• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Campomelic Dysplasia

Synonyms: Campomelic Dwarfism, Campomelic Syndrome, Camptomelic Dwarfism, Camptomelic Dysplasia. Includes: Acampomelic Campomelic Dysplasia

, MD, , PhD, and , MD.

Author Information
, MD
ESDN Clinical and Radiological Review Coordinator
Medical Genetics Service
Centre Hospitalier Universitaire Vaudois
Lausanne, Switzerland
, PhD
Head, Clinical and Experimental Molecular Genetics Laboratory
Institute of Human Genetics
University of Freiburg
Freiburg, Germany
, MD
Leenaards Professor of Pediatrics, University of Lausanne
Centre Hospitalier Universitaire Vaudois
Lausanne, Switzerland

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

Summary

Disease 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 club feet. 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.

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

Management. Treatment of manifestations: Care of children with cleft palate by a craniofacial team using routine measures; care of club feet and hip subluxation using standard protocols; surgery as needed for cervical vertebral instability and progressive cervico-thoracic 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 mutation 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 disease-causing mutation in the family is known.

Diagnosis

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
  • Eleven 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)
  • Club feet

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

Figure

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

Figure 2. Mutation-proven “acampomelic” campomelic dysplasia
A. Tracheostomy tube is in place and the scapulae are markedly hypoplastic (arrows).
B. Vertically oriented narrow iliac wings
C. Straight femora and (more...)

Figure 3

Figure

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 club feet. (more...)

  • 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)

Testing

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 mutations are known to cause CD [Meyer et al 1997, Pfeifer et al 1999, Leipoldt et al 2007].

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Campomelic Dysplasia

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
SOX9Sequence analysisCoding regions and splice mutations~90%
Deletion/duplication analysis 2Partial- or whole-gene deletions 3, 4~2% 5

1. The ability of the test method used to detect a mutation that is present in the indicated gene

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

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

4. SOX9 duplication causes XX sex reversal only.

5. 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]

Test characteristics. Information on test sensitivity, specificity, and other test characteristics can be found at EuroGentest [Scherer et al 2012 (full text)].

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

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.
  • Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having CD is use of a multi-gene panel.

Prenatal diagnosis. Prenatal diagnosis for pregnancies at risk as a result of a mildly affected parent or potential somatic or germline mosaicism requires prior identification of the disease-causing mutation in a previously affected child or the mildly affected parent.

Preimplantation genetic diagnosis (PGD) for pregnancies at risk as a result of a mildly affected parent or potential somatic or germline mosaicism requires prior identification of the disease-causing mutation in a previously affected child or the mildly affected parent.

Clinical Description

Natural History

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 make generalizations about the natural history. The following have been observed:

  • Intellectual abilities are 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].

Ischio-pubic-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, mutations 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:

Penetrance

SOX9 coding region mutations are completely penetrant.

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

Nomenclature

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).

Prevalence

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 mutations) 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.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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
  • Medical genetics consultation

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. Club feet 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 cervico-thoracic 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.

Surveillance

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 ClinicalTrials.gov 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 mutation. 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

Offspring of a proband. Many individuals with CD do not survive infancy; some, however, have reproduced. The risks to offspring of a proband:

Other family members of a proband. Because CD typically occurs as a de novo mutation, 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 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

A priori high-risk pregnancies. Prenatal diagnosis for pregnancies at increased risk as a result of parental mosaicism or the presence of a SOX9 mutation 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 disease-causing allele of an affected family member should be identified before prenatal testing can be performed.

Similarly, prenatal diagnosis 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 mutation 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 diagnosis (PGD) may be an option for some families in which the disease-causing mutation or familial chromosome rearrangement has been identified.

