Hunter Syndrome
What is Hunter Syndrome?
 Hunter syndrome (or MPS II) is an inherited Iysosomal storage disease1
 First described by Charles Hunter in 19172
 Estimated worldwide incidence of 1:154,770 total live births3-11
Incidence of Hunter syndrome
1Neufeld
Country
Incidence (total births)
Germany3
1:155,941
Netherlands4
1:149,692
Australia5
1:162,397
Northern Portugal6
1:91,743
Canada (British Columbia)7-9
1:249,867
Greece10
1:208,347
Northern Ireland11
1:139,920
EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, et al (eds). The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill; 2001:3421–3452; 2Hunter C. Proc R Soc Med.1917;10:104–
116;
et al. J Inherit Metab Dis. 2005;28:1011–1017; 4Poorthuis et al. Hum Genet. 1999;105:151–156; 5Meikle et al. JAMA. 1999;281:249–254; 6Pinto et al. Eur J Hum Genet. 2004;12:87–92; 7Applegarth et al. Pediatrics. 2000;105:e10;
8Lowry et al. N Engl J Med. 1971;284:221–222; 9Lowry et al. Hum Genet. 1990;85:389–390; 10Michelakakis et al. Genet Couns. 1995;6:43–47; 11Nelson. Hum Genet. 1997;101:355–358.
3Baehner
GAG Accumulation1
I2S = iduronate-2-sulfatase
lysosomes
M6P
receptor
transport
vesicle
GAG
ER
GAG
nucleus
I2S cleavage site
Golgi
In the absence of I2S, the GAG degradation pathway
is blocked and lysosomes fill up with GAG.
1. Neufeld, Muenzer. In: The Metabolic and Molecular Bases of Inherited Disease. 2001:3421–3452.
Scenarios of Hunter Syndrome Inheritance
MOST LIKELY:
Female carrier passes on
HS I2S gene to son1
1Neufeld,
Muenzer. In: The Metabolic and Molecular Bases of Inherited Disease. 2001:3421–3452.
LESS COMMON BUT POSSIBLE:
Hunter syndrome male passes on
HS I2S gene to daughter1
Preliminary Diagnosis of Hunter Syndrome
 Preliminary analysis of urinary GAG levels1,2
 Does not differentiate between phenotypes in the clinical spectrum
 Does not differentiate between different mucopolysaccharidoses unless
electrophoresis is performed
 Accurate urinary samples may be difficult to obtain
 Due to the frequency of false negatives, a negative result cannot exclude a
diagnosis2
1Neufeld,
Muenzer. In: The Metabolic and Molecular Bases of Inherited Disease. 2001:3421–3452. 2Braverman. Mucopolysaccharidosis type II. eMedicine Journal [serial online]. 2006.
Confirming a Diagnosis of Hunter Syndrome
 Bone radiography reveals characteristic
bone changes1
 Skeletal radiography to look for signs of
dysostosis multiplex1
 Definite diagnosis achieved by measuring I2S
activity in white blood cells, skin fibroblasts, or serum1
 Molecular testing is important for identifying carriers in family
 Prenatal diagnosis may be made from
amniotic fluid when family has history of Hunter syndrome1,2
1Braverman.
2Neufeld,
Mucopolysaccharidosis type II. eMedicine Journal [serial online]. 2006.
Muenzer. In: The Metabolic and Molecular Bases of Inherited Disease. 2001:3421–3452.
Importance of Early Diagnosis
 Hunter syndrome is a severe and progressive disorder
 Over time, patients may experience irreversible damage
to organs and systems
 In severe cases, death can occur in the teens; in milder cases
patients can live into their 50s or 60s
Clinical Spectrum of Hunter Syndrome
Neufeld, Muenzer. In: The Metabolic and Molecular Bases of Inherited Disease. 2001:3421–3452. Photograph (left) reprinted with permission from the authors and McGraw-Hill. Photograph (right) is taken from the Shire Human Genetic
Therapies library of images.
Signs and Symptoms: Craniofacial




1Neufeld,
Coarsening1,2
Macroglossia1,2
Deafness and recurrent ear infections3
Chronic rhinorrhea1
Muenzer. In: The Metabolic and Molecular Bases of Inherited Disease. 2001:3421–3452.
Mucopolysaccharidosis type II. eMedicine Journal [serial online]. 2006.
3Finlayson. Pediatr Dermatol. 1990;7:150–152.
2Braverman.
Signs and Symptoms: Skeletal




Joint stiffness, restriction, and contractures
Camptodactyly
Bone dysplasia
Joint pain
X-ray of 18-year old patient with
mucopolysaccharidosis type II showing femoral
head necrosis and the typical features of dysostis
multiplex
Neufeld, Muenzer. In: The Metabolic and Molecular Bases of Inherited Disease. 2001:3421–3452.
Signs and Symptoms: Neurologic





