Genetic disorders of bone
Brig.Naveed Hussain Syed
HOD Surgery Department
CMH Bahawalpur

Pathogenesis
• Usually categorised into 3
……> ½ of cases
– Genetically Inherited
• 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

Types

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
You don’t know anything Jon snow

• 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

Short Stature, Fingertips
reaching to the level of
hips
Frontal bossing,
enlargement of head
Star fish hand, Trident
hand

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 Limbs

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

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
• Short
• Barre
• Angu
• Lum
– D
– G
• Wadd
• Club
stature
neck, widespread eyes
l Shaped chest
lar deformities esp Genu Valgum
bar lordosis
ue to hip flexion contractures
ive abdomen a protrusional app
ling gait – coxa vara
foot
ciated conditions
• Asso
– Cleft Palate
– Retinal detachment
– Nephrotic syndrome - Tarda
- Cataracts
- Deafness

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 j
k
j
j
hep
adi
g
sch
ou
mh
monlyaffected.

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

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 (front
– Maxillary region u
• Maxillary microgn
– Clavicles partially o
• Cause shoulders t
• Shoulders can be
al/parietal/occipital)
nderdvt
athia, exophthalmos
r completely absent (10%)
o drop & neck to appear large
approximated
Absent Clavicles
Dr.Virinderpal Singh Chauhan

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 arthrodesis for symptomatic
shoulder dysfunction
• Coxa vara Rx with valgus rotation

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
lessfrequentthangeneralysuspected
• Dentinogenesis imperfecta
brownish opalescent teeth
• Wormian skull bones
(puzzlepieceintrasuturalskul bones)

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
• 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
• Type 3
– Autosomal recessive
– Normal Sclera
– #s at birth
– Progressive short statu
– MOST Severe survivab
re
le form
• 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
Decrease # Incidence
• 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

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

Osteopetrosis
• Osteopetrosis is a group of rare hereditary skeletal
disorders characterized by a marked increase in bone
density
• it is due to defect in remodeling caused by failure of
normal osteoclast function.
• Defective osteoclastic bone resorption , combined with
continued bone formation and endochondral
ossification, results in thickening of cortical bone and
sclerosis of the cancellous bone.

• However, their increased size does not improve their
strength. Instead, their disordered architecture, results
in weak and brittle bones that results in multiple
fractures with poor healing.
• There are two separate sub types of
osteopetrosis:
▫ Infantile autosomal recessive osteopetrosis
▫ Benign adult autosomal dominant osteopetrosis

Autosomal recessive
osteopetrosis
• Infantile autosomal recessive osteopetrosis is the more
severe form that tends to present earlier.
• Hence, it is referred to as "infantile" and "malignant“,
compared to the autosomal dominant osteopetrosis.
• By age 6, 70% of the affected will die.
• Most of the remainder have a very poor quality of life
with death resulting by the age of ≈ 10.

Clinical Features:
Those who survive childbirth present with :
• Cranial nerve entrapment
• Snuffling (nasal sinus architecture abnormalities)
• Hypercalcaemia
• Pancytopaenia (anaemia, leukopaenia and
thrombocytopaenia)
• Hepatosplenomegaly (extramedullary haemopoesis)
• intracerebral haemorrhage (thrombocytopaenia)
• Lymphadenopathy
• One of the commonest presentations is with ocular
disturbance: failure to establish fixation, nystagmus or
strabismus. The cause of these symptoms is compression
of the cranial nerve roots because of foraminal
overgrowth.

Autosomal dominant osteopetrosis :
• The autosomal dominant type is less severe than
its autosomal recessive mate.
• Hence, it is also given the name "benign" or
"adult" since patients survive into adulthood.
Clinical Features:
• 50% patients are asymptomatic
• Recurrent fractures
• Mild anemia
• Rarely cranial nerve palsy

Radiology
Radiographical Features:
• Bones are uniformly sclerotic.
• Bones appear club like
• Bone within bone (Endo bone) appearance is also seen.
• Vertebrae are extreamly radiodense and they show
alternating bands- rugger- jersey sign.

Treatment and Prognosis:
• Bone marrow transplantation is the only hope for
permanent cure.
• Interferon gamma-l b, often in combination with
calcitriol, has been shown to reduce bone mass, decrease
the prevalence of infections, and lower the frequency of
nerve compression.
• Administration of corticosteroids (to increase circulating
red blood cells and platelets), para thormone,
macrophage colony stimulating factor, and
erythropoietin.
• Limiting calcium intake also has been suggested.
• Additional therapy consists of supportive measures.such
as transfusions and antibiotics for the complications.

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Dr.Virinderpal Singh Chauhan

CMH BWP
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