Early 'red flag' signs and symptoms

The presentation and course of symptoms varies amongst Hunter syndrome patients. However, early non-neuronopathic symptoms that could raise the suspicion of Hunter syndrome include: 1,2
 

  • otitis media
  • abdominal hernia
  • nasal obstruction
  • enlarged liver/spleen
  • enlarged tonsil/adenoids and tongue
  • large head circumference


However, these are non-specific and relatively common occurrences in childhood. This can disguise the underlying Hunter syndrome pathology, hindering early identification and management. 2 Similarly, neuronopathic symptoms such as hyperactivity, obstinacy and aggression can overlap with normal childhood behaviours. 3 The crucial distinction between common childhood problems and Hunter syndrome is the occurrence of non-neuronopathic symptoms repeatedly, and in clusters.

When early symptoms are overlooked, the delay between symptom presentation and diagnosis can be substantial. In such cases, initial suspicion of Hunter syndrome arises due to more advanced features of the disease, such as the observation of facial dysmorphism.

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

Learn more about how Hunter syndrome is diagnosed

Multisystemic involvement

Click on an organ system to view the clusters of symptoms that should raise the suspicion of Hunter syndrome.

Non-Neuronopathic

Neuronopathic

DEVELOPMENTAL

  • Developmental delay (e.g. speech, walking) 3
  • Progressive cognitive debilitation 3
  • Behavioural issues (e.g. hyperactivity, obstinacy and aggression) 3

FACIAL APPEARANCE

  • Normal at birth, with large head circumference 2
  • Facial features from ages 2–4 years: broad nose with flared nostrils, prominent brow, large jowls and thick lips 2

OCULAR

  • Loss of visual acuity or vision (due to elevated intraocular pressure, retinal pigmentary degeneration, optic disc swelling* (papilloedema), scleral thickening*, and optic atrophy*) 2

* Resulting from neuronopathic causes

GASTROINTESTINAL

  • Umbilical and inguinal hernias 2
  • Distended abdomen (due to an enlarged liver and spleen) 2
  • Bladder obstruction 2
  • Chronic diarrhoea *2

* Resulting from neuronopathic causes

CARDIAC

Valve disease leading to left and right ventricle hypertrophy and heart failure 2

NERVOUS SYSTEM

  • Difficulty coordinating chewing and swallowing 2,3
  • Auditory nerve compression 2,3
  • Optic disc swelling 2,3
  • Gastrointestinal tract neuropathy leading to chronic diarrhoea 2,3
  • Carpal tunnel syndrome 3
  • Seizures 3
  • Fine motor skill impairment 3
  • Communicating hydrocephalus 3
  • Spinal cord compression, which leads to muscle weakness and loss of sensation (dysaesthesia) 3

AUDITORY

  • Recurrent ear infections: acute and chronic 2
  • Progressive hearing loss (due to conductive/mechanical ear symptoms such as otitis media, middle ear effusion or tympanic membrane perforation, sensorineural* problems, or a mixture of both) 2

* Resulting from neuronopathic causes

DENTAL AND THROAT

  • Enlarged tongue, tonsils and adenoids 2
  • Enlarged epiglottis 2
  • Difficulty with swallowing and chewing 2
  • Irregular or peg-shaped teeth, with possible delayed eruption 2
  • Hyperplastic or hypertrophic gingival tissue 2

SKELETAL

  • Short stature and claw-like hands 2
  • Stiffened joints (due to abnormal bone thickening and joint contractures) 2
  • Bulky clavicles, thickened and abnormally shaped ribs 2
  • Toe-walking due to tight heel cords 2
  • Irregular epiphyseal ossification of the joints in the hands, shoulders and elbows, notching on the lateral surfaces of vertebrae, destructive hip arthropathies, and eventually spinal cord deformities 3,4

RESPIRATORY

  • Upper airway obstructions (due to enlarged tongue, tonsils and adenoids, constricting skeletal changes in the jaw and neck, tracheal and pharyngeal deformities, mucosal thickening, abnormally shaped and stiff ribs, and constricted rib motion) 3
  • Upper and lower respiratory tract infection 3
  • Sleep apnoea 2

Find out more about how the wide range of symptoms are managed by a multidisciplinary medical team

Disease progression

There isn’t a typical disease course in Hunter syndrome, as each individual has their own unique set of genetic mutations contributing to the disease. 2

However, progressive decline is inevitable in Hunter syndrome as GAGs accumulate. Although there isn’t a typical disease course, there are common trends in the progression of the disease. 2

Neuronopathic
In Hunter syndrome patients with neuronopathic involvement, behavioural problems including hyperactivity and aggression may start from the second year of life. These behavioural issues can become very serious, disrupting the quality of life of both the patient and the family. Patients with neuronopathic involvement can also be obstinate and unruly; these behaviours can be exacerbated by the hearing difficulties and sleep disturbance-induced fatigue. 3

