INHERITED DEFECTS IN BONE STRUCTURE

What is another term for inherited defects in bone structure?

skeletal dysplasia ~ disorder with the development of bone and cartilage

What are three conditions classified as inherited defects in bone structure?

Achondroplasia

Osteogenesis imperfecta

Osteopetrosis

What is a common name for Achondroplasia?

dwarfism

What is a common name for Osteogenesis imperfecta?

brittle bone disease

What is a common name for Osteopetrosis?

marble bone disease

What is the term defined by two copies of the mutated gene, one from each parent, are required to cause the disorder?

Autosomal recessive disorder

With autosomal recessive disorders, if both parents are carriers but do not have the condition, the child has a _____ chance of inheriting it.

25%

What term is defined as a single copy of the mutated gene from one parent is enough to cause the disorder?

Autosomal dominant disorder

With autosomal dominant disorder, a child of a person with an autosomal dominant condition has a ____ chance of inheriting the condition.

50%

Achondroplasia is a genetic disorder that affects _________, leading to disproportionate ______.

bone growth

dwarfism

What kind of dysplasia is seen in Achondroplasia and what segments are affected?

rhizomelic

proximal segment

T/F: With Achondroplasia, the proximal segments are affected more than the distal segments of the appendages. The humerus is affected more than the radius and ulna and the femur is affected more than the tibia and fibia.

True

What is the prevalence of Achondroplasia worldwide?

1 in 15,000 to 1 in 40,000

Achondroplasia accounts for _____ of cases of dwarfism. Less commonly, _____ may be due to ______ dysfunction or secondary to a mutation in the growth hormone receptor, which is known as ________.

70%

dwarfism

pituitary

Laron dwarfism

What is the average height of adult males with achondroplasia? females?

132 cm / 4’4”

123 cm / 4’1”

T/F: Achondroplasia affects males and females equally

true

Achondroplasia is inherited as an:

autosomal dominant

____ of individuals with achondroplasia are _________, or not inherited.

80%

de novo mutations

With de novo mutations leading to achondroplasia, which gene is mutated?

FGFR3 gene

Homozygous achondroplasia describes a condition where:

both parents are affected

Is homozygous achondroplasia severe?

It has the potential to be if a child receives the gene from both parents. most of these cases do not survive pregnancy or live long after delivery

Achondroplasia results from the mutation of genes on chromosome ____, encoding for the ____ gene.

4

FGFR3 (fibroblast growth factor receptor 3)

What is the role of FGFR3 in bone?

regulates bone growth by limiting the formation of bone from cartilage

Is the FGFR3 over or under active in achondroplasia?

overly active

Bones grow from birth until adulthood through growth plates, where ____ is replaced by bone via __________.

cartilage

endochondral ossification

What is the role of chondrocytes in bone development?

chondrocytes (cartilage cells) align to form new bone with signals from receptors controlling the process

______ receptors send signals to slow bone growth, while _______ receptors block these signals to allow growth.

FGFR3

NPR-B

What is the role of FGFR3 in achondroplasia?

a mutation in the FGFR3 gene causes constant signals to slow bone growth, which impairs chondrocyte alignment

What does the mutation of FGFR3 gene in achondroplasia typically involve?

a swap of glycine for arginine at the 380th amino acid of the FGFR3 protein, which keeps the receptor constantly active

what does the constant activation of the FGFR3 gene cause?

It inhibits bone elongation, affecting long bones like the humerus and phalanges

T/F: in achondroplasia, intramembranous bone growth, like in the skull and ribs, and appositional growth (bone widening) remain largely unaffected.

true

T/F:in heterogenous achondroplasia, intelligence, fertility, and lifespan are also affected.

false. but they may be affected in homozygous achondroplasia

What clinical features related to long bone malformations are seen in achondroplasia?

rhizomelic (proximal) shortening of the limbs

varus leg deformity

short metacarpals AKA broad-hand

short phalanges causing brachydactyly - short fingers

fingers form a trident hand shape

What clinical features related to flat bone malformations are seen in achondroplasia?

less commonly seen

large head size with frontal bossing

flattened nasal bridge

narrow foramen magnum - potential spinal cord compression which may lead to breathing issues and sleep apnea

spinal lordosis or kyphosis

What clinical oral findings are seen in achondroplasia?

