What is Hunter syndrome?

Hunter syndrome, also known as mucopolysaccharidosis II (MPS II) is a rare, progressive genetic disorder. It predominantly affects males, occurring in approximately 1 in 162,000 live births. 1

Hunter syndrome is one of a number of lysosomal storage diseases (LSDs), in which molecules build up in the body. In Hunter syndrome specifically, glycosaminoglycans (GAGs) accumulate abnormally in the body. 2

Hunter syndrome is caused by a deficiency or absence of the I2S enzyme. 3 Without I2S, GAGs accumulate in the lysosomes, and in Hunter syndrome patients, the progressive build-up interferes with cell functions across all organ systems. The multisystemic disease is associated with many signs and symptoms, which lie on a spectrum from non-neuronopathic (somatic) symptoms to neuronopathic (cognitive) symptoms. Almost 7 out of 10 patients with Hunter syndrome have neuronopathic involvement. 3,4

Initial signs of GAG accumulation in Hunter syndrome patients occur from ages 2 to 4 years: hernia, otitis media, and enlarged adenoids/tonsils (managed by adenoidectomy/tonsillectomy). The clinical management of Hunter syndrome patients is continual, symptoms are progressive and multisystemic, and the median life expectancy for patients is 13.4 years. 3,5,6

Hunter syndrome presentation

The presentation of Hunter syndrome symptoms is unique in each patient and there is no typical disease course. However, the early symptoms overlap with common childhood complaints, making it challenging to detect and ultimately leading to diagnostic delays. 5 It is important therefore to be able to recognise clusters of symptoms that may indicate an underlying problem:

Many of the signs and symptoms of [MPS II] overlap with common paediatric problems…it’s not coincidental that a patient has three or four or five different medical issues.

- Dr Barbara Burton

Hunter syndrome inheritance

Hunter syndrome is an X-linked recessive genetic disorder, occurring almost exclusively in males. The disease arises from the lack of a normal copy of the IDS gene on the X chromosome, which codes for the lysosomal enzyme iduronate-2-sulfatase (I2S) that clears GAGs. 5

It is extremely rare for females to develop Hunter syndrome; heterozygous females retain 50% of their normal I2S activity, and are usually asymptomatic. 7

The IDS gene contains a little over 28,000 DNA base pairs, and more than 500 different mutations that lead to Hunter syndrome have been documented, including point mutations, splicing defects, gene rearrangements, and even complete deletions. 8,9

Depending on the scope and size of the mutation, there will be an abnormality, or a complete absence of I2S. Such mutations lead to Hunter syndrome conditions of differing severity and course; the presentation cannot be predicted from the mutation type, although large gene rearrangements usually create neuronopathic symptoms. 9

It is essential to check family members of the Hunter syndrome patient for faulty copies of the IDS gene. Genetic testing will identify carriers and undiagnosed children who may be affected. Early management is essential in a progressive disease. 3

Pedigree analysis example

    The patient (male, 4 years) was referred by his paediatrician for evaluation with prominent facial features and joint stiffness. The patient had a history of recurrent otitis media with ear tube placement and obstructive sleep apnoea. This led to a tonsillectomy and adenoidectomy at 3 years of age, and a hydrocele repair was performed at the same time.

    There was no reported family history of genetic conditions, or of bone and joint disorders. Based on the findings of a physical examination, Hunter syndrome was suspected and was confirmed by enzymatic and molecular testing.

    The patient’s mother (II-3) was tested and found to be a carrier. Further family analysis revealed that her sister (II-2) was also a carrier, and Hunter syndrome was also confirmed in one of her sister’s three children: an 18-month old boy (III-3).

Aiden's Story

When he was about 2 years old, I noticed Aiden had speech delay. So, I got him into early intervention and his paediatrician suggested that it’s just something that kids go through, he’ll catch up. He had occupational therapy, physiotherapy and speech therapy for a year. Then his paediatrician suggested we see a geneticist because of Aiden’s facial features; he wanted to have it checked. – Toni Ann, mother of Aiden

Silas' Story

My husband and I felt we were the luckiest people on earth when we actually held our little boy Silas in our arms. When Silas was around 6 months old, we noticed that the back of his head was becoming flatter and that he couldn’t hold his head up properly. Silas always cried when he was laid down to play on his stomach. We saw an osteopath who gave us exercises that Silas didn’t like at all. The osteopath said she thought that Silas was maybe a bit ‘lazy’ as he didn’t invest much effort in trying to reach toys or in crawling. – Nathalie, mother of Silas

References

  • Meikle PJ. Prevalence of lysosomal storage disorders. JAMA 1999; 281(3): 249–254.
  • Neufeld EF and Muenzer J. The Mucopolysaccharidoses. In: The Online Metabolic & Molecular Bases of Inherited Disease. McGraw-Hill Medical. DOI: 10.1036/ommbid.165
  • Burton BK, Giugliani R. Diagnosing Hunter syndrome in pediatric practice: practical considerations and common pitfalls. Eur J Pediatr 2012; 171(4): 631–639.
  • Amartino H. Hunter syndrome (mucopolysaccharidosis II) – the signs and symptoms a neurologist needs to know. Eur Neurol Rev 2015; 10(01): 90–94.
  • Scarpa M et al. Mucopolysaccharidosis type II: European recommendations for the diagnosis and multidisciplinary management of a rare disease. Orphanet J Rare Dis 2011; 6: 72.
  • Jones SA et al. Mortality and cause of death in mucopolysaccharidosis type II—a historical review based on data from the Hunter Outcome Survey (HOS). J Inherit Metab Dis 2009; 32(4): 534–543.
  • Martin R et al. Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome). Pediatrics 2008; 121(2): e377–e386.
  • Genetics Home Reference. IDS gene. U.S. National Library of Medicine. https://ghr.nlm.nih.gov/gene/IDS#location
  • Demydchuk M et al. Insights into Hunter syndrome from the structure of iduronate-2-sulfatase. Nat Commun 2017; 8: 15786.