Introduction

Ellis-Van Creveld syndrome (EVC) is a rare genetic disorder (chondrodysplasia; as it affects cartilage and bone development)⁹ characterised by polydactyly (additional fingers and/or toes), short limbs, fetal growth restriction, and congenital heart defects.^1,2 The disorder was first formally presented in scientific literature in 1940 by Richard Ellis and Simon Van Creveld.^6,7 The exact prevalence of EVC is unknown however, 150-250 cases of EVC in individuals have been reported worldwide.^2,6 The prognosis of EVC varies significantly in infancy, however more than 50% of individuals with EVC are born with abnormalities of the heart, and approximately 50% of these patients die by 18 months of age due to cardiopulmonary complications (a combination of malformations within the heart and lungs).²

Historical background

EVC occurs in many ethnic groups throughout the world and there are no known risk factors for the disorder, however, EVC appears more common in the Old Order Amish population in Lancaster county, Pennsylvania, and USA.^6,7 EVC is of high frequency in the Old Order Amish community due to the founder effect, as the original genetic mutation can be traced back to a single immigrant couple, Samuel King and his wife who arrived in Pennsylvania in 1744.⁷ As the Amish marry within their own community, EVC is more concentrated due to the prevention of new genetic variation entering the small population, therefore, the EVC mutation passes onto their offspring.^7,8

In neonatology (the medical care of newborn infants), early recognition of EVC is crucial because many of its key clinical features are apparent at birth (and prenatal abnormalities can be discovered).⁶ Early diagnosis allows for the immediate clinical management of life-threatening cardiac and pulmonary complications, and facilitates family genetic counselling and a multidisciplinary treatment approach.⁶ 

Aetiology and genetics

EVC is caused by genetic mutations in EVC and EVC2 genes located next to each other on the short arm of chromosome 4.^6,7 However, it has also been suggested that there may be further genetic heterogeneity involved (EVC may be caused by additional genetic mutations other than the EVC genes).⁹ The normal function of EVC and EVC2 is to regulate the signalling pathway in the normal patterning of areas of the body, meaning that these genes are involved in the normal development of bones, tissue, and teeth.^6,7 

EVC follows an autosomal recessive inheritance pattern, this means that a child must inherit two copies of the mutated gene (one from each parent) to have the disorder.^6,7 There is a 25% chance with each pregnancy (with parents that carry the mutated gene) of birthing a child with EVC.^6,7

Clinical features in neonates

Skeletal abnormalities

• Limb shortening (prenatal or postnatal)
• Disproportionate short stature at birth: there is restricted growth where the limbs may be disproportionate to the rest of the body or vice versa
• Shortened and thickened bones (including the ribcage)
• Bilateral postaxial polydactyly of the hands and feet (extra fingers and toes) ¹
• Fusion of the wrist bones (known as capitate-hamate fusion)
• Abnormal pelvic bone development, resulting in a smaller underdeveloped pelvis with acetabular spur projections (tiny bumps on the edge of the hip bones) ^1,2
• Abnormal elbow positioning (cubitus valgus)

Facial and nail features

• Dystrophic (abnormal changes in the nail shape, colour, or texture) and/or hypoplastic (underdeveloped) nails ¹
• Abnormality of the lips (thin vermilion border) ²

Heart features

Congenital heart defects are common and can be detected prenatally (before birth).¹ This can include:

• Septal defects (holes in the heart's wall that separates the four chambers) which can be of atrial (ASD) and ventricular (VSD) form^1,3
• A single atrium (the wall separating the heart’s upper atrium/chambers being absent) is also a common congenital heart defect present in EVC^1,4

Genitourinary features

• Kidney abnormalities²
• Abnormalities of the urine duct
• Abnormal opening of the urine canal in males (hypospadias)
• Abnormal female genitalia

Other neonatal features

• Fetal growth restriction (low birth weight/size after delivery)²
• Underdeveloped lungs (pulmonary hypoplasia), which can result in respiratory challenges^1,2
• Thoracic narrowing/restriction (impairs expansion of the lungs): results in respiratory distress and feeding difficulties⁵

Diagnosis and the importance of early diagnosis

Early diagnosis of EVC is essential to reduce the risk of life-threatening complications in neonates. The diagnosis of EVC can be split into two sections: prenatal and postnatal diagnosis.