mandibular prognathism

delayed eruption of teeth

How can achondroplasia be diagnosed?

prenatal ultrasound with skull width measurement, femur length (higher than normal)

DNA test before or after birth

Skeletal survey - series of radiographs

Treatment options for achondroplasia?

no true treatment

treatments to manage symptoms and complications as they arise

Osteogenesis imperfecta is a ________ disorder.

genetic bone

OI is AKA:

brittle bone disease

How is OI characterized?

it is characterized by the impaired production of type I collagen (an essential protein in the development and maintenance of bones and connective tissue)

Why is collagen important for bones? How is collagen related to OI?

collagen provides strength and support to the bones

in individuals with OI, the collagen produced is weak, leading to bones that are brittle and prone to fractures

What is the prevalence of OI? Does it affect males and females equally?

1 in 10-20,000 live births worldwide

yes

OI is a genetic disorder caused by a mutation in the _______________ gene, which is inherited in an ___________ pattern or occurring through _________.

COL1A1 or COL1A2 gene

autosomal dominant

spontaneous mutation

What are COL1A1 and COL1A2 genes responsible for?

the production of type I collagen

Type I collagen is a major component of which 4 things?

bones, teeth, ligaments, sclera

describe the pathophysiology of OI.

The defect in the DNA (COL1A1 and COL1A2 genes) leads to faulty RNA transcription and translation. This results in defective alpha chains that cannot form a proper triple helix

In the 3 alpha chains within the collagen fibril triple helices, every third AA is a:

glycine

The primary unit of the alpha chains is glycine amino acid which allows the chain to:

twist and bind tightly to form collagen ~ strong triple helix structure

In OI, a mutation occurs at any of the nucleotide position coding for:

glycine

What does the OI mutation of nucleotide position coding lead to?

disruption of the tight twisting of the collagen triple helix leading to reduced tensile strength in collagen fibers, leading to brittle bone disease.

People with OI are born with it. They either don’t have enough ____ in their bones or the _____ does not work as it should

collagen

collagen

How many types of OI are there

8

OI type I is known as:

Osteogenesis imperfecta AKA classic non-deforming osteogenesis imperfecta

Is osteogenesis imperfecta a severe form or mild form?

it is the mildest and most common form of brittle bone disease

What is the key identifying characteristic associated with Type I OI? What causes it?

blue sclera

whites of the eyes may have a bluish tint due to collagen defect the tissue is abnormally thin and can see the vascular underneath tissue

What happens to collagen in type I OI?

the collagen produced is normal but insufficient in quantity

How are the bones affected in type I OI?

bones break more easily but typically maintain normal shape and patient maintains normal height

When do patients with Type I OI typically have fractures?

first fracture often happens when the child starts walking

fractures tend to become less frequent after puberty

What are 6 clinical features of type I OI?

blue sclera

hearing loss may develop in adulthood

kyphosis/scoliosis

loose joints

low muscle tone

opalescent teeth due to dentinogenesis imperfecta (DI) ~ soft dentin erodes easily —> translucent teeth with soft dentin

In type II OI, how is the collagen affected?

it is not formed normally

How severe is Type II OI?

it is the MOST severe type

Describe perinatally lethal osteogenesis imperfecta

babies with type II OI are usually born with many fractures, missing bones, are very small, and have severe breathing problems. As a result, most do not survive or die shortly after birth

What are the clinical features of Type II OI?

underdeveloped lungs

severe bone deformity and small stature

narrowed chest

How severe is type III OI?

most severe form that can be survived after birth

In type III OI, collagen doesn’t form normally and so babies are often born with:

broken bones

Why are children with type III OI shorter than their peers and what is this condition called?

as they grow, their bones break easily leading to shorter stature

progressively deforming osteogenesis imperfecta

What are some clinical features of Type III OI?

curved spine - scoliosis

outward-pointing ribcage

triangular shaped face

bowed legs

loose joints

bluish sclera

respiratory problems

hearing loss

brittle teeth

short stature

Type VI OI affects collagen by:

having a normal quantity but not forming normally, poorer quality

Order the four types of OI from highest severity to lowest severity.

