Ellis-van Creveld syndrome
Ellis-van Creveld syndrome (EvC) is a rare genetic condition caused by a recessively inherited defect affecting the development of various ectodermally and mesodermally derived structures in the body. Characterized by features such as short stature, polydactyly (extra fingers or toes), dental abnormalities, and congenital heart defects, EvC has a particularly high prevalence in the Old Order Amish community in Pennsylvania. The syndrome arises from mutations in the EVC or EVC2 genes located on chromosome 4, which play crucial roles in regulating body patterning and cell growth. Symptoms can vary, but common manifestations include short-limb dwarfism, malformed nails, and heart conditions that may lead to neonatal mortality.
Diagnosis of EvC can be performed prenatally via ultrasound or through genetic testing, although the latter is not widely available. Postnatal diagnosis involves various imaging techniques to assess skeletal and cardiac features. Treatment typically focuses on managing symptoms, which may include orthopedic surgery for polydactyly, cardiac surgery for heart defects, and dental care for associated abnormalities. While there is no preventive measure for EvC, genetic counseling is recommended for families in at-risk populations. Despite the challenges, many individuals who survive infancy can lead lives with a relatively normal life expectancy.
Ellis-van Creveld syndrome
ALSO KNOWN AS: EvC; chondroectodermal dysplasia; mesoectodermal dysplasia; six-fingered dwarfism
DEFINITION Ellis-van Creveld syndrome (EvC) is a recessively inherited defect that affects development of several ectodermally and mesodermally derived structures in the body. It is commonly characterized by short stature, extra digits, tooth and nail defects, and heart malformations.
Risk Factors
There are no known risk factors for this disease. It is at an unusually high frequency in the Old Order Amish community of Lancaster County, Pennsylvania.
Etiology and Genetics
This syndrome was first formally described in the literature in 1940 by Richard Ellis of Edinburgh and Simon van Creveld of Amsterdam. The majority of mutations causing Ellis-van Creveld syndrome are located on the short arm of chromosome 4 in either of two adjacent genes, EVC or EVC2. These loci are proximal to the gene involved in achondroplasia, another form of inherited dwarfism. The normal functions of EVC and EVC2 are believed to involve regulation of a signaling pathway involved in the normal patterning of many areas of the body, as well as cell growth and specialization. The histopathology of fetuses with EvC syndrome showed chondrocyte disorganization in the growth zone of developing long bones and sometimes of vertebrae.
EvC syndrome is relatively uncommon. In the US population, the frequency of homozygotes is approximately 1 in 60,000 (allele frequency 0.004 percent) which gives a frequency of 0.008 percent carriers (heterozygotes) in the population. In the Old Order Amish of Lancaster County, Pennsylvania, however, the frequency of homozygotes is approximately 1 in 229 (allele frequency 6.6 percent) which gives a carrier frequency of 12.3 percent in that genetically isolated population. The original mutant allele in the Old Order Amish can be traced to a single immigrant couple, Samuel King and his wife, who arrived in southeastern Pennsylvania in 1744. The actual mutation in this population is in the fifth of 13 of the EVC gene and causes an abnormal splicing of exons of this gene. Cases of the disorder outside the Old Order Amish subpopulation are at different positions in either the EVC or EVC2 gene. Among those mutations are six mutations leading to a truncated protein and one mutation with a single deletion in EVC and one frame shift mutation, four truncating mutations, and one missence mutation in EVC2. It is interesting to note that a study by S. W. Thompson and colleagues in 2007 found that 31 percent of the EvC patients did not show a mutation in either the EVC or EVC2 gene, indicating that other genes are most likely involved.
