You may have met someone with a cleft lip before. Maybe you have one yourself. It’s a unique feature this individual has and you’ve perhaps never thought much about it. 

What is remarkable about this feature and indeed all other facial features is how they formed in the first place. There is a complex interplay of different tissue structures interacting with each other in the facial features. Our eyes, nose, mouth, ears, eyebrows and more are determined in the womb. 

In this article, we will explore what happens when facial development goes wrong and how scientific research has pushed our understanding of these disorders. With advances in technology, there are now new avenues to treat and detect these disorders. 

Overview of Frontofacionasal Dysplasia (FFND)

What is FFND?

FFND is a rare genetic disorder in which the head and face become malformed due to problems with the embryonic development of the facial midline.¹ These malformations become apparent at birth and FFND  is often classified as a congenital disorder.

These facial defects can take many forms including a cleft palate, increased distance between the eyes and underdeveloped nasal tips. Other features of this disorder include hair loss on the head and eyebrows or a V-shaped hairline known as ‘widow’s peak’. 

Genetic basis of FFND

Many different facial defects associated with FFND can be linked to the disorder’s genetic origin. The genes responsible for FFND can also determine the severity of the disease.

Key genes involved in FFND

Three genes which have been linked to FFND: ALX3, ALX4 and ALX1. This family of genes encodes proteins that help with the normal development of the head and face. 

Especifically, ALX1 is responsible for the early formation of the mouth, nose and eyes whilst ALX3 and ALX4 help with normal skull formation and the shaping of soft tissue surrounding the nose. 

When genes become mutated, the amount of proteins that are produced becomes significantly reduced. This means that the proteins cannot perform their functions and can disrupt normal biological functions. In the case of FFND, if the ALX family of genes becomes mutated, this can lead to abnormal head and face development. 

Differing subtypes of FFND

The subtype and the severity of FFND is determined by the mutation of ALX genes. Despite two individuals having the same mutation for FFND,  it doesn’t mean they will share the same facial defects. This is because FFND is a heterogeneous disorder meaning that the specific defects and complications can differ between individuals with the disorder.  

Frontonasal dysplasia type 1 (FND1) 

FND1 or frontorhiny, is caused by mutations of the ALX3 gene. This leads to facial defects of widely spaced eyes, clefts of the upper lip or palate and a groove of the nasal tip. This was first identified in a research study in which 7 different families with similar facial defects had the same mutation of the ALX3 gene.² FND1 is considered the least severe type of FFND due to the non-life-threatening facial defects.

Frontonasal dysplasia type 2 (FND2) 

FND2 is caused by mutations of the ALX4 gene. These mutations lead to facial defects including widely spaced eyes, flat noses and flat cheekbones and cleft nostrils. In addition, head defects can occur including hair loss, having a misshapen head and brain abnormalities leading to behavioral and developmental problems in later life. In one study, almost all of these defects were present in 2 families with the cause being a mutation of ALX4.³ FND2 is of moderate severity of FFND as the quality of life for individuals with brain abnormalities can be greatly impacted.

Frontonasal dysplasia type 3 (FND3) 

FND3 is caused by mutations of ALX1 leading to the complete deletion of the ALX1 protein. This means that ALX1 cannot perform its function at all. This manifests into facial defects including widely spaced eyes, a wide nose bridge and low set ears. In addition, babies born with FND3 can be born with small eyes or eyes that are missing and have clefts running from the corner of the eye to the upper lips. This is because, without functional ALX1, the structures and tissues that form the face are unable to fuse properly leading to facial defects. FND3 is considered the most severe type of FFND as these malformations can lead to blindness, feeding and breathing problems which can greatly impact life expectancy. The first   ALX1 mutation in humans was reported in 2 children of different families that shared the same facial defects of widely spaced eyes, low-set ears and a complete cleft palate⁴.

Current treatments for FFND

Currently, the main treatment for FFND is structural reconstructive surgeries to correct the facial defects. These surgeries require close communication with plastic surgeons and neurosurgeons to ensure no further complications arise during or after surgery. 

Surgical procedures can include rhinoplasty to correct the shape of the nose whilst facial bipartition is a surgery procedure used to reposition the face and correct the eye position. 

However, surgical intervention methods are invasive, complicated, and are not without risk. The very nature of using anesthetics, especially in children, requires great care to get the dosage correct. For the individuals with FFND, extreme caution is required when administering anesthetics for surgery to not compromise patient airways any further. 

Despite these challenges, reconstructive surgeries are largely successful in the treatment of FFND.  The X-rays and computer tomography (CT) scans have been invaluable tools to help visualise bone and tissue structures of the face and appropriately plan out surgery. These medical tools can help reduce complications from surgery. 

Emerging Treatments for FFND

As FFND is a heterogeneous disease, there is not a single treatment to use on individuals with the disorder. This means that research has pivoted towards personalized treatments and assessing the severity of the disorder, can help guide the appropriate patient management plan. 

Gene editing 

Gene editing is becoming a promising avenue to treat congenital diseases with a genetic basis. Gene editing works by first identifying if the embryo is carrying the genetic mutation. Then the mutated genes of the embryo can be repaired using a range of gene editing tools. The now-edited embryo can be implanted into the host where the embryo can be carried to full term. 

Due to ethical issues with using human embryos for scientific study, animal embryos from rats, sheeps, and monkeys have been used to investigate if gene editing of embryos can produce viable offspring. One experiment used mouse embryos to correct a muscular disorder in which a mutation of the gene encoding the protein dystrophin is deleted. By using gene editing tools, the research team was able to prevent the dystrophin gene from being deleted. The offspring of the mice with the edited embryos were found to have an increased amount of the protein dystrophin suggesting that the gene editing was successful.⁵

In the case of FFND, gene editing holds great potential in treating the root cause of FFND. By correcting the gene mutations associated with FFND, it can prevent the abnormal development of the head and face from occurring and remove the need for risky surgical procedures in later life. However, it is only until birth facial defects and ultimately the success of gene editing are determined. 

Tissue engineering 

Tissue engineering refers to a bioengineering technique that uses stem cells to build and create tissue structures. Stem cells are specialised cells that can self renew and regenerate. Tissue engineering has transformed the way people with chronic wounds and burns are treated. Tissue engineered skin grafts can be created from the same cells as the individuals affected and can then reduce the risk of immune rejection. In addition, tissue engineered grafts are particularly useful for the individuals with limited amounts of healthy skin in the first place e.g. a heavily burnt individual.   

Tissue engineering holds great potential for the treatment of FFND. As the facial abnormalities stem from the abnormal development of bone and other tissues, tissue engineering could be used to construct normal tissue structures including bone, skin, cartilage and nerves. 

Summary

FFND is a rare disorder usually identified at birth with individuals presenting with facial abnormalities such as  wide set eyes, cleft lips, wide nose bridges and low-set ears. In more severe cases, the individuals with FFND can have misshapen heads, missing eyes and behavioral problems as infants. The severity of these facial defects can be linked to specific gene mutations linked to the disease. Under normal function, these genes are responsible for the proper development of facial tissues but if these genes become mutated, this disrupts the fusing of tissues leading to facial abnormalities at birth. Whilst surgery can be done to correct facial defects, it can be a risky procedure. Gene editing tools and tissue engineering have the potential to transform the way FFND is treated and may even prevent it from manifesting.