eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Mucopolysaccharidosis Type II

Nancy E Braverman, MS, MD, Associate Professor, Department of Human Genetics, McGill University
Vinayak Kottoor, MD, Resident, Department of Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University Hospital; Mary Kay Conover-Walker, MSN, PNP, Pediatric Nurse Practioner, Institute of Genetic Medicine, Johns Hopkins Hospital; Cydney L Fenton, MD, FAAP, Consulting Staff, Department of Pediatric Endocrinology, Children's Hospital Medical Center of Akron

Updated: Jul 14, 2009

Introduction

Background

Hunter syndrome, or mucopolysaccharidosis type II (MPS II), is a member of a group of inherited metabolic disorders collectively termed mucopolysaccharidoses (MPSs). The MPSs are caused by a deficiency of lysosomal enzymes required for the degradation of mucopolysaccharides or glycosaminoglycans (GAGs). Eleven distinct single lysosomal enzyme deficiencies are known to cause 7 recognized phenotypes of MPS. All of the MPSs are inherited in an autosomal recessive fashion, except for Hunter syndrome, which is X-linked.

In the early 1900s, Gertrud Hurler and Charles Hunter first described patients with MPS, whose diseases now bear their names; subsequent MPSs have been assigned numbers and eponyms loosely associated with the chronology and origin of their report. MPS II was first described by Hunter in 1917. This X-linked disorder results from the deficiency of iduronate sulfatase and subsequent accumulation of heparan and dermatan sulfate.

Hunter, an internist in Canada, described a case of 2 brothers with what came to be called Hunter syndrome at the Royal Society of Medicine in London. In 1933, Binswanger and Ullrich coined the term dysostosis multiplex to describe the constellation of skeletal findings specific to patients with MPS and other lysosomal storage disorders. These included a large skull with a J-shaped sella, anterior hypoplasia of the thoracic and lumbar vertebral bodies, hypoplasia of the pelvis with small femoral heads and coxa valga, oar-shaped ribs (narrow at the vertebrae and widening anteriorly), diaphyseal and metaphyseal expansion of long bones with cortical thinning, and tapering of the proximal phalanges. However, this family of diseases was not described as the MPSs until 1952, when Brante isolated the stored mucopolysaccharides in these patients.

In 1957, Dorfman and Lorincz developed clinical assays to detect urinary mucopolysaccharides. The work of Neufeld et al from the late 1960s demonstrated that mucopolysaccharide accumulation in fibroblasts from patients with Hurler and Hunter syndromes could be corrected by co-culturing them with fibroblasts or tissue extracts from patients with a different MPS. This led to the purification and subsequent identification of each defective enzyme.

The MPSs share a chronic progressive course with multisystem involvement, several physical features, laboratory findings, and radiographic abnormalities; these include facial coarsening, hepatomegaly, excretion of urinary GAG fragments, and leukocyte inclusion bodies. Patients with Hunter syndrome are distinguished from patients with other MPSs because of the male dominant pattern due to the X-linked transmission. Females in whom preferential inactivation of the nonmutant paternal allele occurs can have features of Hunter syndrome. Also, corneal clouding is not seen in Hunter syndrome.

Pathophysiology

Frequency

United States

Incidence is unknown at present, but estimates may soon be available, following the institution of newborn screening for lysosomal storage disorders. Development of newborn screening strategies is underway.⁵

International

The estimated incidence of MPS type II widely varies. The estimated incidence is 1 case per 34,000 in Israel, 1 case per 111,000 in British Columbia, and 1 case per 132,000 in the United Kingdom.^6,7,8 Recent studies from Germany and the Netherlands report an incidence of 1 case in 140,000-330,000 live births, and 1.3 cases per 100,000 male births.⁹

Mortality/Morbidity

Two forms of Hunter syndrome are recognized: a severe form, designated as type A, and a milder form, designated as type B. These forms represent two ends of a clinical spectrum of severity.  The distinction is clinical because IDS activity is equally depressed in the assay used in both forms of Hunter syndrome. In the more severe form, clinical manifestations become evident in the first few years of life, with the subsequent slow and systematic somatic and neurologic progression that ultimately leads to death by adolescence. The cause of death is frequently cardiorespiratory failure secondary to upper airway obstruction and cardiovascular involvement. Incidence of unexpected sudden death is about 11%.¹⁰

Type A MPS II is the more severe form and has clinical features very similar to those observed with Hurler syndrome, except that corneal clouding is not seen and clinical features do not progress as quickly as they do in Hurler syndrome. Development is delayed. 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.

