Skeletal Dysplasias

  • Diagnosis
  • Background
  • Lab Tests
  • References

Indications for Testing

  • Confirm diagnosis of a specific skeletal dysplasia to aid in prognosis and recurrence risk in the following
    • Pregnancies with ultrasound findings suggestive of a skeletal dysplasia in the fetus
    • Newborns or children suspected to be affected with a skeletal dysplasia
    • Pregnancies in which both parents are affected, and the fetus is at risk for homozygosity or compound heterozygosity
  • Determine the specific causative mutation(s) in affected adults prior to pregnancy

Laboratory Testing

  • Molecular genetic panels are available that evaluate for the most common skeletal dysplasias as well as those that are more rare

Skeletal dysplasias, also known as osteochondrodysplasias, are a heterogeneous group of >350 disorders characterized by abnormal growth of cartilage or bone. Half of affected fetuses are stillborn or die within six weeks of birth. Some skeletal dysplasias are detected prenatally, while others are not detected until after birth or in later childhood. Only 40% of affected fetuses presenting prenatally are correctly identified by ultrasound alone.

The most common types of skeletal dysplasias detected prenatally include

  • Thanatophoric dysplasia
  • Osteogenesis imperfecta
  • Achondroplasia
  • Achondrogenesis types IB and II
  • Campomelic dysplasia
  • Diastrophic dysplasia

Epidemiology

  • Incidence – 1/5,000; however, most syndromes are rare

Clinical Presentation

  • Symptoms may include but are not limited to
    • Shortening of bones of the arms and legs >3 standard deviations below the mean
    • Head circumference >75th percentile
    • Bowed or fractured bones
    • Irregular, thickened, or thin bones
    • Undermineralization of the bones
    • Abnormal ribs and/or small chest circumference
    • Polydactyly

Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Skeletal Dysplasia Panel, Sequencing (39 Genes) and Deletion/Duplication (35 Genes), Fetal 2012010
Method: Massively Parallel Sequencing

Limitations

Deep intronic or regulatory region mutations and breakpoints for large deletions/duplications are not detected

Not all mutations in the tested genes are identified

Not all predisposing genes are interrogated

Diagnostic errors can occur due to rare sequence variations

Skeletal Dysplasia Panel, Sequencing (39 Genes) and Deletion/Duplication (35 Genes) 2012015
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Limitations

Deep intronic or regulatory region mutations and breakpoints for large deletions/duplications are not detected

Not all mutations in the tested genes are identified

Not all predisposing genes are interrogated

Diagnostic errors can occur due to rare sequence variations

Skeletal Dysplasia Panel, Sequencing, 39 Genes 2012018
Method: Massively Parallel Sequencing

Limitations

Deep intronic or regulatory region mutations and breakpoints for large deletions/duplications are not detected

Not all mutations in the tested genes are identified

Not all predisposing genes are interrogated

Diagnostic errors can occur due to rare sequence variations

Skeletal Dysplasia Panel, Deletion/Duplication, 35 Genes 2012007
Method: Exonic Oligonucleotide-based CGH Microarray

Limitations

Deep intronic or regulatory region mutations and breakpoints for large deletions/duplications are not detected

Not all mutations in the tested genes are identified

Not all predisposing genes are interrogated

Diagnostic errors can occur due to rare sequence variations

Achondroplasia (FGFR3) 2 Mutations 0051266
Method: Polymerase Chain Reaction/Fluorescence Resonance Energy Transfer

Limitations

Rare diagnostic errors may occur due to primer-site mutations

Achondroplasia (FGFR3) 2 Mutations, Fetal 0051265
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Limitations

Rare diagnostic errors may occur due to primer-site mutations

Hypochondroplasia (FGFR3) 2 Mutations 0051367
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Limitations

Rare diagnostic errors may occur due to primer-site mutations

Thanatophoric Dysplasia, Types 1 and 2 (FGFR3) 13 Mutations 0051506
Method: Polymerase Chain Reaction/Fragment Analysis

Limitations

Rare diagnostic errors may occur due to primer-site mutations

Thanatophoric Dysplasia, Types 1 and 2 (FGFR3) 13 Mutations, Fetal 0051508
Method: Polymerase Chain Reaction/Fragment Analysis

Limitations

Specificity may be compromised by rare primer-site mutations

General References

Baujat G, Legeai-Mallet L, Finidori G, Cormier-Daire V, Le Merrer M. Achondroplasia. Best Pract Res Clin Rheumatol. 2008; 22(1): 3-18. PubMed

Bober M, Bellus G, Nikkel S, Tiller G. Hypochondroplasia. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews, University of Washington, 1993-2015. Seattle, WA [Last updated Sep 2013; Accessed: Nov 2015]

Friez MJ, Wilson JA P. Novel FGFR3 mutations in exon 7 and implications for expanded screening of achondroplasia and hypochondroplasia: a response to Heuertz et al. Eur J Hum Genet. 2008; 16(3): 277-8. PubMed

Horton WA, Hall JG, Hecht JT. Achondroplasia. Lancet. 2007; 370(9582): 162-72. PubMed

Hurst JA, Firth HV, Smithson S. Skeletal dysplasias. Semin Fetal Neonatal Med. 2005; 10(3): 233-41. PubMed

Karczeski B, Cutting G. Thanatophoric Dysplasia. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews. University of Washington, 1993-2015. Seattle, WA [Last updated Sep 2013; Accessed: Nov 2015]

Krakow D, Rimoin DL. The skeletal dysplasias. Genet Med. 2010; 12(6): 327-41. PubMed

Pauli R. Achondroplasia. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews, University of Washington, 1993-2015. Seattle, WA [Last updated Feb 2012; Accessed: Nov 2015]

Savarirayan R, Rimoin DL. The skeletal dysplasias. Best Pract Res Clin Endocrinol Metab. 2002; 16(3): 547-60. PubMed

Medical Reviewers

Last Update: December 2015