What is Ellis-Van Creveld Syndrome?

Overview

Ellis-Van Creveld syndrome (EVC) is a rare genetic developmental disorder, therefore a disorder caused by genetic abnormalities that affect an individual’s normal process of growth. Symptoms of EVC include abnormally short limbs and extra fingers and toes (polydactyly). Around half of those affected also have heart defects. The syndrome is passed on by autosomal recessive inheritance, meaning that both parents carry a copy of the faulty gene, but none of the two exhibits symptoms. If both of those copies are then passed down to their offspring, it will have EVC.

Key symptoms of Ellis-Van Creveld syndrome are:

• Short stature
• Short arms and legs
• Additional fingers or toes (polydactyly)
• Nail and tooth abnormalities
• Knock-knees (genu valgum)
• Fine sparse hair
• Chest abnormalities - short ribs and narrow thorax
• Over 50% have heart defects

Brief explanation of Ellis-Van Creveld syndrome

EVC is a rare genetic form of disproportionate dwarfism, also known as mesenchymal-ectodermal dysplasia and chondroectodermal dysplasia.¹ This is a developmental disorder caused by a faulty gene, resulting in abnormally short limbs and a narrow thorax with short ribs. Both males and females can be affected.

Individuals present with an additional finger next to their fifth finger (polydactyly), dental abnormalities, nail abnormalities, and thin, sparse hair. Another common feature is Genu Valgum, where the knees touch but the ankles remain apart, which can cause pain and difficulties in walking and with posture. Individuals with EVC have a high mortality rate due to heart defects and cardiorespiratory problems.² Most patients exhibit normal intelligence, though in some cases of EVC, mild intellectual disability has been reported.¹

EVC may be referred to as a ‘ciliopathy’, which is a disorder linked to cilia. This is attributed to the expression of EVC genes in individuals’ primary cilia (hairlike cells involved in growth, development, and organ function).²

EVC may be diagnosed prenatally through ultrasound scanning, or at birth, by noting the short limbs, short stature, and polydactyly. Some cases are missed at birth and are diagnosed later in childhood or, rarely, later in life.¹

History of Ellis-Van Creveld syndrome

EVC was first documented by Richard W.B. Ellis and Simon van Creveld in 1940, and the terminology given to the syndrome at the time was “mesenchymal-ectodermal dysplasia”.“Dysplasia” means abnormal cell growth or development, whilst the mesenchymal cells are the cells that develop into cells which make up our bones and cartilages, and ectodermal cells form the embryo’s outer layer in development.

Reportedly, the two Dutch doctors met by chance on a train in England and discussed the conditions of their patients who had similar symptoms, and then combined their findings in their 1940 publication. They referred to an earlier case of EVC found in 1933 by Rustin McIntosh. Later, in 1964, Victor McKusick published a report on a group of Amish patients from Lancaster County, Pennsylvania, USA, showing short stature and dental abnormalities.³

It has been found that the Old Order Amish of Pennsylvania have a prevalence of 1/5000 live births, compared to 7/1000000 in non-Amish populations.^1,4 In the Amish, the frequency of EVC carriers could be as high as 13%.⁵ This is due to “the founder effect”, where the frequency of EVC occurrence increases due to marrying within the community. As the disorder is passed on by recessive genes, consanguineous (blood-related) parents increase the risk of the condition presenting.

Clinical features

Skeletal issues

The most apparent skeletal issue in EVC is short stature and disproportionate dwarfism. This is typically represented by particularly shortened limbs and an average-length torso. Short stature occurs due to skeletal dysplasia (abnormal growth and development of the cells making up our skeleton), and potentially due to growth hormone deficiency in some cases.⁶

The shortening of limbs is most severe in the proximal rather than the distal regions of individuals. This means that the forearm of an individual may be very short, but their distal interphalangeal bones, or their fingertips, are shortened to a higher degree.⁶ Furthermore, the tibial segment of the leg (from the knee to the ankle) is likely to be more shortened, relative to the femoral segment (thigh) of an individual with EVC.⁷

Commonly, EVC patients have chest abnormalities such as a narrow thorax and short ribs. This can cause respiratory issues due to this change in anatomical features, therefore restricting breathing.