Resources

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
    6645 West North Avenue
    Oak Park IL 60302
    Phone: 800-362-4423 (Toll-free Parent Help Line); 708-383-0808
    Fax: 708-383-0899
    Email: info@magicfoundation.org
  • Human Growth Foundation (HGF)
    997 Glen Cove Avenue
    Suite 5
    Glen Head NY 11545
    Phone: 800-451-6434 (toll-free)
    Fax: 516-671-4055
    Email: hgf1@hgfound.org
  • 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
    Email: info@lpaonline.org
  • Skeletal Dysplasia Group Freiburg
    University Hospital Freiberg, Centre for Pediatrics and Adolescent Medicine
    Mathildenstrasse 1
    Freiburg 79106
    Germany
    Phone: 001-497-6127 0-4363
    Email: violetta.volz@uniklinik-freiburg.de
  • International Skeletal Dysplasia Registry
    Cedars-Sinai Medical Center
    116 North Robertson Boulevard, 4th floor (UPS, FedEx, DHL, etc)
    Pacific Theatres, 4th Floor, 8700 Beverly Boulevard (USPS regular mail only)
    Los Angeles CA 90048
    Phone: 310-423-9915
    Fax: 310-423-1528
  • Skeletal Dysplasia Network, European (ESDN)
    Institute of Genetic Medicine
    Newcastle University, International Centre for Life
    Central Parkway
    Newcastle upon Tyne NE1 3BZ
    United Kingdom
    Email: info@esdn.org

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

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
SOX917q24​.3Transcription factor SOX-9SOX9 homepage - Mendelian genesSOX9

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Campomelic Dysplasia (View All in OMIM)

114290CAMPOMELIC DYSPLASIA
608160SRY-BOX 9; SOX9

Molecular Genetic Pathogenesis

Mutations 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.

Normal allelic variants. The coding sequence of 5.4-kb SOX9 is distributed over three exons separated by introns of 0.9 kb and 0.6 kb. There are no known normal allelic 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 Allelic Variants Discussed in This GeneReview

Class of Variant AlleleDNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference Sequences
Normalc.507C>T
(879C>T)
p.(=) 2
(His169His)
NM_000346​.3
NP_000337​.1
Pathologicc.1320C>A
(1692C>A)
p.Tyr440*
c.1320C>G
(1692C>G)
p.Tyr440*

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. 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.

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

Pathologic allelic variants. Numerous pathogenic nonsense and frameshift mutations of SOX9 are distributed over the entire coding region; there is no mutation hot spot with the exception of the recurrent nonsense mutation p.Tyr440* [Pop et al 2005]. Missense mutations cluster in the HMG domain (a DNA-binding domain) or in the dimerization domain and are occasionally recurrent. A few splice mutations 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 mutations 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. Nonsense and most frameshift mutations in SOX9 predict a prematurely truncated protein that misses all or part of the TA domain and, when the mutation is located toward the N terminus, all or part of the HMG domain as well. Resultant mutant proteins missing both domains constitute loss-of-function alleles, whereas mutant proteins retaining the HMG domain may function as dominant-negative alleles. More C-terminally located frameshift mutations are predicted to encode an extended SOX9 protein with a mutant C terminus in place of the TA domain. Missense mutations 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].

