Ellis-van Creveld syndrome

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Ellis-van Creveld syndrome

Definition

Ellis-van Creveld syndrome is an individually recognized genetic condition characterized by short stature and malformations of the heart, limbs, nails, and teeth. The name given to this condition originates from Richard W.B. Ellis of Scotland and Simon van Creveld of the Netherlands. Each had a patient with this syndrome in his care when the two met by chance in an English train car on the way to a pediatric conference in the late 1930s.

Description

Ellis-van Creveld (EvC) syndrome primarily affects the skeletal system, but is also associated with congenital heart defects . EvC syndrome is one of the six short rib polydactyly syndromes, or SRPS. There is considerable overlap between the features of these six syndromes. Clinical, radiological, and pathological studies are being conducted to determine if there are indeed six distinct SRPS, or if each is a different mutation at the gene that also causes Ellis-van Creveld syndrome.

Ellis-van Creveld syndrome is alternatively known as chondroectodermal dysplasia or mesoectodermal dysplasia. The name chondroectodermal dysplasia is meant to indicate a dysplasia, or abnormal growth or development, of the skeleton (chondro-) and the skin (ectodermal). The name mesoectodermal dysplasia is meant to indicate an abnormal growth or development of the skin (ectodermal) and primarily the middle portion of the bone (meso-). However, neither medically descriptive term defines the syndrome completely, and Ellis-van Creveld syndrome remains the most used name for both medical and common purposes.

Ellis-van Creveld syndrome is characterized by short arms and legs; short ribs; short fingers; polydactyly, or extra fingers or toes; and dysplastic, or abnormal, teeth and nails. Limb shortening is more noticeable in the legs than in the arms. Many older children affected by EvC syndrome develop knock-knee, or genu valgum, which may have to be corrected by orthopedic surgery. The underdeveloped ribs generally cause a condition known as pectus carinatum, in which the chest is narrow and elongated. A sixth finger on both hands occurs in all patients with EvC syndrome, while extra toes are observed in approximately 20% of the EvC syndrome population. Polydactyly in affected individuals is always symmetric. That is, if the left hand possesses a sixth finger, the right hand will also possess a sixth finger.

Dysplastic, or abnormal, teeth and nails are observed in all individuals with EvC syndrome. The most common dental anomalies are: teeth present at birth; wide spaces between permanent teeth; the late eruption of, or the complete lack of, some permanent teeth; and permanent teeth that more closely resemble baby teeth than permanent teeth. The most common nail abnormalities are absent or malformed fingernails or toenails. Thin, brittle hair is also observed in a majority of patients with EvC syndrome.

Congenital heart defects occur in approximately 50-60% of affected individuals. The most common cardiac abnormality observed is a common atrium rather than the normal two-chambered atrium. This "hole in the heart" can often be surgically repaired, resulting in normal heart function.

Genetic profile

Ellis-van Creveld syndrome is an autosomal, or nonsex linked, recessive condition. The gene responsible for EvC syndrome has been identified and its locus determined on the distal short arm of chromosome 4p. In 2000, it was shown that the EvC gene is the same gene that causes Weyers acrofacial dysostosis.

Certain mutations in the EvC gene cause EvC syndrome. In order for EvC syndrome to appear, the affected child must inherit a mutation of this gene from each parent. The child must receive two abnormal genes.

When the child receives only a single copy of an abnormal gene that would cause EvC syndrome, that child is affected with Weyers acrofacial dysostosis. Weyers acrofacial dysostosis is an autosomal dominant condition characterized by tooth and nail abnormalities, extra fingers and toes, and milder limb anomalies than those observed in Ellis-van Creveld syndrome. As is often the case in homozygous disorders, EvC syndrome presents much more pronounced physically observable and potentially life-threatening signs than the corresponding heterozygous condition, Weyers acrofacial dysostosis.

Demographics

Ellis-van Creveld syndrome has an incidence of approximately one out of 150,000 live births. Ellis-van Creveld syndrome has a much higher occurrence among the Old Order Amish, an isolated and inbred religious community in Lancaster County, Pennsylvania.

As a homozygous condition, both parents of an affected child must carry the abnormal EvC gene. The parents of an affected child have a one in four chance of having additional children affected with EvC syndrome. The transmission of such homozygous genetic disorders is facilitated by the close association among potentially related individuals in a relatively small and isolated population such as that of the Amish. Also, a relatively high frequency of Ellis-van Creveld syndrome has been observed in the Aboriginal people of Western Australia. This high frequency has been attributed to a founder effect from Dutch castaways and genetic drift caused by the isolation and interbreeding of these peoples.

Signs and symptoms

Ellis-van Creveld syndrome is characterized by short limbs and short body length identifiable at birth. The average adult height range for those affected by EvC syndrome is 43–60 in (109–152 cm). The head and neck are generally unaffected other than possible abnormalities of the upper lip, and dental anomalies including delayed eruption of the permanent teeth, which are generally underdeveloped and more similar to a child's teeth than to those of an adult. EvC syndrome is further characterized by congenital heart defects, usually a single upper chamber (atrium) rather than the normal two upper chambers. Affected individuals have short, poorly developed ribs, which leads to a narrow chest; this is termed pectus carinatum.

