Introduction 

Ellis-van Creveld syndrome (EVC syndrome) and Short Rib-Polydactyly Syndromes (SPRS) are rare genetic conditions. Genetic disorders are caused by mutations, affecting your genes or chromosomes.1 Chromosomes carry our genes; genes essentially tell the human body how to grow, function, and develop. However, sometimes there are mistakes, known as mutations. Often, these mistakes are harmless, but other times they can cause health problems, known as genetic disorders/conditions.² 

Ellis-van Creveld syndrome is inherited, meaning that the faulty genes are passed down through generations. However, for the condition to arise, two faulty copies of the gene are needed. This is called an ‘autosomal recessive’ disease, meaning there is a 25% risk of inheriting the condition if one parent is a carrier.³ If a person inherits only one faulty copy, they are a carrier - carriers usually do not exhibit symptoms. The syndrome is characterised by short limbs, extra fingers/toes (called polydactyly), abnormal fingernail development, dental abnormalities, and possible heart problems.⁴  

Short Rib-Polydactyly Syndrome is the name for a group of bone malformations which are characterised by a narrow thorax, which is the area between the neck and the abdomen, short ribs and limbs, and additional fingers/toes.⁵ It is a severe and often lethal genetic condition that affects fetuses, which can be diagnosed during pregnancy by an ultrasound. The condition can also cause heart and kidney defects, abnormal bone formation, and/or a cleft lip.⁶ SPRS also follows the same inheritance pattern as EVC, meaning it is an autosomal recessive disease. 

Short Rib-Polydactyly Syndromes are often fatal due to the smaller chest cavity, which is too narrow to support adequate breathing, causing respiratory distress soon after birth, which leads to death.⁶ 

There are four types of short-rib polydactyly syndrome:⁷

• Type I - Saldino-Noonan
• Type II - Majewski
• Type III - Naymoff 
• Type IV - Beemer-Langer

Short rib-polydactyly syndromes vs ellis-van creveld syndrome

EVC syndrome shares many features with SRPS, such as short limbs and polydactyly, but it is usually less severe. Those with EVC syndrome often live into adulthood with adequate treatment for associated illnesses (such as heart, dental, and bone abnormalities). Within this article, we will explore further comparisons of the two conditions, specifically focusing on the genetic and phenotypic overlaps between the two. 

The genetic basis

Both syndromes are due to mutations in specific genes, with the syndromes having an ‘autosomal recessive’ inheritance pattern. In general, we have two copies of each gene, one inherited from our mother and another from our father. In autosomal recessive conditions, two faulty copies of the same gene must be inherited for the condition to arise. 

^{Table 1 - Outline of Autosomal Recessive Inheritance Pattern}

Ellis-van creveld syndrome 

EVC syndrome is caused by mutations in either of these two genes: EVC or EVC2, with more than 25 mutations in the EVC gene being reported to cause Ellis-van Creveld syndrome.⁸ The two genes are located very close together, so it can be theorised that they may have related functions and/or coordinated activity. The exact function of these two genes is unknown, but we do know they provide instructions to make a protein; however, the function of this protein is unclear.8 But it has been shown that the protein plays an important role in the development of bones and teeth. The two genes are found in things called ‘primary cilia’.⁹ These are microscopic structures, which stick out from the surface of cells, involved in signalling pathways which allow communication between two cells. More specifically, the EVC and EVC2 genes are theorised to regulate the ‘Sonic Hedgehog’ signalling pathway, which plays an important role in cell growth, specialisation, and body development. 

Short rib-polydactyly syndromes

SRPS are caused by mutations in several genes, differing from those affected in EVC syndrome.¹⁰ However, the genes affected in SRPS are also involved in cilia function, impacting cell signalling and bone development.

Both syndromes involve mutations in the genes associated with cell signalling and body development, specifically bone development, explaining the similar overlap in physical symptoms. 

To summarise, the genetic cause of EVC is limited to mutations in the EVC and EVC2 gene, with rarely other genes involved, whilst SRPS involves mutations in multiple different genes, which is referred to as ‘gene heterogeneity’. 

The phenotypic overlap 

Ellis-Van Creveld Syndrome and Short Rib-Polydactyly Syndromes are often discussed together due to their similar physical presentation, which is what we refer to as ‘phenotypic overlap’. The term ‘phenotype’ refers to the physical features that we can see, such as shorter limbs and additional fingers/toes. 

Shared physical features include: 

• Polydactyly (extra fingers/toes): Both syndromes result in having extra digits, usually found on the outside edge of the hands/feet
• Shortened bones and short stature: Both syndromes result in a shorter than average stature due to impaired bone development
• Rib and chest abnormalities: In both conditions, the ribs are often shorter than average. In EVC, this is often manageable and not fatal, but in SRPS, the chest is so narrow that it often restricts proper lung development, leading to impaired breathing
• Nail and dental impairments: This can present as thin nails and smaller or fewer teeth than normal. This is more common in EVC but can also appear in some cases of SRPS

The overlap of phenotypic features can make diagnosis challenging, especially during pregnancy, as doctors can only rely on an imaging technique called an ultrasound. An ultrasound is a diagnostic tool used in medicine which utilises sound waves to produce an image of an organ, soft tissues, and fetuses.¹¹ To combat this, genetic testing can be used to identify the exact condition or cause.¹²

Key differences

While the two conditions share similar characteristics, there are also key differences which highlight the importance of correctly diagnosing each syndrome. 

Those with ECV syndrome typically present with shorter arms and legs, additional fingers/toes, abnormal nails and teeth, and often accompanying heart problems. Despite this, the majority with ECV live into adulthood with appropriate medical care. ECV is also often commonly associated with heart defects, which is the most common cause of death among patients, but this is not the case regarding SRPS, as the heart is rarely involved.⁴ 

On the other hand, Short Rib-Polydactyly Syndromes cause much more severe limb shortening and short ribs and a narrow thorax, which result in abnormal lung development, leading to severe breathing difficulties, which is why many with the syndrome do not live long after birth. Additionally, organs such as the liver and/or kidneys can be affected, making survival into childhood rare. Ascites, which is the name for the build-up of fluid in the space between the abdominal lining and organs, are seen in many cases of SRPSs. This can have several negative impacts on an individual, such as abdominal pain, breathing difficulties, and increased chances of a life-threatening infection.¹³

^{Table 2 - Summary of Key Differences}

Summary

To summarise, while Ellis-Van Creveld Syndrome and Short Rib-Polydactyly Syndromes share similar, overlapping features - such as shorter than average bones, extra fingers/toes, and certain genetic similarities, such as the fact that both involve mutations in genes which play an important role in cell signalling -they differ greatly when it comes to their severity and outcomes. Understanding the key differences between these similar rare conditions highlights the importance of genetic testing and shows how small changes in our genes can lead to a variety of physical differences, with some syndromes being manageable with proper medical care, whilst others may cause fatal health problems from birth. Properly understanding the genetic and phenotypic overlaps between these conditions helps doctors make accurate diagnoses which ultimately lead to better care.

Key takeaways

• Ellis-Van Creveld syndrome (EVC) and Short Rib-Polydactyly Syndrome (SRPS) are rare genetic conditions that affect both bone and organ development; they both follow an autosomal recessive inheritance pattern
• Both conditions share similar physical traits, such as short stature, extra fingers/toes, and smaller ribs/chest
• EVC is manageable, and many survive into adulthood
• SRPS is more fatal and life-limiting due to breathing impairments
• Genetic testing alongside medical diagnostic imaging, such as ultrasounds, is key to confirming a diagnosis