VIP Call Girls Pune Vrinda 9907093804 Short 1500 Night 6000 Best call girls S...
genetic disorders of bone.pptx
1.
2. Genetic disorders of bone
Brig.Naveed Hussain Syed
HOD Surgery Department
CMH Bahawalpur
3. 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
6. 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)
8. • 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
9. • 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
11. 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
12. 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
13. 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
14. 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
15. Spondyloepiphyseal Dysplasia
• Mutation – COL2A1
• 2 types
– SED Congenita – Autosomal dorminant – severe
– SED Tarda – X-linked, Milder form
• Usually affects vertebrae and epiphysis
16. 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
17. 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
18. 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.
19. 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
20. Mx of MED
• Ortho rx rarely necessary in children
• Osteotomies to correct angular deformities
esp around knee
• Degenerative Arthritis – symptomatic rx
– ?Early THR
21. 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
22. 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
23. 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
24. 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
26. Clinical Diagnosis
• Symptoms
– Mild Cases – multiple #s during childhood
– Severe - #s at birth. Maybe fatal
• Signs
– Sabre Shin Appearance
– Bowing of bones
– Scoliosis
27. 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
28. 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 #
29. 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
30. 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
31. 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.
32. • 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
33. 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.
34. 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.
35. 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
36. 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.
37.
38. 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.