Download as PPTX, PDF, TXT or read online from Scribd
Download as pptx, pdf, or txt
You are on page 1of 16
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
Predicting Future Dysgraphia Therapy? The Application of A Word Prediction Package To An Adult Client With Acquired Dysgraphia and A Plan For Therapeutic Intervention