Skeletal Dysplasias

Skeletal dysplasias, also known as osteochondrodysplasias, are a heterogeneous group of more than 450 disorders characterized by abnormal growth of cartilage or bone.  Some skeletal dysplasias manifest in utero, whereas others are not detected until after birth or in later childhood. Many skeletal dysplasias are lethal before or within 6 weeks of birth, while others do not affect lifespan. Ultrasound findings are often the initial indicators of a skeletal dysplasia, but genetic testing is essential for definitive diagnosis, which can improve clinical care, inform management and treatment decisions,  and assist in determining familial risk of recurrence. Genetic tests, which can be performed prenatally or postnatally, are available for individual genes or as a panel of genes. Panel testing is especially helpful when clinical findings suggest more than one type of skeletal dysplasia, as ordering several individual gene tests can be costly and time consuming. Single-gene tests are appropriate when the causative variant has been previously identified in an affected parent or family member or when a patient’s indications are very specific for a certain type of skeletal dysplasia.

Quick Answers for Clinicians

What clinical features suggest a skeletal dysplasia?

Signs and symptoms are dependent upon the specific skeletal dysplasia, but common findings may include 

  • Shortening of the 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 bones
  • Abnormal ribs and/or a small chest circumference
  • Polydactyly
When is prenatal or postnatal testing appropriate?

Prenatal testing should be considered when ultrasound findings are suggestive of a skeletal dysplasia, when a previous pregnancy was affected, or when one or both parents are affected. Postnatal testing is appropriate at any time after delivery when a skeletal dysplasia is suspected (ie, in stillborns, newborns, children, and adults).

When should single-gene tests as opposed to a panel be ordered?

Targeted testing for a specific gene variant can be ordered when a previously affected family member was tested and the causative variant was identified. Testing for a specific skeletal dysplasia (eg, achondroplasia) should be performed when the ordering provider desires molecular confirmation of a suspected clinical diagnosis. A panel should be ordered when the differential diagnosis includes more than one type of skeletal dysplasia, as it can be costly and time consuming to order several individual gene tests simultaneously or consecutively.

What is the benefit of prenatal molecular testing for skeletal dysplasias?

Only 40% of affected fetuses presenting prenatally are correctly identified by ultrasound alone,  emphasizing the importance of diagnostic confirmation by genetic testing. Identification of the genetic etiology of a skeletal dysplasia can help optimize clinical care for both mother and newborn,  such as mode and place of delivery. Developing a delivery and resuscitation plan with clinical geneticists, neonatologists, obstetricians, and anesthesiologists can improve postnatal management of the newborn. 

Indications for Testing

Molecular testing for skeletal dysplasias is useful to  

  • Confirm a clinical diagnosis based on prenatal or postpartum findings suggestive of a skeletal dysplasia
  • Help exclude a skeletal dysplasia when there is suspicion of nonaccidental injury
  • Determine specific causative variant(s) in affected adults planning a pregnancy
  • Provide accurate genetic counseling, recurrence risk, and prenatal testing options

Laboratory Testing

Diagnosis

Molecular analysis, in addition to clinical assessment and radiography, is recommended for definitive diagnosis of a skeletal dysplasia in affected individuals and can be performed prenatally or postnatally. Such testing can also determine the mode of inheritance and risk of recurrence in future pregnancies. Targeted testing of variants identified in an affected child may be recommended in unaffected parents to confirm whether the identified variants are on opposite chromosomes. The genetic cause has been determined for more than 350 of the over 450 known skeletal dysplasias.  A list of tested genes and their corresponding disorder(s) can be found in the Skeletal Dysplasia Panel Test Fact Sheet.

Panel Testing

Because some skeletal disorders are due to variants in more than one gene and because one clinical feature may not be specific to a certain skeletal dysplasia, a multigene panel is often recommended to identify the pathogenic variant(s). Panels are especially useful when a differential diagnosis includes more than one type of skeletal dysplasia. Panel testing can also reduce the time to diagnosis and, therefore, can be more cost- and time-efficient than testing individual genes. 

Disorder-Specific Testing

Testing for a single condition may be appropriate when there is high clinical suspicion for a particular skeletal dysplasia. Otherwise, panel testing is preferred, as testing for a specific disorder targets only the particular variants known to cause the condition. For example, disorder-specific testing is offered for the following three common skeletal dysplasias caused by FGFR3 gene variants.

Achondroplasia is the most common nonlethal skeletal dysplasia in humans and is characterized by short stature with disproportionately short arms and legs, a large head, and normal intelligence. Although individuals with achondroplasia have increased risk for death in infancy from compression of the spinal cord and/or upper airway obstruction, most have a normal lifespan. Two FGFR3 gene variants, c.1138G>A and c.1138G>C, are causative for >99% of cases. Achondroplasia is autosomal dominant, and 80% of cases are due to de novo variants. 

Hypochondroplasia is characterized by short stature, stocky build, a large head, shortening of the proximal or middle segments of the extremities, short, broad hands and feet, limitation of elbow extension, and mild joint laxity. It is an autosomal dominant condition, usually arising from a de novo mutation, with 70% of cases resulting from an adenine or guanine substitution for cytosine at nucleotide 1620 in the FGFR3 gene. Clinical features are not evident in infancy but become apparent in childhood.

Thanatophoric dysplasia (TD) is characterized by micromelia, macrocephaly, short ribs, and a narrow thorax. It is divided into TD type 1 (bowed femurs) and TD type 2 (straight femurs and a cloverleaf skull).  Death usually occurs from respiratory insufficiency or brain stem compression within hours or days of birth. There are 13 pathogenic variants in the FGFR3 gene known to be causative for TD.

ARUP Lab Tests

Panel Tests

Confirm diagnosis of a skeletal dysplasia in a symptomatic fetus or determine if a fetus that is at risk for a skeletal dysplasia based on a positive family history is affected

Confirm diagnosis of a skeletal dysplasia in a symptomatic individual or determine the causative gene variant(s) in an affected individual

Disorder-Specific Tests

Confirm clinical or suspected diagnosis of achondroplasia

Confirm diagnosis in at-risk fetuses or those with ultrasonographic features consistent with achondroplasia

Confirm diagnosis of hypochondroplasia in individuals with clinical or radiologic evidence of the condition

Confirm clinical diagnosis of TD type 1 or type 2

Confirm diagnosis in fetuses with ultrasonographic features consistent with TD type 1 or 2

Targeted Sequencing

Recommended test for a known familial sequence variant previously identified in a family member

Test Fact Sheet(s)

Medical Experts

Contributor

Ji

Yuan Ji, PhD, DABCP, FACMG
Associate Professor of Clinical Pathology, University of Utah
Medical Director, Molecular Genetics and Genomics, Pharmacogenomics, ARUP Laboratories
Contributor

References

Additional Resources
  • GeneReviews - Hypochondroplasia

    Bober MB, Bellus GA, Nikkel SM, et al. Hypochondroplasia. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last Update: Sep 2013; Accessed: Feb 2020]

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