morquio a: musculoskeletal manifestations
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Morquio A: Musculoskeletal manifestations
Skeletal dysplasia– Spinal abnormalities– Pectus carinatum– Hip dysplasia– Genu valgum– Ankle valgus– Hand abnormalities– Flat facial features– Mandibular protrusionShort statureJoint instabilityJoint subluxationJoint degenerationAbnormal gaitWeak hand grip
Left image: Kalteis et al, Arthroscopy, 2005Top and bottom right images: Atinga et al, J Bone Joint Surg Br, 2008
Morquio A patients present with marked musculoskeletal abnormalities
n = 325 subjectsData based on medical history reviews
Musculoskeletal abnormalities are the most common presenting features in Morquio A
Harmatz et al, Mol Genet Metab, 2013
Pectus
carin
atum
Abnor
mal ga
it
Short s
tature
Genu va
lgum
Short n
eck
Joint
laxit
y
Kypho
scoli
osis
Joint
stiffn
ess/p
ain
Hip dy
splasia
0%
20%
40%
60%
80%
100% 97% 94% 93% 93% 91% 87% 85% 83%
71%
% S
ubje
cts
MorCAP Baseline data
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
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
Key radiographic findings in Morquio A
Dysostosis multiplex
Spine:Dens hypoplasiaPlatyspondylyInferiorly beaked vertebral bodiesPosterior scalloping of vertebraeThoracolumbar kyphosis
Hips and lower extremities:Rounded iliac wingsAcetabular dysplasiaCoxa valgaGenu valgumAnkle valgus
Upper extremities:Short, broad metacarpalsProximal metacarpal roundingIrregular/hypoplastic carpal bones
Thorax:Pectus carinatumPaddle-shaped ribsShort, thick clavicles
(Findings vary and can be subtle)
Spine: Normal
Image courtesy of Ralph Lachman, MD
Dens hypoplasiaPlatyspondylyAnterior beakingPosterior scalloping Thoracolumbar kyphosis
Solanki et al, J Inherit Metab Dis, 2013
Spine: Dysostosis multiplex
Hips: Normal
Image courtesy of Ralph Lachman, MD
6 year old Morquio AImage courtesy of Klane White, MDWhite, Curr Orthop Prac, 2012
8 year old Morquio AImage courtesy of Ralph Lachman, MD
Rounded iliac wingsUnderdeveloped acetabulaDysplastic capital femoral epiphysesCoxa valgaGenu valgumAnkle valgus
Hips and lower extremities: Dysostosis multiplex
Thorax: Normal
Image courtesy of Ralph Lachman, MD
Paddle-shaped ribsPectus carinatumShort, thick clavices
Thorax: Dysostosis multiplex
8 year old Morquio AImage courtesy of Christina Lampe, MD
Hands: Normal
Image courtesy of Ralph Lachman, MD
8 year old Morquio AImage courtesy of Ralph Lachman, MD
Short, broad metacarpalsProximal metacarpal roundingHypoplastic carpal ossification
Hands: Dysostosis multiplex
n=325 Morquio A subjectsMorCAP 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
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
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
abnormalitiesSubluxations of the hip and atlantoaxial joints are commonJoint 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
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
Embed Dawn video (Youtube)http://www.youtube.com/watch?v=ugeVScsV0oM
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
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 old At 7 years old
Assessment At diagnosis Frequency
Neurological exam Yes 6 monthsPlain radiography cervical spine (AP, lateral neutral and flexion-extension) Yes 2-3 years
Plain radiography spine (AP, lateral thoracolumbar) Yes
2-3 years if evidence of kyphosis or scoliosis
MRI neutral position, whole spine Yes 1 yearFlexion-extension of cervical spine by MRI Yes 1-3 years
CT neutral region of interest Preoperative planning
Solanki et al, J Inherit Metab Dis, 2013
Regular assessments of the spine are recommended for improved patient outcomes
Image courtesy of Klane White, MDWhite, 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
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, 1988.
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, MDWhite, J Bone Joint Surg Am, 2009
Assessment Initial assessment Annually
As clinically indicated
Hips/pelvis: AP pelvis radiograph X X
Lower extremities: Standing AP radiographs X X
White, Rheumatology, 2011
Regular assessments of the hips and lower extremities are recommended for optimal outcomes
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 outcomesPelvic 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, 2012 Lewis et al, J Bone Joint Surg Br, 2010
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 valgumOsteotomy for patients with limited growth potential and severe genu valgumRecurrence 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, 2012de Waal Malefijt et al. Arch Orthop Trauma Surg, 2000
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
Physical therapyWalker/wheelchair usePain 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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