Normal configuration of extremities by 10wks, ossification begins
structure & function of joints depends on normal movement during gestation
    Prox Humeral epiphysis never calcifies before 38wk
        if these are seen you know the lungs are mature

Skeletal Dysplasias (0.03% of all births), with half being lethal
    present at >4SD below mean GA is diagnostic bone dysplasia (ie <1st %ile)
    associated small fetal thorax is confirmation of lethality (pulmonary hypoplasia)
    check for cardiac anomalies: increased cardiothoracic ratio with normal thoracic ratio
    shorter than 2 SD below mean at risk for dwarfism, or may be related to IUGR
    some dysplasias are not evident until after 22wks, especially the lethal forms
    look for poor mineralization: decreased echogenicity, absent shadowing, bones appearing too thick because of less attenuation, increased falx prominence, brain seen "too well", fractures (OI type 2)
    look for polydactyly (Jeune syndrome, Ellis-van Creveld syndrome, short rib polydactyly syndrome)
    micromelic (severe shortening lethal): thanatophoric dysplasia, achondroplasia, OI type 2, hypophosphatasia, short rib polydactyly)
    micromelic (mild): Jeune syndrome (usually lethal), Ellis-van Creveld (may be lethal), camptomelic dwarf (usually not lethal)
    rhizomelic (femur&humerus shortening): chondrodysplasia punctata (lethal)
    mesomelia (radius/ulna and/or tib/fib) rare and nonlethal
    acromelia (hands and feet bone shortening)
   
LETHAL SKELETAL DYSPLASIAS
many described but 3 account for the vast majority:

Thanatophoric Dysplasia
Achondrogenesis
Osteogenesis Imperfecta types II & III
 
DYSPLASIA'S WITH GOOD OR VARIABLE PROGNOSIS
Tend to present later in gestation, difficult to detect prior to <22wks

Achondroplasia (heterozygotes)
Asphyxiating Thoracic Dysplasia
Chondroectodermal dysplasia
Diastrophic dysplasia
Osteogenesis Imperfecta type IV

OSTEOCHONDRODYSPLASIAS(after International Nomenclature for Skeletal Dysplasias)

Thanatophoric dysplasia: pic
    most common lethal dysplasia with 1/10000 occurence
    severe shortening of the limbs;held at 90 deg angle to body, narrow thorax, normal trunk length and large head with prominent forehead.
    most present with polyhydramnios, large for dates
    type I (sporadic) the femurs are curved (telephone receiver)
    type II (autosomal recessive) the femurs are straight but the skull is cloverleaf skull (seen 14%)
DDx - Homozygous Achondroplasia, only in affected parents
  
Achondrogenesis pic
    lethal 1/40 000
   profound limb shortening secondary to disorganized cartilage
   severe shortening of the limbs, narrow thorax, short trunk and large head
   type I (autosomal recessive) there is poor mineralization of both the skull and vertebral bodies as well as rib fractures
   type II (sporadic with induced autosomal dominant mutations) there is hypomineralization of the vertebral bodies but normal mineralization of the skull, and there are no rib fractures

Osteogenesis Imperfecta
    genetically heterogeneous group with fragility of bones, blue sclerae, loose joints and growth deficiency. 
    Exuberent callous is typical
    Calvaria may be compressible with hypomineralization
    platyspondyly possible
    defect is a dominant negative mutation affecting COL1A1 or COL1A2 alleles, which encode the proA1(I) and proa2(I) chains of type I collagen which is a protein important for normal skin and bone development.
    The mutations result in the production of abnormal quantity (type I) or quality (types II, III and IV) of collagen.
   
    type I (autosomal dominant) prevalence of about 1 in 30 000, affected individuals have fragile bones, blue sclerae and progressive deafness, but life expectancy is normal. Prenatal diagnosis is available by DNA analysis. Ultrasonography in the second and third trimesters may demonstrate fractures of long bones.
     type II lethal disorder (new AD mutations) prevalence of about 1 in 60 000
        early prenatal onset of severe bone shortening and bowing due to multiple fractures affecting all long bones and ribs, and poor mineralization of the skull
    type III is a progressively deforming condition
        multiple fractures, usually present at birth, resulting in scoliosis and very short stature. Bowing of the femur has been described in these cases in utero. Both autosomal dominant and recessive modes of inheritance
    type IV  (AD with variable expressivity)
        deformities of the long bones due to fractures, but no blue sclera or deafness
    Prenatal diagnosis of types III and IV can be made by chorion villous sampling and DNA analysis, or by demonstration of abnormal collagen production in cultured fibroblasts
    Vaginal delivery of all types only presents minimal risk

