Campomelic Dysplasia

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.

Diagnosis/testing.

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.

Management.

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.

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

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. 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)

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.
• 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 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:

• 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 pathogenic variants 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 overrepresented 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 pathogenic variants in the SOX9 coding region have ACD. Notably, these are mostly missense variants in the DNA-binding domain [Staffler et al 2010, Corbani et al 2011]. Furthermore, the single missense variant 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 variant.

Penetrance

Pathogenic variants in the SOX9 coding region 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
• 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.

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 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.