Skeletal Dysplasia

Question 1

What is the frequency of Achondroplasia?

Answer 1

1 in 15,000-40,000 live births

Question 2

What percentage of Achondroplasia is de novo?

Answer 2

80% (Increased risk with advanced paternal age)

100% penetrant

Question 3

What are the characteristics of Homozygous achondroplasia?

Answer 3

• Biallelic pathogenic variants at nucleotide 1138 of FGFR3
• Severe disorder
• Early death results from respiratory insufficiency because
  of the small thoracic cage and neurologic deficit from
  cervicomedullary stenosis

Question 4

When can achondroplasia be detected on ultrasound?

Answer 4

3rd trimester because of shortened long bones

Question 5

What is a fact about a pregnant person with achondroplasia?

Answer 5

The must have a cesarean section because of small pelvic size

Question 6

What is the frequency of Hypochondroplasia?

Answer 6

1 in 15,000-40,000 live births

Question 7

True or false: there can be mild to moderate ID in Hypochondroplasia?

Answer 7

True (not seen in achondroplasia)
Also epilepsy

Question 8

Can Hypochondroplasia be detected at birth?

Answer 8

Not always
May present later in life

Question 9

What percentage of individuals with Cleidocranial dysplasia (CCD) spectrum disorder will have conductive hearing loss?

Answer 9

39%

Question 10

What is Diastrophic dysplasia?

Answer 10

(Think dad from Little People Big World)
* Limb shortening
* Normal-sized head
* Slight trunk shortening
* Hitchhiker thumbs *
* Symphalangism (fusion of the joints of the fingers or toes) with missing interphalangeal creases *
* Small chest
* Protuberant abdomen
* Normal intelligence
* Contractures of large joints
* Dislocation of the radius
* Cleft palate (in ~1/3 of individuals)
* Cystic ear swelling in the neonatal period (in ~2/3 of infants) *
* Ulnar deviation of the fingers, gap between the first and second toes, clubfoot, and flat hemangiomas of the forehead

Prevalence unknown, suspected to be 1 in 100,000
1/33,000 in Finland (founder mutation)

Question 11

What is the genetic cause of Diastrophic dysplasia?

Answer 11

SLC26A2

Autosomal recessive

Question 12

What is Hereditary multiple osteochondromas syndrome?

Answer 12

Multiple osteochondromas (cartilage-capped bony growths) arising from the area of the growth plate in the juxtaphyseal region of long bones or from the surface of flat bones (e.g., the scapula)

• Approximately 70% of affected individuals have a clinically apparent osteochondroma about the knee
• Radiographs of the knees may detect non-palpable osteochondromas in mildly affected individuals
• Family history consistent with autosomal dominant inheritance
• No consensus clinical diagnostic criteria for hereditary multiple osteochondromas (HMO) have been published.

Question 13

What is the genetic cause of Hereditary multiple osteochondromas syndrome?

Answer 13

EXT1 or EXT2
Autosomal Dominant

10% de novo

96% penetrant in females/100% in males

Question 14

What is the phenotype of Spondyloepiphyseal dysplasia congenita (SEDC)?

Answer 14

(Think Willow)

• Present neonatally
• severe disproportionate short stature, short extremities (<5th percentile)
• characteristic facial features (hypertelorism, flat
  profile, PRS)
• myopia, and hearing loss
• barrel chest

Question 15

What is the genetic cause of Spondyloepiphyseal dysplasia congenita (SEDC)?

Answer 15

COL2A1 (AD)

Question 16

What genes are associated with more than 90% of osteogenesis imperfecta cases?

Answer 16

COL1A1 or COL1A2

Mostly AD

Question 17

What is the phenotype of OI type 1?

Answer 17

Blue sclerae
Normal stature (or shorter than family members)
Possible femoral bowing at birth
May have fractures at birth
Fracture few to several per year; decrease after puberty; increase after menopause or men in 5th decade
Fractures usually heal without deformity
Joint hypermobility
Dentinogenesis imperfecta (DI)
* 50% conductive hearing loss with sensorineural with time

Question 18

What is the phenotype of OI type 2?

Answer 18

Perinatally lethal
Small for gestational age
Dark blue sclerae
Fragile connective tissue
Large, soft skull
Callus formation on ribs
Extremities short and bowed
Hips usually flexed (“frog-leg”)

60% die on DOL1
80% die within first week

Question 19

What is the phenotype of OI type 3?

Answer 19

Apparent at birth
Can lead to death from pulmonary failure
Most do not walk without assistance
Extreme growth delay
Intellect normal
DI (dental)
Relative macrocephaly and barrel chest deformity
Blue sclerae in infancy but lighten with age
Hearing loss in teenage years
Basilar impression (descent of skull on cervical spine)
*Popcorn calcifications around growth plate

Question 20

What is the phenotype of OI type 4?

Answer 20

• Most variable form of OI
• Mild (diagnosis can be difficult) to moderately severe
• Mild short stature (variable)
• DI (may be mild)
• Adult-onset hearing loss (in some)
• Normal-to-gray sclerae (can lighten to near normal)
• Basilar impression can occur

Question 21

What is Protrusio acetabuli

Answer 21

medial displacement of the femoral head
common in OI

Question 22

What type of hearing loss is associated with the different types of OI?

Answer 22

Type 1: present in ~50%
Type 2: -
Type 3: Frequent
Type 4: Some

Question 23

In what type of OI do you see protrusio acetabuli?

Answer 23

Type 4