Neurodegeneration due to GAG deposition leads to fine motor skill impairment in some patients, with a median onset at 4 years old. Children may become particularly boisterous if their tolerance to pain has increased due to loss of sensation (dysaesthesia). However, behavioural problems typically only continue until the age of 8 to 9 years, at which point neurodegeneration causes cognitive functions to wholly decline. Around this point, the ability to walk and talk diminishes. At the same time, cognitive decline means that learning and maintaining new skills will become harder. 3

Severe neuronopathic decline leads to the complete loss of the ability to communicate and chew or swallow, as well as extreme cognitive disability and the inability to control gastrointestinal function. 3,4

Advanced nervous system symptoms will also be observed in patients as they decline cognitively. Many patients suffer from carpal tunnel syndrome, which has a median onset at age 8 years. 5 A few patients develop communicating hydrocephalus, which exacerbates the cognitive decline and can result in behavioural changes, headaches and vision disturbances. 3 Patients can also suffer from spinal cord compression due to dura mater thickening, which leads to a general muscle weakness, loss of sensation, neurogenic bladder dysfunction, and further deterioration of fine motor skills and gait problems. 3

Non-neuronopathic
As a patient with Hunter syndrome grows, the non-neuronopathic symptoms will become increasingly obvious and debilitating. The characteristic facial features and prominent brow begin to show around 2 years of age.1 Patients can be of average height for their first few years, before growth begins to slow, eventually leading to a short stature. 3

A noticeable consequence of Hunter syndrome is that patients require numerous surgeries, even before the underlying disorder has been diagnosed. 6 The repeated ear infections and hernias, and presence of enlarged tonsils and adenoids are early symptoms of Hunter syndrome that require treatment, and many Hunter syndrome patients will undergo multiple hernia repairs, tympanostomies, adenoidectomies and tonsillectomies before Hunter syndrome is identified. 6

After these early symptoms, the disease continues to progress, and patients will often suffer from auditory, ocular and dental complications that require more surgeries. Other common developments are joint contractures and skeletal deformities, which gradually limit mobility, and eventually prevent the patient from walking and standing erect. 3

The management of Hunter syndrome patients and their symptoms requires that physicians are aware of the special underlying and multisystemic nature of Hunter syndrome. Therefore it is extremely important to diagnose Hunter syndrome early in order to ensure timely and appropriate management. 3

Learn more about the specialist multidisciplinary management of Hunter syndrome patients in Monitoring and management section of this website.

Cardiac and respiratory complications can be life-threatening. Cardiac involvement through valve disease is common in Hunter syndrome patients, from a median onset age of 6 years, and cardiac complications which develop include abnormal heart frequency, cardiomyopathy, left and right ventricle hypertrophy, arrhythmia, hypertension, and ultimately, heart failure. 5,7

Respiratory tract infections such as pneumonia are common and can develop to be life-threatening. Respiratory failure, cardiac arrest, pneumonia, and cardiac failure are the most common causes of 60% of Hunter syndrome patient deaths as recorded in the HOS. 8

Remember – if you suspect Hunter syndrome: REFER TO A SPECIALIST TODAY

Aiden

Aiden appeared to be a healthy baby boy when he was born. However, gradually though his first year of life, he began suffering from frequent ear infections. The family’s paediatrician believed that these were ‘typical’ symptoms for a child at his age.

At age 18 months (around the time when his brother, AJ, was born), Aiden also had his adenoids removed. He was still cheerful, and enjoyed playing with his younger brother, but by the age of 2 years, Aiden’s parents had noticed a delay in his speech development, and they sought speech assessments for him.

Silas

Silas was normal when he was born, but at around the age of 6 months, his parents noticed that the back of his head was becoming flat, and that he had difficulties holding his head up. He also didn’t like being laid down upon his stomach. At age 1 year Silas fell ill with a severe cold, high temperature, and obstructive bronchitis. A doctor then investigated whether his head circumference had ever been recorded.

At age 2 years, Silas went for an MRI scan, which showed an abnormality. He was then referred for genetic testing, which confirmed a diagnosis of Hunter syndrome.

References

  • Burton BK, Giugliani R. Diagnosing Hunter syndrome in pediatric practice: practical considerations and common pitfalls. Eur J Pediatr 2012; 171(4): 631–639.
  • 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.
  • Muenzer J et al. Multidisciplinary management of Hunter syndrome. Pediatrics 2009; 124(6): e1228–e1239.
  • Martin R et al. Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome). Pediatrics 2008; 121(2): e377–e386.
  • Wraith JE et al. Initial report from the Hunter outcome survey. Genet Med 2008; 10(7): 508–516.
  • 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.
  • Kampmann C et al. Prevalence and characterization of cardiac involvement in Hunter syndrome. J Pediatr 2011; 159(2): 327–331.e2.
  • Burton BK et al. Survival in idursulfase-treated and untreated patients with mucopolysaccharidosis type II: data from the Hunter Outcome Survey (HOS). J Inherit Metab Dis 2017; 40(6): 867–874.