Males affected by EvC syndrome may present abnormalities of the penis in which the urethral opening occurs on the underside of the penis rather than at the tip of the glans (hypospadias); they may also have one or both testicles undescended (cryptorchidism). Further skeletal anomalies associated with EvC syndrome include: low hips; a spur-like projection at the acetabula, the socket in the hipbone that accepts the head of the thighbone; a fusion of the capitate and hamate bones; two carpal bones, the fusion of which makes the formation of a fist difficult or impossible; knock-knee; clubfeet that turn down and in; and postaxial polydactyly, or extra fingers/toes that arise outside the normal fifth digit. Fingernails and toenails are generally malformed. Neurologically, mental retardation has been observed in patients with EvC syndrome, but it is not the norm. A brain abnormality of one of the normal cavities of the brain (Dandy-Walker syndrome) is also occasionally associated with EvC syndrome.

Diagnosis

Ultrasound imaging of developing fetuses can reveal the limb shortening and underdeveloped ribs that are characteristic of the short rib polydactyly syndromes (SRPS), which includes Ellis-van Creveld syndrome. An ultrasound scan is now available after the sixteenth week of gestation that may identify extra digits in the developing fetus.

Ellis-van Creveld syndrome is generally differentially diagnosed from the other SRPS by the additional presence of atrial abnormalities. However, it is often difficult to distinguish Ellis-van Creveld syndrome from two other forms of skeletal dysplasia. These are asphyxiating thoracic dysplasia (ATD), also known as Jeune syndrome; and short rib polydactyly syndrome (SRPS) type III, or Verma-Naumoff type SRPS. Individuals with Jeune syndrome often die of respiratory distress shortly after birth, whereas individuals diagnosed with EvC syndrome are more likely to die from congenital heart failure. Patients with Jeune syndrome often have extra fingers or toes; but, unlike those with EvC syndrome, this polydactyly is often not symmetric. Jeune syndrome does not present the nail and hair abnormalities seen in EvC syndrome. Older children can often be differentially diagnosed with Jeune syndrome rather than EvC syndrome if they develop kidney problems, which may also later lead to kidney failure as adults. Kidney dysfunction is not associated with Ellis-van Creveld syndrome.

Verma-Naumoff type SRPS is virtually indistinguishable from EvC syndrome prior to birth. However, individuals with Verma-Naumoff type SRPS also exhibit heart, kidney, and intestinal malformations that are not present in the Ellis-van Creveld population. Verma-Naumoff type SRPS has an essentially 100% mortality rate within hours of birth, as those affected die from respiratory distress. All three of these conditions arise from autosomal recessive inheritance . As of 2001, the genetic evidence is beginning to further the hypothesis that these three conditions are the result of mutations of the same gene on chromosome 4p that has been identified as the cause of Ellis-van Creveld syndrome.

Treatment and management

Genetic counseling of individuals affected with either Ellis-van Creveld syndrome or the allelic disorder, Weyers acrofacial dysostosis, may prevent the conception of children with EvC syndrome. Congenital heart defects associated with Ellis-van Creveld syndrome may be surgically corrected. The potential outcome of such a procedure is normal heart function. Extra fingers or toes (polydactyly) can be surgically removed shortly after birth. This is more a cosmetic treatment than a necessary one in the case of fully developed extra digits. If a person affected with EvC syndrome develops genu valgum (knock-knee), he or she may require orthopedic surgery to straighten the legs at the knee. Dental treatment also has an important role in management of Ellis-van Creveld syndrome.

Many people of extremely short stature adapt their surroundings to their size. Others choose to undergo one of the bone lengthening procedures that have increasingly become available. These bone lengthening procedures are generally performed only on the limbs. They often do not offer complete relief to the patient who may also have a smaller than normal thoracic cavity caused by undersized ribs.

Prognosis

Ellis-van Creveld syndrome is generally non-lethal with approximately two-thirds of those affected surviving to adulthood. Mortality is higher when the congenital heart defects associated with EvC syndrome are also present. Approximately half of those affected with Ellisvan Creveld syndrome with heart abnormalities die in childhood due to cardiorespiratory problems associated with these congenital heart defects or associated with pressure on the chest, primarily the lungs, caused by an underdeveloped rib cage. Of these, approximately one-half die within the first six months of life.

Resources

PERIODICALS

Polymeropoulos, M., et al. "The gene for the Ellis-van Creveld syndrome is located on chromosome 4p16." Genomics (July 1996): 1–5.

Ruiz-Perez, V., et al. "Mutations in a new gene in Ellis-Van Creveld syndrome and Weyers acrodental dysostosis." Nature Genetics (March 2000): 283–86.

ORGANIZATIONS

Ellis-Van Creveld Foundation. Farthingdale Farm, Hackmans Lane, Purleigh, Chelmsford, CM3 6RW. UK 01-621-829675. <http://www.cafamily.org.uk/Direct/e24.html>.

Genetic Alliance. 4301 Connecticut Ave. NW, #404, Washington, DC 20008-2304. (800) 336-GENE (Helpline) or (202) 966-5557. Fax: (888) 394-3937 info @geneticalliance. <http://www.geneticalliance.org>.