Hunter Syndrome Information for Medical Geneticists

You may be seeing Hunter syndrome before anyone else.

Hunter syndrome (mucopolysaccharidosis II, MPS II) is a serious progressive genetic disorder that affects boys almost exclusively. It is caused by a deficiency or absence of the lysosomal enzyme iduronate-2-sulfatase (I2S). This enzyme is required for the degradation of specific glycosaminoglycans (GAGs); thus its absence results in a harmful accumulation of these substances in cells throughout the body.

As a medical geneticist, you may have patients referred to you who have signs and symptoms of Hunter syndrome. As with many rare diseases, patients with Hunter syndrome historically have experienced considerable delays from the onset of symptoms to a confirmed diagnosis.1 However, you can help to address this diagnostic gap by broadening awareness of Hunter syndrome among referring physicians.

To help increase awareness of Hunter syndrome, we encourage you to share the information on www.hunterpatients.com with referring physicians and others.

To read more about Hunter syndrome, select a topic below:

 

Overview of Hunter syndrome

Hunter syndrome is an X-linked recessive genetic disease that affects approximately 1 in 162,000 live births, almost exclusively males.1,2 Also known as mucopolysaccharidosis II (MPS II), Hunter syndrome is a chronic, progressive, metabolic disease.2 It is a type of lysosomal storage disorder (LSD) that arises from a specific genetic defect in cell metabolism.2 Hunter syndrome results in progressive damage and dysfunction in cells, tissues, and organs throughout the body.2

 

  1. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999;281(3):249-254.
  2. Martin R, Beck M, Eng C, et al. Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome). Pediatrics. 2008;121(2):e377-e386.

 

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Pathophysiology of Hunter syndrome

Within a healthy cell, intracellular lysosomes contain enzymes that metabolize proteins, nucleic acids, carbohydrates, and lipids.1 For example, the enzyme iduronate-2-sulfatase, or I2S, is essential for the breakdown of two specific glycosaminoglycans, or GAGs-heparan sulfate and dermatan sulfate.2 GAGs, previously called mucopolysaccharides, are a type of long unbranched polysaccharide.3

In healthy people, the I2S enzyme helps to remove sulfate from alpha-L-iduronic acid, which is present in the GAGs heparan sulfate and dermatan sulfate.2

However, in Hunter syndrome, there is a defect in the gene (IDS) that directs production of the I2S enzyme.4 Due to IDS gene mutations, the I2S enzyme is deficient or absent in people who have Hunter syndrome.2 More than 300 different mutations in the IDS gene have been identified, including whole and partial deletions, large gene rearrangements, point mutations, and other changes. In general, genotype-phenotype correlations are poor in Hunter syndrome.

Without sufficient I2S enzyme activity, the undegraded or partially degraded GAGs accumulate in the lysosome and are also excreted in excess in the urine.2 Widespread pathological lysosomal storage of GAGs leads to progressive damage and dysfunction in cells, tissues, and organs throughout the body.2 This results in a wide variety of signs and symptoms of Hunter syndrome.2

 

  1. Hopkin RJ, Grabowski GA. Lysosomal storage diseases. In: Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 17th ed. New York, NY: McGraw Hill; 2008:2452-2456.
  2. Martin R, Beck M, Eng C, et al. Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome). Pediatrics. 2008;121(2):e377-e386.
  3. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, et al, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2001:3421-3452.
  4. Genetics Home Reference. IDS. http://ghr.nlm.nih.gov/gene/IDS. Accessed February 1, 2011.

 

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Early signs and symptoms

A newborn infant who has Hunter syndrome may appear normal in the first months and years of life and achieve his early developmental milestones.1,2

However, Hunter syndrome follows a progressive course of development. By 2 to 4 years of age, physical abnormalities begin to emerge, and, in some cases, cognitive impairment may develop.1 The phenotype spectrum ranges from severe to attenuated, with a variable age of onset and variable rate of progression.1 Some individuals may remain asymptomatic longer than others. In general, genotype-phenotype correlations are poor in Hunter syndrome.

