1. Hunter Syndrome

2. What is Hunter Syndrome?  Hunter syndrome (or MPS II) is an inherited Iysosomal storage disease 1  First described by Charles Hunter in 1917 2  Estimated worldwide incidence of 1:154,770 total live births 3-11 Incidence of Hunter syndrome CountryIncidence (total births) Germany 3 1:155,941 Netherlands 4 1:149,692 Australia 5 1:162,397 Northern Portugal 6 1:91,743 Canada (British Columbia) 7-9 1:249,867 Greece 10 1:208,347 Northern Ireland 11 1:139,920 1 Neufeld 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; 2 Hunter C. Proc R Soc Med.1917;10:104– 116; 3 Baehner et al. J Inherit Metab Dis. 2005;28:1011–1017; 4 Poorthuis et al. Hum Genet. 1999;105:151–156; 5 Meikle et al. JAMA. 1999;281:249–254; 6 Pinto et al. Eur J Hum Genet. 2004;12:87–92; 7 Applegarth et al. Pediatrics. 2000;105:e10; 8 Lowry et al. N Engl J Med. 1971;284:221–222; 9 Lowry et al. Hum Genet. 1990;85:389–390; 10 Michelakakis et al. Genet Couns. 1995;6:43–47; 11 Nelson. Hum Genet. 1997;101:355–358.

3. GAG Accumulation 1 GAG M6P receptor transport vesicle nucleus Golgi lysosomes ER GAG I2S cleavage site I2S = iduronate-2-sulfatase 1. Neufeld, Muenzer. In: The Metabolic and Molecular Bases of Inherited Disease. 2001:3421–3452. In the absence of I2S, the GAG degradation pathway is blocked and lysosomes fill up with GAG.

4. Scenarios of Hunter Syndrome Inheritance 1 Neufeld, Muenzer. In: The Metabolic and Molecular Bases of Inherited Disease. 2001:3421–3452. MOST LIKELY: Female carrier passes on HS I2S gene to son 1 LESS COMMON BUT POSSIBLE: Hunter syndrome male passes on HS I2S gene to daughter 1

5. Preliminary Diagnosis of Hunter Syndrome  Preliminary analysis of urinary GAG levels 1,2  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 diagnosis 2 1 Neufeld, Muenzer. In: The Metabolic and Molecular Bases of Inherited Disease. 2001:3421–3452. 2 Braverman. Mucopolysaccharidosis type II. eMedicine Journal [serial online]. 2006.

6. Confirming a Diagnosis of Hunter Syndrome  Bone radiography reveals characteristic bone changes 1 Skeletal radiography to look for signs of dysostosis multiplex 1  Definite diagnosis achieved by measuring I2S activity in white blood cells, skin fibroblasts, or serum 1  Molecular testing is important for identifying carriers in family  Prenatal diagnosis may be made from amniotic fluid when family has history of Hunter syndrome 1,2 1 Braverman. Mucopolysaccharidosis type II. eMedicine Journal [serial online]. 2006. 2 Neufeld, Muenzer. In: The Metabolic and Molecular Bases of Inherited Disease. 2001:3421–3452.

7. 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

8. 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.

9. Signs and Symptoms: Craniofacial  Coarsening 1,2  Macroglossia 1,2  Deafness and recurrent ear infections 3  Chronic rhinorrhea 1 1 Neufeld, Muenzer. In: The Metabolic and Molecular Bases of Inherited Disease. 2001:3421–3452. 2 Braverman. Mucopolysaccharidosis type II. eMedicine Journal [serial online]. 2006. 3 Finlayson. Pediatr Dermatol. 1990;7:150–152.

