Patho: Exam 2 Bone Diseases Flashcards
Congenital Malformations (Dysotoses)
what is it ?
is it common?
- Uncommon
* Failure of a bone to develop: Congenital absence of a bone: phalanx, rib, clavicle
Formation of extra bones:
Fusion of two adjacent digits:
Formation of extra bones: supernumerary digit (Polydactyl)
Fusion of two adjacent digits: (Syndactyl)
Pathology of Dysotoses
Mutation in homeobox gene, HOXD13
Loss of function mutations in RUNX2
o It is the enzyme that turns Progentor cells turns into osteoblast
o Normally produces transcription factors important in osteoblastogenesis but if its mutated you get a mutated form
Mutation in homeobox gene, HOXD13 results in:
Extra digit between third and fourth fingers and syndactyly
Loss of function mutations in RUNX2 results in:
o Mutation results in cleidocranial dysplasia: abnormal development of bones in the skull and clavicle cuased by a RUNX2 mutation
• Patent fontanelles
• Delayed closure of cranial sutures
• Wormian bones: extra sutures
• Delayed eruption of secondary teeth: two sets of deformed teeth.
• Primitive clavicles: no clavicles or small, so shoulders can touch anteriorly.
• Shortened height
Achondroplasia, dwarf (non-lethal)
- Most common disease of the growth plate and major cause of dwarfism.
- Major cause of dwarfism
what is the causes of Achondroplasia
- Autosomal dominant: Only need one gene to be affected.
* spontaneous mutations 80%- Almost all in paternal allele: almost all of spontaneous mutations is from paternal
Pathology of Achondroplasia
• Mutation in the FGF receptor 3 (FGFR3)(Chr 4)
o FGF (Fibroblast growth factor, normally blocks cartilage proliferation, acts like its always activated therefore collegen is never formed
o Collagen is the back bone for all bone growth.
- Normally FGF3 inhibits cartilage proliferation
- Mutations in FGFR3 cause constitutive activation and therefore suppresses growth
Manifestations of Achondroplasia
- Shortened proximal extremities
- Trunk of relative normal length
- Enlarged head with bulging forehead
- Depression of the root of the nose.
- Skeletal abnormalities usually not associated with changes in longevity, intelligence, or reproductive status
-
-“gain-
- Most common lethal form of dwarfism
- 1:20,000 live births
- –“gain of function” of FGFR3 receptor- Gene product gains a new and abnormal function
Manifestations of a Thanatophoria
- Micromelic shortening of limbs
- Frontal bossing
- Macrocephaly
- Small chest cavity: Leads to respiratory insufficiency- torsal cannot grow chest cavity is to small for the lungs and hear to function and therefore severe pulmonary and cardiac problems
- Bell shaped abdomen
Diseases Associated with Defects In EXTRACELLULAR STRUCTURAL PROTEINS
Type 1 Collagen Diseases
Types of Collegen: 1, 2, 3 , 4.
bone, caTWOlage, THREEticulum (fibrotic tissue), Basement Membrane FOUR.
OSTEOGENESS IMPERFECTA TYPES
Deficiencies in the synthesis of type 1 collagen. It primarily affects the bones but can also impact other tissues what are rich in type 1 collagen which include joints, eyes, ears skin and teeth. Osteogenesis imperefecta usually results from an autosomal dominate mutation in the gene that encodes the alpha1 and alpha2 chains of collagen. Mutations result in decreased synthesis of qualitatively normal collagen and are associated with mild skeletal abnormalities.
- Most common inherited disorder of connective tissue
- Principally affects bone
- Other findings: blue sclera: cuased by decreased collagen content making the sclera translucent and allowing partial visulation of the underlying choioid.
Pathogenesis of Osteogeness Imperfecta
•Autosomal dominant
o Mutations in genes which code for the alpha-1 and alpha-2 chains of COLLAGEN 1
o Point mutation affecting glycine residue.