Children with type B MPS II resemble children with Hurler/Scheie (MPS IH/S) or Scheie syndromes (MPS IS). These children usually have 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. Most of these patients develop cardiac valvular disease.

Race

Hunter syndrome is panethnic and rare; however, a higher incidence has been noted in the Jewish population living in Israel.

Sex

Inheritance is X-linked recessive, and affected males do not usually reproduce. The disorder is occasionally diagnosed in females consequent to skewed X inactivation, with the active X carrying the mutant IDS allele.¹¹

Age

The severe form of Hunter syndrome is typically diagnosed in children aged 2-4 years. The mild form of Hunter syndrome may not be diagnosed until the teenage years or well into adulthood.

Clinical

History

• Type A mucopolysaccharidosis type II (MPS II) disease (severe form)
  • Disease presentation is usually between age 2-4 years and is characterized by progressive involvement of the nervous system and somatic effects.¹⁰  
  • Upon initial presentation, suggestive features may include coarse facies, short stature, skeletal deformities, joint stiffness, and mental retardation.
  • Given the age of presentation, the physical characteristics tend to prompt an evaluation earlier than developmental concerns might.
  • Additional features at presentation or thereafter may include hyperactivity, progressive hearing loss, hepatomegaly, carpal tunnel syndrome, progressive retinal degeneration, and recurrent ear infections.
  • Involvement of the GI system both via autonomic dysregulation and, possibly, mucosal dysfunction causes chronic diarrhea in younger patients; significant constipation may be a problem later on.
  • Communicating hydrocephalus can develop and can further contribute to neurological deterioration. The neurologic involvement is progressive and profound in the late stages of life (typically the second and third decades of life). 
  • Cause of death is commonly complications of obstructive airway disease, cardiac failure, or both. 
  • Glycosaminoglycan (GAG) accumulation involves the cardiac valvular leaflets, leading to dysfunction. The myocardium causes thickening and eventually leads to coronary artery compromise, myocardial disease, and, in conjunction with the airway disease, pulmonary hypertension. 
  • Other features occasionally seen, especially in those patients considered most severely affected, include seizures and an overall severity approaching that of Hurler syndrome. 
  • Some of these severely affected patients have extensive genomic deletions involving iduronate sulfatase (IDS) and contiguous genes.³
• Type B disease (milder form)^{12,13,14,15,16,17,18}
  • Presentation is typically later in adolescence or adulthood.  
  • Somatic involvement is distinguished from that seen in severe Hunter syndrome by the rate of progression and the degree of eventual handicap.  
  • Intelligence is usually preserved. 
  • Hearing impairment, joint stiffness, coarse facial features, upper airway disease, and carpal tunnel syndrome remain hallmarks, even in the milder form of disease, only with a more protracted time frame.  
  • Communicating hydrocephalus is not as often encountered, although papilledema has been seen in the absence of intracranial pressure elevation, suggesting a localized process involving the optic nerve within the eye.  
  • Also, although corneal clouding is a feature that, by its absence, differentiates MPS II from MPS I (Hurler), reports of discrete corneal opacities seen on slit-lamp examination and of no significant effect on visual acuity have been reported.
    
    

    

    Clouding of the cornea.

    
    
  • Retinal degeneration is also seen to a lesser degree in type B disease. 
  • Death is often secondary to airway disease (obstructive) and cardiac failure, as is seen in type A disease, although usually beyond the fifth decade of life.

Physical

Both types A and B MPS II have deficient IDS activity and are retained as terms useful in clinically describing the extremes of a disease spectrum.

• Children with classic type A MPS II 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 tend to have severe mental retardation and deafness. Other presentations include cerebral ventricular dilation and dysostosis multiplex. Skin findings include hypertrichosis, thickened skin, and multiple Mongolian spots. Children with type A and B MPS II may have papular skin lesions that are ivory in color and are located on the upper back and on the lateral upper arms and thighs.
  • 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 symmetrically distributed 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. When biopsied, the description is of a dermal mucinosis. 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. Data from the Hunter Outcome Survey indicates that patients display normal, average height until age 9-10 years and then height below the third percentile thereafter.⁹
  • The hearing loss observed with MPS II is often 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 retinal degeneration and a chronic form of papilledema that leads to visual impairment.^15,16,17
• Children with type B disease do not usually have mentally retardation 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 and femoral heads with premature osteoarthritis.

