Campomelic Dysplasia

Campomelic dysplasia is a skeletal dysplasia with multiple congenital anomalies, mainly characterized by shortening and bowing of long bones, abnormal face, hypoplastic scapulae, ambiguous genitalia and male-to-female sex reversal (1). The term is based on the Greek words “campo” and “melic”, meaning “bent limbs”, describing the typical pattern of skeletal abnormalities. The diagnosis is suspected by the skeletal findings on routine prenatal ultrasound and can be confirmed with prenatal or postnatal molecular genetic testing or radiologic evaluation.

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Campomelic dysplasia is a rare skeletal dysplasia and specific incidence data are missing. The prevalence of this abnormality is estimated to be approximately 1 in 200,000 births (2). There is no sex or ethnicity preponderance.

Campomelic dysplasia is an autosomal dominant disorder caused by de novo mutations in or near the SOX9 gene (3). The SOX9 gene is abundantly expressed in chondrocytes as well as in other tissues. The mutations may be missense mutations, nonsense mutations, deletion mutations of the coding region and rarely chromosomal rearrangements that disrupt the regulatory region of SOX9 gene (4-6). The SOX9 protein defect blocks the normal development of long bones and facial bones. SOX9 stands for SRY-Box Transcription Factor 9, thus mutations in SOX9 affect the expression of sex-determining region Y (SRY)-related gene and can influence gonadal development. The above mechanism may explain the observed differences between phenotypic sex and genetically confirmed sex and frank sex reversal or ambiguous genitalia in certain cases.  

The femora and tibiae are the most frequently bent bones. Also all endochondral bones of the face are defective or absent (7).

Apart from the usual sonographic findings (bent shortened long bones, hypoplastic scapulae, and ambiguous genitalia) other associated abnormal findings can be: nuchal edema, clubfeet, hydrocephalus (due to atlanto-occipital occlusion) and polyhydramnios (2). The clinical presentation may also include: pretibial skin dimples, dysmorphic face (flattened midface, long philtrum, micrognathia, cleft palate), dolichocephaly and relative macrocephaly, low set ears, dislocated hips (1). Other clinical manifestations may be: hypoplastic pubic bones, hypoplastic cervical vertebrae and bell-shaped thorax with 11 pairs of ribs (1).

In the majority of cases the underlying cause is a de novo mutation, so there is no increased risk of recurrence. In the rare case of autosomal recessive inheritance the recurrence risk is estimated to be 25% (2).

The diagnosis is suspected by the skeletal findings on routine prenatal ultrasound and can be confirmed with prenatal or postnatal molecular genetic testing or radiologic evaluation. The ultrasound characteristic findings are: shortening and bowing of the long bones of the legs (bilateral acute femoral angulation), narrow chest, hypoplastic scapulae, large calvarium with disproportionately small face, micrognathia (2, 8). Early-stage diagnosis is rarely feasible. In a case report of 2004 a fetus affected with campomelic acampomelic dysplasia presented with increased nuchal translucency (5.6 mm), but still diagnosis was made after the first trimester as simple karyotype was normal (9).

Differential diagnosis includes other skeletal dysplasias, such as osteogenesis imperfecta, hypophosphatasia, Stuve-Wiedemann syndrome, Antley-Bixler syndrome, Cousin syndrome, Ischiopubic patellar syndrome (7).

Detailed ultrasound examination is mandatory in order to detect the upper structural abnormalities. Even more, in about 70% of male fetuses, there is sex reversal and invasive testing is necessary to determine the genetic sex (8).

As with other skeletal dysplasias, the diagnosis is usually performed at the routine anatomy scan in the second trimester and rarely later in the third trimester (10). There is no specific prenatal screening test performed for this condition.

Infants with campomelic dysplasia generally die shortly after birth. The mortality rate in the first year of life is 95%, due to severe laryngeotracheomalacia (7). Other causes of neonatal death are respiratory failure secondary to airway compromise or cervical spine instability (11). The fact that newborns with campomelic dysplasia die of respiratory failure, even if their chest size is normal, which is usually the case, suggests underlying lung pathology (7). For infants who survive further, surgical repair may be required for cleft palate, clubfeet and cervical spine instability. Intellect may be variable. Kyphoscoliosis, short stature and hearing loss are common issues (7).

No prenatal treatment options exist for the condition. In general campomelic dysplasia is considered a lethal disorder and pregnancy termination is an option (7). If pregnancy continues, follow-up and obstetric care should be standard. Delivery should take place in a tertiary center. Palliative and therapeutic treatment options should be discussed with the parents in cases of pregnancy continuation (7).

1.    S Unger, G Scherer, A Superti-Furga: Campomelic dysplasia. RA Pagon MP Adam HH Ardinger et al. Gene Reviews. 1993 Seattle (WA): Gene Reviews.
2.    The Fetal Medicine Foundation.
3.    S McDowall, A Argentaro, S Ranganathan, et al.: Functional and structural studies of wild type SOX9 and mutations causing campomelic dysplasia. J Biol Chem. 1999; 274(34):24023-24030.
4.    J Meyer, P Sudbeck, M Held, et al.: Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations. Hum Mol Genet. 1997; 6 (1):91-98.
5.    PN Olney, LS Kean, D Graham, et al.: Campomelic syndrome and deletion of SOX9. Am J Med Genet. 1999; 84 (1):20-24.
6.    M Fukami, T Tsuchiya, S Takada, et al.: Complex genomic rearrangement in the SOX9 5’ region in a patient with Pierre Robin sequence and hypoplastic left scapula. Am J Med Genet A. 2012; 158A (7):1529-1534.
7.    Joshua A. Copel, Mary E. D’Alton, Helen Feltovich, Eduard Gratacós, Deborah Krakow, Anthony O. Odibo, Lawrence D. Platt, Boris Tutschek. Obstetric imaging: fetal diagnosis and care. Second edition. Philadelphia, PA: Elsevier, 2018.
8.    T Schramm, KP Gloning, S Minderer, et al.: Prenatal sonographic diagnosis of skeletal dysplasias. Ultrasound Obstet Gynecol. 2009; 34 (2):160-170.
9.    Michel-Calemard L, Lesca G, Morel Y, Boggio D, Plauchu H, Attia-Sobol J. Campomelic acampomelic dysplasia presenting with increased nuchal translucency in the first trimester. Prenat Diagn. 2004; 24 (7):519-23.
10.    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 (3):315-23.
11.    S Thomas, RB Winter, JE Lonstein: The treatment of progressive kyphoscoliosis in camptomelic dysplasia. Spine. 1997; 22 (12):1330-1337.

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