TII >TIII> TVI> TI

Type VI OI is AKA:

variable osteogenesis imperfecta with normal sclerae due to mild to moderate bone deformities

What are the clinical features of Type VI OI?

frequent bone breaks

bowed legs that may lessen with age

short stature

hearing impairment

spinal curvature

What are three methods of diagnosis of Type VI OI?

genetic testing to determine which, where, and what glycine is affected

postnatal x-ray: determine current broken bones or defects in bones

prenatal ultrasound: lethal form: severe micromelia - small undeveloped extremities, decreased bone mineralization, multiple bone fractures, missing or underdeveloped bones

Treatment options for Type VI OI:

• no true cure

• presence of supportive therapies: phyiostherapy, occupational therapy, physical aids/assistive devices

• non-opioids (NSAIDS and paracetamol) to reduce pain

• bisphosphonates strengthen bone and help increase quality

• low impact exercise

• surgery - metal rods to support bones

What is the name of the rare genetic disorder characterized by osteoclast dysfunction but normal osteoblast function?

osteopetrosis

Osteopetrosis is AKA:

osteosclerosis

Marble bone disease

~ due to hardening of the bone

In osteopetrosis, what do the dysfunctional osteoclasts lead to?

• inability to break down old bone

• building up new boens continuously on top of old bones lading to very fragile bones

• increased bone density and overgrowth of bone

What is the prevalence of osteopetrosis?

1 in 20-250,000 depending on the type

What is the cause of osteopetrosis?

a genetic mutation affecting an enzyme or protein involved in bone resportion ~ osteoclast

What are the two types of osteopetrosis?

• autosomal recessive AR

• autosomal dominant AD

Which type of osteopetrosis is the most severe? which one is more common and less severe?

Most severe: AR

Most common and Least severe: AD

What is another term for autosomal recessive osteopetrosis?

infantile malignant type

When does AR osteopetrosis present?

present soon after birth

What causes AR osteopetrosis?

caused by mutations in CA2 gene encoding for carbonic anhydrase II (CAII) enzyme

In AR osteopetrosis, what does the deficiency in CAII lead to?

• inhibition of proton pumping

• increased pH to less acidic (acidity is responsible for demineralizing bone to extract calcium and phosphate

• osteoclast fail to resorb bone

• less bone resorption

What are other terms for autosomal dominant osteopetrosis?

adult benign type

Albert-Schonberg Disease

~normal childhood symptoms manifest in adulthood

What causes AD osteopetrosis?

caused by mutations in the chloride channel 7 (CLCN7) gene

In AD osteopetrosis, what does the deficiency in CLCN7 cause?

• no exchange of Cl with H

• increased pH leading to less acidity

• osteoclast fails to resorb bone

• less bone resorption

What are the clinical features of AR osteopetrosis?

• infections: will eventually compress the bone marrow, decreasing RBC and platelet formation leading to an increased risk of infection

• easy bruising and bleeding

• hepatosplenomegaly

• cranial nerve compression: diminish muscle tone in one side of the face

• renal tubular acidosis: impacts kidney systemically

• delayed eruption of teeth

• dental and jaw malformations

what are the clinical features of AD osteopetrosis?

• can be asymtpomatic

• osteoarthritis of the hip

• pathologic fractures of the femur

• cranial nerve compression

• fatigue secondary to anemia

• increased dental caries

• mandibular osteomyelitis: infection of mandibular bone

• increased risk of infection

What are two diagnostic methods for osteopetrosis?

• imaging: radiographs: “stone/marble bone” —> diffuse symmetric osteosclerosis on both sides of body; bone in bone; erlenmeyer flask appearance where diaphysis appears thinned and metaphysis appears thickened

• laboratory tests: CBC —> blood tests may show pancytopenia & demonstrate the compression on the bone (anemia, leukopenia, thrombocytopenia); hypocalcemia due to increased build up of bone density and decreased blood calcium availability

Treatment of osteopetrosis includes:

• medications and supplementation: high levels of vitamin D, which helps stimulate osteoclast activity; interferon-gamma 1 B therapy is an injected drug that aids in delaying disease progression; corticosteroids help improve some blood cells; antibiotics when patient has infection(s)

• RBC transfusion in severe cases

• bone marrow transplant —> may be curative for some AD cases

• surgical interventions

• treatment of dental problems and abnormalities