Symptoms
A variably expressed clinical of symptoms defines this syndrome: chondrodystrophy (83 percent of patients), polydactyly of the hands (98 percent of patients), nail dystrophy/hypoplasia (78 percent of patients), short stature (73 percent of patients), congenital heart anomalies (66 percent of patients), and dental anomalies (59 percent). Chondrodystrophy is usually expressed as short-limb dwarfism (approximate adult height 109 to 155 centimeters) and progressive distal limb shortening. Polydactyly (extra fingers and/or toes) is most commonly seen in the hands but can occasionally be seen in the feet. Hidrotic ectodermal dysplasia is seen in nails, teeth, and occasionally hair. Nails are small or absent and often malformed. Tooth abnormalities such as partial adontia, natal teeth, delayed tooth eruption, small teeth, and malformed teeth are common. Hair can occasionally be sparse. Cardiac abnormalities include common atrium, atrial, or ventricular septal defects and patent ductus arteriosus. The cardiac abnormalities are the leading cause of neonatal death. Approximately 50 percent of infants born with EvC syndrome die from these cardiac defects, but those who survive infancy have a relatively normal life expectancy. Other anomalies that may be present include musculoskeletal defects, which may lead to misshapen bones and a narrow chest. The latter, when present, can lead to respiratory difficulties. Oral malformations, urogenital abnormalities, and (very rarely) mental retardation may also occur.
Screening and Diagnosis
EvC can be diagnosed prenatally by ultrasound at eighteen weeks. Fetal echocardiaography can also be used to detect cardiac abnormalities. DNA extracted by amniocentesis or chorionic villus sampling could be analyzed for mutations of the EVC and EVC2 genes; however, this is not a generally available genetic test. Postnatally, skeletal surveys, chest x-rays, ECG, MRI, echocardiography, and ultrasound are used to diagnose the clinical tetrad of EvC characteristics.
Treatment and Therapy
Orthopedic care needed to address polydactyly and bone malformations may include surgery, braces, and physical therapy. Cardiac surgery may be needed to repair heart anomalies. Dental care is often necessary and may include crowns to repair malformed or small teeth and partial dentures to replace missing teeth. For those patients with a smaller chest, respiratory care is often needed. Polydactyly is often addressed through surgical amputation of the additional digits.
Prevention and Outcomes
There is no way of preventing EvC syndrome. Genetic counseling of couples in high-risk groups is recommended. Prenatal testing for the skeletal and cardiac abnormalities is available. Many EvC pregnancies end in spontaneous abortion or stillbirth. Of those that make it to birth, about 50 percent of babies die in infancy from cardiac or respiratory problems. Those patients that survive infancy generally have a normal life span.
Bibliography
Da Silva, Jorge Diogo, Nataliya Tkachenko, and Ana Rita Soares. "Ellis-van Creveld Syndrome." National Library of Medicine, 26 Oct. 2023, www.ncbi.nlm.nih.gov/books/NBK596643/. Accessed 5 Sept. 2024.
"Ellis-van Creveld Syndrome." Genetics Home Reference. US Nat'l. Lib. of Medicine, Dec. 2012. Web. 21 July 2014.
"Ellis-van Creveld Syndrome." MedlinePlus. US Nat'l. Lib. of Medicine, 8 Sept. 2013. Web. 21 July 2014.
"EVC2 Gene." National Library of Medicine, 1 Dec. 2012, medlineplus.gov/genetics/gene/evc2/. Accessed 5 Nov. 2024.
McKusick, V. A. “Ellis-van Creveld Syndrome and the Amish.” Nature Genetics 24.3 (2000): 203–4. Print.
McKusick, V. A., J. A. Egeland, and R. Eldridge. “Dwarfism in the Amish.” Bulletin of the Johns Hopkins Hospital 115 (1964): 306–36. Print.
McKusick, V. A., R. Eldridge, J. A. Hostetler, U. Ruangwit, and J. A. Egeland. “Dwarfism in the Amish II: Cartilage-Hair Hypoplasia.” Bulletin of the Johns Hopkins Hospital 116 (1965): 285–6. Print.
Muensterer, Oliver, et al. "Ellis-van Creveld Syndrome: Its History." Pediatric Radiology 43.8 (2013): 1030–36. Print.
Thompson, S. W., V. L. Ruiz-Perez, H. J. Blair, et al. “Sequencing EVC and EVC2 Identifies Mutations in Two-Thirds of Ellis-van Creveld Syndrome Patients.” Human Genetics 120 (2007): 663–70. Print.