Polydactyly is a consistent feature in all EVC cases and is described by the addition of small fingers on each hand, or occasionally extra toes on each foot as well. These extra digits may or may not have movement and functionality. Additionally, sometimes there is an abnormality of the wrist with fused carpal bones.

Genu valgum

One common feature of EVC is Genu Valgum, or Knock-knees, where the knees touch and turn outwards whilst the ankles do not touch. This is a normal phenomenon in many young children, however it is pathological if still present after 7 years old. In severe cases, this can be corrected by surgery.

Cardiac features 

50-60% of EVC patients suffer from cardiac defects. This is a key cause of early mortality. In some cases, heart surgery can be carried out to correct the defects and improve individuals’ chances of survival.¹

1.) Atrial septal defect

The most common congenital (a defect present from birth) heart defect in this syndrome is the atrial septal defect (ASD). In ASD, the patient lacks the atrial septum that normally separates the two upper chambers of the heart. This allows blood to flow from the left to the right atrium uncontrollably, which can lead to an excess of blood in the right side of the heart. The presence of an ASD may result in symptoms such as fatigue, shortness of breath, and an increased risk of respiratory infections.⁸

Patients with this condition rarely survive to adulthood, although a case study presented by Prajapati et al. of a 60-year-old man proved that this is not always the case. The individual had life-long shortness of breath, short stature, and polydactyly of both hands and one foot. The man was found to lack his atrial septum, showing that patients with EVC can occasionally reach old age.⁸

2.) Ventricular septal defect

Another heart defect found in EVC cases is described as a ventricular septal defect (VSD). In VSD, there is a hole in the septum or wall between the lower chambers of the heart. This means that oxygen-rich blood goes back into the lungs, instead of going out to the body, resulting in symptoms such as shortness of breath and fast heart rate.¹⁵

3.) Patent ductus arteriosus

Some EVC patients may present with patent ductus arteriosus, a condition involving irregular blood flow in the heart and lungs. The ductus arteriosus is described as an opening in the major blood vessels of the heart which is typically present in newborns but should close shortly after birth to allow normal blood flow. A large opening may lead to the build-up of high pressure and damage to blood vessels in the lungs. This can also weaken the heart muscle, leading to heart failure.¹⁶

Dental features

EVC patients also develop abnormal teeth. Children may be referred for EVC diagnosis after complaining of delayed tooth growth.

Dental features include hypodontia (developmental lack of teeth) in the maxillary (upper jaw) and mandibular (lower jaw) incisor region, where individuals have an absence of teeth, with irregular spaces between them. They may also show gingival enlargement, a condition characterised by enlarged gums. Although there is usually a reduction in teeth, on the contrary, sometimes patients present with supernumerary (extra) teeth.⁷ 

Often patients show conical teeth, affecting their ability to chew and speak.

Some patients also present with a fusion of the middle portion of their upper lip to their upper gums, or the development of numerous frenula (soft tissue) between their upper lip and gums.^1,7 EVC patients may also present with the development of a partial cleft lip, which can be repaired via surgery.¹⁷

1.) Nail abnormalities

Commonly in EVC, patients develop hypoplastic nails. This means that their nails are not fully developed or may be partially absent. Their nails may be dystrophic, thickened or deformed, and friable or brittle. They can also be soft, thin, and spoon-shaped.¹

Mortality rate

Due to the common cardiac, skeletal, and respiratory issues, unfortunately, 50% of EVC cases die during infancy.¹¹ Very rarely, cases of older adults with EVC have been reported. For example, da Silva et al. published a case of an 82-year-old living with EVC.¹²

Genetic basis of Ellis-Van Creveld syndrome

EVC is caused by mutations of the EVC-1 and EVC-2 genes located on chromosome 4P16.^4,5 The EVC-1 gene codes for a protein that seems to be key in development and growth, discovered in 2000. EVC-2 was also linked to EVC in 2002.⁵

