Morquio A: Musculoskeletal manifestations. Skeletal dysplasia –Spinal abnormalities –Pectus...

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

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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


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


Paddle-shaped ribsPectus carinatumShort, thick clavices

Thorax: Dysostosis multiplex

8 year old Morquio AImage courtesy of Christina Lampe, MD

Hands: Normal


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

Height

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


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;


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; 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 months

Plain radiography cervical spine (AP, lateral neutral and flexion-extension)

Yes 2-3 years

Plain radiography spine (AP, lateral thoracolumbar)

Yes2-3 years if evidence

of kyphosis or scoliosis

MRI neutral position, whole spine Yes 1 year

Flexion-extension of cervical spine by MRI

Yes 1-3 years

CT neutral region of interest Preoperative planning


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, MD

White, J Bone Joint Surg Am, 2009

AssessmentInitial

assessmentAnnually

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 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, 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

Morquio A: Musculoskeletal manifestations. Skeletal dysplasia –Spinal abnormalities –Pectus...

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