Skeletal dysplasias

Skeletal Dysplasias
An Overview
Dr V Singh Chauhan
Orthopedic Resident
Moderator : Dr Gakuya
Dr. Virinderpal Singh Chauhan

Scope
• Definition + Terminology
• Pathogenesis
• Classification
• Some dysplasias in Detail
– Achondroplasia
– Hypochondroplasia
– Thanatotrophic dysplasia
– Kniest Dysplasia
– SED
– MED
– Cleidocranial Dysplasia
– Osteogenesis Imperfecta

Definition + Terminology
• A.k.a Osteochondrodysplasias
• “Dys” – Disordered “Plassein” – To form
• Disorders of growth and development that affect bone and
Cartilage.
• Rare – 1:4000/5000 births
• Most result in short stature …….”??Dwarfism”
– Proportionate
– Disproportionate
• Short Limbed
• Short Trunk

Terminology

Pathogenesis
• Usually categorised into 3
– Genetically Inherited ……> ½ of cases
• Dorminant / Recessive / X-linked
– Spontaneous Mutations
– Secondary to exposure to toxic substances or
infectious agents resulting in disruption of normal
skeletal dvt
• Mechanisms
– Alteration in transcription of or intra or Extracelluar
processing of structural molecules of skeleton
– Defects in receptor/ Signal transduction pathways of
skeletal differentiation + Proliferation

Classification
• Initially based on clinical manifestation /
radiological findings
• Rubin et al
– Acc. To anatomical distribution of bone changes
– Most of mutated genes encode proteins involved in
growth plate
• 1997
– International Nomenclature & Classification of
Osteochondrodysplasia (OCD)
• Gene + Protein defects included
• Modified in 2012 into 33 groups (OCD) & 3 groups dystocias

Dynamic Classification (Rubin et al)

Examples of Mutations
• Resting Zone
– Sox 9 mutation = camptomelic dysplasia….short
curved bone ass with sex reverse (female genetalia
not like male)
• Prolif. Zone
– FGFR3 mutation…….achondroplasia /
Hypochondroplasia / Thanatophoric dysplasia
• Hypertrophic Zone
– PTHR 1……….MED

Evaluation

Prenatal Diagnosis
• Currently popular, usually 2nd Trimester
• U/s Shows shortening of skeleton
– Femur length used………..Most Common
– Other – Skull, Spine
• Additional testing can be done by Chorionic Villous Sampling +
Mutation Analysis
• Problems
– Skeletal Dysplasias Rare (Similar xtics but diff. molecularly)
– Some not apparent during 2nd trimester (only evident in 3rd or after birth)
– U/s is a limited tool (Sensitivity 40-60%, experience)

Some Dysplasias in Detail

• Commonest form of Dwarfism…….approx 1.5 : 10000 live births
• Genetics
– Autosomal Dorminant. 80-90% due to spontaneous mutation
– Risk increases with increasing paternal age (>36 yrs)
– Mutations in the gene for FGFR3. (gly for arg)
– FGFR overexpression also inhibits PTHrP causing abnormal apoptosis of chondrocytes
– The common mutations cause a gain of function of the FGFR3 gene, resulting in :
↓ Endochondral ossification.
↓ Proliferation of chondrocytes in growth plate cartilage.
↓ Cellular hypertrophy.
↓ Cartilage matrix production.
Achondroplasia

• Short Stature………Seen at Birth
– Truncal Height Normal, Arm Span + Standing height reduced
– Rhizomelic Micromelia
– Fingertips reach Greater Trochs (normal – Mid thigh)
– Height approx 4 ft 3” males, 4ft 1” females
• Arms & Legs
– Trident Hand – Inability to approx extended middle + ring finger
– Star fish Hand – All digits of equal length
– Radial Head subluxations………..may lead to elbow contractures
– Bowed Legs (Genu varum)………Occasionally
– Relative shortening of tibia compared to fibula
– Coxa Breva like appearance due to shortening of femoral neck
• Face
– Enlarged Head with frontal bossing and mandibular protrusion
– Mid face hypoplasia ( Dental crowding / Otitis Media / Flat nose bridge / Obst. Apnea)
Clinical Features - Achondroplasia