Causes

• Hunter syndrome differs from the other MPSs in that it is transmitted in an X-linked recessive fashion.
• Defects in the gene encoding IDS are causative. Molecular analysis shows a wide variety of defects in IDS that cause Hunter syndrome. No single mutation has a high frequency of occurrence. Identical mutations have been found in patients with both mild and severe disease, implicating the contribution of other genetic or environmental modifiers on the phenotype.^19,20  
• Although no strong point mutation correlations between genotype and phenotype are recognized, all patients with large deletions or rearrangements of the IDS gene have severe disease. Patients with contiguous deletions have additional findings attributed to the other genes involved.^3,21  Such contiguous gene deletions are identified in around 20% of patients.^22,23
• Finally, skewed inactivation of the nonmutant allele in a heterozygous female can lead to clinical disease. Severity is related to the type of mutation on the active X chromosome, as is seen in male patients, and is also related to the ratio of active mutant and nonmutant alleles in the female patient.²⁴

Differential Diagnoses

Mucopolysaccharidosis Type I H/S
Mucopolysaccharidosis Type IH
Mucopolysaccharidosis Type III
Mucopolysaccharidosis Type IS
Mucopolysaccharidosis Type VII
Multiple Sulfatase Deficiency

Other Problems to Be Considered

Carrier status of the mother determines the recurrence risk to the family and can be accurately determined by molecular testing once the IDS mutation in the male proband is identified.

Workup

Laboratory Studies

• Urine spot tests are readily available to screen for mucopolysaccharidoses (MPSs). These tests are associated with false-positive and false-negative results; testing more than one urine sample is recommended.
• Semiquantification of urinary glycosaminoglycan (GAG) can be obtained by spectrophotometric assays with dimethylmethylene blue.
• Heparan sulfate, keratan sulfate (KS), and dermatan sulfate can be distinguished by electrophoretic techniques to narrow the differential among the MPSs.
• Clinical suspicion should take precedence over screening test results because the results vary.
• A new enzyme-linked immunoassay (ELISA) technique has recently been shown to accurately quantify GAGs in urine and blood.
• Lysosomal enzymes are present in all cells except mature erythrocytes.
• The diagnosis is confirmed by direct enzymatic assay in leukocytes or fibroblasts.
• The enzyme deficient in Hunter syndrome is iduronate-2-sulfatase. In males without a family history, normal activity of another sulfatase is required to rule out multiple sulfatase deficiency.
• University hospitals with expertise in metabolic genetics perform these assays on heparinized blood or fibroblasts cultured from a small (2 mm) skin biopsy.
• For prenatal diagnosis, enzyme activity can be measured in amniocytes or chorionic villi. Determination of the carrier state by enzyme analysis is not always possible because the range of enzyme activity in noncarriers and carriers overlaps. Carriers can be diagnosed by molecular analysis of the IDS gene. Usually the mutation is first identified in the affected proband.
• GeneTests lists several institutions that offer enzymatic and mutation analysis for Hunter syndrome. Obtaining specific instructions from the laboratory performing these assays prior to collecting samples from patients is beneficial.

Imaging Studies

• A full skeletal survey should be obtained in a patient with suspected MPS. The following views are recommended:
  • Anteroposterior (AP) and lateral views of the skull with visualization of the sella
  • Flexion and extension radiographs of the cervical spine
  • AP and lateral views of the odontoid
  • AP and lateral views of the chest
  • Standing AP and lateral views of entire spine
  • Standing pelvis view with visualization of the femoral heads articulating with the acetabulum
  • Preferably, standing AP views of the lower extremities, including the entire femur, articulation with tibia (knees for genu valgus), and ankles
  • AP views of at least one foot, one hand, forearm, elbow in extension, humerus, and shoulder
• CT scanning or MRI of the brain stem and cervical spine should be performed to evaluate odontoid hypoplasia and cord compression. The authors recommend additional cerebrospinal fluid (CSF) flow studies in flexion and extension in older patients as indicated.

