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Campomelic Dysplasia

Synonyms: Campomelic Dwarfism, Campomelic Syndrome, Camptomelic Dwarfism, Camptomelic Dysplasia

, MD, , PhD, and , MD.

Author Information

Initial Posting: ; Last Update: May 9, 2013.

Estimated reading time: 18 minutes


Clinical characteristics.

Campomelic dysplasia (CD) is a skeletal dysplasia characterized by distinctive facies, Pierre Robin sequence with cleft palate, shortening and bowing of long bones, and clubfeet. Other findings include laryngotracheomalacia with respiratory compromise and ambiguous genitalia or normal female external genitalia in most individuals with a 46,XY karyotype. Many affected infants die in the neonatal period; additional problems identified in long-term survivors include short stature, cervical spine instability with cord compression, progressive scoliosis, and hearing impairment.


The diagnosis of CD is usually based on clinical and radiographic findings. Molecular genetic testing of SOX9, the only gene in which pathogenic variants are known to cause CD, detects pathogenic variants or chromosome rearrangements in approximately 95% of affected individuals.


Treatment of manifestations: Care of children with cleft palate by a craniofacial team using routine measures; care of clubfeet and hip subluxation using standard protocols; surgery as needed for cervical vertebral instability and progressive cervicothoracic kyphoscoliosis that compromises lung function. In persons with a 46,XY karyotype and undermasculinization of the genitalia, the gonads should be removed because of the increased risk for gonadoblastoma. Hearing aids for those with hearing impairment.

Surveillance: Annual monitoring of growth and spinal curvature.

Genetic counseling.

CD is inherited in an autosomal dominant manner. To date, most probands have CD as the result of a de novo pathogenic variant in SOX9; thus, parents of probands are not typically affected. However, a few adults have been diagnosed with CD following the birth of an affected child. Recurrence in sibs has occurred and somatic and germline mosaicism have been reported. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family is known.

GeneReview Scope

Campomelic Dysplasia: Included Phenotype
  • Acampomelic campomelic dysplasia

For synonyms and outdated names see Nomenclature.


Clinical Diagnosis

The diagnosis of campomelic dysplasia (CD; derived from the Greek for "bent limb") can usually be clearly established based on clinical and radiographic findings. Although no single clinical feature is obligatory, the radiographic features are consistent and are the most reliable diagnostic clues.

Clinical features

  • Relatively large head
  • Pierre Robin sequence with cleft palate
  • Flat face
  • Laryngotracheomalacia
  • Respiratory distress
  • 11 pairs of ribs
  • Ambiguous genitalia or normal female external genitalia in an individual with a 46,XY karyotype
  • Dislocatable hips
  • Short bowed limbs (lower limbs more frequently than upper limbs)
  • Pretibial skin dimples (bowing of the lower leg is often associated with a skin dimple over the apex of curve)
  • Clubfeet

Note: Bowing of the limbs, the feature that gave the disorder its name, is not an obligatory finding. When the limbs are not bowed, the term "acampomelic campomelic dysplasia" is used.

Radiographic findings (Figure 1, Figure 2, Figure 3)

Figure 1. . Cervical spine changes (i.

Figure 1.

Cervical spine changes (i.e., abnormal AP curvature and anterior dislocation of C2 on C3) (arrow) in a boy age 11 months with classic campomelic dysplasia

Figure 2.

Figure 2.

Molecularly confirmed "acampomelic" campomelic dysplasia A. Tracheostomy tube is in place and the scapulae are markedly hypoplastic (arrows).

Figure 3. . Classic radiographic features of campomelic dysplasia in a 24-week fetus.

Figure 3.

Classic radiographic features of campomelic dysplasia in a 24-week fetus. Note cervical spine abnormalities, hypoplastic thoracic vertebral pedicles, scapular hypoplasia, narrow iliac wings, bowing of the femora and the tibiae, and clubfeet.

  • Cervical spine anomalies (variable, often kyphosis) (Figure 1)
  • Scapular hypoplasia (Figure 2A, Figure 3)
  • Hypoplastic thoracic vertebral pedicles (Figure 3)
  • 11 pairs of ribs
  • Scoliosis or kyphoscoliosis
  • Vertically oriented narrow iliac wings (Figure 2B)
  • Bowed femora and/or tibiae (occasionally upper limb) (Figure 3)


Cytogenetic testing. In approximately 5% of individuals with CD, routine karyotype analysis may identify one of the following:

Note: In rare cases, the translocation may be familial; thus, parental karyotypes should be analyzed when an abnormality is found in the proband.

