Bone Anamolies

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DEVELOPMENTAL DISORDERS

OF
BONE AND CARTILAGE

DR MUHAMMAD ALI SOOMRO


INTRODUCTION:

Developmental anomalies can result from localized


disruption of the migration and condensation of
mesenchyme (dysostosis) or global disorganization
of bone and/ or cartilage (dysplasia).
There are about 350 skeletal dysostoses and
dysplasias recognised, the majority of which are
extremely rare. The classification has progressed
from clinical and radiographic descriptions to one
that includes the genetic flaws that cause the disease.
DEFECTS IN NUCLEAR PROTEINS AND
TRANSCRIPTION FACTORS:

Nuclear proteins and transcription factors, especially


homeobox proteins, disrupt mesenchymal condensation and
osteoblast and chondrocyte differentiation, causing aberrant
bone growth.
Mutations in the homeobox HOXD13 gene cause
BRACHYDACTYLY types D and E, which shorten the thumb
and big toe terminal phalanges.
CLEIDOCRANIAL DYSPLASIA, an autosomal dominant
disorder, is caused by RUNX2 (Runt-related transcription
factor 2) loss-of-function mutations and is characterised by
patent fontanelles, delayed closure of cranial sutures, Wormian
bones, delayed secondary tooth eruption, primitive clavicles,
and short stature.
BRACHYDACTYLY:
DEFECTS IN HORMONES AND SIGNAL
TRANSDUCTION PROTEINS:

The most prevalent skeletal dysplasia and dwarfism


cause is ACHONDROPLASIA. It is an autosomal
dominant condition caused by gain-of-function
mutations in the FGF receptor 3 (FGFR3) gene.
Despite a normal trunk length, slowed cartilage
formation causes shortened proximal extremities, an
enlarged head with bulging forehead, and nose root
depression. Skeletal defects rarely affect longevity,
IQ, or reproduction.
ACHONDROPLASIA:
DEFECTS IN HORMONES AND SIGNAL
TRANSDUCTION PROTEINS:

THANATOPHORIC DYSPLASIA kills most dwarfs.


FGFR3 gain-of-function mutations separate from those
that cause achondroplasia induce larger elevations in
FGFR3 signalling and a more severe phenotype, affecting
~1 in 20,000 live births.
 Severe limb shortening, frontal bossing, relative
macrocephaly, a small chest cavity, and a bell-shaped
belly characterise affected people.
These infants die from respiratory insufficiency due to the
undeveloped thoracic cavity. Growth plate histology
shows lower chondrocyte proliferation and
disorganisation in the proliferation zone.
DEFECTS IN EXTRACELLULAR STRUCTURAL PROTEINS:

Mutations in the major bone and cartilage collagens


(types I, II, IX, X, and XI) cause deadly illness to
premature osteoarthritis (OA).
The most prevalent inherited connective tissue
illness, OSTEOGENESIS IMPERFECTA (OI), or
brittle bone disease, is phenotypically heterogenous
and caused by type I collagen production deficits.
OI primarily affects bone but also affects type I
collagen-rich tissues such joints, eyes, ears, skin, and
teeth. Mutations in collagen α1 and α2 genes cause it.
DEFECTS IN EXTRACELLULAR STRUCTURAL PROTEINS:

OI's bone deficiency causes significant skeletal fragility.


Other findings include blue sclerae caused by decreased
collagen content, making the sclera translucent and
allowing partial visualisation of the underlying choroid;
hearing loss due to a sensorineural deficit and impeded
conduction due to abnormalities in the middle and inner
ear bones; and dental imperfections (small, misshapen,
and blue-yellow teeth) due to dentin deficiency occur.
Mutations that diminish qualitatively normal collagen
production cause modest skeletal deformities. Mutant
collagens that disrupt triple helix formation cause severe
or fatal abnormalities.
OSTEOGENESIS IMPERFECTA (OI):
DEFECTS IN METABOLIC PATHWAYS
(ENZYMES, ION CHANNELS, AND TRANSPORTERS):

OSTEOPETROSIS is a category of rare hereditary


illnesses that cause extensive, symmetric skeletal
sclerosis due to osteoclast deficiency. Osteopetrosis
bones are brittle, not stonelike. Osteopetrosis variants
are based on inheritance and clinical severity.
Osteopetrosis is a category of rare hereditary illnesses
that cause extensive, symmetric skeletal sclerosis due to
osteoclast deficiency. Osteopetrosis bones are brittle,
not stonelike. Osteopetrosis variants are based on
inheritance and clinical severity.
DEFECTS IN METABOLIC PATHWAYS
(ENZYMES, ION CHANNELS, AND TRANSPORTERS):

Most of the mutations underlying osteopetrosis interfere


with acidification of the osteoclast resorption pit, which is
required for the dissolution of calcium hydroxyapatite
within the matrix.
Osteopetrosis bones lack a medullary canal and have
bulbous (Erlenmeyer flask deformity) ends. Small neural
foramina compress departing nerves. The primary
spongiosa, which is ordinarily eliminated during growth,
fills the medullary cavity, blocking the hematopoietic
marrow and preventing mature trabeculae. Woven rather
than lamellar, deposited bone is not remodelled. Osteoclast
numbers vary depending on the genetic abnormality.
DEFECTS IN METABOLIC PATHWAYS
(ENZYMES, ION CHANNELS, AND TRANSPORTERS):

Severe infantile osteopetrosis is an autosomal


recessive disorder that usually becomes evident in
utero or soon after birth. Fracture, anemia, and
hydrocephaly are often seen, resulting in postpartum
mortality.
Hematopoietic stem cell transplantation is beneficial
for osteopetrosis because osteoclasts are produced
from precursors. Donor stem cell-derived normal
osteoclasts correct various skeletal defects.
OSTEOPETROSIS:
DISEASES ASSOCIATED WITH DEFECTS IN DEGRADATION
OF MACROMOLECULES:

The MUCOPOLYSACCHARIDOSES are lysosomal


storage diseases. Defects in acid hydrolases that degrade
dermatan, heparan, and keratan sulphates cause them.
Chondrocytes breakdown extracellular matrix
mucopolysaccharides.Mucopolysaccharides cause
chondrocyte apoptosis in several disorders.
Extracellular mucopolysaccharide causes articular cartilage
structural abnormalities. Thus, anomalies in the cartilage
anlage, growth plates, costal cartilages, and articular
surfaces cause numerous mucopolysaccharidoses skeletal
symptoms. Short-statured patients may have chest wall
defects and deformed bones.
THE END

THANKS

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