L15- Disorders of Skeletal Development (diseases)

Question 1

list the types of abnormalities seen in skeletal development (+ some of the associated diseases)

Answer 1

• abnormal Mesenchymal Condensations (fetal skeleton blueprint): sydactyly
• abnormal Chondrocyte Proliferation / Cartilage Development: dwarfism
• abnormal Matrix Production (less or defective collagen): OI
• abnormal Modeling/Remodeling (osteoblast/osteoclast dysfunction or uncoordinated activity): osteopetrosis

Question 2

(1) results from failure of chondrocyte proliferation due to a mutation on (2) gene. Although (1) results from a de novo mutation in (3)% of cases, it can be passed on in a (4) pattern.

Answer 2

1- achondroplasia (most common type of dwarfism)
2- FGFR3 gene (fibroblast GF receptor, gain of function mutation)
3- 90% via mostly paternal germ cells
4- AD

Question 3

In achondroplasia, there is a (gain/loss)-of function in the (2) gene which will then function to (3) leading to (4) and disrupting (5) overall. (6) is the final result of achondroplasia.

Answer 3

1- gain of function
2- FGFR3 gene (fibroblast GF receptor)
3- inhibit chondrocyte function in cartilaginous growth plate
4- dec proliferation, dec hypertrophy of chondrocytes
5- endochondral ossification (incomplete)
6- early termination of longitudinal growth plate (long bones) => shortened limbs, ribs (= dwarfism)

Question 4

______ is the severe form of achondroplasia

Answer 4

thanatotropic dwarfism (lethal form)

Question 5

list the clinical features of achondroplasia

Answer 5

• Short stature: short extremities, normal trunk length (disproportionate)
• enlarged head, frontal bossing, saddle nose, exaggerated lumbar lordosis

(note- intelligence and reproduction unaffected as in some other forms of dwarfism)

Question 6

how does achondroplasia differ from other forms of dwarfism

Answer 6

no effect on intelligence or reproductive functions:

• cretinism (thyroid deficiency)
• GH deficiency

Question 7

(1) is a group of diseases with deficiencies in type I collagen synthesis. (1) is usually inherited in a (2) pattern. (3) is the most critical and common sign of (1) and (4) is the main method of diagnosis.

Answer 7

1- osteogenesis imperfecta (OI)
2- AD mostly + AR (more severe)
3- frequent fractures with trivial trauma
4- clinical criteria and or DNA sequencing

Question 8

list the clinical features of OI

Answer 8

(osteogenesis imperfecta)

• recurrent bone fractures (with trivial traumas) –> may lead to deformities
• short stature
• dental abnormalities (dentinogenesis imperfecta)
• hearing loss (via malformed middle ear bones or compression of CN-VIII)
• blue sclera

Question 9

______ is the fatal form of OI

Answer 9

type-2 OI, inherited in AR fashion

Question 10

Ehler-Danlos syndrome is defined as…..

Answer 10

group of CT disorders mostly involving collagen: poor synthesis or defective formation (qualitative or quantitative)

Question 11

list the clinical features of Ehler-Danlos syndrome

Answer 11

• hyperextensibility of skin
• easily bruised
• hypermobile joints
• aortic dissection
• osteopenic bone, kyphoscoliosis (kyphosis + scoliosis), spondylolisthesis (pars interarticularis fracture + vertebrae displacement)
• *possibly blue sclera

Question 12

Marfan’s syndrome:

• mutation of (1) gene on chromosome (2), inherited in a (3) pattern
• mainly affects (4) organs

Answer 12

1- fibrillin gene
2- chr.15
3- AD
4- bones, heart, aorta, eyes

Question 13

Marfan’s syndrome:

• (1) skeletal features
• (2) CVS features
• (3) eye features

Answer 13

1:

• tall w/ long extremities, fingers, toes
• joint hyperflexibility
• kyphosis, scoliosis
• pectus excavatum (sunken chest)

2: mitral valve prolapse, aortic dilatation (via cystic medial necrosis), aortic dissection
3: subluxation of lens - ectopia lentis (lens displacement)

Question 14

Osteopetrosis, aka (1), is generally defined as genetic mutation causing (2). The genetic mutation is inherited in a (3) fashion. (4) is the most common genetic defect.

Answer 14

1- marble bone disease
2- osteoclast dysfunction –> defective bone modeling / remodeling via dec bone resorption
3- AD (mild), AR (severe)
4- CA2 gene = carbonic anhydrase-2, mild AD form

Question 15

describe the effects of defective osteoclast activity as seen in Osteopetrosis

Answer 15

abnormal matrix turnover

• osteoclasts cannot degrade pre-existing cartilage and bone
• -> persistent cartilage anlage (primary spongiosum) in medullary cavity
• -> progressive bone deposition on pre-existing matrix

Question 16

Osteopetrosis:

• severe form, aka (1), is inherited in (2) fashion
• (3) are the many features
• (4) is the general outcome

Answer 16

1- infantile form
2- AR

3:

• pancytopenia, hepatosplenomegaly –> infections, anemia, bleeding
• sclerosis at basal cranium –> CN compression
• short stature
• intellectual diability
• renal tubular acidosis (CA-2 defect, AR form)

4- death during fetal life, stillbirth, or early infancy / childhood

Question 17

Osteopetrosis:

• mild form, aka (1), is inherited in (2) fashion
• (3) is the main presentation
• (4) are the additional features

Answer 17

1- adult form
2- AD

3- (in early adolescence) bone pain + recurrent fractures [bones are dense, but brittle]

4- CN defects, mild anemia

Question 18

Osteopetrosis:

• (1) Dx (include results)
• (2) Tx

Answer 18

(marble bone disease- bones break like chalk)
1:
-X-Ray: bones are diffusely sclerotic, poorly formed, and lack cortico-medullary differentiation (solid white appearance)
-genetic analysis: CA-2 defect + others

2- bone marrow transplant

Question 19

Osteopetrosis microscopic appearance

Answer 19

bone: cortex is present — medullary cavity is filled with primary spongiosum –> replacing hematopoetic elements