Bone & joints
Developmental abnormalities
Skeletal dysplasias


Topic Completed: 1 January 2017

Minor changes: 11 February 2021

Copyright: 2017-2021, PathologyOutlines.com, Inc.

PubMed search: pediatric skeletal dysplasias

Erdener Özer, M.D., Ph.D.
Dariusz Borys, M.D.
Page views in 2020: 650
Page views in 2021 to date: 172
Cite this page: Özer E, Borys D. Skeletal dysplasias. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/boneskeletaldysplasias.html. Accessed March 5th, 2021.
Definition / general
  • Skeletal dysplasias are a heterogeneous group of conditions associated with abnormalities of the skeleton, including abnormalities of bone shape, size and density, that manifest as abnormalities of the limbs, chest or skull
  • The latest classification lists 456 disorders under 40 group headings differentiated by specific clinical, radiographic and molecular criteria (J Back Musculoskelet Rehabil 2015;28:575)
  • The 4 most common conditions are thanatophoric dysplasia, achondroplasia, osteogenesis imperfecta and achondrogenesis
Essential features
  • Skeletal dysplasias differ in natural histories, prognoses, inheritance patterns and etiopathogenetic mechanisms
Terminology
  • Osteochondrodysplasias
Epidemiology
  • The prevalence of skeletal dysplasias (excluding limb amputations) is estimated at 2.14 per 10,000 births (Am J Med Genet 1996;61:49)
  • Males are primarily affected in X linked recessive disorders; otherwise, males and females are usually equally affected
Pathophysiology
  • Based on the underlying molecular genetic cause, the dysplasias can be broadly grouped by the function of the protein product of the causative gene
  • Many of the genes mutated in skeletal dysplasias encode proteins that play critical roles in the growth plate
  • Radiographics 2008;28:1061
Etiology
  • FGFR3 gene mutation causes achondroplasia, hypochondroplasia and thanatophoric dysplasia
  • Mutations in the procollagen I genes (COL1A1, COL1A2) cause various types of osteogenesis imperfecta
  • Mutations in the diastrophic dysplasia sulfate transporter gene (DTDST) cause diastrophic dysplasia, achondrogenesis type IB and atelosteogenesis type II
  • Mutations in the procollagen II gene (COL2A1) cause achondrogenesis type II
  • SOX9 gene mutation causes campomelic dysplasia
  • J Back Musculoskelet Rehabil 2015;28:575
Clinical features
  • Typically presents with disproportionate short stature in childhood or premature osteoarthritis in adulthood
  • In addition to the skeletal disorder, individuals frequently demonstrate abnormalities of hearing, vision, neurological, pulmonary, renal or cardiac function


Achondrogenesis
  • Type I:
    • Rare, lethal
    • Extreme limb shortening
    • Marked discrepancy between head and trunk size
    • Severely delayed ossification
  • Type IA:
    • Autosomal recessive
    • No ossification of vertebral pedicles
    • Rib fractures
    • Chondrocytes have inclusion bodies, but cartilage matrix is near normal
  • Type IB:
    • Distinctly abnormal cartilage matrix with rarefaction of ground substance and peculiar ringlike pericellular arrangement of collagen fibers
    • Lethal osteochondrodysplasia due to mutations in transporter gene for diastrophic dysplasia sulfate
    • Genetic defect causes complex derangement in cartilage matrix assembly
    • Impaired decorin deposition causes lack of development of normal interterritorial matrix, preventing necessary structural substrate for proper endochondral bone formation and severe skeletal phenotype
  • Reference: Emedicine: Achondrogenesis


Achondroplastic dwarfism
  • Major cause of dwarfism
  • Reduction in chondrocytes at growth plate is due to defect in fibroblastic growth factor receptor 3 gene (FGFR3)
  • FGFR3 inhibits cartilage proliferation, and is constitutively active in these patients
  • Autosomal dominant, but 80% of cases are new mutations
  • Clinical image
  • Clinical features:
    • Short proximal extremities, normal trunk, enlarged head (bulging forehead, depression of root of nose)
    • Normal intramembranous bone formation, so bone cortices seem thickened compared to short bone length
    • Normal life, IQ, reproductive status
  • Micro description: narrow / disorganized zones of proliferation and hypertrophy in growth plates; chondrocytes in clusters, not columns; base of growth plate has prematurely deposited struts of bone which seal the plate


