotor Retardation and Regression: Mucopolysaccharidoses. In: Clinical Pediatric Neurology: A Signs and Symptoms Approach. Philadelphia, Pa: WB Saunders Co; 1993: 138.
• Gorlin RJ, Cohen MM, Levin LS: Mucopolysaccharidosis II (Hunter Syndrome). In: Syndromes of the Head and Neck. 3rd ed. New York, NY: Oxford University Press; 1990: 106-107.
• Hishitani T, Wakita S, Isoda T, et al: Sudden death in Hunter syndrome caused by complete atrioventricular block. J Pediatr 2000 Feb; 136(2): 268-9[Medline].
• Isoyama K, Ohnuma K, Ikuta K, et al: Unrelated cord blood transplantation for second hemopoietic stem cell transplantation. Pediatr Int 2003 Jun; 45(3): 268-74[Medline].
• Ito K, Ochiai T, Suzuki H, et al: The effect of haematopoietic stem cell transplant on papules with 'pebbly' appearance in Hunter's syndrome. Br J Dermatol 2004 Jul; 151(1): 207-11[Medline].
• Jones KL: Hunter Syndrome (Mucopolysaccharidosis II). In: Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, Pa: WB Saunders Co; 1997: 462-463.
• Lonergan CL, Payne AR, Wilson WG, et al: What syndrome is this? Hunter Syndrome. Pediatr Dermatol 2004 Nov-Dec; 21(6): 679-81[Medline].
• Maria BL, Medina CD, Hoang KB, Phillips MI: Gene therapy for neurologic disease: Benchtop discoveries to bedside applications. 2. The bedside. J Child Neurol 1997 Feb; 12(2): 77-84[Medline].
• Matalon RH: Disorders of Mucopolysaccharide Metabolism. In: Nelson Textbook of Pediatrics. Philadelphia, Pa: WB Saunders Co; 1992: 372-375.
• McKinnis EJ, Sulzbacher S, Rutledge JC, et al: Bone marrow transplantation in Hunter syndrome. J Pediatr 1996 Jul; 129(1): 145-8[Medline].
• Ochiai T, Ito K, Okada T, et al: Significance of extensive Mongolian spots in Hunter's syndrome. Br J Dermatol 2003 Jun; 148(6): 1173-8[Medline].
• Sapadin AN, Friedman IS: Extensive Mongolian spots associated with Hunter syndrome. J Am Acad Dermatol 1998 Dec; 39(6): 1013-5[Medline].
• Spranger J: Mucopolysaccharidoses. In: Emery and Rimoin's Principles and Practice of Medical Genetics. Vol 2. 3rd ed. New York, NY: Churchill Livingstone; 1997: 2074.
• Tuschl K, Gal A, Paschke E: Mucopolysaccharidosis Type II in Females: Case Report and Review of Literature. Pediatric Neurology 2005; 32: 270-272.
• Ullrich K, Kresse H: Mucopolysaccharidoses. In: Physician's Guide to the Laboratory Diagnosis of Metobolic Diseases. London, England: Chapman & Hall; 1996: 303-317.
• Walker RW, Colovic V, Robinson DN, Dearlove OR: Postobstructive pulmonary oedema during anaesthesia in children with mucopolysaccharidoses. Paediatr Anaesth 2003 Jun; 13(5): 441-7[Medline].
• Wappner RS, Brandt IK: Lysosomal Storage Disorders. In: Principles and Practice of Pediatrics. Philadelphia, Pa: JB Lippincott Company; 1994: 115-118.

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