Early identification of Hunter syndrome is challenging because some initial features — such as chronic runny nose, otitis media, and hernias — are also commonly seen in healthy children. This often leads to delays in diagnosis.1

The earliest visible signs of Hunter syndrome are typically facial dysmorphism, hepatosplenomegaly, and enlarged tongue and tonsils.2 Common early signs and symptoms include:

  • Facial dysmorphism. Notable facial features are a broad nose with flared nostrils, prominent supraorbital ridges, thick lips and large jowls, and large head circumference.1
  • Enlarged liver and spleen. The abdomen is distended due to an enlarged liver and spleen, which may become massive from lysosomal GAGs storage but not necessarily dysfunctional.2
  • Hernias. Umbilical hernias are commonly observed; inguinal hernias are sometimes seen.1
  • Respiratory problems. Progressive airway obstruction is a common early finding in the respiratory tract.1 Contributing factors include narrowed and abnormally shaped trachea and bronchi, enlarged tongue, hypertrophic adenoids and tonsils, large epiglottis, frequent upper respiratory infections, recurrent pneumonia, and thick nasal and tracheal secretions.1
  • Otitis media. Recurrent otitis media is a common early finding in the middle ear.2
  • Skeletal and joint problems. A hallmark of Hunter syndrome is skeletal changes, progressive joint stiffness, and contractures. Over time, these can profoundly restrict mobility and range of motion.1 The skeletal findings of Hunter syndrome are collectively known as dysostosis multiplex.1

 

  1. Martin R, Beck M, Eng C, et al. Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome). Pediatrics. 2008;121(2):e377-e386.
  2. Wraith JE, Beck M, Giugliani R, Clarke J, Martin R, Muenzer J. Initial report from the Hunter Outcome Survey (HOS). Genet Med. 2008;10(7):508-516.

 

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Cognitive involvement

In Hunter syndrome, the phenotype spectrum ranges from severe to attenuated, with a variable age of onset and variable rate of progression.1

While the attenuated form is defined by somatic features only, individuals with the severe form have somatic involvement as well as prominent neurological involvement, progressing to severe mental impairment.2

Behavioral problems, cognitive problems, and hyperactivity are prevalent clinical features of the severe phenotype.2 The attenuated phenotype is spared cognitive involvement.2

 

  1. Martin R, Beck M, Eng C, et al. Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome). Pediatrics. 2008;121(2):e377-e386.
  2. Wraith JE, Beck M, Giugliani R, Clarke J, Martin R, Muenzer J. Initial report from the Hunter Outcome Survey (HOS). Genet Med. 2008;10(7):508-516.

 

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Signs and symptoms later in childhood

As childhood progresses, additional signs and symptoms may emerge beyond clinical features that develop early.1

  • Short stature. Most boys with Hunter syndrome develop short stature later in childhood.1
  • Kyphosis and scoliosis. Kyphosis and scoliosis, curvatures of the spine, are commonly seen.2,3
  • Spinal cord compression. Spinal cord compression may occur because of narrowing of the spinal canal and instability of the atlantoaxial joint.4
  • Progression of skeletal and joint problems. Skeletal problems contribute to gait disturbances and loss of fine motor skills.1 Patients may walk on their toes because of joint stiffness and tight heel cords.4
  • Carpal tunnel syndrome. Gradual loss of hand function may result from carpal tunnel syndrome and progressive stiffness of joints and joint contractures in the hands, including curvature of the fingers.4
  • Cardiovascular problems. Cardiovascular involvement is common in childhood, with cardiac valve disease the most prevalent cardiac condition.5

 

  1. Wraith JE, Beck M, Giugliani R, Clarke J, Martin R, Muenzer J. Initial report from the Hunter Outcome Survey (HOS). Genet Med. 2008;10(7):508-516.
  2. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, et al, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2001:3421-3452.
  3. Semenza GL, Pyeritz RE. Respiratory complications of mucopolysaccharide storage disorders. Medicine (Baltimore). 1988;67(4):209-219.
  4. Martin R, Beck M, Eng C, et al. Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome). Pediatrics. 2008;121(2):e377-e386.
  5. Braunlin EA, Harmatz PR, Scarpa M, et al. Cardiac disease in patients with mucopolysaccharidosis: presentation, diagnosis and management. J Inherit Metab Dis. 2011;34(6):1183-1197.

