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

Mucopolysaccharidosis Type II

Author: Nancy E Braverman, MS, MD, Associate Professor, Department of Human Genetics, McGill University
Coauthor(s): 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
Contributor Information and Disclosures

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.

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    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

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