Looking for a cause of repeat respiratory and ear infections: are you seeing Hunter syndrome?

Hunter syndrome (also known as mucopolysaccharidosis type II; MPS II) is a chronic, progressive, multisystemic disease that ultimately leads to reduced life expectancy. 1,2 Hunter syndrome causes insidious anatomical and biochemical changes, as a result of its genetic-metabolic basis, that can predispose pediatric patients to repeat respiratory and ear infections. 3 In a global survey of Hunter syndrome patients, 72% experienced otitis media,3 and 70% had pulmonary involvement, which included patients with lower or upper airway infections. 4 These symptoms often begin at an early age, with a median age of onset less than 3 years [see figure 1]. 3,4 The median age of diagnosis of Hunter syndrome is 3.3 years. 5 Alongside these recurrent infections, other symptoms, including chronic rhinorrhoea, nasal obstruction, noisy breathing, hearing loss and enlarged adenoids and tonsils, in addition to a distended abdomen (hepatosplenomegaly) and chronic diarrhoea, may all contribute to Hunter syndrome being mistaken to have an infectious/immune-related cause. 1,6,7 Therefore, prior to diagnosis, a Hunter syndrome patient may be referred to an immunologist or allergist to evaluate causes of recurrent infections and pulmonary symptoms.

Humoral immunodeficiency disorders, including hypogammaglobulinemia of infancy (THI), X-linked agammaglobulinemia (XLA) or common variable immunodeficiency (CVID), may be investigated as possible differential diagnoses of these Hunter syndrome symptoms because their key manifestations are also recurrent upper and lower respiratory tract infections. 8 In addition, the Hunter syndrome symptoms of chronic rhinorrhoea, nasal obstruction and noisy-breathing may be differentially diagnosed as allergic rhinitis or asthma, either as a component of THI/CVID, or standalone. 7,8,9,10 Furthermore, XLA and THI affect males more than females, and an XLA patient may report similar symptoms in maternal male relatives; 8 THI and CVID patients may experience chronic diarrhoea; 8,11,12 and some CVID patients may have splenomegaly (as a result of developing a lymphoproliferative disorder)8– all of which are Hunter syndrome characteristics. 1,7

When investigating the cause of pulmonary symptoms and infections in young children, it is key to possess a high suspicion index for uncommon causes hidden among the plethora of normal childhood respiratory infections, allergies, and asthma. 8 The American Academy of Allergy, Asthma & Immunology (AAAAI) and the American College of Allergy, Asthma & Immunology (ACAAI) have produced a practice parameter for evaluating immunodeficiency as a possible cause of repeat infection.8 This guideline notes the need to exclude the possibility of anatomical or biochemical causes of infection susceptibility before focusing on investigating immunodeficiency. 8

Figure 1. Pre-diagnosis recurrent infections and pulmonary symptoms (data from the Hunter Outcome Survey) 3,4,5



Download a poster highlighting the key exclusion step in the AAAAI/ACAAI practice parameters.

Hunter syndrome is a rare X-linked genetic disease (almost exclusively affecting males) characterised by a deficiency of the lysosomal enzyme, iduronate-2-sulfatase, which has a specific role in glycosaminoglycan (GAG) degradation. 13 Biochemical changes in Hunter syndrome include pathogenic lysosomal GAG storage in cells and connective tissue throughout the body and elevated GAG excretion in urine. 13 This pathogenic GAG accumulation leads directly and indirectly to a range of anatomical changes, shown in figure 2.14 It is these biochemical/anatomical changes that are the predisposing cause of the recurrent infections seen in Hunter syndrome patients; for example, adenotonsillar hypertrophy and subsequent eustachian tube dysfunction can contribute to recurrent otitis media. 3,15 Applying the AAAAI/ACAAI practice parameters, it is important to distinguish the adenotonsillar hypertrophy seen in MPS II that could contribute to infection-predisposition (which may require adenotonsillectomy, a common surgery in MPS II), from infection-related inflammation of the adenoids and tonsils. 5,6,8 However, Hunter syndrome diagnosis is not straightforward because several Hunter syndrome symptoms, including otitis media and enlarged adenoids, can easily be overlooked as common childhood complaints. 6,7

Diagnosis of Hunter syndrome is further complicated by the fact that symptom presentation and severity and onset and progression are all heterogeneous; therefore, there is no symptom checklist that can be applied to all Hunter syndrome patients. 1,7 For example, patients at the two extremes of the clinical severity spectrum, designated as the presence or absence of cognitive involvement, may present very differently; some with developmental delays and some without, and even siblings can have different presentation. 1,7,16 Therefore, the key to differentiating Hunter syndrome from immunodeficiency disorders or common childhood ailments is recognising a combination of any of the multisystemic biochemical/anatomical changes and related symptoms shown in figure 2.7 In Hunter syndrome, the hypertrophic adenoids are just one component of airway obstruction caused by GAG deposition in soft tissues, and they are just one component of generalised organomegaly, including the enlarged tongue, enlarged liver and spleen and enlarged cardiac ventricles. 1,13,15,17

Figure 1. Pre-diagnosis recurrent infections and pulmonary symptoms (data from the Hunter Outcome Survey) 3,4,5


