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Campomelic dysplasia (CD) is a rare genetic disorder characterized by variable involvement of skeletal and extra-skeletal abnormalities. It is a severe skeletal dysplasia inherited in an autosomal dominant pattern, with most cases arising from de novo mutations. The term ‘campomelic’ comes from the Greek “kampylos,” meaning curved, and “melos,” meaning limb. CD occurs due to pathogenic variants affecting the SOX9 gene or its regulatory regions. Most affected people have recognizable mutations. Diagnosis of CD is usually difficult due to its rare presentation and poor prognosis.
Understanding the mutational spectrum underlying campomelic dysplasia is essential for accurate diagnosis, prognosis, and appropriate genetic counseling. The prevalence of this condition at birth is 1 in 40,000 to 1 in 80,000, while the incidence ranges from 0.5 to 1.6/10,000.[1] CD patients generally die shortly after birth due to respiratory distress secondary to airway compromise or due to instability of the cervical spine.
Causes of Campomelic Dysplasia
Campomelic dysplasia is an autosomal dominant condition, but can also occur due to de novo mutations that encode SRY-box containing gene 9 (SOX9). This gene is localized to chromosome 17q24.3.[2] The SOX9 gene is essential for normal skeletal development and also plays a role in sexual development.
In most cases, mutations within the SOX9 gene cause inhibition of SOX9 protein production or result in a protein with impaired function. Rarely, the disorder can also occur due to chromosomal recombination (translocation or deletion) involving the region 17q24.[3] This syndrome is often lethal in the first year of life, although survival beyond infancy has been reported.
Symptoms or Clinical Features of Campomelic Dysplasia
The clinical features of CD include:
- Bowed long bones
- Congenital muscular torticollis (a baby born with a shortened and tight neck muscle)
- Chest and pelvic abnormalities
- Pierre Robin sequence with micrognathia and cleft palate
- Facial deformities, including a flat face and a small or underdeveloped jaw
- Ambiguous genitalia or female external genitalia in individuals with a 46, XY karyotype
- Eleven pairs of ribs instead of the usual twelve
- Relative macrocephaly
- Scoliosis
- Hearingloss
- Club foot[4]
Other Clinical Manifestations
Other clinical features include:
- Heart anomalies
- Respiratory distress
- Laryngotracheomalacia
- Dislocated hips
- Pretibial skin dimples
- Short bowed tibia and femur
- Underdeveloped cervical and upper thoracic vertebrae
Bowing of the limbs in CD is not always present. When long-bone bowing is absent, the condition is referred to as acampomelic campomelic dysplasia.
Dysplastic hip: A clinical manifestation of CD.
Diagnosis of Campomelic Dysplasia
If the doctor suspects CD based on the parental ultrasound, you might need some additional tests during pregnancy. The genetic counselor helps you decide which tests are most suitable for your family.
Prenatal Tests
The most essential prenatal tests that you and your baby may need are:
Fetal Ultrasound
A careful examination of the fetus with a targeted, detailed ultrasound to examine the signs of CD. Ultrasound findings are suggestive but not diagnostic.
Amniocentesis
This test is performed by using a small sample of amniotic fluid. Doctors collect amniotic fluid by inserting a thin needle through the abdomen into the uterus. Amniocentesis detects chromosomal and genetic disorders like campomelic dysplasia.[5]
Chorionic Villus Sampling (CVS)
Just like amniocentesis, CVS detects genetic and chromosomal anomalies. Doctors take a small sample of tissue from the placenta. The placenta is an organ inside your uterus that nourishes your baby. They collect the sample by inserting a needle in the female’s abdomen or a thin tube through the vagina or cervix.[6]
Postnatal Diagnosis
When a baby is born, doctors can diagnose CD with the help of the following:
- Physical examination of the newborn.
- X-rays of the whole body of the baby are taken to examine the bone anomalies.
- Genetic testing on a small sample of the newborn’s blood. Identification of a heterozygous pathogenic variant in SOX9 in genetic testing confirms the diagnosis.[7]
Genetic testing includes gene sequencing and chromosomal microarray analysis.
Gene Sequencing
SOX9 gene sequencing detects point mutations (small deletions or insertions and other sequence variants) in approximately 90 to 95% of karyotype-normal CD cases.[8]
Chromosomal Microarray Analysis (CMA)
CMA identifies large deletions or duplications encompassing one or more SOX9 exons in about 5% of cases, complementing sequence by detecting copy number variants missed by sequence-based methods.[9]
Management and Treatment of Campomelic Dysplasia
Campomelic Dysplasia cannot be treated before birth. Newborns with this condition have a higher risk of stillbirth. However, CD is not always fatal; some patients survive. Most of the babies with CD survive less than a year after birth. They pass away usually due to severe breathing difficulty because of laryngotracheomalacia (weak windpipe and voice box).
Newborns with respiratory compromise may require oxygen support, mechanical ventilation, or tracheostomy, depending on severity. Survivors require supportive and multidisciplinary care. Babies who survive need advanced care according to their condition. The following treatment is usually essential.
Airway Management
Early airway support is essential due to laryngotracheomalacia and small thoracic cages in CD patients. Initial interventions include oxygen supplementation or mechanical ventilation,bronchoscopy, or polysomnography to guide escalation. Tracheostomy is often required for ventilator dependence, which is a feasible method for airway reconstruction.
