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

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

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

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:

• A de novo reciprocal translocation with one breakpoint in chromosome region 17q24.3-q25.1 where SOX9 is located
• A de novo interstitial deletion of 17q

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

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.

Genetically Related (Allelic) Disorders

Isolated Robin sequence. Although it is likely to be rare, chromosomal translocations in the vicinity of SOX9 may cause isolated Pierre Robin sequence without other obvious findings of CD [Jakobsen et al 2007, Benko et al 2009, Gordon et al 2009].

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:

• Chromosomal rearrangements. In long-term survivors with CD and those with acampomelic campomelic dysplasia (ACD), de novo translocations or inversions with breakpoints upstream of SOX9 are more likely to be seen than mutations in the SOX9 coding region [Pfeifer et al 1999, Leipoldt et al 2007, Gordon et al 2009, Jakubiczka et al 2010, Fukami et al 2012]. In general, the farther the breakpoint is from SOX9, the milder the phenotype, including the effect on male external genitalia [Leipoldt et al 2007] and skeletal findings:
  • In two individuals with very distal translocation breakpoints (at 899 kb and 932 kb), the skeletal findings were so mild that they were transmitted through several generations [Hill-Harfe et al 2005, Velagaleti et al 2005].
  • Misregulation of SOX9 has been implicated in individuals with isolated Pierre Robin sequence and translocation breakpoints 1.13 Mb upstream of SOX9 [Jakobsen et al 2007, Benko et al 2009, Gordon et al 2009, Fukami et al 2012].
• Acampomelic campomelic dysplasia (ACD). Mild campomelia and ACD are over-represented in those with translocations or inversions, accounting for nine of 15 cases with well-defined breakpoints [Leipoldt et al 2007]. In contrast, only approximately 10% of individuals with SOX9 coding region mutations have ACD. Notably, these are mostly missense mutations in the DNA-binding domain [Staffler et al 2010, Corbani et al 2011]. Furthermore, the single missense mutation not located in this domain was located in the SOX9 dimerization domain in two unrelated individuals with ACD [Bernard et al 2003, Sock et al 2003]. In addition, the few individuals with SOX9 upstream deletions all had ACD [Pop et al 2004, Lecointre et al 2009, White et al 2011]. Thus, compared to individuals with CD, individuals with ACD have a significantly higher probability of having either a genomic rearrangement with breakpoint upstream of SOX9, a SOX9 upstream deletion, or a SOX9 missense mutation.

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.

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.

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

• To date, most probands with CD have the disorder as the result of a de novo mutation; thus, parents of probands are not typically affected.
• A few adults have been diagnosed with CD following the birth of an affected child [Mansour et al 2002, Savarirayan et al 2003, Lecointre et al 2009].
• Parents of a proband with a chromosome translocation or deletion are at risk of having the chromosome rearrangement themselves and should be offered chromosome analysis. Familial translocations have been reported but are rare. One family has been reported with somatic mosaicism for a small deletion encompassing SOX9; this appears to be a very rare occurrence [Smyk et al 2007].

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 mutation 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 disease-causing mutation 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. The risks to offspring of a proband:

• Offspring with a non-mosaic SOX9 mutation. 50%
• Offspring 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 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.

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).

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].

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Author Notes

www.esdn.org
www.isds.ch
www.skeldys.org

Revision History

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