Book Reading

Francisco Gilbert Timothy

dr. Adam Moeljono, Sp.OT (K) Spine
Section 1
General Orthopaedics
Chapter 8
Genetic disorders, skeletal
dysplasias and malformations

2
The human genome
• Chromosome→ DNA→ gene→ nucleotides→ deoxyribose
sugar, phosphate molecule, purine/pyrimidine base
• Genetic mutations
• Point mutations
• Deletions/insertions

Genetic disorders
• Chromosome disorders
• Single gene disorders
• Polygenic and multifactorial disorders
• Non-genetic developmental disorders

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Patterns of inheritance

• Characteristics of pattern • Genetic markers

inheritance • Linked to other loci
• Autosomal dominant • Predisposing factor
disorder
• Autosomal recessive disorder
• Genetic mapping
• X-link disorder
• Inbreeding
• Genetic heterogenicity
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Pre natal diagnosis

• Indications
• Maternal age over 35 years or high paternal age
• Previous history of chromosomal abnormalities or genetic
abnormalities
• Confirm non-invasive test suggesting an abnormality
• Maternal screening
• Amniocentesis
• Chorionic villus sampling
• Pre-implantation genetic diagnosis
• Fetal imaging

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Diagnosis in childhood
• Clinical features • Previous medical history
• Retarded growth and • Teratogenic agents
shortness of stature
• Disproportionate length of • The family history
trunk and limbs
• Localized malformations
(dysmorphism)
• Soft-tissue contractures
• Childhood deformity
• X-rays
• Chest, pelvis, knees, hand,
thoracolumbar spine, skull
• Special investigations
• Routine blood and urine
analysis
• Bone biopsy
• Gene mutation
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Diagnosis in adulthood
• Disproportionate short
stature
• Local bone deformities
• Spinal stenosis
• Repeated fracture
• Secondary osteoarthritis
• Joint laxity or instability

Principles of management
• Communication • Intrauterine surgery
• As much as possible without
causing unnecessary distress • Prevention and correction
of deformities
• Counselling
• Surgery
• Outcome, requirement, risk
• Conservative
• Maintaining an
independent lifestyle • Gene therapy
• Patient condition, goals for
adult life

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Classifying the skeletal dysplasia

• Specific genomic abnormality vs clinical phenotype and

common radiological features

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Osteochondrodysplasia
Primarily affecting the physis
Achondroplasia
• Autosomal dominant, FGFR3 mutation
• Infant
• Proximal spinal cord compression
• Older children
• Disproportionate short limbs
• Characteristics facial features
• Adults
• Spinal stenosis
• 132 cm (men) 125 cm (women)
• Radiologic
• Involvement of metaphysis
• Short iliac wing
• Inverted V distal femoral epiphysis
• Long fibula and genu varum
• Metacarpal shortening and splaying

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• Management
• Medical management
• Short stature surgical management
• Symptomatic lower limb malalignment
• Symptomatic foramen magnum or upper cervical spine stenosis
• Infantile kyphoscoliosis
• Lumbar stenosis

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Hypochondroplasia
• Autosomal dominant, FGFR3 mutations
• Less marked clinical features
• Broad hands and feet
• Loss of elbow extension
• Lumbar lordosis
• 135-165 cm (men), 125-150 cm (women)
• Limb lengthening

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Primarily affecting the epiphysis
Multiple epiphyseal dysplasia
• Autosomal dominant • Management
(COMP, MATN3) • Activity modification
• Autosomal recessive • Avoiding repetitive loading
(SLC26A2) • Physiotherapy
• Analgesic and anti-
• Clinical manifestations inflammatory medication
• Asymptomatic, severe pain • Osteotomies, arthroplasty
and joint stiffness
• Radiographic features
• Delayed epiphyseal
ossification
• Progressive epiphyseal
flattening
• Double-layered patella

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Spondyloepiphyseal dysplasia
• Mutation in COL2A1
• SED congenita, SED tarda
• Clinical manifestations
• Cranial, axial skeleton
• Radiographic
• Platyspondyly, odontoid hypoplasia,
narrowed IV disc, unossified pubic
bones at birth, coxa vara, delayed
ossification of the femoral head
• Management
• Physiotherapy, core strengthening,
analgesic and anti-inflammatory
medication and activity modification,
corrective osteotomies, arthroplasty

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Primarily affecting the meta-diaphysis
Metaphyseal chondrodysplasia
Type Schmid Type Jansen
• Autosomal dominant, • Autosomal
COL10A1, dominant, mutation
hypertrophic zone of at PTH-related
the physis
peptide receptor
• Short tubular bone,
metaphyseal flaring • Severe limb
• Coxa vara shortening,
micrognathia,
Type McKusick prominent forehead
• Cartilage hair • Flexion contractures
hypoplasia of hip and knees
• Autosomal recessive
• Progressive short
stature, fine
hairgrowth
• T-cell function and
neutropenia

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Mixed abnormalities
Pseudoachondroplasia
• Autosomal dominant,
COMP gene
• Neonatal
• Delayed motor milestones
• Adult
• 120 cm
• Polyaxial knee instability
• Epiphyseal and articular
cartilage formation
• Management
• Preserving joint function
• Preserving ROM
• Maintaining muscle strength

