Achondrogenesis Workup

Updated: Jun 26, 2013
  • Author: Harold Chen, MD, MS, FAAP, FACMG; Chief Editor: Bruce Buehler, MD  more...
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Workup

Laboratory Studies

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  • Molecular studies for achondrogenesis are performed on ethylenediaminetetraacetic acid (EDTA)–anticoagulated blood for DNA analysis.
  • Mutation analysis of the DDST gene identifies the following: point mutations, deletions leading to premature stop codons, substitutions or deletions of amino acids within transmembrane domains, substitutions of amino acids in intracellular or extracellular domains, and presumed mutations lying outside the coding region but causing low mRNA levels.
  • Several mutations of the DDST gene have been reported in patients with type IB (the most severe form), patients with atelosteogenesis type II (an intermediate form), and patients with diastrophic dysplasia (the mildest form).
  • Mutation analysis can be used to ascertain carriers, particularly in consanguineous families. However, biochemical analysis of fibroblast cultures has not been able to distinguish heterozygotes from normal homozygotes.
  • Mutation analysis of the COL2A1 gene detects a single base change that has been observed in a patient with achondrogenesis type II in the type II procollagen gene (ie, substitution of serine for glycine in the alpha 1 [II] chain).
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Imaging Studies

Radiological features may vary, and no single feature is obligatory. Distinction between type IA and type IB on radiographs is not always possible. Degree of ossification is age dependent, and caution is needed when comparing radiographs at different gestational ages.

Achondrogenesis type I (Fraccaro-Houston-Harris type)

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  • Skull - Varying degree of deficient cranial ossification consisting of small islands of bone in membranous calvaria
  • Thorax and ribs - Short and barrel-shaped thorax; thin ribs with marked expansion at costochondral junction, frequently with multiple fractures
  • Spine and pelvis - Poorly ossified spine, ischium, and pubis; poorly ossified iliac bones with short medial margins
  • Limbs and tubular bones - Extreme micromelia, with limbs much shorter than in type II; flipper-like appendages; prominent spike-like metaphyseal spurs; femur and tibia frequently presenting as bone segments
  • Subtype IA (Houston-Harris type) - Poorly ossified skull, thin ribs with multiple fractures, unossified vertebrae, arched ilium, hypoplastic but ossified ischium, wedged femur with metaphyseal spikes, short tibia and fibula with metaphyseal flare, "rectangular bones"
  • Subtype IB (Fraccaro type) - Adequately ossified skull, absence of rib fractures, ossified posterior vertebral pedicles, crenated ilium, unossified ischium, trapezoid femur, stellate tibia, unossified fibula, arms and legs shorter than in type IA

Achondrogenesis type II (Langer-Saldino type)

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  • Skull - Normal cranial ossification, relatively large calvaria
  • Thorax and ribs - Short and flared thorax; bell-shaped cage with broader, shorter ribs without fractures
  • Spine and pelvis - Relatively well-ossified iliac bones with long, crescent-shaped medial and inferior margins
  • Limbs and tubular bones - Short, broad bones, usually with some diaphyseal constriction and flared, cupped ends; metaphyseal spurs usually smaller than type I; disproportionately long fibula; mushroom-stem bones
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Other Tests

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  • Obtain bone and cartilage tissue for histological and biochemical studies.
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Procedures

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  • Skin and cartilage biopsies for fibroblast and chondrocyte cultures allow study of sulfate incorporation.
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Histologic Findings

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  • Achondrogenesis type IA has a normal cartilage matrix. No collagen rings are present around the chondrocytes. Vacuolated chondrocytes, intrachondrocytic inclusion bodies (periodic acid-Schiff stain [PAS] positive, diastase resistant), extraskeletal cartilage involvement, enlarged lacunas, and woven bone are all present.
  • Achondrogenesis type IB has a cartilage matrix that shows coarsened collagen fibers that are particularly dense around the chondrocytes, forming collagen rings. Cartilage has reduced staining with cationic dyes, such as toluidine blue or Alcian blue, probably because of a deficiency in sulfated proteoglycans. This distinguishes type IB from type IA, in which the matrix is close to normal and inclusions can be seen in chondrocytes, and from achondrogenesis type II, in which cationic dyes give a normal staining pattern. Thus, the coarsening of fibers and collagen rings are not seen.
  • Achondrogenesis type II has slightly larger than normal and grossly distorted (lobulated and mushroomed) epiphyseal cartilage. Severe disturbance is noted in endochondral ossification and hypercellular reserve cartilage with large, primitive mesenchymal (ballooned) chondrocytes with abundant clear cytoplasm. The cartilaginous matrix is markedly deficient. Overgrowth of membranous bones results in cupping of the epiphyseal cartilages. In addition, a decreased amount and altered structure of proteoglycans, lower relative content of chondroitin 4-sulfate, lower molecular weight and decreased total chondroitin sulfation, absent type II collagen, and increased amounts of type I and type III collagen that are atypical for hyaline cartilage are present.
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