References

Literature Cited

  1. Akiyama H, Lefebvre V. Unraveling the transcriptional regulatory machinery in chondrogenesis. J Bone Miner Metab. 2011;29:390–5. [PMC free article: PMC3354916] [PubMed: 21594584]
  2. Benko S, Fantes JA, Amiel J, Kleinjan DJ, Thomas S, Ramsay J, Jamshidi N, Essafi A, Heaney S, Gordon CT, McBride D, Golzio C, Fisher M, Perry P, Abadie V, Ayuso C, Holder-Espinasse M, Kilpatrick N, Lees MM, Picard A, Temple IK, Thomas P, Vazquez MP, Vekemans M, Roest Crollius H, Hastie ND, Munnich A, Etchevers HC, Pelet A, Farlie PG, Fitzpatrick DR, Lyonnet S. Highly conserved non-coding elements on either side of SOX9 associated with Pierre Robin sequence. Nat Genet. 2009;41:359–64. [PubMed: 19234473]
  3. Benko S, Gordon CT, Mallet D, Sreenivasan R, Thauvin-Robinet C, Brendehaug A, Thomas S, Bruland O, David M, Nicolino M, Labalme A, Sanlaville D, Callier P, Malan V, Huet F, Molven A, Dijoud F, Munnich A, Faivre L, Amiel J, Harley V, Houge G, Morel Y, Lyonnet S. Disruption of a long-distance regulatory region upstream of SOX9 in isolated disorders of sex development. J Med Genet. 2011;48:825–30. [PubMed: 22051515]
  4. Bernard P, Tang P, Liu S, Dewing P, Harley VR, Vilain E. Dimerization of SOX9 is required for chondrogenesis, but not for sex determination. Hum Mol Genet. 2003;12:1755–65. [PubMed: 12837698]
  5. Cameron FJ, Hageman RM, Cooke-Yarborough C, Kwok C, Goodwin LL, Sillence DO, Sinclair AH. A novel germ line mutation in SOX9 causes familial campomelic dysplasia and sex reversal. Hum Mol Genet. 1996;5:1625–30. [PubMed: 8894698]
  6. Corbani S, Chouery E, Eid B, Jalkh N, Ghoch JA, Mégarbané A. Mild campomelic dysplasia: report on a case and review. Mol Syndromol. 2011;1:163–8. [PMC free article: PMC3042119] [PubMed: 21373255]
  7. Cox JJ, Willatt L, Homfray T, Woods CG. A SOX9 duplication and familial 46,XX developmental testicular disorder. N Engl J Med. 2011;364:91–3. [PubMed: 21208124]
  8. Fukami M, Tsuchiya T, Takada S, Kanbara A, Asahara H, Igarashi A, Kamiyama Y, Nishimura G, Ogata T. Complex genomic rearrangement in the SOX9 5' region in a patient with Pierre Robin sequence and hypoplastic left scapula. Am J Med Genet. 2012;158A:1529–34. [PubMed: 22529047]
  9. Gentilin B, Forzano F, Bedeschi MF, Rizzuti T, Faravelli F, Izzi C, Lituania M, Rodriguez-Perez C, Bondioni MP, Savoldi G, Grosso E, Botta G, Viora E, Baffico AM, Lalatta F. Phenotype of five cases of prenatally diagnosed campomelic dysplasia harboring novel mutations of the SOX9 gene. Ultrasound Obstet Gynecol. 2010;36:315–23. [PubMed: 20812307]
  10. Gordon CT, Tan TY, Benko S, Fitzpatrick D, Lyonnet S, Farlie PG. Long-range regulation at the SOX9 locus in development and disease. J Med Genet. 2009;46:649–56. [PubMed: 19473998]
  11. Hill-Harfe KL, Kaplan L, Stalker HJ, Zori RT, Pop R, Scherer G, Wallace MR. Fine mapping of chromosome 17 translocation breakpoints > or = 900 kb upstream of SOX9 in acampomelic campomelic dysplasia and a mild, familial skeletal dysplasia. Am J Hum Genet. 2005;76:663–71. [PMC free article: PMC1199303] [PubMed: 15717285]
  12. Jakobsen LP, Ullmann R, Christensen SB, Jensen KE, Molsted K, Henriksen KF, Hansen C, Knudsen MA, Larsen LA, Tommerup N, Tumer Z. Pierre Robin sequence may be caused by dysregulation of SOX9 and KCNJ2. J Med Genet. 2007;44:381–6. [PMC free article: PMC2740883] [PubMed: 17551083]
  13. Jakubiczka S, Schröder C, Ullmann R, Volleth M, Ledig S, Gilberg E, Kroisel P, Wieacker P. Translocation and deletion around SOX9 in a patient with acampomelic campomelic dysplasia and sex reversal. Sex Dev. 2010;4:143–9. [PubMed: 20453475]
  14. Lecointre C, Pichon O, Hamel A, Heloury Y, Michel-Calemard L, Morel Y, David A, Le Caignec C. Familial acampomelic form of campomelic dysplasia caused by a 960 kb deletion upstream of SOX9. Am J Med Genet. 2009;149A:1183–9. [PubMed: 19449405]
  15. Leipoldt M, Erdel M, Bien-Willner GA, Smyk M, Theurl M, Yatsenko S, Lupski JR, Lane AH, Shanske AL, Stankiewicz P, Scherer G. Two novel translocation breakpoints upstream of SOX9 define borders of the proximal and distal breakpoint cluster region in campomelic dysplasia. Clin Genet. 2007;71:67–75. [PubMed: 17204049]
  16. Mansour S, Offiah AC, McDowall S, Sim P, Tolmie J, Hall C. The phenotype of survivors of campomelic dysplasia. J Med Genet. 2002;39:597–602. [PMC free article: PMC1735206] [PubMed: 12161603]
  17. McDowall S, Argentaro A, Ranganathan S, Weller P, Mertin S, Mansour S, Tolmie J, Harley V. Functional and structural studies of wild type SOX9 and mutations causing campomelic dysplasia. J Biol Chem. 1999;274:24023–30. [PubMed: 10446171]
