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Morquio A: Musculoskeletal manifestations. Skeletal dysplasia –Spinal abnormalities –Pectus carinatum –Hip dysplasia –Genu valgum –Ankle valgus –Hand.

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Presentation on theme: "Morquio A: Musculoskeletal manifestations. Skeletal dysplasia –Spinal abnormalities –Pectus carinatum –Hip dysplasia –Genu valgum –Ankle valgus –Hand."— Presentation transcript:

1 Morquio A: Musculoskeletal manifestations

2 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 Morquio A patients present with marked musculoskeletal abnormalities

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

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

5 Articular cartilage chondrocyte in (A) control, (B) Morquio A patient Collagen fibrils in articular cartilage of (A) control, (B) Morquio A patient 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 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 Morquio A disrupts normal development and maturation of cartilage and bone Bank et al, Mol Genet Metab, 2009

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

9 Hips: Normal Image courtesy of Ralph Lachman, MD

10 6 year old Morquio A Image courtesy of Klane White, MD White, Curr Orthop Prac, 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 Hips and lower extremities: Dysostosis multiplex

11 Thorax: Normal Image courtesy of Ralph Lachman, MD

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

13 Hands: Normal Image courtesy of Ralph Lachman, MD

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

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

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

17 Atinga et al, J Bone Joint Surg Br, 2008 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 Joint abnormalities are common in Morquio A patients 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 Aslam et al, JIMD Rep, 2013; Harmatz et al, Mol Genet Metab, 2013; BioMarin data on file Hand function is compromised Hand dysfunction contributes significantly to difficulties with activities of daily living 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

19 Embed Dawn video (Youtube) 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 Dhawale et al, J Pediatr Orthop B, 2012 Abnormal gait results from bone and joint defects

20 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. 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. Radiographs from Dhawale et al, J Pediatr Orthop B, 2012 Solanki et al, J Inherit Metab Dis, 2013 Solanki et al, J Inherit Metab Dis, 2013; Dhawale et al, J Pediatr Orthop B, 2012; White, Rheumatology, 2011; White, Curr Orthop Prac, 2012 Orthopedic management of the spine, hips and lower extremities is essential for optimal patient outcomes At 4 years oldAt 7 years old

21 AssessmentAt diagnosisFrequency Neurological examYes6 months Plain radiography cervical spine (AP, lateral neutral and flexion-extension) Yes2-3 years Plain radiography spine (AP, lateral thoracolumbar) Yes 2-3 years if evidence of kyphosis or scoliosis MRI neutral position, whole spineYes1 year Flexion-extension of cervical spine by MRI Yes1-3 years CT neutral region of interestPreoperative planning Solanki et al, J Inherit Metab Dis, 2013 Regular assessments of the spine are recommended for improved patient outcomes

22 Image courtesy of Klane White, MD White, Curr Orthop Prac, 2012 Ain et al, Spine, 2006 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 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 Surgical interventions

23 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 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, Outcomes of spine surgery 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

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

25 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 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 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 Dhawale et al, J Pediatr Orthop, 2012Lewis et al, J Bone Joint Surg Br, 2010

26 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 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 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 Knee deformity correction and outcomes Dhawale et al, J Pediatr Orthop, 2012 de Waal Malefijt et al. Arch Orthop Trauma Surg, 2000

27 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 Airway and anesthetic management of Morquio A patients presenting for surgery is challenging 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 Physical therapy Walker/wheelchair use Pain management Non-surgical interventions 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


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