Molecular Genetic Testing

Gene. SOX9 is the only gene in which pathogenic variants are known to cause CD [Meyer et al 1997, Pfeifer et al 1999, Leipoldt et al 2007].

Table 1.

Molecular Genetic Testing Used in Campomelic Dysplasia

Gene 1MethodVariants DetectedVariant Detection Frequency by Method 3
SOX9Sequence analysis 4Coding regions and splice variants~90%
Deletion/duplication analysis 5Partial- or whole-gene deletions 6, 7~2% 8

See Molecular Genetics for information on allelic variants.


The ability of the test method used to detect a pathogenic variant that is present in the indicated gene


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), array CGH and chromosomal microarray (CMA) that includes this gene/chromosome segment.


Depending on the method employed by the laboratory, the extent of the deletion can be more or less precisely defined.


SOX9 duplication causes XX sex reversal only.


Partial- and whole-gene SOX9 deletions in individuals with CD and a normal karyotype [Olney et al 1999, Pop et al 2004, Smyk et al 2007]

Testing Strategy

To confirm/establish the diagnosis in a proband

  • Clinical and radiologic features can strongly suggest the diagnosis of CD.
  • Single-gene testing. One strategy for molecular diagnosis of a proband suspected of having CD is molecular genetic testing of SOX9. It is appropriate to initiate karyotype and sequence analysis at the time of clinical and radiographic diagnosis, followed by deletion analysis if the first two analyses are negative.
  • Multigene panel. Another strategy for molecular diagnosis of a proband suspected of having CD is use of a multigene panel. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Prenatal testing. Prenatal testing for pregnancies at risk as a result of a mildly affected parent or potential somatic or germline mosaicism requires prior identification of the pathogenic variant in a previously affected child or the mildly affected parent.

Preimplantation genetic testing for pregnancies at risk as a result of a mildly affected parent or potential somatic or germline mosaicism requires prior identification of the pathogenic variant in a previously affected child or the mildly affected parent.

Clinical Characteristics

Clinical Description

Campomelic dysplasia (CD) is sometimes identified on prenatal ultrasound examination but may escape detection until after birth if the limbs are not bowed.

Many newborns with CD die shortly after birth secondary to respiratory insufficiency. In comparison with other lethal skeletal dysplasias, the cause of death in CD is not related to thoracic cage hypoplasia but rather airway instability (tracheobronchomalacia) or cervical spine instability. Nonetheless, a number of infants with CD have survived the neonatal period [Mansour et al 2002].

The facies in CD resembles the type 2 collagen disorders, such as Stickler syndrome, with marked micrognathia. In the newborn period, the midface is hypoplastic and the eyes are prominent. Relatively large head size (in comparison to total body length) is common. The limbs are short with body length often below the third percentile. Bowing of the limbs is often present but not obligate.

Approximately 75% of individuals with CD who have a 46,XY karyotype have either ambiguous external genitalia or normal female external genitalia. The internal genitalia are variable, often with a mixture of müllerian and wolffian duct structures.

Given the relatively small number of survivors described in the literature, it is difficult to generalize about the natural history. The following have been observed:

  • Intellect is normal.
  • Height is variably affected. Some newborns have significant short stature whereas others are within the normal range.
  • When present, scoliosis is usually progressive, contributes to the short stature, and may result in neurologic signs and symptoms.
  • Vertebral hypoplasia or malformation, particularly of the cervical spine, may lead to neurologic signs of cord compression unless surgically stabilized.
  • Hearing impairment/loss in some can be significant enough to require hearing aids.
  • A variety of congenital heart defects have been reported in a minority of cases.
  • Histologic pancreatic abnormalities have been described in three newborns who died at term from CD; however, pancreatic dysfunction has not been seen in survivors with CD [Piper et al 2002].

