Skeletal Dysplasias – diagnostic guidance

Denise P. Cavalcanti, PhD

The Osteochondrodysplasias or Skeletal Dysplasias comprise a group of inherited genetic diseases that generally produce short stature and are associated with gene mutations related to the growth and development of chondro-bone tissue. Although rare, the skeletal dysplasias contributes to infant morbidity and mortality. Currently, there are about 300 different types of skeletal dysplasias, about a third of which are early recognition, during the prenatal or neonatal period [1, 2]. Among those that manifest early, approximately 50 different conditions are lethal or semi-lethal.

Although the vast majority are very rare, in total they affect about 3 individuals per 10,000 births [2, 3]. This prevalence, however, is still an underestimate considering that the majority of epidemiological studies on skeletal dysplasias are carried out from newborn populations, leaving out those of later manifestation. Currently the vast majority have known molecular bases and, as the vast majority of them are associated with gene mutations, the etiological definition can be made using genetic sequencing techniques in most patients [1].

Usually the suspicion of the skeletal dysplasias occurs in the following situations:

  1. In the perinatal period due to shortening of the long bones detected in the prenatal ultrasound examination or at birth due to reduced length and/or body disproportion;
  2. In childhood due to short stature, often, but not always, disproportionate.

In both situations, the first examination to be ordered is a simple skeletal radiograph. It is, in several situations, sufficient to define the specific diagnosis (ex: Thanatophoric Dysplasia, Campomelic Dysplasia, McKusick’s Dysplasia). In most patients, skeletal radiography serves to classify the skeletal dysplasias into one or more possible groups (eg, spondyloepimetaphyseal dysplasia, osteopetrosis, metaphyseal dysplasia).

Although the most frequent of DESQ, Achondroplasia, is very homogeneous from a clinical, radiological and molecular point of view, for most other DESQ heterogeneity, especially molecular, is the rule [1].

Why to do the molecular study of a patient with a clinical-radiological diagnosis of skeletal dysplasias?

Even though some skeletal dysplasias can be well diagnosed from the radiological pattern of alterations observed in the examination of the skeleton, the identification of the mutation may, in some situations, allow the orientation of clinical management due to already known genotype-phenotype correlations [4, 5] . Even if there is no known genotype-phenotype correlation, continuing to investigate the molecular bases can lead to some correlation, since the universe of patients and a known molecular diagnosis is still small. In other patients, for whom the radiological study is not sufficient to define a specific type of the skeletal dysplasias, molecular investigation is mandatory.

What are the genetic tests used in the investigation?

Genetic sequencing is the main test. The classic Sanger sequencing can be used for the etiological confirmation of the skeletal dysplasias previously diagnosed by the clinical-radiological picture and for which the associated gene has some hot spot region (ex: Achondroplasia associated with the FGFR3 gene, Hall-type leptodactyl spondylepimetaphyseal dysplasia associated with gene KIF22), or for those conditions in which the gene is small and thus easy to analyze by this type of sequencing (ex: Diastrophic Dysplasia associated with the DTDST/SLC26A2 gene).

For skeletal dysplasias with very large genes and, in general, with “private” mutations (ex: Congenital Spondyloepiphyseal Dysplasia, associated with the COL2A1 gene, Larsen’s Syndrome associated with the FLNB gene), Sanger sequencing is not viable, so the technique of choice is the Next-Generation Sequencing (NGS), due to the ease/possibility of studying many genes including several patients at the same time with a reduction in costs and time in performing the exam. With NGS techniques, it is possible to specifically study skeletal dysplasias with a molecular basis known through a panel of target genes or to analyze the exome or even the individual’s genome.

The performance of the NGS with a panel of genes will be all the better the more precise the clinical-radiological orientation is, in other words the ideal situation is when the clinical-radiological diagnosis guides the molecular investigation [6]. Although the NGS with a gene panel is not the indicated technique to find new genes associated with already known phenotypes, the great genetic heterogeneity of the skeletal dysplasias can lead to the identification of new associations with the use of panels [7, 8].

Exome and genome techniques are indicated in front of an NGS with a negative gene panel or directly if the clinical-radiological evaluation of the patient by a skeletal dysplasia specialist suggests an unprecedented condition.

