1. Morquio A: Musculoskeletal manifestations

2. Morquio A patients present with marked musculoskeletal abnormalities
Skeletal dysplasia
Spinal abnormalities
Pectus carinatum
Hip dysplasia
Genu valgum
Ankle valgus
Hand abnormalities
Flat facial features
Mandibular protrusion
Short stature
Joint instability
Joint subluxation
Joint degeneration
Abnormal gait
Weak hand grip
Left image: Kalteis et al, Arthroscopy, 2005
Top and bottom right images: Atinga et al, J Bone Joint Surg Br, 2008

3. Musculoskeletal abnormalities are the most common presenting features in Morquio A
% Subjects
n = 325 subjects
Data based on medical history reviews
Harmatz et al, Mol Genet Metab, 2013
MorCAP Baseline data

4. Musculoskeletal abnormalities are the most common presenting symptoms in Morquio A
Common initial presenting symptoms in Morquio A
n = 326 subjects
Montano et al, J Inherit Metab Dis, 2007
International Morquio A Registry

5. Morquio A disrupts normal development and maturation of cartilage and bone
Articular cartilage is altered in Morquio A patients:
KS accumulation in chondrocytes
Poorly organized tissue structure
Increased Type I collagen and reduced Type II collagen
Thicker, irregularly shaped collagen fibrils
Role of GAG-mediated inflammation?
Identification of biomarkers is critical for elucidation of pathogenesis
Articular cartilage chondrocyte in
(A) control, (B) Morquio A patient
CTX-1 = C-terminal telopeptide of Type I collagen
Collagen fibrils in articular cartilage of (A) control, (B) Morquio A patient
Bank et al, Mol Genet Metab, 2009
Dvorak-Ewell et al, PLoS, 2010; Bank et al, Mol Genet Metab, 2009; De Franceschi et al, Osteoarthritis Cartilage, 2007;
Kalteis et al, Arthroscopy, 2005; McClure et al, Pathology, 1986

6. Key radiographic findings in Morquio A
Dysostosis multiplex
Spine:
Dens hypoplasia
Platyspondyly
Inferiorly beaked vertebral bodies
Posterior scalloping of vertebrae
Thoracolumbar kyphosis
Hips and lower extremities:
Rounded iliac wings
Acetabular dysplasia
Coxa valga
Genu valgum
Ankle valgus
Upper extremities:
Short, broad metacarpals
Proximal metacarpal rounding
Irregular/hypoplastic carpal bones
Thorax:
Pectus carinatum
Paddle-shaped ribs
Short, thick clavicles
(Findings vary and can be subtle)

7. Spine: Normal
Image courtesy of Ralph Lachman, MD

8. Spine: Dysostosis multiplex
Dens hypoplasia
Platyspondyly
Anterior beaking
Posterior scalloping
Thoracolumbar kyphosis
Solanki et al, J Inherit Metab Dis, 2013

9. Hips: Normal
Image courtesy of Ralph Lachman, MD

10. Hips and lower extremities: Dysostosis multiplex
8 year old Morquio A
Image courtesy of Ralph Lachman, MD
Rounded iliac wings
Underdeveloped acetabula
Dysplastic capital femoral epiphyses
Coxa valga
Genu valgum
Ankle valgus
6 year old Morquio A
Image courtesy of Klane White, MD
White, Curr Orthop Prac, 2012

11. Thorax: Normal
Image courtesy of Ralph Lachman, MD

12. Thorax: Dysostosis multiplex
Paddle-shaped ribs
Pectus carinatum
Short, thick clavices
8 year old Morquio A
Image courtesy of Christina Lampe, MD

13. Hands: Normal
Image courtesy of Ralph Lachman, MD

14. Hands: Dysostosis multiplex
Short, broad metacarpals
Proximal metacarpal rounding
Hypoplastic carpal ossification
8 year old Morquio A
Image courtesy of Ralph Lachman, MD

15. Short stature is a characteristic feature of Morquio A
Growth retardation in Morquio A
71% of Morquio A subjects ≤ 18 years are below 3rd percentile in height
Majority of adults are < 120 cm in height
n=325 Morquio A subjects
MorCAP baseline data
Harmatz et al, Mol Genet Metab, 2013; BioMarin data on file

16. Short stature is a characteristic feature of Morquio A
Growth retardation in Morquio A
Montano et al, J Inherit Metab Dis, 2007
International Morquio A registry