Ischiopubic-patella syndrome (IPP). The phenotypic description of IPP is limited to findings in the pelvis and legs including hypoplastic patellae, hypoplastic lesser trochanters, and defective ischiopubic ossification. In several persons with this diagnosis, pathogenic variants of SOX9 or cytogenetic alterations in the vicinity of SOX9 have been reported [Mansour et al 2002]. It is now recognized that individuals with IPP have a mild form of campomelic dysplasia with survival to adulthood.

Genotype-Phenotype Correlations

Clear-cut genotype-phenotype correlations are not readily apparent in CD [Meyer et al 1997]. However, correlations of some degree are observed in those with the following two findings:


Pathogenic variants in the SOX9 coding region are completely penetrant.

Breakpoints at long distance from SOX9 may not be completely penetrant.


The name "campomelic dysplasia," first proposed by Maroteaux in 1971, is derived from the Greek for "bent limb."

Although the name "campomelic dysplasia" is well established, it can lead to confusion as not every child with CD has bowed limbs (ACD) and, conversely, most children with bowed limbs do not have CD but another of the frequent genetic disorders of bone, including osteogenesis imperfecta (OI), hypophosphatasia, cartilage-hair hypoplasia, and others (see Differential Diagnosis).


No reliable data exist regarding the prevalence of CD. The authors estimate it to be in the range of 1:40,000 to 1:80,000.

Differential Diagnosis

In the prenatal period, the most common error is to confuse osteogenesis imperfecta (OI) types 2 or 3 with campomelic dysplasia (CD). As OI is more common than CD, it is a more frequent cause of bowed limbs on antenatal ultrasound examination.

Other genetic disorders of the skeleton with prenatal limb bowing to consider include hypophosphatasia, cartilage hair hypoplasia, and even thanatophoric dysplasia.

After birth, the differential diagnosis is mainly spondyloepiphyseal dysplasia congenita (SEDC; COL2A1 pathogenic variants) because of the facial features, cleft palate, and short limbs. The milder type 2 collagenopathy, Stickler syndrome, may also be considered in the differential as the facial features are very similar. Radiographs distinguish between these conditions. See also Type 2 Collagen Disorders Overview.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with campomelic dysplasia (CD), the following investigations are recommended:

  • Karyotype analysis to identify abnormalities involving the SOX9 locus on 17q24.3-q25.1 and especially in phenotypic females to identify those with a 46,XY karyotype
  • Full skeletal survey including views of the cervical spine to identify cervical vertebral abnormalities
  • Hearing screening
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

In children with CD and cleft palate, care by a craniofacial team and surgical closure are recommended.

In individuals with a 46,XY karyotype and female genitalia, gonadectomy is recommended because of the increased risk of gonadoblastoma. (No data regarding the appropriate age for this procedure are available.)

Most survivors with CD require orthopedic care. Clubfeet require surgical correction. The hips should be checked for luxation.

Cervical fusion surgery is sometimes needed for cervical vertebral instability resulting from vertebral malformations.

Surgery is often required in childhood for progressive cervicothoracic kyphoscoliosis that compromises lung function [Thomas et al 1997]. Bracing is usually not helpful.

Prevention of Secondary Complications

Risk associated with use of anesthesia prior to imaging or surgery. If a cervical spine abnormality is identified, special care should be exercised for any surgical procedure.


Most long-term survivors require annual monitoring of growth and spinal curvature by clinical and radiographic measurements.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Campomelic dysplasia (CD) is inherited in an autosomal dominant manner but is most commonly the result of a de novo dominant pathogenic variant. Rarely, CD is the result of a chromosome rearrangement (e.g., deletion, de novo translocation, or inversion) upstream to or involving SOX9.

Risk to Family Members

Parents of a proband

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents: if a non-mosaic parent of the proband is affected, the risk to the sibs is 50%.
  • Somatic mosaicism for the SOX9 pathogenic variant in an unaffected parent [Wagner et al 1994, Gentilin et al 2010] and for a SOX9 deletion in a mildly/minimally affected father of two affected children has been reported [Smyk et al 2007]. An unaffected father of three affected children had germline, but not somatic, mosaicism [Cameron et al 1996].
  • Because parental mosaicism has been documented, the sibs of a proband are at an estimated 2%-5% risk even if the pathogenic variant found in the proband cannot be detected in the DNA of either parent.
  • The risk to sibs of a proband with an unbalanced chromosome constitution depends on the chromosome findings in the parents:
    • If neither parent has a chromosome rearrangement, the risk to sibs is negligible.
    • If a parent has a balanced chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement and the possibility of other variables.