 

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Signs and symptoms in adolescence

Signs and symptoms that first appear early in life often continue to progress into adolescence; new symptoms may continue to emerge.1 Keep in mind that Hunter syndrome has a variable age of onset and variable rate of progression.1

Mild hearing loss may be caused by conductive deficits early in the course of the disease.1,2 Middle-ear effusion contributes to hearing loss, and tympanomastoid abnormalities may play a role.1,2 Also, as the child ages, a sensorineural element often appears.1,2 In patients with attenuated disease who survive into adulthood, moderate to severe hearing loss may develop over time.1

In patients who have the severe phenotype of Hunter syndrome, death usually occurs in the second decade of life because of respiratory obstruction, neurologic involvement, or cardiac failure.1 In contrast, patients with attenuated disease typically survive into adulthood.1

 

  1. Martin R, Beck M, Eng C, et al. Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome). Pediatrics. 2008;121(2):e377-e386.
  2. Wraith JE, Beck M, Gugliani R, Clarke J, Martin R, Muenzer J. Initial report from the Hunter Outcome Survey (HOS). Genet Med. 2008;10(7):508·516.

 

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Diagnosis of Hunter syndrome

One of the challenges in identifying patients who may have Hunter syndrome is that the signs and symptoms are not specific to Hunter syndrome, and not all of them will be present in each patient. The resulting delay between the presentation of signs and symptoms and the ultimate diagnosis may be substantial.1 In one study, the delay between median age of symptom onset and diagnosis of Hunter syndrome was 2 years.2

Early identification of Hunter syndrome is especially challenging because some initial features — such as chronic runny nose, otitis media, and hernias — are also seen in common childhood diseases. This often leads to delays in diagnosis.1-3

Physicians may refer patients to be tested for Hunter syndrome when symptoms of the disease are present and cannot be explained by other causes. Diagnosis is suggested by history, physical examination, and bone abnormalities. The visible signs of Hunter syndrome, such as changes in facial features, are usually the first clues.1,4

Because glycosaminoglycans (GAGs) may be excreted in excess in the urine as Hunter syndrome develops,1 analysis of urinary GAGs can be a useful preliminary diagnostic test. However, while this analysis may confirm suspicion of a mucopolysaccharidoses (MPS) disorder, it is not specific for Hunter syndrome. Not all individuals with Hunter syndrome have GAGs levels higher than unaffected individuals.1

Definitive diagnosis is established by simple enzyme assays measuring the activity of the enzyme iduronate-2-sulfatase (I2S) in the blood, serum, or skin fibroblasts. Absolute enzyme activity cannot be used to predict the severity of the disease or identify female carriers.1

Prenatal diagnosis is routinely carried out on cultured cells from amniotic fluid or chorionic villus biopsies using the same enzymatic assays as for cultured fibroblasts.4

 

  1. Martin R, Beck M, Eng C, et al. Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome). Pediatrics. 2008;121(2):e377-e386.
  2. Wraith JE, Beck M, Giugliani R, Clarke J, Martin R, Muenzer J. Initial report from the Hunter Outcome Survey (HOS). Genet Med. 2008;10(7):508-516.
  3. Heese BA. Current strategies in the management of lysosomal storage diseases. Semin Pediatr Neurol. 2008;15(3):119-126.
  4. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, et al, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2001:3421-3452.

