Morquio A: Musculoskeletal manifestations - PowerPoint Presentation

Slide1

Morquio A: Musculoskeletal manifestationsSlide2

Skeletal dysplasia

Spinal abnormalitiesPectus carinatumHip dysplasiaGenu valgumAnkle valgusHand abnormalitiesFlat facial featuresMandibular 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 Slide3

n = 325 subjects

Data based on medical history reviewsMusculoskeletal abnormalities are the most common presenting features in Morquio AHarmatz et al, Mol Genet Metab, 2013

% SubjectsMorCAP Baseline dataSlide4

International Morquio A Registry

Common initial presenting symptoms in Morquio A Montano et al,

J Inherit Metab Dis, 2007Musculoskeletal abnormalities are the most common presenting symptoms in Morquio A

n = 326 subjectsSlide5

Articular

cartilage chondrocyte in (A) control, (B) Morquio A patientCollagen fibrils in articular cartilage of (A) control, (B) Morquio A patient

Articular cartilage is altered in Morquio A patients: KS accumulation in chondrocytesPoorly organized tissue structure Increased Type I collagen and reduced Type II collagenThicker, 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

, 2009Slide6

Key radiographic findings in Morquio A

Dysostosis multiplex Spine:Dens

hypoplasiaPlatyspondyly

Inferiorly beaked vertebral bodiesPosterior 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)Slide7

Spine: NormalImage courtesy of Ralph Lachman, MDSlide8

Dens hypoplasiaPlatyspondylyAnterior beakingPosterior scalloping Thoracolumbar kyphosisSolanki et al, J Inherit Metab Dis

, 2013Spine: Dysostosis multiplexSlide9

Hips: NormalImage courtesy of Ralph Lachman, MDSlide10

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 wings

Underdeveloped acetabulaDysplastic capital femoral epiphysesCoxa valgaGenu valgumAnkle valgusHips and lower extremities: Dysostosis multiplexSlide11

Thorax: NormalImage courtesy of Ralph Lachman, MDSlide12

Paddle-shaped ribs

Pectus carinatumShort, thick clavicesThorax: Dysostosis multiplex8 year old Morquio AImage courtesy of Christina Lampe, MD Slide13

Hands: NormalImage courtesy of Ralph Lachman, MDSlide14

8 year old Morquio

AImage courtesy of Ralph Lachman, MDShort, broad metacarpalsProximal metacarpal roundingHypoplastic carpal ossification

Hands: Dysostosis multiplexSlide15

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 Slide16

Growth retardation in Morquio A

Montano et al, J Inherit Metab Dis, 2007

International Morquio A registryShort stature is a characteristic feature of Morquio ASlide17

Atinga et al, J Bone Joint Surg Br, 2008Joint instabilityfloppy wrists with weak grip and loss of fine motor skillsexacerbates knee valgus and gait abnormalitiesSubluxations of the hip and atlantoaxial joints are common

Joint degeneration due to bone defects, cartilage deterioration and altered mechanics Joint painJoint 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

, 2007Slide18

Aslam

et al, JIMD Rep, 2013; Harmatz et al, Mol Genet Metab, 2013; BioMarin data on fileHand 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 subjectsAverage 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 shoelacesSlide19

Embed Dawn video (Youtube)

http://www.youtube.com/watch?v=ugeVScsV0oMA 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 normalTrunk, pelvis, hip: increased forward tilt of trunk and pelvis, increased hip flexionKnee: 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, 2012Abnormal gait results from bone and joint defectsSlide20

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 outcomesAt 4 years oldAt 7 years oldSlide21

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)

Yes

2-3 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

Solanki et al,

J Inherit

Metab

Dis

, 2013

Regular assessments of the spine

are recommended for improved patient outcomesSlide22

Image courtesy of Klane White, MD

White, Curr Orthop Prac, 2012Ain et al, Spine, 2006

Indications include:Neurological deficits + instabilityCord compression with signal change on MRICervical spine:Posterior fusion for C1-C2 subluxation

and instability, often with posterior occipito-cervical fixationIf 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, 1977Surgical interventionsSlide23

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 importantLong-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

, 2009Slide24

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 outcomesSlide25

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 osteotomyHip subluxation may recur

Shelf acetabuloplasty + femoral varus derotation osteotomy (VDRO) reported to yield good outcomes with no recurrent hip subluxationTotal 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,

2010Slide26

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 arthrosisDhawale 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

, 2000Slide27

Morquio

A patients are at high risk of anesthesia-related morbidity and mortality due to:Cervical instability and myelopathyCompromised respiratory functionUpper and lower airway obstructionRestrictive lung disease

Cardiac abnormalitiesAny elective surgery requires:Thorough pre-operative ENT, pulmonary and cardiac evaluationsPre-operative radiological assessment of the cervical spine Skilled personnel in airway managementSpectrum of airway management equipment

Morquio A patients should be managed by experienced anesthesiologists at centers familiar with MPS disordersAirway 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 Slide28

Physical therapy

Walker/wheelchair usePain managementNon-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