Other Tests

• Ophthalmologic examination: An ophthalmology examination with slit lamp should be performed at the time of initial evaluation to look for corneal and retinal disease.
• Cardiac echocardiography and ECG
• Airway evaluation: This is performed to assess for upper airway obstruction, sleep apnea, and pulmonary functions.²⁵
• Audiology evaluation

Histologic Findings

• Histologic examination of either peripheral granulocytes or bone marrow cells may reveal Alder-Reilly granulations.
• When stained with toluidine blue, peripheral lymphocytes exhibit metachromatic granules within vacuoles.

Treatment

Medical Care

Although no curative treatment for lysosomal storage disorders is available, numerous treatment options are becoming available to improve the quality of life in these patients. The relevant enzyme (iduronate sulfatase [IDS] in the case of mucopolysaccharidosis type II [MPS II]) can be given in the form of enzyme replacement therapy (ERT) or by bone marrow transplantation (BMT). Factors that affect outcome include the type of MPS, the donor genotype (in the case of BMT), and the age and degree of clinical involvement at the start of therapy or transplantation.  

In order to identify individuals that might benefit from treatment before the onset of irreversible organ damage, newborn screening for these disorders is being developed.²⁶  Gene therapy is a promising but inadequately developed modality of treatment. Difficulties with vector selection and efficiency of delivery persist; thus, this therapy is still in the early stages of development.

• BMT
  • In 16 children with Hunter syndrome who have undergone BMT, marked deterioration in mental retardation continued in 15.²⁷ 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 may not improve after BMT.
  • In addition to the study of BMT, the use of umbilical cord blood transplantation from an unrelated donor has been attempted at least once.²⁸
• ERT: See Medication.

Surgical Care

• Many children with Hunter syndrome require surgical intervention for complications of their disorder. These include intervention for chronic hydrocephalus, nerve entrapment (carpal tunnel syndrome), abdominal wall hernias, tracheostomy, and joint contractures.
• Individuals with Hunter syndrome should undergo anesthesia at a center with experienced personnel.
• Problems can occur with airway management, postobstructive pulmonary edema, and reactive airway disease.

Consultations

• Care for the patient with Hunter syndrome involves a multidisciplinary approach and includes pediatricians, neurologists, orthopedists, otolaryngologists, ophthalmologists, and occupational and physical therapists, as well as geneticists and counselors.
• The recognition and diagnosis of MPS II was recently reviewed.²⁹

Medication

Idursulfase, a purified form of human iduronate sulfatase (IDS) was approved by the US Food and Drug Administration (FDA) as an orphan drug in July 2006. It is distributed as Elaprase (Shire Human Genetics Therapies, Inc). FDA approval was based on the study of 96 patients in a double-blind, placebo-controlled study over one year.^30,31 This study demonstrated improvement in a 6-minute walk test and reduction in liver and spleen volumes and urinary glycosaminoglycan (GAG) levels.

The extent to which enzyme replacement therapy (ERT) delays disease progression and whether or not it can prevent premature death is still unknown. Severely affected patients were not enrolled, and thus the benefit to them remains to be determined. ERT does not enter the CNS and has no impact on cognitive function. Thus, the role of ERT in the management of Hunter syndrome is under debate.³²

Enzymes

ERT is a life-long therapy that may improve the quality of life for patients with mucopolysaccharidosis type II (MPS II).

Idursulfase (Elaprase)

Purified form of human iduronate-2-sulfatase, a lysosomal enzyme. Hydrolyzes 2-sulfate esters of terminal IDS residues from the GAGs dermatan sulfate and heparan sulfate in the lysosomes of various cell types. Indicated for MPS II (Hunter syndrome) because it replaces the deficiency of iduronate-2-sulfatase in this disease. The drug is continued throughout life, and, thus, both the time and financial commitment can be extensive. Administration should be done by a health care professional in an experienced infusion center.