Thanatophoric dwarfism
  • Also called thanatophoric dysplasia
  • “Thanato”: denoting death
  • Lethal form of dwarfism
  • Occurs in 1 per 20,000 live births
  • Case report: variant in 18 week male fetus (Arch Pathol Lab Med 1993;117:322)
  • Micro description: diminished proliferation of chondrocytes and poor columnization of zone of proliferation
Diagnosis
  • Prenatal evaluation of skeletal dysplasias includes a detailed ultrasound of the fetal skeleton in the second or third trimester of gestation and an extensive genetic family history work up
  • Low dose fetal CT is a powerful imaging tool that aids in diagnosing skeletal dysplasias (Radiographics 2008;28:1061, AJR Am J Roentgenol 2013;200:989)
Radiology description
  • No single unifying features exist; referring to the specific types of skeletal dysplasia for individual features is recommended (World J Radiol 2014;6:808, Radiographics 2008;28:1061)

  • Thanatophoric dysplasia is associated with:
    • Polyhydramnios
    • Thickened soft tissues
    • Micromelia
    • Extremities at 90° to trunk
    • Bowed femur (telephone receiver)
    • Platyspondyly
    • Frontal bossing, depressed nasal bridge
    • Cloverleaf skull (type II)

  • Achondrogenesis is associated with:
    • Polyhydramnios
    • Thickened soft tissues
    • Micromelia
    • Absent ossification of vertebral bodies
    • Normal calvarial ossification (type II)
    • Small thorax, some with rib fractures (type IA)

  • Osteogenesis imperfecta IIA is associated with:
    • Asymmetric micromelia
    • Irregular / thickened bones
    • Angulated bones
    • Beaded ribs, small thorax
    • Poorly ossified skull

  • Osteogenesis imperfecta IIB is associated with:
    • Lower extremities more affected
    • Less beading of ribs
    • Poorly ossified skeleton

  • Osteogenesis imperfecta IIC is associated with:
    • Thin bones, multiple fractures
    • Thin beaded ribs
    • Poorly ossified skull

  • Achondroplasia is associated with:
    • Rhizomelia, mild mesomelia
    • Stubby fingers
    • Frontal bossing
    • Narrowed interpediculate distance
Prognostic factors
  • The prognosis is widely variable, ranging from very mild cosmetic deficits to being lethal
  • Thanatophoric dysplasia and achondrogenesis account for 62% of all lethal skeletal dysplasias
  • Achondroplasia is the most common nonlethal skeletal dysplasia
Case reports
Treatment
  • Treatment is supportive
  • Mild cosmetic deficits can be treated surgically
Clinical images

Images hosted on other servers:

Thanatophoric dysplasia:
micromelia, platyspondyly, frontal
bossing, depressed nasal bridge,
bowed femur (telephone receiver)

Osteogenesis imperfecta:
Postmortem photograph shows
deformed extremities, findings
that are consistent with fractures

Microscopic (histologic) description
Achondrogenesis
  • Abnormal endochondral bone formation with curved cartilage-bone junction at growth plates, periosteal bony spurs
  • Sponge-like cartilage matrix due to lack of interterritorial matrix
  • Epiphyseal cartilage composed of multiple discrete units of chondrocytes encased in territorial capsule and separated from each other by clefts containing fibroblast like cells
  • Mosaic of chondrocyte units (chondrons) due to breakdown of usual matrix continuity of epiphyseal cartilage
Microscopic (histologic) images

Images hosted on other servers:

Osteogenesis imperfecta:
area of microfractures

Achondrogenesis: hypercellular
and hypervascular cartilage

Differential diagnosis
Back to top
Image 01 Image 02