• Spine
– Kyphosis at Thoracolumbar jxn
• Usually corrects within a few months of ambulation
– Excessive Lordosis
• Growth & Development
– Intelligence Normal, Delayed Motor Dvt due to combo
of
• Hypotonia
• Hyper-extensible joints esp of lower limb
• Mechanical difficulty balancing large heads
• Foramen Magnum stenosis with brain stem
compression……..can be fatal
Clinical Features - Achondroplasia

Short Stature, Fingertips
reaching to the level of
hips
Frontal bossing,
enlargement of head
Star fish hand, Trident
handDr. Virinderpal Singh Chauhan

Radiographic Features
• Short tubular long bones, with a relative increase in bony diameter &
density.
• Metaphyses - widened & flared, epiphyses - uninvolved.
• Growth plates - U or V shaped (best seen at distal femur).
• Metacarpal, metatarsal, & phalangeal bones - short & thick.
• Pelvis - broad & flat, squared iliac wings, small sciatic notches,
horizontal & notched acetabulum.
• Shape of pelvis - champagne glass – as width of pelvic inlet is
greater than its depth.

• Widened proximal femoral metaphyses, short femoral necks
are short - abnormalities in longitudinal growth.
• Ossification of proximal femoral epiphysis is delayed to more
than 1 year of age.
• Greater trochanter is normal in size as formed by periosteal
ossification - decrease in articulotrochanteric distance.
• True coxa vara is absent, but overgrowth of greater trochanter
- appearance of varus.
•

• Spine
– Narrowing of intrapedicular distance from L1-L5 (Normally
this increases)
– Pedicles in achondroplasia 30 – 40% thicker than normal
– Vertebral Bodies – Scalloped appearance
– Lumbar Lordosis seen up to sacral segment
• Skull
– Smaller Foramen Magnum
– Protrusion of frontal region to accommodate enlarging
brain

Orthopedic Considerations
• Most related to spine
• Craniocervical Stenosis
– Commonest cause of mortality. Sympts include:
• Hypotonia
• Sleep Apnea
– Central – compression of upper cervical spinal cord
– Obstructive – upper airway obst. due to midface hypoplasia
• Hydrocephalus
– Rare in achondroplasia, communicating type
• Thoracolumbar kyphosis
– Usually seen in almost all children at thoracolumbar jxn
– As child learns to walk, muscle tone + trunk control improves =
resolution

Management of Achondroplasia
• Usually centered around mx of complications
• Spinal Kyphosis
– Non Op… Bracing
– Op………..Ant. Corpectomy + posterior fusion (Kyp >60 by 5yrs)
• Lumbar Stenosis
– Non Op….Wt Loss, Physical therapy, Corticosteroid injections
– Op…………Laminectomy + fusion
• Foramen Magnum Stenosis
– Urgent Decompression
• Genu Valgum
– Tibial osteotomies + Hemiepiphysiodesis
• Controversial
– Growth Hormone therapy + Surgical lengthening of LimbsDr. Virinderpal Singh Chauhan

Hypochondroplasia
• Less severe form of dwarfism
• Autosomal Dorminant, 50% chance of passing to
offspring
• Mutation – FGFR3 but difference in affected a.a
(tyrosine)
• Mild forms usually undetected at birth
• Foramen Magnum stenosis + thoracolumbar stenosis
rare

Hypochondroplasia
• Ht discrepancy less than achondroplasia
• Less pronounced facial xtics
• Mesomelic limbs
• <10% associated with Mental Retardation (unlike
Achondroplasia)
• Rx
– Surgery rare
– Growth Hormone can have +ve impact……controversial

Thanatotropic Dysplasia
• Most lethal form of dwarfism
• Mutation – FGFR gene
• Dx fatal, all cases are spontaneous mutations
• Severe platyspondyly is the xtic feature on both u/s
and plain xrays
• Severe brain malformations seen
• Death due to cardioresp failure