Dosing

Adult

0.5 mg/kg IV qwk; total volume typically infused over 1-3 h, although longer infusion time (up to 8 h) may be required because of infusion reactions; 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;
If an infusion reaction occurs, infusion may be slowed, temporarily stopped, or discontinued for the visit, based on clinical judgment

Pediatric

<5 years: Not established
>5 years: Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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, corticosteroids, or both recommended prior to infusion; common adverse effects include infusion-related reactions (eg, pyrexia, headache, arthralgia, pruritus, malaise, visual disturbance, musculoskeletal pain, urticaria); about 50% of patients in clinical studies produced anti-idursulfase IgG antibodies during treatment, and these patients had an increase in infusion reactions; the presence of antibodies on the effectiveness is unknown

Follow-up

Further Outpatient Care

• A Hunter Outcome Survey was established by Shire to better understand the variability and progression of Hunter syndrome (mucopolysaccharidosis type II [MPS II]) and to monitor long-term treatment effects of Elaprase.
• The authors encourage patient participation to gather additional data regarding response to enzyme replacement therapy (ERT). Both patients receiving treatment and those who are not can participate. As of May 2007, 263 patients from 16 countries were enrolled; 24% were being treated with ERT.⁹
• Annual follow-up includes the following:
  • Echocardiography and ECG
  • Pulmonary function tests
  • Liver and spleen volume (MRI)
  • Skeletal survey 
  • 6-minute walk test (every 6 mo) 
  • Quality of life and pain assessment 
  • Urinary glycosaminoglycan (GAG) level and iduronate sulfatase (IDS) antibody measurement
  • Audiography 
  • Baseline sleep study, repeated as needed 
  • CBC count, comprehensive metabolic panel, and routine urinalysis

Complications

Various complications may arise in the severe form of MPS II, including cardiac valvular disease and neurological complications³³ .

• Thickening of the tracheal walls may lead to obstructive airway disease.
• As 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.
• The Hunter Outcome Survey noted that 33% of patients develop hypertension, and neurological involvement is reported in 84% of patients (mostly behavioral and cognitive abnormalities).⁹

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

Patient Education

Support groups can be a good source of information for families, some of which include the following:

• 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
• 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
  email: 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

Other sources of information include the following:

• Shire Medical Information (medinfoglobal@shire.com)
• Medline Plus - Information on Hunter syndrome
• Online Mendelian Inheritance in Man (OMIM) - In-depth information on the genetics of Hunter syndrome, sponsored by Johns Hopkins University
• MPS/ML Forum - A message board for those caring for a special needs child, specifically those with MPS and/or mucolipidosis (ML) disorders
• Alliance of Genetic Support Groups - Contains a newsletter, resources, and forum for anyone affected by a genetic disease; promotes advocacy, education, and empowerment for genetic support groups
• Lysosomal Storage Disorders Support - Online forum about lysosomal storage disorders
• A Parent's Guide: Accessing Programs for Infants, Toddlers, and Preschoolers With Disabilities - National Information Center for Children and Youth with Disabilities guide intended to assist families in obtaining help for their young children with special needs (birth through age 5 y); answers commonly asked questions about early intervention services for infants and toddlers (birth to age 2 y) and related services for children aged 3-5 years; identifies early intervention policies and contacts in the state and surrounding area
• MPS Society Resources Family Assistance Program - Provides grant funding for parents of a child with MPS/ML or an adult with MPS/ML (Those who reside in the United States and are members in good standing with the MPS Society are eligible.)

Miscellaneous

Medicolegal Pitfalls

• Mucopolysaccharidoses (MPSs) 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

• Prenatal testing can be performed using chorionic villus sampling or using cells collected via amniocentesis.

Multimedia

Media file 1: Clouding of the cornea.

References

1. Clarke LA. Idursulfase for the treatment of mucopolysaccharidosis II. Expert Opin Pharmacother. Feb 2008;9(2):311-7. [Medline].

2. Timms KM, Lu F, Shen Y, et al. 130 kb of DNA sequence reveals two new genes and a regional duplication distal to the human iduronate-2-sulfate sulfatase locus. Genome Res. Aug 1995;5(1):71-8. [Medline].

3. Timms KM, Bondeson ML, Ansari-Lari MA, et al. Molecular and phenotypic variation in patients with severe Hunter syndrome. Hum Mol Genet. Mar 1997;6(3):479-86. [Medline].

4. Garcia AR, Pan J, Lamsa JC, Muenzer J. The characterization of a murine model of mucopolysaccharidosis II (Hunter syndrome). J Inherit Metab Dis. Sep 16 2007;[Medline].

5. Matern D. Newborn screening for lysosomal storage disorders. Acta Paediatr Suppl. Apr 2008;97(457):33-7. [Medline].

6. Lowry RB, Applegarth DA, Toone JR, MacDonald E, Thunem NY. An update on the frequency of mucopolysaccharide syndromes in British Columbia. Hum Genet. Aug 1990;85(3):389-90. [Medline].