Particular situations are those conditions for which there is a possibility of large deletions in the target gene being frequent, also requiring molecular research through arrays. For example, in Campomelic Dysplasia associated with the SOX9 gene, it is estimated that about 5% of patients who present negative SOX9 sequencing may be carriers of large upstream deletions and, for this, investigation by means of array or other methods would be necessary. investigation of great deletions.

In summary, from the suspicion of skeletal dysplasia, a simple skeletal radiograph should be the first exam to be ordered and the interpretation of that exam must be done by a skeletal dysplasia specialist for most of these conditions. Molecular investigation, usually by means of genetic sequencing, is usually the main test for the etiological diagnosis, as a rule it can be done with NGS with a gene panel, or directly by exome analysis when it is the case of a picture with a genetic heterogeneity or with a high possibility of being an unprecedented phenotype.

Finally, it is worth mentioning here the website for the diagnosis of skeletal dysplasias, a tool that can be used by doctors or family members of patients with a suspected DESQ [].

About the author:

Denise Pontes Cavalcanti, is graduated in Medicine from the Federal University of Paraíba, residency in Medical Genetics at the Ribeirão Preto Medical School (USP), master’s degree in Biological Sciences (USP) and doctorate in Medical Sciences (Genetics) by Unicamp, where she is currently an associate professor in the Department of Medical Genetics.


[1] Mortier G, Cohn DH, Cormier-Daire V, Hall C, Krakow D, Mundlos S, Nishimura G, Rovertson S, Sangiorgi L, Savarirayan R, Sillence D, Superti-Furga A, Unger S, Warman ML. Am J Med Genet 2019 179:2393-2419. doi: 10.1002/ajmg.a.61366

[2] Barbosa-Buck CO, Orioli IM, da Graça Dutra M, Lopez-Camelo J, Castilla EE, Cavalcanti DP. Clinical epidemiology of skeletal dysplasias in South America. Am J Med Genet A. 2012; 158A:1038-45. doi: 10.1002/ajmg.a.35246. 

[3] Stevenson DA, Carey JC, Byrne JLB, Srisukhumbowornchai S, Feldkamp ML. Analysis of Skeletal Dysplasias in the Utah Population. Am J Med Genet 2012 158A:1046-54. doi: 10.1002/ajmg.a.35327. 

[4] Silveira KC, Bonadia LC, Superti-Furga A, Bertola DR, Jorge AA, Cavalcanti DP. Six Additional Cases of SEDC Due to the Same and Recurrent R989C Mutation in the COL2A1 Gene–The Clinical and Radiological Follow-Up. Am J Med Genet 2017 167A:894-901. doi: 10.1002/ajmg.a.36954. 

[5] Baujat G, Huber C, El Hokayem J, Caumes R, Thanh CN, David A, DElezoiDE AL, Dieux-Coeslier A, Estournet B, Francannet C, Kayirangwa H, Lacaille F, Le Bourgeois M, Martinovic J, Salomon R, Sigaudy S, Malan V, Munnich A, Le Merrer M, Le Quan Sang QH, Cormier-Daire V. Asphyxiating thoracic dysplasia: clinical and molecular review of 39 families. J Med Genet 2013 50:91–98. doi:10.1136/jmedgenet- 2012-101282 

[6] Cavalcanti DP, Silveira KC, Kanazawa TY, Silveira C, Fenz TA, Lacarrubba-Flores MDJ, Moreno CA. High success in molecular studies among 215 skeletal dysplasias in Brazil. Oral presentation in the 13th ISDS (International Skeletal Dysplasia Society) MEETING, BRUGES 2017. 

[7] Silveira KC, Moreno CA, Cavalcanti DP. Beemer-Langer syndrome is a ciliopathy due to biallelic mutations in IFT122. Am J Med Genet A 2017 173:1186-1189. Doi: 10.1002/ajmg.a.38157. 

[8] Medina TMN, Sandoval R, Oliveira G, Silveira KC, Cavalcanti DP, Pogue R. Pathogenic variants in the TRIP11 gene cause a skeletal dysplasia spectrum from odontochondrodysplasia to achondrogenesis 1A. Am J Med Genet 

[9] Unger S, Scherer G, Superti-Furga, A. Campomelic dysplasia. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews. 

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