Manifestations of Osteogeness Imperfecta
• “Brittle” bone disease, too LITTLE bone, BLUE sclera ( due to underlying choroid’s blue cast (its very vascular))
Types of Osteogeness Imperfecta
Type 1:
- Autosomal dominant-decrease synthesis of alpha-1 chain
- Compatible with survival: Normal life span
- Childhood fractures which decrease in puberty
- Blue sclera, hearing loss (fusion of ossicles) , dental imperfections (misshaped/Blue yellow color)
Type 2:
oAutosomal dominant or recessive-alpha 1 and 2
o perinatal lethal (multiple intrauterine fractures)
o Mother puts on clothes and fetus clothes fracture.
Type 3:
o Autosomal dominant 75%, recessive 25%-alpha 2
o progressive, deforming
o Get more and more fractures as they age.
Type 4:
o Autosomal dominant – short alpha 2 chain
o compatible with survival
o Simmilar to type 1 however the sclera does not appear to be as blue
o When the alpha 2 chain is shortened there is problem with cross linking and collegen is thinner.
Diseases Associated with Defects In FOLDING AND DEGRADATION OF MACROMOLECULES (glycosaminoglycans)
Diseases Associated with Defects In FOLDING AND DEGRADATION OF MACROMOLECULES (glycosaminoglycans)
Mucopolysaccharidoses
Overview:
o Mesenchymal cells especially chondrocytes normally metabolize
o A lysosomal storage disease caused by deficiencies in the acid hydrolase enzymes which degrades Dematan sulfate, Heparan sulfate, and keratan sulfate.
• Dematan Sulfate
• Heparan Sulfate
• Keratan Sulfate
o Mesenchymal cells especially chondrocytes normally metabolize extracellular matrix mucopolysaccharides, hence cartilage formation is severely affected.
o This results in many of the skeletal abnormalities in hyaline cartilage and articular surfaces. Therefore the affected pts have short stature and have chest wall abnormalities and malformation of bones. (Chiefly a cartilage disorder)
Mutation in Mucopolysaccharidoses
o Autosomal recessive trair: with 6 abnormal phenotypes.
o Undegraded GAGs accumulate in connective tissue, neurons, and hepatocytes.
Treatment of Mucopolysaccharidoses
Elaprase: This is a treatment option, it is an enzyme that can degrade some of the sulfates that will decrease the progression of the disease.
Diseases Associated with Defects In METABOLIC PATHWAYS (ENZYMES, ION CHANNELS, AND TRANSPORTERS)
Diseases Associated with Defects In METABOLIC PATHWAYS (ENZYMES, ION CHANNELS, AND TRANSPORTERS)
OSTEOPETROSIS (marble bone disease), 4 types
Summary
Refers to a group of rare genetic diseases that are characterized by reduced bone resorption and diffuse systemic skeletal sclerosis due to impaired formation or function of the osteoclast. Even through the bones are stone like they are abnormally brittle and fracture easily like a piece of chalk.
Osteopetrosis is classified into variants based on the mode of inheritance and clinical findings
Autosomal Dominant: due to CARBONIC ANHYDRASE deficiency
• Carbonic Anhydrase is necessary for osteoclasts to generate protons from CO2 and water. Get the protons from Co2 and H20, this prevents the osteoclast form acidifying the resorption pit.
• Relatively benign, some anemia
• (Osteoclast is not breaking down so it is constantly building leading to impinge on hematopoietic cells make them become anemic)
Autosomal Recessive (severe form): Affects the proton pump in osteoclasts
• Make it inside of the cell but can not get it out of the cell
• Severe, death due to anemia, cranial nerve entrapment, hydrocephalus and infection. Also see extramedullary hematopoiesis
• If the BM is not doing the work the liver and spleen can activate stem cells and make blood cells, the liver and spleen will increase in size
The autosomal recessive will show up before the autosomal dominant types.
Appearance of the bone in Osteopetrosis
Diffusely DENSE bone with Erlenmeyer Flask deformity of distal humerus