EVC is passed on by autosomal recessive inheritance, which means that for the offspring to exhibit the disorder, a copy of the mutant gene must be carried by both parents. EVC-1 has 21 coding exons (gene sections containing instructions for building essential proteins), and encodes a protein made up of 992 amino acids (building blocks for proteins). The gene is expressed in the developing skeleton, affecting the ribs, arms, and legs of the individual. EVC-2 is found near EVC-1 on chromosome 4, and encodes a 1308 amino acid-long protein, which is expressed in similar areas with the EVC-1 protein.⁹

EVC-1 and EVC-2 are found as a protein complex in primary cilia and are involved in hedgehog-mediated signalling, a crucial cell-signalling pathway required in the process of development. A mutated EVC-1 or EVC-2 gene disrupts the hedgehog pathway by impairing a vital protein in this pathway called the Smoothened protein.

This then affects downstream processes and therefore growth signals are not sent to their target regions as they should normally be. This pathway is required for normal tooth development, growth of the axial skeleton including the ribs, and proper formation of the heart. Another gene, CRMP1, has been identified as a genetic modifier of EVC severity.⁹

Treatment and management

1.) Cardiac treatments

For some patients, cardiac defects such as ASD and ventricular septal defects can be corrected by surgery. This may involve sealing the gap with an implant, or through a catheter, a thin tube inserted into a blood vessel in the leg which is then guided into the heart. If the defect is large, patients can undergo heart surgery instead, where the surgeon cuts into the chest of the patient and directly stitches the atrial septum hole.¹³

2.) Orthopaedic interventions

Musculoskeletal experts can help manage and correct the skeletal issues seen in EVC.

Polydactyly can be easily treated during infancy by the surgical removal of additional fingers and toes.

Genu valgum may be sometimes corrected through surgery. For example, soft tissue release may allow the deformity to be corrected, allowing patients to walk more easily while experiencing less pain.¹⁴ The knee bone may be cut (osteotomy) and reshaped to correct the abnormal angle of the legs. However, recurrence of genu valgum is common so follow-up surgeries may be necessary.

3.) Dental care

Dental care is very important for patients with EVC due to tooth and gum abnormalities. Patients are at a higher risk of common dental issues such as caries. Surgery may be carried out for aesthetic reasons, or to improve eating and chewing capabilities. Issues such as a partial cleft lip can be easily corrected surgically.

4.) Other treatment options

Other treatment options include respiratory support due to shortness of breath, with a combination of medication administration such as beta-blockers for heart failure, or asthma treatments.

Some patients may undergo speech therapy due to speech challenges which might occur as a result of the oral abnormalities.

Additionally, pain management may be important for some patients due to their skeletal issues. Genu valgum can sometimes be very painful, therefore patients may undergo physiotherapy and/or take pain relief medication.

Significance of raising awareness of rare genetic disorders

EVC is a particularly rare genetic condition, with a prevalence of 7/1000000 in the general population.¹ Raising awareness is crucial in the attempt to increase diagnoses, and offer early treatment to those with EVC. Individuals residing especially in rural or poorer communities may live for years without having a diagnosis. Early diagnosis means that therapies and surgeries can be used to correct skeletal (related to the skeleton) issues or cardiac (related to the heart) issues, therefore increasing an individual’s quality of life.

The study of rare disorders helps the community affected by the condition and furthers our general medical understanding of rare genetic disorders. Understanding the role of the EVC gene in the body contributes valuable information to medical science, which helps scientists understand the physiology of humans.

Summary

EVC is a rare congenital disorder caused by disruption to cell growth and development, due to mutations in the EVC-1 or EVC-2 genes. Although the incidence of early mortality is high, patient outcomes can be improved by surgery to improve painful skeletal features, heart surgery to correct cardiac defects, and dental surgery to correct tooth abnormalities. With quicker surgery and interventions to reduce cardiac and respiratory issues, patient survival can be improved, therefore it is important to diagnose individuals with this disorder as soon as possible.