17. Joint abnormalities are common in Morquio A patients
Joint instability
floppy wrists with weak grip and loss of fine motor skills
exacerbates knee valgus and gait abnormalities
Subluxations of the hip and atlantoaxial joints are common
Joint degeneration due to bone defects, cartilage deterioration and altered mechanics
Joint pain
Atinga et al, J Bone Joint Surg Br, 2008
Harmatz et al, Mol Genet Metab, 2013; Aslam et al, JIMD Rep, 2013; Tomatsu et al, Curr Pharm Biotechnol, 2011;
Montano et al, J Inherit Metab Dis, 2007

18. Hand function is compromised
A study of 10 Morquio A patients (Aslam et al, 2012) revealed:
Wrist instability in all subjects
Average difference of 93 between active and passive ROM at wrist joint
Reduced hand grip strength in all subjects
Difficulties with tasks requiring strength, e.g. lifting heavy objects and pouring from a bottle
Of the 153 subjects ≥ 12 years of age in the MorCAP baseline study (Harmatz et al, 2013):
30% could not cut their fingernails
22% could not tuck in shirts
22% were unable to open jars
20% were unable to tie shoelaces
Hand dysfunction contributes significantly to difficulties with activities of daily living
ROM = range of motion Aslam study based on subjective (activity of daily living questionnaire) and objective (ROM and strength) measures.
Aslam et al, JIMD Rep, 2013; Harmatz et al, Mol Genet Metab, 2013; BioMarin data on file

19. Abnormal gait results from bone and joint defects
A study of 9 children with Morquio (subtype not specified) with no previous lower extremity surgery revealed a consistent gait pattern:
Slower walking speed, reduced cadence and reduced stride length vs normal
Trunk, pelvis, hip: increased forward tilt of trunk and pelvis, increased hip flexion
Knee: increased knee flexion, genu valgus, and external tibial torsion; dynamic knee varus-valgus joint laxity
Joint moments and power: reduced hip and ankle joint moments, reduced power generation
Youtube =
Embed Dawn video (Youtube)
Dhawale et al, J Pediatr Orthop B, 2012

20. Orthopedic management of the spine, hips and lower extremities is essential for optimal patient outcomes
Cervical instability, spinal stenosis and spinal cord compression are common in Morquio A. Early diagnosis and timely intervention can reduce the risk of myelopathy, quadriparesis and death.
At 4 years old
At 7 years old
Progressive genu valgum and hip deformity in Morquio A. Surgical correction can improve mechanics, increase walking ability and endurance, reduce pain, and delay onset of arthritis.
Solanki et al, J Inherit Metab Dis, 2013
Radiographs from Dhawale et al, J Pediatr Orthop B, 2012
Solanki et al, J Inherit Metab Dis, 2013; Dhawale et al, J Pediatr Orthop B, 2012; White, Rheumatology, 2011; White, Curr Orthop Prac, 2012

21. Regular assessments of the spine are recommended for improved patient outcomes
At diagnosis
Frequency
Neurological exam
Yes
6 months
Plain radiography cervical spine (AP, lateral neutral and flexion-extension)
2-3 years
Plain radiography spine (AP, lateral thoracolumbar)
2-3 years if evidence of kyphosis or scoliosis
MRI neutral position, whole spine
1 year
Flexion-extension of cervical spine by MRI
1-3 years
CT neutral region of interest
Preoperative planning
Solanki et al, J Inherit Metab Dis, 2013

22. Surgical interventions
Indications include:
Neurological deficits + instability
Cord compression with signal change on MRI
Cervical spine:
Posterior fusion for C1-C2 subluxation and instability, often with posterior occipito-cervical fixation
If subluxation is irreducible and cord compression is present, decompression + fusion is indicated
Prophylatic fusion recommended by some
Thoracolumbar kyphosis:
Decompression, segmental instrumentation and fusion
Anterior discectomy and fusion strongly recommended to augment posterior fusion in cases of rigid kyphosis
Ain et al, Spine, 2006
Image courtesy of Klane White, MD
White, Curr Orthop Prac, 2012
Solanki et al, J Inherit Metab Dis, 2013; White, Curr Orthop Prac, 2012; Ain et al, Spine (Phila PA 1976), 2006; Ransford et al, J Bone Joint Surg Br, 1996; Lipson, J Bone Joint Surg Am, 1977

