1. Skeletal Dysplasias

2. Skeletal dysplasia is a generalized structural abnormality of bone growth and modelling. Bone modelling is a consequence of osteoblast and osteoclast activity and growth / morphogenetic factors are important in development. The main structural protein of bone and cartilage is collagen. Mutations in collagen genes cause generalized dysplasia.

4. The skeletal dysplasias are genetically heterogenous and can be inherited as autosomal dominant, autosomal recessive, X-linked recessive, and X-linked dominant disorders, and rarer genetic mechanisms of disease including chromosomal deletions/duplications, germline mosaicism, and uniparental disomy have been seen.

5. Although each skeletal dysplasia is relatively rare, collectively the birth incidence of these disorders is almost 1/5000. Skeletal dysplasia can be associated with variety of orthopedic, neurologic, auditory, visual, pulmonary, cardiac, renal complications, usually referred with deformity or short stature.

6. Skeletal Dysplasias short stature and deformities of limbs and spine
01/21/98
Skeletal Dysplasias
short stature and deformities of limbs and spine
respiratory problems
chest wall or upper airway abnormalities
central nervous system problems
hydrocephaly
spinal stenosis
spinal cord injury from cervical spine and/or cervicovertebral junction instability
muscle hypotonia, contractures, intrinsic muscle disease
hearing loss, dental problems, myopia, retinal detachment are also more common with some of the skeletal dysplasias 8

7. Achondroplasia most common short limbed bone dysplasia.
Diagnosed at birth
rhizomelic limb shortening
large head with broad, prominent forehead
fingers are short, tapered and splayed

8. Achondroplasia if both parents affected - homozygotes can occur
Autosomal dominant
Gene maps to chromosome 4p
mutation identified in the Fibroblast Growth Factor Receptor 3 (FGFR3) gene
most cases are denovo mutations
in these cases recurrence risk is small
germ-line mosaicism - small risk to normal parents of having recurrence
if both parents affected - homozygotes can occur
infants more severely affected and usually die early from compression of foramen magnum and respiratory failure

9. Hypochondroplasia Diagnosis might be difficult in the neonatal period
Clinical features include:
presence of mild rhizomelic limb shortening
less severe than in achondroplasia / some bossing of the forehead
fibula seem to be disproportionately long
Interpedicular distance in the spine narrows caudally
Findings may not be present or noted until second or third year of life
Autosomal dominant inheritance - FGFR3 receptor mutations

10. Thanatophoric Dysplasia
characterized by extreme rhizomelia, bowed long bones, normal trunk length but narrow thorax, and a relatively large head
Most cases of thanatophoric dysplasia are sporadic.
The limbs show rhizomelic shortening. The femurs are extremely short and bowed, and, in the most severe forms, may be shaped like a telephone receiver. The thorax is narrow in the anteroposterior dimension, with short ribs.

11. Thanatophoric Dysplasia
Limbs are very short
(extreme rhizomelia)
Chest is narrow
bowed long bones
Most infants die within a few
hours of birth from respiratory
failure
Clinical features:
head is large with prominent forehead
depressed nasal bridge

12. Thanatophoric Dysplasia - X-ray feature
shortening of the long bones with metaphyseal flaring and cupping
characteristically curved femurs (“telephone receiver”)
Iliac wings are hypoplastic
Severe flattening of vertebral bodies
gives an inverted “H” or inverted “U” shape
Incidence - 1/20,000 live births

13. ThanatophoricDysplasia
Autosomal dominant
Mutations in FGFR3 receptor
Most cases are sporadic
Condition probably caused by a lethal AD gene

14. Achondrogenesis
(AR )Lethal chondrodystrophy characterized by extreme micromelia, short trunk, and a disproportionately large cranium
disorder of both endochondral and membranous ossification

