B101 Congenital diseases of bone

Question 1

List the congintal bone diseases

Answer 1

Osteogenesis imperfecta

• brittle bone diseases, a group of defects in the synthesis of collagen 1.

Achondroplasia

• The most common cause of dwarfism, caused by activating mutations in the FGFR3 receptor. FGFR3 actually inhibits proliferation and function of growth plate condrocytes, severely stunting the growth of long bones.

Thanatophoric Dwarfism

• Caused by inactivating mutations to the FGFR3 gene, and is lethal.
• Inactivation of FGFR3 causes extreme shortening of the limbs and small development of all the bones.
• Invariably causes fatal respiratory failure shortly after birth due to the extremely small chest and lungs.

OsteopeTrosis

• Stone bone disorders,
• Caused by defective osteoclast bone resorption resulting from many possible mutations of osteoclast function or differentiation. Very dense, hard bones that are structurally weak and prone to fractures.

Question 2

Osteogenesis imperfecta, causes and pathogenesis

Answer 2

Mutations to type 1 collagen, to either of the genes for alpha1 or alpha2 chains. Autosomal dominant inactivating mutations.

• Type 1 collagen is a heterotrimer of two alpha1 chains and one alpha2 chains
• Mutations to either gene slow the synthesis process or disrupt the stability of the whole molecule, causing premature degradation and decreased synthesis and excretion. Thus, the mutations are autosomal dominant.
• The mutations can simply cause decreased levels, or can cause altered collagen structure/function - these have worse symptoms.

The fundamental pathology is that there is too little bone matrix, causing extreme fragility and frequent fractures.

Hearing loss is also common, due to damage of the ossicles,

Teeth are small and misshapen.

Up to 4 subtypes

• Type 1: mild disease, with the canonical finding of blue sclera of the eyes. Less collagen in the sclera, making them semi-transparent, and colored by the blue choroid.
• Type 2: very severe, always fatal in utero or immediately following birth due to massive fracturing during and before birth.

Question 3

Achondroplasia, causes and pathogenesis

Answer 3

Activating mutations to the FGFR3 receptor.

• The FGFR3 receptor inhibits chondrocyte proliferation and function.
• Increased FGFR3 receptor activity suppresses chondrocytes function and limits proliferation at the epiphyseal growth plates
• Inhibited growth of long bones.
• Can be inherited as autosomal dominant disorder, or arise spontaneously
• Affects bones that form by endochondral ossification
  
  • endochondral ossification: long bones. ribs, and vertebrae
  • membranous ossification: bones of the skull and face, mandible, maxilla, and clavicles

Symptoms: Short stature, disproportionate shortening of the proximal extremities, bowing of the legs, frontal bossing (large/protruding frontal bone/forehead), and hypoplasia of the middle of the face.

Question 4

Thanatophoric dwarfism, cause, and pathogenesis

Answer 4

Inactivating mutations to FGFR3 receptor in the extracellular domain.

Causes extreme shortening of all the bones of the limbs and trunk. Frontal bossing of the skull.

The extremely small thorax/ribs causes death soon after birth due to respiratory insufficiency.

Question 5

Osteopetrosis, causes and pathogenesis, and treatment

Answer 5

An extremely rare disorder caused by mutations that reduced activity or development of osteoclasts.

• Reduces bone resorption
• Causes excessively dense and structurally weak, brittle bones.

They also develop hematopoeitic deficiencies due to the excessive bone tissue occluding the medullary hematopoeitic cavity, a type of myelopthesis.

• Anemia and immune deficiency.
• Hepatosplenomegaly due to compensatory extramedullary hematopoeisis.

Blindness, Deafness, and Facial paralysis due to compression of the cranial nerves by the skull bones.

Hydrocephalus from narrowing of the foramen magnum increased CSF pressure

Renal Tubular acidosis in cases that have mutations of carbonic anhydrase - H2O + CO2 = H2CO3, generate H+ and HCO3- in the tubules. Can’t get the net gain of HCO3- and reabsorb the HCO3- in the tubule by excreting H+

Identified mutations include: carbonic anhydrase II deficiency, proton pump deficiency and chloride channel defect, all of which interfere with the ability of osteoclasts to resorb bone.

Treatment:

Bone marrow transplant: Transplanted marrow can generate normal functional osteoclasts from hematopoeitic cells.