Kniest Dysplasia
• Rare
• Autosomal dorminant
• Defect – COL1A1
• Abnormality – Type 2 collagen
• Presentation
– Disproportionate Short trunk dwarfism
– Enlarged Joints and stiffness
– Scoliosis / Kyphosis
– Cleft lip
– Flat face
– Prominent eyes due to shallow sockets
– Bell Shaped chest

Kniest Dysplasia
• Orthopedic Manifestations
– Short stature
– Club foot
– Disprop short trunk dwarfism
– Early OA
– Joint stiffness / contractures
– Scoliosis / Kyphosis
– Hypoplastic pelvis
• Medical manifestations
– Respiratory complications - Cleft Palate
– Otitis Media with hearing loss - Retinal Detachment

Kniest Dysplasia
• Imaging
– Osteopenia
– Dumbell shaped metaphyseal bone
– Coxa vara
– Genu valgum
– Swiss cheese appearance of bone cartilage
• Small holes in bone cartilage
• Rx
– Early therapy for joint contractures
– Reconstructive procedures for early hip degenerative
arthritis

Spondyloepiphyseal Dysplasia
• Mutation – COL2A1
• 2 types
– SED Congenita – Autosomal dorminant – severe
– SED Tarda – X-linked, Milder form
• Usually affects vertebrae and epiphysis

Orthopedic Manifestations
• Short stature
• Short neck, widespread eyes
• Barrel Shaped chest
• Angular deformities esp Genu Valgum
• Lumbar lordosis
– Due to hip flexion contractures
– Give abdomen a protrusional app
• Waddling gait – coxa vara
• Club foot
• Associated conditions
– Cleft Palate - Cataracts
– Retinal detachment - Deafness
– Nephrotic syndrome - Tarda

Xrays
• Delayed appearance of epiphysis
– Femoral heads not seen until pt = 5ys
• Normal – 4-6/12
– When seen – flattened & irregular epiphysis
• Coxa Vara
• Platyspondyly
• Kyphoscoliosis
• Odontoid hypoplasia / os odontoideum
– Check for atlanto-axial instability
Delay in ossification of femoral heads + coxa vara
Platyspondyly (flattened vertebrae)
Severe degenerative arthritis 15yr old with dislocated hipsDr. Virinderpal Singh Chauhan

SED
• Rx
– Atlantoaxial instability a concern
• Early occipitocervical spondylodesis
– Coxa Vara
• Valgus corrective osteotomy if angle <100 or is
progressive
– Scoliosis
• Manage operatively if angle>40

Multiple Epiphyseal Dysplasia (MED)
– Dwarfism xtised by delayed + irreg ossification at
multiple epiphysis
– Genetic
• Defect – COMP (Cartilage Oligomeric Matrix Protein) gene
• Mutation – COL9A1/A2/A3
– Ass. With Type 2 collagenopathy since type 9 acts as link points for
type 2
• Autosomal dorminant
• Autosomal recessive – rare (Early OA/Clubfoot/multiple layered
patella/brachydactyly)
Issue – Failure of formation of secondary ossification centre
Femoral + humeral heads commonly affected.Dr. Virinderpal Singh Chauhan

• Types
– Fairbank
– Ribbing – milder form
• Clinically
– Short limbed dwarf
– Joint pains – often don’t manifest until 5-14 yrs
– Waddling gait
– Flexion contractures of knee/elbow
– SPINE + PELVIS - NORMAL

Xrays
• Pelvis
– Bilateral epiphyseal defects
• Mimics Perthes
– In MED – its simultaneous + bilateral + acetab changes seen
• Knee
– Valgus knee
– Double Layered Patella
• Due to irreg ossification of patella
– Tibial slant sign
• Hand & Foot
– Short, stunted metacarpals/metatarsals
– Hyperextensible fingers
Irregular ossification + Double
layered patella

Mx of MED
• Ortho rx rarely necessary in children
• Osteotomies to correct angular deformities
esp around knee
• Degenerative Arthritis – symptomatic rx
– ?Early THR