7. Schaap T, Bach G. Incidence of mucopolysaccharidoses in Israel: is Hunter disease a "Jewish disease"?. Hum Genet. 1980;56(2):221-3. [Medline].

8. Young ID, Harper PS. Incidence of Hunter's syndrome. Hum Genet. 1982;60(4):391-2. [Medline].

9. Wraith JE, Beck M, Giugliani R, Clarke J, Martin R, Muenzer J. Initial report from the Hunter Outcome Survey. Genet Med. Jul 2008;10(7):508-16. [Medline].

10. Young ID, Harper PS. The natural history of the severe form of Hunter's syndrome: a study based on 52 cases. Dev Med Child Neurol. Aug 1983;25(4):481-9. [Medline].

11. Clarke JT, Wilson PJ, Morris CP, et al. Characterization of a deletion at Xq27-q28 associated with unbalanced inactivation of the nonmutant X chromosome. Am J Hum Genet. Aug 1992;51(2):316-22. [Medline].

12. Young ID, Harper PS, Newcombe RG, Archer IM. A clinical and genetic study of Hunter's syndrome. 2. Differences between the mild and severe forms. J Med Genet. Dec 1982;19(6):408-11. [Medline].

13. Young ID, Harper PS. Mild form of Hunter's syndrome: clinical delineation based on 31 cases. Arch Dis Child. Nov 1982;57(11):828-36. [Medline].

14. Spranger J, Cantz M, Gehler J, Liebaers I, Theiss W. Mucopolysaccharidosis II (Hunter disease) with corneal opacities. Report on two patients at the extremes of a wide clinical spectrum. Eur J Pediatr. Aug 17 1978;129(1):11-6. [Medline].

15. Caruso RC, Kaiser-Kupfer MI, Muenzer J, Ludwig IH, Zasloff MA, Mercer PA. Electroretinographic findings in the mucopolysaccharidoses. Ophthalmology. Dec 1986;93(12):1612-6. [Medline].

16. Beck M. Papilloedema in association with Hunter's syndrome. Br J Ophthalmol. Mar 1983;67(3):174-7. [Medline].

17. Beck M, Cole G. Disc oedema in association with Hunter's syndrome: ocular histopathological findings. Br J Ophthalmol. Aug 1984;68(8):590-4. [Medline].

18. Hobolth N, Pedersen C. Six cases of a mild form of Hunter syndrome in five generations. Three affected males with progeny. Clin Genet. 1978;20:121.

19. Isogai K, Sukegawa K, Tomatsu S, et al. Mutation analysis in the iduronate-2-sulphatase gene in 43 Japanese patients with mucopolysaccharidosis type II (Hunter disease). J Inherit Metab Dis. Feb 1998;21(1):60-70. [Medline].

20. Crotty PL, Braun SE, Anderson RA, Whitley CB. Mutation R468W of the iduronate-2-sulfatase gene in mild Hunter syndrome (mucopolysaccharidosis type II) confirmed by in vitro mutagenesis and expression. Hum Mol Genet. Dec 1992;1(9):755-7. [Medline].

21. Birot AM, Delobel B, Gronnier P, Bonnet V, Maire I, Bozon D. A 5-megabase familial deletion removes the IDS and FMR-1 genes in a male Hunter patient. Hum Mutat. 1996;7(3):266-8. [Medline].

22. Hopwood JJ, Bunge S, Morris CP, et al. Molecular basis of mucopolysaccharidosis type II: mutations in the iduronate-2-sulphatase gene. Hum Mutat. 1993;2(6):435-42. [Medline].

23. Rathmann M, Bunge S, Beck M, Kresse H, Tylki-Szymanska A, Gal A. Mucopolysaccharidosis type II (Hunter syndrome): mutation "hot spots" in the iduronate-2-sulfatase gene. Am J Hum Genet. Dec 1996;59(6):1202-9. [Medline].

24. Clarke JT, Willard HF, Teshima I, Chang PL, Skomorowski MA. Hunter disease (mucopolysaccharidosis type II) in a karyotypically normal girl. Clin Genet. May 1990;37(5):355-62. [Medline].