  18. Meyer J, Sudbeck P, Held M, Wagner T, Schmitz ML, Bricarelli FD, Eggermont E, Friedrich U, Haas OA, Kobelt A, Leroy JG, van Maldergem L, Michel E, Mitulla B, Pfeiffer RA, Schinzel A, Schmidt H, Scherer G. Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations. Hum Mol Genet. 1997;6:91–8. [PubMed: 9002675]
  19. Olney PN, Kean LS, Graham D, Elsas LJ, May KM. Campomelic syndrome and deletion of SOX9. Am J Med Genet. 1999;84:20–4. [PubMed: 10213041]
  20. Pfeifer D, Kist R, Dewar K, Devon K, Lander ES, Birren B, Korniszewski L, Back E, Scherer G. Campomelic dysplasia translocation breakpoints are scattered over 1 Mb proximal to SOX9: evidence for an extended control region. Am J Hum Genet. 1999;65:111–24. [PMC free article: PMC1378081] [PubMed: 10364523]
  21. Piper K, Ball SG, Keeling JW, Mansoor S, Wilson DI, Hanley NA. Novel SOX9 expression during human pancreas development correlates to abnormalities in campomelic dysplasia. Mech Dev. 2002;116:223–6. [PubMed: 12128229]
  22. Pop R, Conz C, Lindenberg KS, Blesson S, Schmalenberger B, Briault S, Pfeifer D, Scherer G. Screening of the 1 Mb SOX9 5´ control region by array CGH identifies a large deletion in a case of campomelic dysplasia with XY sex reversal. J Med Genet. 2004;41:e47. [PMC free article: PMC1735745] [PubMed: 15060123]
  23. Pop R, Zaragoza MV, Gaudette M, Dohrmann U, Scherer G. A homozygous nonsense mutation in SOX9 in the dominant disorder campomelic dysplasia: a case of mitotic gene conversion. Hum Genet. 2005;117:43–53. [PubMed: 15806394]
  24. Savarirayan R, Robertson SP, Bankier A, Rogers JG. Variable expression of campomelic dysplasia in a father and his 46,XY daughter. Pediatr Pathol Mol Med. 2003;22:37–46. [PubMed: 12687888]
  25. Scherer G, Zabel B, Nishimura G. Clinical Utility Gene Card for: campomelic dysplasia. Eur J Hum Genet. 2012 [PMC free article: PMC3722939] [PubMed: 23047745]
  26. Schramm T, Gloning KP, Minderer S, Daumer-Haas C, Hörtnagel K, Nerlich A, Tutschek B. Prenatal sonographic diagnosis of skeletal dysplasias. Ultrasound Obstet Gynecol. 2009;34:160–70. [PubMed: 19548204]
  27. Smyk M, Obersztyn E, Nowakowska B, Bocian E, Cheung SW, Mazurczak T, Stankiewicz P. Recurrent SOX9 deletion campomelic dysplasia due to somatic mosaicism in the father. Am J Med Genet. 2007;143A:866–70. [PubMed: 17352389]
  28. Sock E, Pagon RA, Keymolen K, Lissens W, Wegner M, Scherer G. Loss of DNA-dependent dimerization of the transcription factor SOX9 as a cause for campomelic dysplasia. Hum Mol Genet. 2003;12:1439–47. [PubMed: 12783851]
  29. Staffler A, Hammel M, Wahlbuhl M, Bidlingmaier C, Flemmer AW, Pagel P, Nicolai T, Wegner M, Holzinger A. Heterozygous SOX9 mutations allowing for residual DNA-binding and transcriptional activation lead to the acampomelic variant of campomelic dysplasia. Hum Mutat. 2010;31:e1436–44. [PubMed: 20513132]
  30. Thomas S, Winter R, Lonstein J. The treatment of progressive kyphoscoliosis in Camptomelic dysplasia. Spine. 1997;22:1330–7. [PubMed: 9201836]
  31. Velagaleti GV, Bien-Willner GA, Northup JK, Lockhart LH, Hawkins JC, Jalal SM, Withers M, Lupski JR, Stankiewicz P. Position effects due to chromosome breakpoints that map approximately 900 Kb upstream and approximately 1.3 Mb downstream of SOX9 in two individuals with campomelic dysplasia. Am J Hum Genet. 2005;76:652–62. [PMC free article: PMC1199302] [PubMed: 15726498]
  32. Vetro A, Ciccone R, Giorda R, Patricelli MG, Mina ED, Forlino A, Zuffardi O. XX males SRY negative: a confirmed cause of Infertility. J Med Genet. 2011;48:710–2. [PMC free article: PMC3178810] [PubMed: 21653197]
  33. Vidal VP, Chaboissier MC, de Rooij DG, Schedl A. Sox9 induces testis development in XX transgenic mice. Nat Genet. 2001;28:216–17. [PubMed: 11431689]
  34. Wagner T, Wirth J, Meyer J, Zabel B, Held M, Zimmer J, Pasantes J, Bricarelli FD, Keutel J, Hustert E. et al. Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell. 1994;79:1111–20. [PubMed: 8001137]
  35. White S, Ohnesorg T, Notini A, Roeszler K, Hewitt J, Daggag H, Smith C, Turbitt E, Gustin S, van den Bergen J, Miles D, Western P, Arboleda V, Schumacher V, Gordon L, Bell K, Bengtsson H, Speed T, Hutson J, Warne G, Harley V, Koopman P, Vilain E, Sinclair A. Copy number variation in patients with disorders of sex development due to 46,XY gonadal dysgenesis. PLoS ONE. 2011;6:e17793. [PMC free article: PMC3049794] [PubMed: 21408189]