10. Signs and Symptoms: Skeletal  Joint stiffness, restriction, and contractures  Camptodactyly  Bone dysplasia  Joint pain Neufeld, Muenzer. In: The Metabolic and Molecular Bases of Inherited Disease. 2001:3421–3452. X-ray of 18-year old patient with mucopolysaccharidosis type II showing femoral head necrosis and the typical features of dysostis multiplex

11. Signs and Symptoms: Neurologic  Cognitive impairment 1 /hyperactivity in some patients 1  Progressive mental retardation in many patients 1  Communicating hydrocephalus 1,2,3  Spinal cord compression 4  Carpal tunnel syndrome 1,2,5 1 Braverman. Mucopolysaccharidosis type II. eMedicine Journal [serial online]. 2006. 2 Neufeld, Muenzer. In: The Metabolic and Molecular Bases of Inherited Disease. 2001:3421–3452. 3 Van Aerde et al. Acta Paediatr Belg. 1981;34:93–96. 4 Ballenger et al. Ann Neurol. 1980;7:382–385. 5 Norman-Taylor et al. J Pediatr Orthop B. 1995;4:106–109.

12. Signs and Symptoms: Cardiovascular  Valve disease 1  Pulmonary hypertension 1 with secondary congestive heart failure  Biventricular hypertrophy with cardiomyopathy 1  Arrhythmias 1  Congestive heart failure 1,2 1 Kettles et al. Cardiovasc Pathol. 2002;11:94–96. 2 Braverman. Mucopolysaccharidosis type II. eMedicine Journal [serial online]. 2006. 3 Wraith et al. Genet Med. 2008;10(7):508–516. Cardiac Symptom 3 NPrevalence (%)Age at Onset (years) Valvular disease34536.2 (2.9–13.8) Murmur32526.4 (3.7–12.3) Cardiomyopathy497.6 (5.2–27.3) Any cardiovascular sign/symptom 49726.0 (2.9–13.7)

13. Signs and Symptoms: Pulmonary  History of frequent pneumonias 1  Restrictive lung disease due to small rib cage and stiff joints 1  Upper airway obstruction/sleep apnea 1  Tracheobronchomalacia 1  Respiratory insufficiency 1,2  Increased risk during anesthesia 2 1 Morehead, Parsons. Int J Pediatr Otorhinolaryngol. 1993;26:255–261. 2 Braverman. Mucopolysaccharidosis type II. eMedicine Journal [serial online]. 2006.

14. Signs and Symptoms: Gastrointestinal  Abdominal distension 1  Hepatosplenomegaly 1  Umbilical and inguinal hernias 1  Watery diarrhea 2 1 Braverman. Mucopolysaccharidosis type II. eMedicine Journal [serial online]. 2006. 2 Neufeld, Muenzer. In: The Metabolic and Molecular Bases of Inherited Disease. 2001:3421–3452.

15. 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.

16. Recommended Evaluations for Hunter Syndrome From an International Panel of Physicians Organ System/InvolvementAssessmentRecommendation Neurologic Hydrocephalus Spinal cord compression Atlantoaxial instability Progressive cognitive involvement Carpal tunnel syndrome MRI or CT scan of head MRI of cervical spine Cervical spine flexion/extension Neurobehavioral Nerve conduction Hand function test At diagnosis, every 1–3 years At diagnosis, every 2–3 years, before anesthesia At diagnosis, yearly Age 4–5 years, 1 to 2 year intervals At diagnosis, yearly Heart Valvular dysfunction Echocardiogram, EKG, and Holter monitoring if indicated At diagnosis, 1 to 3 year intervals HearingOtologic and audiologicAt diagnosis, every 6–12 months based on symptoms VisionStandard ophtalmologic examYearly Muenzer J et al. Pediatrics. 2009;1241:e1–e12.

17. Recommended Evaluations for Hunter Syndrome From an International Panel of Physicians(cont) Organ System/InvolvementAssessmentRecommendation RespiratoryPulmonary function Sleep study Bronchoscopy 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 Skeletal involvementJoint range of motion Radiograph of spine and hip At diagnosis, yearly At diagnosis, when symptoms warrant General Inguinal hernia Hepatosplenomegaly Clinical evaluation At every exam DentalStandard dental careEvery 6 months Muenzer J et al. Pediatrics. 2009;1241:e1–e12.