25. Kamin W. Diagnosis and management of respiratory involvement in Hunter syndrome. Acta Paediatr Suppl. Apr 2008;97(457):57-60. [Medline].

26. Meikle PJ, Grasby DJ, Dean CJ, et al. Newborn screening for lysosomal storage disorders. Mol Genet Metab. Aug 2006;88(4):307-14. [Medline].

27. Vellodi A, Young E, Cooper A, Lidchi V, Winchester B, Wraith JE. Long-term follow-up following bone marrow transplantation for Hunter disease. J Inherit Metab Dis. Jun 1999;22(5):638-48. [Medline].

28. Mullen CA, Thompson JN, Richard LA, Chan KW. Unrelated umbilical cord blood transplantation in infancy for mucopolysaccharidosis type IIB (Hunter syndrome) complicated by autoimmune hemolytic anemia. Bone Marrow Transplant. May 2000;25(10):1093-7. [Medline].

29. Martin R, Beck M, Eng C, et al. Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome). Pediatrics. Feb 2008;121(2):e377-86. [Medline].

30. Muenzer J, Gucsavas-Calikoglu M, McCandless SE, Schuetz TJ, Kimura A. A phase I/II clinical trial of enzyme replacement therapy in mucopolysaccharidosis II (Hunter syndrome). Mol Genet Metab. Mar 2007;90(3):329-37. [Medline].

31. Muenzer J, Wraith JE, Beck M, et al. A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome). Genet Med. Aug 2006;8(8):465-73. [Medline].

32. [Guideline] Wraith JE, Scarpa M, Beck M, et al. Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy. Eur J Pediatr. Mar 2008;167(3):267-77. [Medline].

33. Al Sawaf S, Mayatepek E, Hoffmann B. Neurological findings in Hunter disease: pathology and possible therapeutic effects reviewed. J Inherit Metab Dis. Aug 2008;31(4):473-80. [Medline].

34. Neufeld EF, Muenzer J. The Mucopolysaccharidoses. In: The Metabolic Bases of Inherited Disease. 8^th ed. McGraw-Hill; 2000:3421-52.

Keywords

mucopolysaccharidosis type II, Hunter syndrome, MPS II, type A MPS II, type B MPS II, iduronate sulfatase deficiency, lysosomal enzyme deficiency, dysostosis multiplex, lysosomal storage disorders, coarse facial features, corneal clouding, thickened skin, organomegaly, mental retardation, growth failure, skeletal dysplasia, upper airway obstruction, carpal tunnel syndrome, short stature, hyperactivity, progressive hearing loss, hepatomegaly, progressive retinal degeneration, recurrent ear infections, hydrocephalus

Contributor Information and Disclosures

Author

Nancy E Braverman, MS, MD, Associate Professor, Department of Human Genetics, McGill University
Nancy E Braverman, MS, MD is a member of the following medical societies: Alpha Omega Alpha, American Society of Human Genetics, Society for Inherited Metabolic Disorders, and Society for the Study of Inborn Errors of Metabolism
Disclosure: Nothing to disclose.

Coauthor(s)

Vinayak Kottoor, MD, Resident, Department of Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University Hospital
Disclosure: Nothing to disclose.

Mary Kay Conover-Walker, MSN, PNP, Pediatric Nurse Practioner, Institute of Genetic Medicine, Johns Hopkins Hospital
Mary Kay Conover-Walker, MSN, PNP is a member of the following medical societies: American Academy of Allergy Asthma and Immunology and Association of Clinical Research Professionals
Disclosure: Nothing to disclose.

Cydney L Fenton, MD, FAAP, Consulting Staff, Department of Pediatric Endocrinology, Children's Hospital Medical Center of Akron
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
Disclosure: Nothing to disclose.

Medical Editor

Karl S Roth, MD, Professor and Chair, Department of Pediatrics, Creighton University School of Medicine
Karl S Roth, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Nutrition, American Pediatric Society, American Society for Clinical Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, and Southern Society for Pediatric Research
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Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
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Managing Editor

Margaret M McGovern, MD, PhD, Professor and Chair of Pediatrics, Stony Brook University, New York
Margaret M McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics and American Society of Human Genetics
Disclosure: Genzyme Grant/research funds PI

CME Editor

Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine
Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine
Disclosure: Baxter Honoraria Consulting

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author William Rogers, MD, to the original writing and development of this article.

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