Prenatal diagnosis

Ultrasound examination

EVC can be diagnosed during the prenatal period, usually from the 18th week of gestation (pregnancy) onwards, by an ultrasound examination.¹⁰ However, if individuals have a family genetic history of EVC or general skeletal dysplasia, examinations can be conducted towards the end of the first trimester.¹² EVC markers that would be identifiable in an ultrasound examination are:¹¹

• Short limbs
• Short ribcage
• Polydactyly (extra fingers and/or toes)

Chen et al. (2012) demonstrated that congenital heart defects could be detected by ultrasound examination in the late first trimester (typically weeks 12-13).¹² A fetal echocardiography can also be used to confirm cardiac abnormalities.⁷ 

Molecular genetic testing

Prenatal testing is conducted for individuals with a family genetic history of EVC, where the individual's DNA will be sequenced to identify the mutation in EVC and EVC2 genes.^6,7 Genetic testing is done by chorionic villus sampling or amniocentesis.

Chorionic villus sampling

Chorionic villus sampling (CVS) involves collecting a small sample of chorionic villi, which are small projections from the placenta that share genetic material with the fetus.¹³ This procedure is typically performed between 9-13 weeks of pregnancy, and the sample is obtained through the cervix or abdomen, guided by ultrasound examination to ensure accuracy.¹³ Results from this procedure are available 1-2 weeks later.¹³

Amniocentesis

Amniocentesis is a medical procedure that was introduced in the 1950s and is used to obtain a sample of amniotic fluid, which can be used to assess for EVC.¹⁴ The procedure involves inserting a needle into the amniotic sac (using ultrasound examination guidance) to collect a small sample of fluid, which contains fetal cells to be genetically analysed.¹⁴

Postnatal diagnosis

Postnatal diagnosis (not as common as prenatal diagnosis) involves a combination of a clinical examination of the neonate to identify prominent characteristics of EVC, accompanied by radiographic findings to identify the short ribcage and dysplastic bones.¹ Additionally, molecular genetic testing will be used to confirm EVC diagnosis.

Clinical management in neonates

As EVC itself is not treatable, the clinical management of EVC in neonates exhibits a multidisciplinary care approach to manage urgent complications of the disease, and it typically involves neonatologists, cardiologists, orthopedists, geneticists, and dentists.⁷ 

Immediate neonatal care

Immediate neonatal care after birth could involve the treatment of respiratory distress (difficulty breathing) due to underdeveloped lungs, thoracic restriction/narrow chest, and heart failure.⁶ If feeding difficulties occur (potentially due to structural abnormalities with the face, teeth, and jaw etc), feeding support and a nutritional management plan will be created.^1,2 Neonatal teeth should be removed as they may impair the feeding support.⁶

Surgical intervention

Surgery to remove the polydactyly defect can be recommended.² Cardiac abnormalities can be monitored using echocardiographic screening, and surgical correction of heart defects can be conducted during early childhood.^2,6 Dentists are involved in the control of dental/oral manifestations and common abnormalities such as small, missing, or abnormally aligned teeth can be corrected.⁶ Due to the high incidence of cardiac defects in EVC patients, dental treatment must be performed using prophylactic antibiotics to reduce the risk of infection.⁶ EVC patients undergo regular orthopaedic monitoring due to the possibility of skeletal deformities. Also, the surgical correction of knock-knees can be conducted to help to guide normal bone growth.^2,6 

Summary

Ellis-Van Creveld syndrome (EVC) is a rare genetic disorder caused by genetic mutations in EVC and EVC2 genes. EVC is characterised by polydactyly (additional fingers and toes), short limbs, thoracic restriction, fetal growth restriction, and congenital heart defects. EVC appears more common in the Old Order Amish population in Lancaster county, Pennsylvania, and the USA. 

EVC can be diagnosed prenatally or postnatally. Early diagnosis is vital to allow immediate clinical management of life-threatening cardiac and pulmonary complications in neonates. Prenatal diagnosis involves ultrasound examinations and molecular genetic testing. Postnatal diagnosis involves a clinical examination of the neonate, accompanied by radiographic examination and confirmation via molecular genetic testing.

Clinical management of EVC in neonates involves multidisciplinary care to treat symptoms and urgent complications arising from the disease. Immediate neonatal care is provided to treat respiratory distress and feeding difficulties, while surgical intervention can be conducted to correct heart defects and skeletal deformities during early childhood.