Cervical Spine Monitoring
Instability of the cervical spine poses risks of craniocervical compression, hypotonia, and respiratory compromise. Imaging is recommended when instability is suspected, and surgical intervention may be required in selected cases. Doctors also recommend an MRI of the craniocervical junction to detect the compression. If compression or instability is confirmed, then spinal fusion or suboccipital decompression may be indicated.
Table 1 includes the treatment of CD manifestations.[10]
Table 1: Treatment of Manifestations in Individuals with Campomelic Dysplasia
| Manifestations | Treatment options |
|---|---|
| Cleft palate | It requires surgical closure and care by the craniofacial team. |
| Hearing Impairment | Treatment as per audiologists, including hearing aids. |
| 46, XY karyotype, and female genitalia | Gonadectomy because of the risk of gonadoblastoma. |
| Club feet, hip dislocations, bowed long bones, bowed tibia, cervical instability, andscoliosis | Splints, casts, and surgery. MRI spine monitoring addresses cervical instability. |
| Respiratory manifestations | Require early evaluation with polysomnography andbronchoscopyafter four weeks of age, potentially involving supplemental oxygen, tracheostomy, or ventilator support. |
Genetic Counselling
Genetic counselling is a process of providing families with information on the nature, modes of inheritance, and implications of genetic disorders to help them make informed personal and medical decisions. It can help in family planning and DNA banking.[11]Genetic counselling guides you towards prenatal diagnosis using CVS or amniocentesis for SOX9 sequencing and CMA, when ultrasound shows bowed femurs, a small thorax, or a family history. Couples with an affected child should pursue counseling to quantify personalized risk via molecular testing of parents.
Most CD cases arise from de novo heterozygous pathogenic variants in SOX9. It confers low recurrence risk in siblings of sporadic cases.Rare familial cases may involve parental chromosomal rearrangements near SOX9, making parental karyotyping or targeted testing important for risk assessment.
Campomelic Dysplasia Versus Muscular Dystrophy
CD is a rare skeletal dysplasia, while muscular dystrophies (MD) are a group of inherited muscle disorders. Comparison of the key characteristics is given in Table 2.
Table 2: Comparison of Key Features of CD and MD
| Features | CD | MD |
|---|---|---|
| Onset | Prenatal or congenital, visible on ultrasound. | Usually occurs in childhood and can progress further. |
| Primary Pathology | Skeletal | Muscular |
| Genetics | Autosomal dominant, often de novo. | Mostly X-linked recessive or autosomal dominant or recessive. |
| Prognosis | Often lethal neonatal due to respiratory failure. Survivors are rare. | Prognosis is variable. It can pose progressive disability and cardiorespiratory complications. |
| Diagnostic Considerations | Usually rely on radiographic findings such as bowed femurs and tibias, 11 rib pairs, and genetic testing for SOX9 variants. | MD requires a muscle biopsy. Biopsy indicates abnormal dystrophic changes. While its skeletal radiographs are normal, which distinguishes it from CD. |
Final Remarks
CDs are fatal bone development associated with genetic mutations and have low survival rates. Treatment of these patients requires an organized multidisciplinary approach. Stable monitoring of these patients is also crucial.
References
[1] Unger, S., Scherer, G., & Superti-Furga, A. (2021). Campomelic dysplasia.
[2] Larasati, N., Zahra, P. K., & Auerkari, E. I. (2021, July). A Review of Campomelic Dysplasia Syndrome. In Journal of Physics: Conference Series (Vol. 1943, No. 1, p. 012094). IOP Publishing.
[3] Mansour, S., Hall, C. M., Pembrey, M. E., & Young, I. D. (1995). A clinical and genetic study of campomelic dysplasia.Journal of medical genetics,32(6), 415-420.
[4] Khoshhal, K., & Letts, R. M. (2002). Orthopaedic manifestations of campomelic dysplasia.Clinical Orthopaedics and Related Research (1976-2007),401, 65-74.
[5] Eger, K. J. (2005). Campomelic dysplasia.Journal of Diagnostic Medical Sonography,21(4), 343-349.
[6] Scherer, G., Zabel, B., & Nishimura, G. (2013). Clinical utility gene card for: campomelic dysplasia.European Journal of Human Genetics,21(7), 792-792.
[7] Patel, B., Byrne, J. L., Phillips, A., Hotaling, J. M., & Johnstone, E. B. (2018). When standard genetic testing does not solve the mystery: a rare case of preimplantation genetic diagnosis for campomelic dysplasia in the setting of parental mosaicism.Fertility and Sterility,110(4), 732-736.
[8] Unger, S., Scherer, G., & Superti-Furga, A. (2021). Campomelic dysplasia.
[9] Unger, S., Scherer, G., & Superti-Furga, A. (2021). Campomelic dysplasia.
[10] Unger, S., Scherer, G., & Superti-Furga, A. (2021). Campomelic dysplasia
[11] Gimovsky, M., Rosa, E., Tolbert, T., Guzman, G., Nazir, M., & Koscica, K. (2008). Campomelic dysplasia: case report and review. Journal of Perinatology, 28(1), 71-73.