Offspring of a proband. Many individuals with CD do not survive infancy; some, however, have reproduced.

  • Each child of an individual with a non-mosaic SOX9 pathogenic variant has a 50% chance of inheriting the pathogenic variant.
  • The risk to children of an individual with a chromosome rearrangement involving SOX9 depends on the cytogenetic abnormality.

Other family members of a proband. Because CD typically occurs as a de novo pathogenic variant, other family members of a proband are not at increased risk. If a parent has a balanced chromosome rearrangement, his or her family members are at risk and can be offered chromosome analysis.

Related Genetic Counseling Issues

Family planning. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

A priori high-risk pregnancies. Prenatal testing for pregnancies at increased risk as a result of parental mosaicism or the presence of a SOX9 pathogenic variant in a parent is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~16-18 weeks' gestation) or chorionic villus sampling (usually performed at ~10-12 weeks' gestation). The pathogenic allele of an affected family member should be identified before prenatal testing can be performed.

Similarly, prenatal testing for pregnancies at increased risk for a familial chromosome rearrangement is possible by chromosome analysis of fetal cells obtained by amniocentesis or CVS.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

A priori low-risk pregnancies. Routine prenatal ultrasound examination may identify skeletal findings such as increased nuchal translucency, micrognathia, short bowed limbs, and hypoplastic scapulae that raise the possibility of CD in a fetus not known to be at increased risk [Schramm et al 2009, Gentilin et al 2010]. Once a skeletal dysplasia is identified prenatally, it is often difficult to establish the diagnosis based on ultrasound findings alone. Consideration of molecular genetic testing for a SOX9 pathogenic variant in these situations is appropriate only when specific features of CD have been identified; however, such testing is usually best deferred until after pregnancy termination or delivery when a diagnosis can be confirmed by radiographs.

Preimplantation genetic testing may be an option for some families in which the pathogenic variant or familial chromosome rearrangement has been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • MAGIC Foundation
    4200 Cantera Drive #106
    Warrenville IL 60555
    Phone: 800-362-4423 (Toll-free Parent Help Line); 630-836-8200
    Fax: 630-836-8181
  • My46 Trait Profile
  • Human Growth Foundation (HGF)
    997 Glen Cove Avenue
    Suite 5
    Glen Head NY 11545
    Phone: 800-451-6434 (toll-free)
    Fax: 516-671-4055
  • Little People of America, Inc. (LPA)
    250 El Camino Real
    Suite 201
    Tustin CA 92780
    Phone: 888-572-2001 (toll-free); 714-368-3689
    Fax: 714-368-3367
  • Skeletal Dysplasia Group Freiburg
    University Hospital Freiberg, Centre for Pediatrics and Adolescent Medicine
    Mathildenstrasse 1
    Freiburg 79106
    Phone: 001-497-6127 0-4363
  • International Skeletal Dysplasia Registry
    615 Charles E. Young Drive
    South Room 410
    Los Angeles CA 90095-7358
    Phone: 310-825-8998
    Fax: 310-206-5266
  • Skeletal Dysplasia Network, European (ESDN)
    Institute of Genetic Medicine
    Newcastle University, International Centre for Life
    Central Parkway
    Newcastle upon Tyne NE1 3BZ
    United Kingdom

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Campomelic Dysplasia: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
SOX917q24​.3Transcription factor SOX-9SOX9 databaseSOX9SOX9

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Campomelic Dysplasia (View All in OMIM)

608160SRY-BOX 9; SOX9

Molecular Pathogenesis

Pathogenic variants within the SOX9 coding region lead to an altered SOX9 protein with impaired activity to function as a transcription factor. In contrast, chromosomal rearrangements (translocations, inversions) with breakpoints as far as approximately 1 Mb upstream of SOX9 as well as SOX9 upstream deletions leave the SOX9 coding region intact but most likely lead to reduced expression of SOX9 by interrupting its extended cis-regulatory domain. In either case, SOX9 function as a developmental regulator is compromised.

SOX9 is a proven key regulator at various steps of chondrocyte differentiation, regulating expression of the collagen genes COL2A1 and COL11A2 as well as of CD-RAP and ACAN (also known as AGGRECAN) [Akiyama & Lefebvre 2011].