Cleidocranial Dysplasia
• Affects bones of membranous origin
• Defect – RUNX2/ CFBA1 gene (Chr 6)
– Codes for osteoblastic specific transc. Factor req for osteoblastic
differentiation
• Features
– Short Stature
– Skull bossing (frontal/parietal/occipital)
– Maxillary region underdvt
• Maxillary micrognathia, exophthalmos
– Clavicles partially or completely absent (10%)
• Cause shoulders to drop & neck to appear large
• Shoulders can be approximated
Absent Clavicles

Cleidocranial Dysplasia
• Pelvis narrow, hips may be unstable at birth
• Coxa Vara + Trendelenburg Gait
• Increased incidence of scoliosis
• Ortho implications
– No rx for clavicles
– Scapulothoracic arthodesis for symptomatic shoulder
dysfxn
– Coxa Vara rx with valgus rotational osteotomy if neck
shaft angle <100
– C/s often required

Osteogenesis Imperfecta
• A.k.a Fragilitus Ossium / Brittle Bone Dx
• Pathogenesis
– Impaired mutation Type 1 collagen
– Mutation – COL1A1 & COL1A2 genes
– Impaired cross links preventing production of
polymerized collagen
– Fracture Healing not impaired with large amounts of
callus formation

Clinical Manifestations
• Bone fragility and fractures
fractures heal in normal fashion initially
but the bone is does not remodel
can lead to progressive bowing
• Ligamentous laxity
• Short stature
• Scoliosis
• Codfish vertebrae (compressionfx)
• Olecranon apophyseal avulsion fx

Non-Orthopaedic manifestations
• Blue sclera
• Hearing loss
lessfrequentthangenerallysuspected
• Dentinogenesis imperfecta
brownish opalescent teeth
• Wormian skull bones
(puzzlepieceintrasuturalskullbones)

Clinical Diagnosis
• Symptoms
– Mild Cases – multiple #s during childhood
– Severe - #s at birth. Maybe fatal
• Signs
– Sabre Shin Appearance
– Bowing of bones
– Scoliosis

Classification of OI - Sillence
• Type 1
– Mildest
– Presents at Pre-school age
– Autosomal Dorminant
– Blue Sclera
– Hearing deficit in 50%
– Avulsion #s common due to decreased tensile
strength of bone
• Type 2
– Autosomal Recessive
– Lethal in perinatal period
– Blue Sclera

Classification of OI - Sillence
• Type 3
– Autosomal recessive
– Normal Sclera
– #s at birth
– Progressive short stature
– MOST Severe survivable form
– Xtic triangular face due to large skull and underdeveloped facial
bones
• Type 4
– Moderately severe
– Autosomal Dorminant
– Bowing of bones + Vertebrae #s common
– Normal Hearing
– White Sclera
Type 5,6,7 added to original
classification.
No real mutation but Abnormal
bone on microscopy
5 – Hypertorphic Callus after #

Management
• Fracture
– Prevention
• Early Bracing
• Bisphosphonates
– Suppress activity of osteoclasts hence px bone mass loss &
resorption
– Role of cyclic IV Palmidronate….drug holiday/efficacy??
– Issues
» Jaw necrosis
» Atypical Subtroch & femoral stress #s
» Radiographic Changes consistent with Osteopetrosis
Decrease Deformities
Stabilize Lax Joints
Decrease # Incidence

Management
• Fracture Treatment
– Non op if < 2ys
– Op
• Pt > 2ys
– Telescopic rods
• Sofield Miller Procedures
– Correctional for Severe deformities
– “Sausage” procedure
– Scoliosis
• Observe if <45 degrees
• Bracing ineffective
• Operative – posterior fusion

Further Reading
• Metatrophic Dysplasia
• Chondroectodermal Dysplasia
• Diastrophic Dysplasia
• Pseudoachondroplasia
• Chondrodysplasia Punctata
• Diaphyseal Aclasia (Multiple Osteocartilagenous Exostosis)
• Leri Weill Syndrome
• Larsen Syndrome
• Pyknodysostosis
• Osteopetrosis

References
• Lowell & Winters Pediatric Orthopedics 7th
Ed
• Tachdjian Pediatric Orthopedics 4th Ed

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