What Is Frontonasal Dysplasia?

What is frontonasal dysplasia?

Frontonasal Dysplasia (FD) is a rare disorder affecting bone development, causing facial deformities in the forehead, eyes and nose. Patients with this disease have been found to have a broader nasal root, a larger nasal tip, hypertelorism (distance between two body parts) and a widow’s peak, although these can vary between different patients. Other characteristics include a cleft lip, nasal tags, hearing loss, and ocular deformities, such as cataracts and coloboma. In rare cases, the disease is known to cause an intellectual abnormality found in the extra development of the cranium.¹ 

This disease was first recognised in the mid-1800s; however, in 1996, only around 100 familial cases were reported around the world.²  De Meyer first defined the malformation in 1967 as ‘median cleft face syndrome’ affecting the five swellings which form the face. However, various ideas have been introduced in more recent years, allowing us to develop an understanding of the condition based on types, genetics, and clinical appearance. 

Types of frontonasal dysplasia  

FD is characterised by dysfunctional genes and their outcomes on facial structure development. A diagnosis may be made on the appearance of an affected individual alone. These include:

• Craniofrontonasal dysplasia - particularly found in females with extreme hypertelorism (increase in the distance where eye orbits are), premature cranial sutures (a defect which causes the baby’s skull to fuse too early), and facial asymmetry. The gene causing the syndrome is present at the X chromosome, where it causes mosaicism, resulting in fewer functional cells producing irregular tissue partitions. Despite being X-linked, this type of FD is paradoxically more frequent in females than in males.⁴
• Acromelic frontonasal dysplasia - This is the rarest type of FD. Patients present with very severe craniofacial mutations involving the median cleft face, spaced nasal tip, limp mutations and intellectual disabilities. This condition is autosomal dominant.⁵ 
• Oculoauriculofrontonasal syndrome - This is found in patients with frontonasal dysplasia and the oculoauriculovertebral spectrum. Some of the symptoms include facial asymmetry, undeveloped ears, and eye tumours. The cause is unknown, so some patients with mild symptoms may not be diagnosed.⁶
• Frontorhiny - The mutations affecting this condition cause patients to show hypertelorism (increased distance between facial features), cleft nasal tip, longer philtrum (creating a longer groove in the nose and upper lip), nasal swelling, and broad nasal bridge. This type of FD is recessive, caused by mutations in the ALX1, ALX3, and ALX4 genes, with varying severity.⁵

Causes of frontonasal dysplasia

Genetic mutations

Different types of frontonasal dysplasia are known to be caused by mutations in the ALX family of genes. The ALX genes control the production of proteins essential for the normal development of the face and head during pregnancy. ALX proteins are responsible for the regulation of cell division and movement, including cessation of cell growth to form the facial structures during foetal development.^5,7

Both ALX3 and ALX4 genes are mainly associated with the development of the nose and the surrounding tissues, whereas the ALX1 gene is associated with the development of the nose, eyes and mouth. 

Therefore, mutations in one, or a combination of, these genes can cause a reduction or an elimination of the corresponding protein. This results in the dysregulation of the cell organisation throughout the development of the facial features and cranial structure.^4,5 

Frontonasal dysplasia is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must be mutated to display symptoms. Thus, parents carrying one copy of the mutation-causing gene do not display any signs or symptoms of the disease.

Environmental factors

There is evidence to suggest that the diet of the mother during pregnancy and changes in the ambient womb environment due to stress or illness can cause the development of frontonasal dysplasia.²

Clinical presentation

A child born with FD can have several anomalies which are not specific to frontonasal syndrome; however, they may be more common in patients with the syndrome than it is in the wider population. These include:

• Nasal deformities include broad nasal root, cleft of the nose, nostrils that are present to be farther apart, accessory nasal tags, and the absence of nasal tip.
• Cranial and midfacial malformations- These are enlarged distances between the corners of the eye, the widow’s peak hairline, and a cleft present in the middle of the upper lip.
• Ocular anomalies - These are abnormalities affecting the eyes. They include almond-shaped eyes, access to eyelid tissue, benign tumours in the eye, one or both eyes smaller in size, cataracts, and deterioration of the eye.
• Other symptoms - These include extra fingers or toes, low ears, protrusion of the brain, deafness, and absence of tragus in ears.⁸

In addition to this, frontonasal dysplasia patients may affect other organ systems in the body. These include: 

• Central nervous system - Issues relating to this include a split spine, protrusion of both meninges in the brain, protrusion of the brain
• Cardiovascular disease - heart diseases from birth (congenital)
• Developmental delays - decrease in intellectual ability.⁹

Diagnosis

There are a few ways in which this syndrome can be diagnosed as early as in the womb. A prenatal diagnosis is conducted using a 3D Ultrasound technique, where there is an observation for craniofacial abnormalities. After birth, having the presence of two or more of the symptoms is enough for the characterisation of frontonasal dysplasia. An X-ray or MRI of the skull for genetic characterisation can also be done. CT scans have also been used for the evaluation of patients with frontonasal dysplasia.^2,3 

There has been an increase in cases that meet minimal diagnostic criteria; however, these do not demonstrate a clear clinical feature that allows the definition of the different types of frontonasal dysplasia.³

Management and Treatment

When it comes to the treatment of frontonasal dysplasia, healthcare professionals can use several approaches. For newborns, postnatal treatment is given soon after birth to ensure proper functioning of the airway. Surgical treatment can only be performed from the age of 6 months. However, most professionals will wait until the patient is 6-8 years old due to the development of the jaw and the cranium. Other ways to correct cranial defects are with the use of facial surgeries depending on the severity of FD present; these may include canthoplasty (eyelid surgery), rhinoplasty (nose surgery), and oculoplasty (eye surgery). Non-surgical therapies can also be needed, such as orthodontic treatment and speech therapy. Alongside these treatments, psychological and social support may also be provided for patients with intellectual disabilities.¹⁰

Prognosis 

The long-term outlook for patients with frontonasal dysplasia may vary depending on the type of the disease and the severity of the symptoms which the patients show. Cases, where patients have shown facial deformities and no breathing/ swallowing problems have been reported to have a normal life span. In cases where the severity of the symptoms is higher, follow-up care and long-term monitoring may be needed. This may also include genetic counselling of the parents is also important.³  

Research and advancements

In the time to come, different research advancements have been made. Since we still don’t have a full understanding of how this condition is inherited, we have only been able to create an understanding based on the mutations that we currently know about. However, with the advancement of parallel sequencing technology in addition to clinical phenotyping, a new understanding of the aetiology of disease has been made. 

New genetic sequencing technology will aid scientific research in molecular recognition, i.e., understanding the specific molecules that indicate a person has this condition.¹¹

Summary

Frontonasal dysplasia is an uncommon disease affecting cranial development, occasionally affecting the heart and cognitive function of an individual in severe cases.  FD is characterised by different genetic mutations and the severity of symptoms. Individuals may be able to live a normal life span if the symptoms are treated with care by a team of healthcare professionals. In recent years, there has been research being conducted in the hopes of understanding the disease on a molecular level for ease of diagnosis.