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Diastrophic dysplasia Cleidocranial Nail-patella syndrome
• Autosomal dysplasia • Autosomal
recessive, SLC26A2 • Autosomal dominant, LMX1B
• Clinical dominant, RUNX2 • Clinical
manifestation • Clinical manifestation
• Severe short manifestation • Hypoplastic or
stature • Short stature absent nail and
• Facial feature • Dysplastic or patellae
• Hitchhiker thumb absent clavicle • Knee instability
• Talipes • Frontal bossing, • Limited elbow
• Spinal Wormian bones movement
manifestation • Coxa vara • Subluxation of the
• Limb manifestation radial head
• Iliac horn
• Scoliosis
• Scapular hypoplasia
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 Cleidocranial
dysplasia
Diastrophic dysplasia Nail-patella syndrome

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Dysplasia with altered bone density
Osteogenesis imperfecta
• COL1A1, COL1A2 gene
• Diagnosis
• DNA analysis, collagen analysis
• Clinical manifestations
• Bone fragility, bone deformity
• Dental abnormalities
• Blue sclera
• Vertebral involvement
• Joint degeneration
• Radiologic
• Shepherd’s crook deformities of femur
• Popcorn metaphysis
• Management
• Pharmacotherapy, conservative
• Surgical
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Osteopetrosis (Albers-Schoenberg disease)
• Osteopetrosis congenita • Osteopetrosis tarda
• Growth retardation • Asymptomatic
• Abnormal skull development • Compressive neuropathies
• Radiograph: rugger jersey and recurrent fractures
• Treatment: vitamin D, gamma
interferon, EPO,
corticosteroid

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Storage disease
Mucopolysaccharidoses
• Hurler (MPS I)
• Alpha-L-iduronidase
• Hunter (MPS II)
• Iduronate sulphate
• Sanfilippo (MPS III)
• Heparan sulphmidase
• Morquio-Brailsford (MPS IV)
• Beta-galactosidase
• Scheie syndrome (MPS V)
• Reclassified to MPS I subtype
• Maroteaux Lamy syndrome
(MPS VI)
• N-acetyl-galactosamine-4-
sulphatase
• Clinical manifestations
• Short stature, coarse facial
features, thick inelastic skin,
hepatosplenomegaly,
neurological abnormalities,
delayed intellectual
development, spinal
abnormalities
• Management
• Enzyme replacement
• Bone marrow transplantation
• Correction of deformity and
stabilization
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23
Gaucher’s disease
• Autosomal recessive,
glucocerebrosidase
• Clinical features
• Hepatosplenomegaly,
pancytopenia, recurrent
infections
• Stiff joints, osteopenia,
osteonecrosis, bone crisis
• Radiological features
• Patchy radiolucency within
cancellous bone, Erlenmeyer
flask appearance
• Management
• Enzyme replacement therapy,
hip arthroplasty

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Tumour-like conditions
Multiple hereditary exostosis (multiple osteochondromatosis
diaphyseal aclasis)
• EXT1, EXT2, EXT3
• Clinical manifestation
• Bony lump
• Shortening and angulation of
long bones
• Local symptoms
• Radiograph
• X-ray: metaphysis of long bone
• CT scan: ilium and scapula
• MRI: extend of cartilaginous
cap
• Management
• Local pressure effect
• Limb deformity

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Dysplasia epiphysealis hemimelica (Trevor’s disease)
• Epiphyseal osteochondromata
at medial or lateral aspect of
the epiphysis, localized to a
single side of the body
• Clinical manifestation
• Restriction of joint movement
• Palpable intra-articular lump
• Asymmetric limb deformity
• Radiology
• Plain radiograph
• CT/MRI
• Management
• Excision yet tricky
• Corrective osteotomies

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Enchondromatosis (dyschondroplasia, Ollier’s disease)
• Discrete island of hyaline
cartilage within the
metaphysis and diaphysis
of long bones
• Maffuci’s syndrome
• Clinical manifestations
• Pain and progressive
deformity
• Radiology
• Radiolucent streaking,
popcorn
• Alignment view
• Management
• Limb equalization surgery
• Debulking and grafting

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Fibrous dysplasia • Radiology
• Replacement of bone with • X-ray: ground glass
appearance, shepherd’s crook
fibrous tissue deformity
• GNAS1 • MRI and bone scan
• Albright McCune syndrome • Management
• Clinical manifestation • Biphosphonate
• Progressive limb deformity • Realignment surgical
stabilization
• Non specific bone pain,
swelling, tenderness • Bone grafting

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Connective tissue disorder
Ehler-Danlos syndrome
• Autosomal dominant,
COL5A1, COL5A2,
COL1A1, COL1A2,
COL3A1
• Clinical manifestation
• Fragile skin, joint
hypermobility, vascular
fragility, severe myalgia
• Cardiac anomalies
• Musculoskeletal
involvement
• Management
• Physiotherapy
• Surgical

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Larsen’s syndrome
• Abnormality in gene
encoding filamin B
• Clinical manifestation
• Joint hypermobility
• Multiple joint dislocation
• Distinct facial features
• Cervical kyphosis
• Talipes
• Radiology
• Cervical spine radiology
• Neonatal ultrasound
• Management
• Cervical kyphosis
• Hip dislocation
• Knee dislocation
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Marfan syndrome
• Autosomal dominant, FBN1
• Clinical manifestation
• Musculoskeletal
• Ocular
• Cardiovascular
• Management
• Scoliosis correction
• Arthroplasty

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Beighton score for generalized joint laxity
• Passive hyperextension of the metacarpophalangeal joints
beyond 90 degrees (score 2)
• Passive stretching of the thumb to touch the radial border
of the forearm (score 2)
• Hyperextension of the elbows (score 2)
• Hyperextension of the knees (score 2)
• Ability to bend forward and place the hands flat on the
floor with the knees held perfectly straight (score 1)

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Thanks!