Transcript Skeletal Dysplasias

Skeletal Dysplasias
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.
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.
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.
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
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
Achondroplasia - X-ray findings
• Pelvis is abnormal with
small, square iliac wings
• Horizontal acetabular roots
and narrowing of the
greater sciatic notch
• long bones are short and
the metaphyses slope
• because of narrow chest respiratory problems are
frequent
• translucent area at
proximal ends of the
femora in neonatal period
Achondroplasia
• 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
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
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. Some
cases in the same sibship have been reported, and therefore
an autosomal recessive pattern of inheritance has been
suggested.
• 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.
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
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
ThanatophoricDysplasia
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Autosomal dominant
Mutations in FGFR3 receptor
Most cases are sporadic
Condition probably caused by a lethal AD gene
Achondrogenesis
• (AR )Lethal chondrodystrophy
characterized by extreme
micromelia, short trunk, and a
disproportionately large cranium
• disorder of both endochondral
and membranous ossification
(partial or complete lack of
ossification of the calvarium and
spine as well as extremely short
long bones and, frequently,
multiple rib fractures )
Achondrogenesis Types I and II
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Type 1 - Parenti-Fraccaro - Autosomal recessive
Type 2 - Langer - Saldino - Autosomal dominant
Difficult to distinguish clinically
Both result in stillbirth or neonatal death
Achondrogenesis - Clinical Features
• severe micromelia
– relatively large head, short neck,
short trunk and protuberant
abdomen
• flat nasal bridge
• nose is short with anteverted
nostrils
Hypochondrogenesis
• Most AD - New mutations
– mutations in Type II collagen genes
• Clinical features:
– flat face, depressed nasal bridge, small thorax, relatively
large head
• Limbs are short
• Infant seems edematous
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
Diastrophic Dysplasia
• respiratory problems due to narrow
chest and micrognathis can be the
cause of death
• X-rays - marked shortening of the first
metacarpals
• Epiphyses and metaphyses are
irregular
• V-shaped deformity at distal ends of
the femora and tibiae
• vertebral bodies are irregular
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
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
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
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
Craniometaphyseal Dysplasia
• Progressive nasal obstruction
and mouth breathing in
childhood
• Later - craniotubular bone
dysplasia can be seen on
skeletal X-ray
– sclerosis of skull, vault and base
– abnormal metaphyseal modeling
of the long bones
Craniometaphyseal Dysplasia
• Bony overgrowth involving the supraorbital ridges
giving visor-like appearance
• Tibia are curved backwards with mild valgus
deformity of knees
• Extension and rotation is limited at elbows
• Deafness and cranial nerve entrappment occur
Short rib polydactyly syndrome
• AR lethal
• characterized by
extremely narrow thorax,
limbed dwarfism,and
polydactyly
• 4 types
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.
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.
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.
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
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
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
Hypophoshatasia
• Two forms - early and late
• Both have reduced chondro-osseous mineralization
– low levels of alkaline phospatase in blood, cartilage and
bone
• Infantile form:
– stillbirth, early death due to respiratory insufficiency
Hypophosphatasia
• Long bones - deformed and sometimes
fractured
• Differential diagnosis - OI bones are very
poorly mineralized and irregular ossification
of the metaphyses which are widened and
frayed
• Skull is poorly ossified
• Concentration of phosphoethanolamine is
elevated in urine
– Late onset - AD
– Early onset - AR