Hypophosphatasia
    lethal (autosomal recessive) prevalence of 1 in 100 000
    severe shortening of the long bones, small thorax, hypomineralization of the skull and long bones absence of liver and bone isoenzymes of alkaline phosphatase, and first-trimester diagnosis is made by measurement of alkaline phosphatase isoenzymes in chorion villous samples


Heterozygous Achondroplasia pic
     nonlethal (autosomal dominant 80%spontaneous new mutations) prevalence 1 in 30,000
    defect in fibroblast growth factor (detect by amniotic fluid)
    normal life expectancy and intelligence
    moderate micromelia, discrepancy relative to BPD best sign
    Basilar invagination saddle-nose/frontal bossing, kyphosis, spinal stenosis
    Trident hand  short proximal & middle phalanges of all fingers

Jarcho-Levin Syndrome pic
    heterogeneous disorder characterized by misalignment of the Cspine and ribs
    short thorax with death in infancy, if not severe, may live into adulthood

Asphyxiating Thoracic Dysplasia (Jeune syndrome)
     Auto recessive with variable expression 1/70k
    narrow chest and rhizomelic limb shortening (may not be apparent until >24wks)  
        vary from lethal to No resp Sx, thoracic size dictates
    Polydactly in 14%

Chondroectodermal Dysplasia (Ellis-van Creveld syndrome)
    auto recessove, mostly in Amish
    acromelic and mesomelic limb shortening with small chest and polydactyly
    50% with congenital heart disease
        good prognosis

Short limb polydactyly sydromes
    short limbs, narrow thorax, polycactyly, congenital heart polycystic kidneys and intestinal atresia
    lethal

Diastrophic Dysplasia
     auto recessive with Rec, variable severe to mild expression
    Cleft palate & fixed elbow & phalanx joints common
    "hitchhiker thumb" due to extended thumb
    Kyphoscoliosis can inhibit cardiac & pulm function
    Normal neurodevelopment

FOCAL LIMB OR EXTREMITY BONE LOSS
Not bone dysplasias

 Radial Ray Defect
    mult disorders lead to thumb & radius agenesis
        Tri 18 & 13, Fanconi, Holt-Oram Syndrome
        Humerus may also be shortened or absent

Amniotic Band Syndrome
     1 in 1200, freq associated with spont abortion
    rupture of amnion causes transient oligo, fetal parts caught
    Large bizarre defects can occur in any portion of fetus
    Limb-Body Wall Complex - related but not proven to be same
        invariable fatal defects in thorax & abd

Roberts Syndrome (Pseudothalidomide syndrome) in mild form
    complete limb absence with only fingers on shoulder
    bilat cleft, hypertelorism, microcephaly & growth retardation

Sirenomelia ("Mermaid Syndrome") lower ext fusion
    a manifestation of caudal regression syn, severe oligo
    Fatal bilat renal agenesis or multicystic kids

Sacral Agenesis - increases in infants of diabetic mothers


CONTRACTURE & POSTURE DEFORMITIES
Fetal Akenesis Deformation Sequence
Result from absense of prenatal joint movement
Physical causes, abn Nerves, abn muscle or defective connective tissue

Arthrogryposis Multiplex Congenita - mult ext contractures
    Oligohydramnios most common cause, but any of above poss
    Curare administered in late fetal life also cause

Pterygium - webbing of skin across a joint
    result of movement restriction
    Popliteal most common


HAND & FOOT DEFORMITIES

Clubfoot pic 1 in 250, often assoc with other anomalies esp w akinesia
Talipes Equinovarus - plantarflexed & varus #1
seen as early as 13wks

Clinodactly - permenant deviation or deflection of finger
    often assoc with overlap, suggests trisomy, not pathognomonic

Polydactly & Syndactly - help in narrowing DDx of other abnormality
    present in dysplasia associated with short-rib polydactly syndrome, NOT Thanatophoric
    associated with chondroectodermal dysplasia NOT asphyxiating thoracic dysplasia
    Syndactly difficult to confirm as isolated finding

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