  • Regulation of COL2A1 by SOX9 may explain some of the phenotypic overlap of campomelic dysplasia (CD) with spondyloepiphyseal dysplasia congenita.
  • SOX9 functions as a testis-determining gene downstream of SRY, inducing the formation of Sertoli cells and production of the anti-müllerian hormone AMH (also known as MIS) [Vidal et al 2001]. Of note, duplication or deletion of a common region ~0.5 Mb upstream of SOX9 causing isolated disorders of sexual development in the absence of any CD symptoms have been reported [Benko et al 2011, Cox et al 2011, Vetro et al 2011].
  • Studies in the mouse provide evidence that the murine ortholog of human SOX9 also plays a role during formation of the pancreas, heart, gut, and inner ear.

Thus, the wide spectrum of pathologic symptoms seen in CD including the skeletal defects, XY sex reversal, pancreatic defects (size reduction of islets of Langerhans and reduced insulin secretion), heart defects, and sensorineural and conductive hearing impairment can be attributed directly to impaired ability of the pleiotropic developmental regulator SOX9 to activate target genes during organogenesis.

Gene structure. The coding sequence of 5.4-kb SOX9 is distributed over three exons separated by introns of 0.9 kb and 0.6 kb. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. There are no known benign variants at the amino acid level. At the nucleotide level, one frequent synonymous variant within codon 169 leaves the encoded amino acid histidine unchanged (see Table 2).

Table 2.

SOX9 Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias 1)
Predicted Protein Change
(Alias 1)
p.(=) 2

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.


Variant designation that does not conform to current naming conventions. For SOX9 these numbers correspond to the first base position of the reference sequence NM_000346​.3.


The designation p.(=) means that the protein has not been analyzed but no change is expected.

Pathogenic variants. Numerous pathogenic nonsense and frameshift variants of SOX9 are distributed over the entire coding region; there is no mutational hot spot with the exception of the recurrent pathogenic nonsense variant p.Tyr440Ter [Pop et al 2005]. Pathogenic missense variants cluster in the HMG domain (a DNA-binding domain) or in the dimerization domain and are occasionally recurrent. A few splice variants and deletions of part of SOX9 or all of SOX9 and of flanking genes have been described [Olney et al 1999, Pop et al 2004, Smyk et al 2007]. Translocation and inversion breakpoints that interrupt the 1-Mb cis-regulatory domain upstream of SOX9 are all unique but concentrate within a proximal and a distal breakpoint cluster [Leipoldt et al 2007]. Approximately 90% of the pathogenic variants are found in the SOX9 coding region and approximately 5% are SOX9 deletions, translocations, or inversions upstream of SOX9.

Normal gene product. The SOX9 protein consists of 509 amino acids and functions as a transcription factor. Like all SOX proteins, it contains a DNA-binding domain (the HMG domain) encompassing 79 amino acids (residues 103-181) by which it binds to regulatory sites at target genes. The activation of these target genes is mediated by a C-terminal transactivation (TA) domain (residues 402-509) and an adjacent auxiliary TA domain (residues 339-379) [McDowall et al 1999]. A fourth functionally relevant domain is a dimerization domain, located N-terminal to the HMG domain [Bernard et al 2003, Sock et al 2003].

Abnormal gene product. Pathogenic nonsense and most frameshift variants in SOX9 predict a prematurely truncated protein that misses all or part of the TA domain and, when the pathogenic variant is located toward the N terminus, all or part of the HMG domain as well. Resulting mutated proteins that are missing both domains constitute loss-of-function alleles, whereas mutated proteins retaining the HMG domain may function as dominant-negative alleles. More C-terminally located frameshift variants are predicted to encode an extended SOX9 protein with a mutated C terminus in place of the TA domain. Pathogenic missense variants are exclusively located in the HMG domain, affecting the DNA-binding capacity of SOX9 [Meyer et al 1997, McDowall et al 1999], or in the dimerization domain, causing loss of SOX9 dimer formation [Bernard et al 2003, Sock et al 2003].


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Chapter Notes

Revision History

  • 9 May 2013 (me) Comprehensive update posted live
  • 31 July 2008 (cg) Review posted live
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