Chapter Notes

Revision History

  • 9 May 2013 (me) Comprehensive update posted live
  • 31 July 2008 (cg) Review posted live
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1760PMID: 20301724
PubReader format: click here to try

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Tests in GTR by Condition

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

  • FLNB-Related Disorders[GeneReviews<sup>®</sup>. 1993]
    FLNB-Related Disorders
    Robertson S. GeneReviews<sup>®</sup>. 1993
  • Loeys-Dietz Syndrome[GeneReviews<sup>®</sup>. 1993]
    Loeys-Dietz Syndrome
    Loeys BL, Dietz HC. GeneReviews<sup>®</sup>. 1993
  • TRPV4-Associated Disorders[GeneReviews<sup>®</sup>. 1993]
    TRPV4-Associated Disorders
    Schindler A, Sumner C, Hoover-Fong JE. GeneReviews<sup>®</sup>. 1993
  • Congenital Muscular Dystrophy Overview[GeneReviews<sup>®</sup>. 1993]
    Congenital Muscular Dystrophy Overview
    Sparks S, Quijano-Roy S, Harper A, Rutkowski A, Gordon E, Hoffman EP, Pegoraro E. GeneReviews<sup>®</sup>. 1993
  • 22q11.2 Deletion Syndrome[GeneReviews<sup>®</sup>. 1993]
    22q11.2 Deletion Syndrome
    McDonald-McGinn DM, Emanuel BS, Zackai EH. GeneReviews<sup>®</sup>. 1993
See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...