Introduction

Klippel-Feil Syndrome, or KFS, is a congenital condition (present from birth) classically characterised as a fusion of two cervical vertebrae.¹ Each of our vertebrae is supposed to have space between them where a disc resides, allowing spine movement. However, in the setting of a congenital fusion, two vertebrae are essentially “glued together” with no disc in between, resulting in a shortened neck and limited mobility. 

Some other visible signs of KFS include facial asymmetry, a shortened neck, and a lower hairline. Patients may also suffer from chronic headaches, limited mobility, and muscle pain.¹ Throughout the rest of this article, we will discuss the causes of KFS, how it is diagnosed, long-term complications and implications, and available treatments for those diagnosed with KFS.

Basic Definition and Clinical Features of KFS

KFS is a condition defined by two or more congenitally fused cervical vertebrae. This condition was first discovered in the early 1900s by French doctors, Maurice Klippel and André Feil. While some cases of KFS are diagnosed by ultrasound en utero, or at birth after noticing visible defects, many patients go on into adulthood with no knowledge of this condition until they obtain an X-ray of their neck. We call this an incidental finding when a patient presents with one problem, maybe neck pain or a herniated disc, and the healthcare provider “accidentally” finds another condition, such as KFS. Many of these individuals who are not diagnosed until later go on to live healthy, everyday, long lives. However, there is quite a variety in the severity of KFS and how it affects a patient's quality of life. 

The location of cervical involvement often determines the severity of KFS in an individual. Typically, cases that involve the upper three cervical vertebrae tend to be more severe than those involving lower cervical vertebrae. While all cases of KFS are defined as a fusion of two or more cervical vertebrae, less than 50% show the classic triad of short neck, low posterior hairline, and limited neck mobility.¹

Some of the more severe cases of KFS will have other abnormalities seen outside of the cervical spine region. About 50% of those diagnosed with KFS are also diagnosed with scoliosis or an abnormal curvature of the spine.¹ Some may also experience torticollis, an abnormal muscular contraction of the neck. A tiny group of patients with KFS, making up 4.4-14%, may also suffer from cardiovascular issues.¹ Due to this, checking the heart of any patient diagnosed with KFS is essential to rule out any heart disorders.¹ About 30% of individuals with KFS may deal with sensorineural deficits such as deafness or renal (kidney) problems.¹ This is why a full workup is essential when any individual is diagnosed with KFS.

Genetic Causes

Inherited vs. Sporadic Cases

Not much is known about the cause of KFS; however, there has been evidence of cases of inheritance, meaning it was passed down through family genes, as well as sporadic, meaning random, causes.¹ Studies have found that about 1 in 40,000 newborns worldwide have KFS, which is slightly more common in females than males. Furthermore, sometimes KFS can be asymptomatic or not have any visible deformities, which means that sometimes patients may not realise until adulthood that they have KFS.¹

Identified Genes Linked to KFS

Some genes potentially responsible for KFS include GDF6, GDF3, and MEOX1.¹ Both GDF6 and GDF3 are genes that influence bone development. MEOX1, on the other hand, is a gene that controls MOX1, which regulates the separation of the vertebrae.¹

Inheritance Patterns

GDF6 and GDF3 are inherited in an autosomal dominant pattern, whereas MEOX1 follows an autosomal recessive pattern.¹ To quickly break down the difference between autosomal dominant and recessive, remember that a parent must carry that gene to pass it down to their child, whether they or the child expresses that trait.  In the case of autosomal dominant, that gene is a bit stronger, so it only takes one parent, or one copy of the gene, for the gene to express itself.  Alternatively, in the case of autosomal recessive traits, both parents must possess the gene to pass it down to their child for it to be expressed.  Thus, inheriting a recessive trait is usually more difficult than inheriting a dominant trait. The odds of inheriting a dominant trait are about 50%, whereas the odds of inheriting a recessive trait are more like 25%.²

Developmental Factors

Embryological Basis and Environmental Influences 

It is known that cervical spine formation and separation occur during the 3rd to 8th week of gestation. Thus, it is believed that any disruption during that time can affect the separation of the vertebrae, potentially resulting in KFS.¹ These disruptions can be genetic, such as a mutation in a gene that controls vertebrae separation, or environmental, such as exposure to certain chemicals or medications that interfere with normal development. While many theories and modern advancements in genetics have given us a lot more context of why people develop KFS, it is still important to note that there is much that we don’t know about how this condition develops.  Research is ongoing, and there may be a much more complicated combination of genetic and environmental factors than we think. 

Classification and Genetic Heterogeneity

There are many different types of KFS.  Type 1 involves one congenitally fused cervical segment, while type 2 involves multiple fused cervical vertebral levels. Type 3 also involves various levels of fusion. However, the most significant difference between types 2 and 3 is that type 3 is defined as multiple fused levels in a row, while type 2 must have gaps between the numerous fused levels. Of all of these types, Type 2 is the most common of those with KFS.¹

Implications for Genetic Counselling

Patients with KFS and their family members can benefit from genetic counselling to help with family planning.¹ There has been evidence that KFS can be inherited, or passed down from the mother or father to the child.  As was discussed earlier in this article, with the genes GDF6 and GDF3 being passed down in an autosomal dominant pattern, it only takes one parent to pass KFS to their child. Despite this, cases can still occur in families with no known history of the disorder.³ This is typically caused by a new mutation in one of those genes, which can’t always be controlled, but has sometimes been associated with other issues during pregnancy, for example, alcohol consumption leading to fetal alcohol syndrome. 

Even if the person does not have KFS, they can be carriers of one of the genes causing KFS. This is why genetic counselling, even for unaffected family members of those with KFS, is essential to help understand the risk of passing the condition to their child.  Some genes only carry a 25% risk, while others have a 50% risk. These odds will also vary based on the partner's genetic makeup.³

Summary

KFS is a complex condition, and much is still to be learned. It is believed to be caused by a mix of both genetic and environmental factors. There have been genes identified that may be responsible for this condition when mutations occur, and it is also known that disruptions in development during early pregnancy, weeks 3-8, may be responsible. As research continues, there is hope that understanding how this condition occurs can help us better prevent future cases and manage current ones. Further understanding this condition can help us develop further treatment methods and provide families with the information they need for future family planning.