 

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Disease management

Individuals with Hunter syndrome have a wide range of signs and symptoms that often must be managed by a variety of specialists. Treatment is multidisciplinary and encompasses both supportive and palliative therapies.1,2

There are several supportive or palliative therapies available that may help manage the signs and symptoms of Hunter syndrome and treat any resulting complications, including1,2:

  • Oxygen therapy and/or surgery for respiratory complications
  • Antibiotic treatment, including long-term antibiotic therapy and/or tympanostomy tubes for chronic ear infections
  • Surgery and/or antihypertensive medications for heart complications
  • Physical therapy and/or surgery for skeletal and connective tissue problems
  • Surgery and/or anticonvulsant medications for neurological complications
  • Hearing aids for hearing loss

 

  1. Wraith JE, Beck M, Giugliani R, Clarke J, Martin R, Muenzer J. Initial report from the Hunter Outcome Survey (HOS). Genet Med. 2008:10(7):508-516.
  2. Martin R, Beck M, Eng C, et al. Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome). Pediatrics. 2008:121(2):e377-e386.

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Routine assessments in Hunter syndrome

The clinical features of Hunter syndrome are multisystemic, involving the nervous, respiratory, and musculoskeletal systems, among others. Involvement may be severe and may affect daily quality of life.1

Because of multisystem involvement in Hunter syndrome, management is typically complex and requires a multidisciplinary approach. Specialist care may involve pediatrics, otolaryngology, neurosurgery, orthopedics, cardiology, anesthesiology, pulmonology, neurodevelopment, physiotherapy, and audiology.1

To help guide the multidisciplinary management of Hunter syndrome, routine monitoring is important for tracking stabilization or progression of disease over time. Medical geneticists can help patients to follow up with regular evaluations. Below is a suggested schedule of routine assessments.2

routine_assessments

Physicians should use their independent medical judgment in determining appropriate assessments and timing based on age appropriateness and disease severity. The assessments listed above are based on suggestions developed by the Hunter Outcome Survey (HOS) Global Executive Board.2 HOS is an international, multicenter, long-term observational survey of patients with a confirmed diagnosis of Hunter syndrome. HOS is sponsored by Shire.

 

  1. Muenzer J, Beck M, Eng CM, et al. Multidisciplinary management of Hunter syndrome. Pediatrics. 2009;124(6):e1228-e1239.
  2. Beck M, Giugliani R, Muenzer J, Suzuki Y, Tylki-Szymanska A, Wraith JE. Suggested schedule of assessments for routine monitoring of patients with Hunter syndrome enrolled in HOS. Hunter Outcome Survey (HOS). Data on file. HOS; 2009.

 

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Resources and links

Find medical geneticists and genetic counselors in your area:

  • American College of Medical Genetics (ACMG). To locate genetics clinics and services in your area, including finding a medical geneticist or genetic counselor, visit the ACMG Web site at www.acmg.net. The Web site also provides educational and other professional resources related to medical genetics.
  • National Society of Genetic Counselors (NSGC). To locate a genetic counselor in your area, or to find information about genetic counseling, visit the NSGC Web site at www.nsgc.org.

Learn more about Hunter syndrome, MPS disorders, and other rare diseases:

  • National MPS Society. The National MPS Society supports professional research and education in MPS disorders, provides educational and financial assistance to families affected by MPS disorders, and works to increase public and professional awareness of MPS disorders. To learn more, visit www.mpssociety.org.
  • National Organization for Rare Disorders (NORD). NORD is a unique federation of voluntary health organizations dedicated to helping people with rare diseases and assisting the organizations that serve them. NORD is committed to the identification, treatment, and cure of rare disorders through programs of education, advocacy, research, and service. To learn more, visit www.rarediseases.org.
  • The Global Genes Project. The Global Genes Project is a leading rare and genetic disease patient advocacy organization with over 500 global organizations. To learn more, visit globalgenes.org.
  • Genetic Alliance. Genetic Alliance is a health advocacy organization committed to transforming health through genetics. Genetic Alliance’s network includes disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations who share resources, creative tools, and innovative programs. To learn more, visit www.geneticalliance.org.
  • Brave Community. Brave Community is a dynamic online source of customizable news feeds, stories, and information about certain rare diseases. To learn more, visit www.BraveCommunity.com. This site is owned and operated by Shire.

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