15. Achondrogenesis Types I and II
Type 1 - Parenti-Fraccaro - Autosomal recessive
Type 2 - Langer - Saldino - Autosomal dominant
Difficult to distinguish clinically
Both result in stillbirth or neonatal death

16. Achondrogenesis - Clinical Features
severe micromelia
relatively large head, short neck, short trunk and protuberant abdomen
flat nasal bridge
nose is short with anteverted nostrils

17. Hypochondrogenesis Most AD - New mutations Clinical features:
mutations in Type II collagen genes
Clinical features:
flat face, depressed nasal bridge, small thorax, relatively large head
Limbs are short
Infant seems edematous

18. Diastrophic Dysplasia
Autosomal recessive
Severe Limb Dysplasia
Short limbs, severe talipes equinovarous
hitch-hiker thumbs
(abducted thumbs)
cleft palate in many
cauliflower ear
characteristic swelling of the pinnae
occasional dislocations of
joints

19. Camptomelic Dysplasia
Hallmark bowing of long bones
particularly the femur and tibia
Large head, small jaw, cleft palate and flat nasal bridge
Ears may be malformed and low set
Chest narrow - respiratory distress is common

20. Camptomelic Dysplasia
Interesting Associations:
1/3 cardiac defects (VSD, ASD, Fallot Tetrology)
1/3 hydronephrosis - unilaterally
medullary cystic disease
Ambiguous Genitalia occur in the majority of patients with XY karyotype
Other frequent malformation include hydrocephalus, arrhinencephaly

21. Camptomelic Dysplasia
Genetics:
Autosomal dominant
Some with balanced translocations in the 17q12-25 region
Mutations in Sox 9 gene have been demonstrated
Most cases are sporadic

22. Fibrodysplasia Ossificans Progressiva
Clue to dx in neonatal period is hypoplasia of great toe
Absent skin crease - single phalanx - deviation laterally
Progressive ossification - birth to 10 years
Baldness and deafness
Synovial osteochondromatosis
Autosomal dominant
ACVR1 gene

23. Short rib polydactyly syndrome
AR lethal
characterized by extremely narrow thorax, limbed dwarfism,and polydactyly
4 types

24. Chondroectodermal dysplasia (Ellis van Creveld syndrome)
characterized by short limbed dwarfism, polydactyly, and nail and tooth abnormalities. It is inherited as autosomal recessive.
Congenital heart disease is present in over half of the cases.

25. Asphyxiating thoracic dysplasia – Jeune Syndrome
The main manifestation of this condition is a small thorax which results in respiratory distress.
In the neonate this disorder may be difficult to differentiate from chondroectodermal dysplasia since occasionally polydactyly may be present.

26. OSTEOGENESIS IMPERFECTA
Osteogenesis imperfecta is a heritable disorder caused by mutations in the gene for type I collagen.
The classification of osteogenesis imperfecta (types I through IV) is based on clinical characteristics
Type I osteogenesis imperfecta is associated with an increased risk of fracture but is usually not deforming.
Type II osteogenesis imperfecta is lethal in the perinatal period, owing to severe fractures and deformity.
Patients with type III or type IV osteogenesis imperfecta survive fractures in infancy and childhood but have progressive deformity.

28. Osteogenesis Imperfecta Type I
Commonest form of OI
Affected Individuals have:
blue sclera and tendency to fracture the long bones
Infants are of normal weight and length at birth and do not have multiple fractures
deafness
Healing occurs without deformity
X-ray may reveal wormian bones of the skull and mild osteoporosis

29. Osteogenesis Imperfecta Type I
Autosomal dominant inheritance
Cells from individuals with OI type I secret about half the normal amount of Type I procollagen
Gene linked to one of the Type I collagen loci
7 q 21-22
17 q 21-22

30. Osteogenesis Imperfecta Type II
Severe, usually lethal form of OI
Chest narrow, sclera blue, nose beaked
Marked reduction of ossification of cranial vault and facial bones
Beading of the ribs - indicates multiple fractures