1Braverman.
Cognitive impairment1/hyperactivity in some patients1
Progressive mental retardation in many patients1
Communicating hydrocephalus1,2,3
Spinal cord compression4
Carpal tunnel syndrome1,2,5
Mucopolysaccharidosis type II. eMedicine Journal [serial online]. 2006. 2Neufeld, Muenzer. In: The Metabolic and Molecular Bases of Inherited Disease. 2001:3421–3452. 3Van Aerde et al. Acta Paediatr Belg. 1981;34:93–96. 4Ballenger et al.
Ann Neurol. 1980;7:382–385. 5Norman-Taylor et al. J Pediatr Orthop B. 1995;4:106–109.
Signs and Symptoms: Cardiovascular





1Kettles
Valve disease1
Pulmonary hypertension1 with secondary congestive heart failure
Biventricular hypertrophy with cardiomyopathy1
Arrhythmias1
Congestive heart failure1,2
Cardiac Symptom3
N
Prevalence (%)
Age at Onset (years)
Valvular disease
34
53
6.2 (2.9–13.8)
Murmur
32
52
6.4 (3.7–12.3)
Cardiomyopathy
4
9
7.6 (5.2–27.3)
Any cardiovascular
sign/symptom
49
72
6.0 (2.9–13.7)
et al. Cardiovasc Pathol. 2002;11:94–96.
Mucopolysaccharidosis type II. eMedicine Journal [serial online]. 2006.
3Wraith et al. Genet Med. 2008;10(7):508–516.
2Braverman.
Signs and Symptoms: Pulmonary

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1Morehead,
History of frequent pneumonias1
Restrictive lung disease due to small rib cage and stiff joints1
Upper airway obstruction/sleep apnea1
Tracheobronchomalacia1
Respiratory insufficiency1,2
Increased risk during anesthesia2
Parsons. Int J Pediatr Otorhinolaryngol. 1993;26:255–261.
Mucopolysaccharidosis type II. eMedicine Journal [serial online]. 2006.
2Braverman.
Signs and Symptoms: Gastrointestinal




1Braverman.
2Neufeld,
Abdominal distension1
Hepatosplenomegaly1
Umbilical and inguinal hernias1
Watery diarrhea2
Mucopolysaccharidosis type II. eMedicine Journal [serial online]. 2006.
Muenzer. In: The Metabolic and Molecular Bases of Inherited Disease. 2001:3421–3452.
Coordinating Care in Patients With Hunter
Syndrome
 Management requires multidisciplinary approach
 Neurologic involvement
 Hydrocephalus, spinal cord compression, atlantoaxial instability,
cognitive involvement, carpal tunnel syndrome (CTS)
 Cardiac involvement
 Valvular dysfunction, conduction abnormalities
 Respiratory involvement
 Upper-airway obstruction, pharyngomalacia/tracheomalacia, restrictive lung disease, obstructive sleep apnea
 Skeletal involvement
 Coxa valga deformity, joint contractures, trigger fingers due to CTS
 Hearing
 Chronic otitis media, ostosclerosis, neurosensory loss
 Eye
 Retinal dysfunction
Muenzer J et al. Pediatrics. 2009;1241:e1–e12.
Recommended Evaluations for Hunter Syndrome
From an International Panel of Physicians
Organ System/Involvement
Assessment
Recommendation
Neurologic
Hydrocephalus
Spinal cord compression
Atlantoaxial instability
MRI or CT scan of head
MRI of cervical spine
Cervical spine flexion/extension
At diagnosis, every 1–3 years
At diagnosis, every 1–3 years
At diagnosis, every 2–3 years, before
anesthesia
Progressive cognitive involvement
Neurobehavioral
At diagnosis, yearly
Carpal tunnel syndrome
Nerve conduction
Hand function test
Age 4–5 years, 1 to 2 year intervals
At diagnosis, yearly
Echocardiogram, EKG, and Holter
monitoring if indicated
At diagnosis, 1 to 3 year intervals
Hearing
Otologic and audiologic
At diagnosis, every 6–12 months
based on symptoms
Vision
Standard ophtalmologic exam
Yearly
Heart
Valvular dysfunction
Muenzer J et al. Pediatrics. 2009;1241:e1–e12.
Recommended Evaluations for Hunter Syndrome
From an International Panel of Physicians(cont)
Organ System/Involvement
Assessment
Recommendation
Respiratory
Pulmonary function
At diagnosis or when patient can
cooperate, then yearly
At diagnosis, every
3–5 years and when OSA
suspected
As needed or before general
anesthesia
Sleep study
Bronchoscopy
Skeletal involvement
Joint range of motion
Radiograph of spine and hip
At diagnosis, yearly
At diagnosis, when symptoms
warrant
General
Inguinal hernia
Hepatosplenomegaly
Clinical evaluation
Clinical evaluation
At every exam
At every exam
Dental
Standard dental care
Every 6 months
Muenzer J et al. Pediatrics. 2009;1241:e1–e12.