23. Outcomes of spine surgery
Short-term post-operative outcomes generally good
Possible post-surgical complications:
Late instability below fusion site may necessitate multiple fusions
Halo pin tract infection
→ Long-term monitoring is important
Long-term outcomes beyond 5 years are less known – few studies
Morquio patient 26 years post-surgery:
complete resolution of quadriparesis achieved
and neurological function maintained 26 years
after C1-C2 decompression and stabilization
Image courtesy of Klane White, MD
White, J Bone Joint Surg Am, 2009
Solanki et al, J Inherit Metab Dis, 2013; White, J Bone Joint Surg Am, 2009; Ain et al, Spine (Phila PA 1976), 2006; Dalvie et al, J Pediatr Orthop B, 2001; Holte et al, Neuro-Orthopedics,1994; Houten et al, Pediatr Neurosurg, 2011; Lipson, J Bone Joint Surg Am, 1977; Ransford et al, J Bone Joint Surg Br, 1996; Stevens et al, J Bone Joint Surg Br 1991; Svensson and Aaro, Act Orthop Scand, 1988.

24. As clinically indicated
Regular assessments of the hips and lower extremities are recommended for optimal outcomes
Assessment
Initial assessment
Annually
As clinically indicated
Hips/pelvis: AP pelvis radiograph X
Lower extremities: Standing AP radiographs
White, Rheumatology, 2011

25. Hip deformity correction and outcomes
Pelvic osteotomy + femoral osteotomy
Hip subluxation may recur
Shelf acetabuloplasty + femoral varus derotation osteotomy (VDRO) reported to yield good outcomes with no recurrent hip subluxation
Total hip arthroplasty
Morquio A patient with hip subluxation: (A) At 12.5 years underwent Pemberton osteotomy + VDRO. (B) At 16 years, hip subluxation recurred. (C) At 18 years, hips well located 2 years post-shelf acetabuloplasty
Morquio adult: satisfactory bilateral hip replacement, 7 year followup
Dhawale et al, J Pediatr Orthop, 2012
Lewis et al, J Bone Joint Surg Br, 2010
Dhawale et al, J Pediatr Orthop, 2012; Tassanari et al, Chir Organi Mov , 2008; Lewis et al, J Bone Joint Surg Br, 2010; White, Curr Orthop Prac, 2012

26. Knee deformity correction and outcomes
Guided growth for younger patients with mild to moderate genu valgum
Osteotomy for patients with limited growth potential and severe genu valgum
Recurrence after genu valgum correction is common
Total knee arthroplasty for patients with advanced arthrosis
Hemiepiphysiodesis (F) of proximal tibia and distal femur with 8 plates in 10 year old Morquio A patient. (G) Maintenance of correction 1 year after removal of 8 plates, at age 13 years. Patient also underwent guided growth for ankle valgus.
Morquio A adult, 4 years after total knee arthroplasty
de Waal Malefijt et al. Arch Orthop Trauma Surg, 2000
Dhawale et al, J Pediatr Orthop, 2012
Dhawale et al, J Pediatr Orthop, 2012; de Waal Malefijt et al. Arch Orthop Trauma Surg, 2000; Atinga et al, J Bone Joint Surg Br, 2008; White, Curr Orthop Prac, 2012

27. Airway and anesthetic management of Morquio A patients presenting for surgery is challenging
Morquio A patients are at high risk of anesthesia-related morbidity and mortality due to:
Cervical instability and myelopathy
Compromised respiratory function
Upper and lower airway obstruction
Restrictive lung disease
Cardiac abnormalities
Any elective surgery requires:
Thorough pre-operative ENT, pulmonary and cardiac evaluations
Pre-operative radiological assessment of the cervical spine
Skilled personnel in airway management
Spectrum of airway management equipment
Morquio A patients should be managed by experienced anesthesiologists at centers familiar with MPS disorders
Theroux et al, Paediatr Anaesth, 2012; Solanki et al, J Inherit Metab Dis, 2013; Walker et al, J Inherit Metab Dis, 2013;
McLaughlin et al, BMC Anesthesiol, 2010; Morgan et al, Paediatr Anaesth, 2002; Shinhar et al, Arch Otolaryngol Head Neck Surg, 2004;
Belani et al, J Ped Surg, 1993; Walker et al, Anaesthesia, 1994

28. Non-surgical interventions
Physical therapy
Walker/wheelchair use
Pain management
MorCAP baseline data (Harmatz et al, 2013) revealed:
49% of 300 Morquio A subjects required wheelchairs (mean age= 14.5 years)
26% of 298 Morquio A subjects used walking aids (mean age= 14.5 years)
Harmatz et al, Mol Genet Metab, 2013