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

Laboratory Testing

Molecular genetic panels are available that evaluate for both most common and rarer skeletal dysplasias

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 6 weeks of birth. Some skeletal dysplasias are detected prenatally, whereas 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

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

Epidemiology

  • Incidence for all syndromes – 1/5,000
    • Hypochondroplasia – 1/15,000-40,000
    • Achondroplasia – 1/25,000

Clinical Presentation

  • Symptoms may include but are not limited to
    • Shortening of bones of the arms and legs >3 standard deviations below the mean (rhizomelia)
    • Head circumference >75th percentile
    • Bowed or fractured bones
    • Irregular, thickened, or thin bones
    • Undermineralization of 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 (36 Genes), Fetal 2012010
Method: Massively Parallel Sequencing

Limitations 

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

Large deletions and duplications in COMP, HSPG2, and TRPV4 genes are not detected

Not all variants in 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 (36 Genes) 2012015
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Limitations 

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

Large deletions and duplications in COMP, HSPG2, and TRPV4 genes are not detected

Not all variants in 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 

Diagnostic errors can occur due to rare sequence variations

Variants other than c.1138G>A and c.1138G>C will not be detected

Refer to Additional Technical Information document for further content

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

Limitations 

Diagnostic errors can occur due to rare sequence variations

Variants other than c.1138G>A (G380R) and c.1138G>C (G380R) will not be detected

Refer to Additional Technical Information document for further content

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

Limitations 

Variants other than FGRF3 c.1620C>A and c.1620C>G will not be detected

Diagnostic errors can occur due to rare sequence variations

Refer to Additional Technical Information document for further content

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

Limitations 

Diagnostic errors can occur due to rare sequence variations

Variants other than those targeted in FGFR3 will not be detected

Analytic sensitivity may be compromised by rare primer site mutations

Refer to Additional Technical Information document for further content

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

Limitations 

Diagnostic errors can occur due to rare sequence variations

Variants other than those targeted in FGFR3 will not be detected

Analytic sensitivity may be compromised by rare primer site mutations

Refer to Additional Technical Information document for further content

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 MB, Bellus GA, Nikkel SM, Tiller GE. Hypochondroplasia. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews. Seattle, WA: University of Washington, 1993-2015. [Last updated Sep 2013; Accessed: Jul 2017]

Friez MJ, Wilson JA. 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

Heuertz S, Le Merrer M, Zabel B, Wright M, Legeai-Mallet L, Cormier-Daire V, Gibbs L, Bonaventure J. Novel FGFR3 mutations creating cysteine residues in the extracellular domain of the receptor cause achondroplasia or severe forms of hypochondroplasia. Eur J Hum Genet. 2006; 14(12): 1240-7. 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. Seattle, WA: University of Washington, 1993-2015. [Last updated Sep 2013; Accessed: Jul 2017]

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. Seattle, WA: University of Washington, 1993-2015. [Last updated Feb 2012; Accessed: Jul 2017]

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

Medical Reviewers

Last Update: August 2017