Hunter syndrome could also be distinguished from humoral immunodeficiency disorders by demonstrating normal antibody (IgG) levels (although it is possible Hunter syndrome may co-exist with THI).8 Another way Hunter syndrome could be distinguished from humoral immunodeficiency disorders and/or allergy and asthma is by lack of response to IgG replacement therapy (IVIG) or asthma/allergy therapies, respectively. 8,10,12 However, any delay in diagnosis of Hunter syndrome while other diagnoses or therapies are tested is concerning because Hunter syndrome is progressive; the pathogenic GAG storage begins in utero and can progress and cause irreversible damage. 17,18 To diagnose Hunter syndrome early, a symptom combination must be recognised; for example, a patient with hernia or hernia repair, alongside the recurrent otitis media, could indicate Hunter syndrome. 7,17 The hernia is very common in Hunter syndrome patients, seen in 78% of patients with a median age of onset of 1.3 years. 6 The hernia is often considered a common, benign condition in infancy that doesn’t require intervention, whereas, among the Hunter syndrome population, hernia repair is common (seen in 50% patients with a median age of 3.0 years). 5

In conclusion, Hunter syndrome is a rare, life-limiting disease that is challenging to diagnose early, often resulting in substantial delays between symptom onset and diagnosis. 17 Hunter syndrome patients may be encountered by immunologists and allergists for evaluation of recurrent respiratory and ear infections or allergy-like symptoms, prior to the diagnosis of the condition. The key to distinguishing recurrent infections caused by Hunter syndrome from immunodeficiency disorders, asthma, allergies, or common childhood ailments is recognising concurrent symptoms, such as enlarged adenoids and tonsils and/or adenotonsillectomy, hernia and/or hernia repair, organomegaly, development delays, coarse facial features, skeletal dysplasia, joint stiffness and/or cardiac involvement, alongside the recurrent infections. 7 Additionally, Hunter syndrome would not be expected to have low antibody levels and would not be expected to respond to IVIG, asthma or allergy therapies. 10,12 As Hunter syndrome is a progressive disorder, it is important that a diagnosis is reached as quickly as possible. 2,17 If you suspect Hunter syndrome, refer to a metabolic geneticist for testing.

  • Download a Hunter syndrome eBook for Immunologists

  • Download an informative eBook about Hunter syndrome for Immunologists

References

  1. Martin R et al. Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome). Pediatrics. 2008; 121(2): e377–386.
  2. Muenzer J. Overview of the mucopolysaccharidoses. Rheumatology (Oxford). 2011; 50 Suppl 5: v4–v12.
  3. Keilmann A et al. Hearing loss in patients with mucopolysaccharidosis II: data from HOS - the Hunter Outcome Survey. J Inherit Metab Dis. 2012; 35(2): 343–353.
  4. Link B et al. Orthopedic manifestations in patients with mucopolysaccharidosis type II (Hunter syndrome) enrolled in the Hunter Outcome Survey. Orthop Rev (Pavia). 2010; 2(2): e16.
  5. Mendelsohn NJ et al. Importance of surgical history in diagnosing mucopolysaccharidosis type II (Hunter syndrome): data from the Hunter Outcome Survey. Genet Med. 2010; 12(12): 816–822.
  6. Wraith JE et al. Initial report from the Hunter Outcome Survey. Genet Med. 2008; 10(7): 508–516.
  7. Burton BK, Giugliani R. Diagnosing Hunter syndrome in pediatric practice: practical considerations and common pitfalls. Eur J Pediatr. 2012; 171(4): 631–639.
  8. Bonilla FA et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015; 136(5): 1186–1205.
  9. Agondi RC et al. Can patients with common variable immunodeficiency have allergic rhinitis? Am J Rhinol Allergy. 2013; 27(2): 79–83.
  10. Dadkhah M et al. Atopic Manifestations: Dermatitis, Allergic Rhinitis and Asthma in Patients With Hypogammaglobulinemia. Iran J Pediatr. 2015; 25(5): e2786.
  11. Justiz Vaillant AA, Wilson AM. Transient Hypogammaglobulinemia of Infancy. [Updated 2019 Nov 18]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: www.ncbi.nlm.nih.gov/books/NBK544356/?report=classic
  12. Rosario NA et al. Oral Immunoglobulin Controls Chronic Diarrhea in Common Variable Immunodefficiency (CVID). J Allergy Clin Immunol. 2017; 139(2): AB219.
  13. Wraith JE et al. Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy. Eur J Pediatr. 2008; 167: 267–277.
  14. Clarke LA. Pathogenesis of skeletal and connective tissue involvement in the mucopolysaccharidoses: glycosaminoglycan storage is merely the instigator. Rheumatology (Oxford). 2011; 50 Suppl 5: 13–18.
  15. Bianchi PM et al. ENT and mucopolysaccharidoses. Ital J Pediatr. 2018; 44(Suppl 2): 127.
  16. Yatziv S et al. Mild and severe Hunter syndrome (MPS II) within the same sibships. Clin Genet. 1977; 11(5): 319–326.
  17. 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.
  18. Chen CP et al. Prenatal diagnosis and genetic counseling of mucopolysaccharidosis type II (Hunter syndrome). Genet Couns. 2007; 18(1): 49–56.
  19. Bigger BW et al. Anatomical changes and pathophysiology of the brain in mucopolysaccharidosis disorders. Mol Genet Metab. 2018; 125(4): 322–331.
  20. Morishita K, Petty RE. Musculoskeletal manifestations of mucopolysaccharidoses. Rheumatology (Oxford). 2011; 50 Suppl 5: v19–25.