Introduction

Frontofacionasal (Frun-toh-fay-shee-o-nay-zal) dysplasia (Dis-play-zhuh) is a rare genetic disorder that affects the development of the midface, mainly the nose and forehead regions. It is sometimes also known as frontonasal dysplasia, depending on the signs and symptoms shown by the affected person. 

A person with this condition can have mild to severe symptoms, such as wide eyes, a broad nasal bridge, absence of the tip of the nose, facial cleft affecting the upper lip or palate, and/or nose, or other deformities affecting facial structure.¹ This can significantly affect a person’s appearance, depending on the severity of symptoms, and can lead to breathing and vision difficulties.

What is the craniofacial region, and why is it important?

The craniofacial region involves the bones of the face and skull. A human baby starts to develop a face during the 4^th to 8^th week of pregnancy. Various cells move from the neural crest (a specialised region with cells that can make different types of cells and tissues) to different parts of the embryo to give rise to different tissues. 

A region named as frontonasal prominence is very important for the formation of the nose, forehead, and midface. Any disruption in the formation of this region can result in disorders related to facial structures, as seen in frontofacionasal dysplasia.²

Inheritance pattern

Frontofacionasal Dysplasia is usually inherited in an autosomal recessive pattern, meaning a child should have two copies of faulty genes from both parents for this condition to appear. If both parents have the condition or if they are carriers, their child will have this condition.²

Some craniofacial conditions have symptoms similar to frontofacionasal dysplasia, and they show autosomal dominant patterns of inheritance. In this case, even a single copy of faulty genes can cause the disorder. Although these types of cases are not common.

Causes of Frontofacionasal Dysplasia

Genetic factors

Genetic mutations are one of the main causes of frontofacionasal dysplasia. Many of these mutations affect the genes involved in the formation or development of the craniofacial region. Different types of mutations can lead to a variety of symptoms ranging from mild to severe.

Genes such as ALX1, ALX3, and ALX4 are essential for the development of craniofacial structures. Mutations in any of these genes can disrupt the normal development and result in a mild (ALX3) to severe (ALX1) form of frontofacionasal dysplasia.³ ALX1 is associated with the most severe type of frontofacionasal dysplasia. The presence of a mutation in this gene leads to a non-functional protein, which prevents midline structure formation in the face.

Genetic mutations in other genes such as FGFR1 (Fibroblast Growth Factor Receptor 1), MSX1 and MSX2, and SHH (Sonic Hedgehog) also affect the r development of the craniofacial structures, resulting in features similar to frontofacionasal dysplasia.²

Genetic mutations in genes of certain signalling pathways, such as WNT signalling, BMP (Bone Morphogenetic Protein) Signalling, etc., can also cause frontofacionasal dysplasia, as these signalling pathways are crucial for the proper development of craniofacial regions.

Environmental factors

Apart from genetic factors, certain environmental factors during crucial periods of fetal growth in pregnancy can have harmful effects and lead to developmental disorders.

Exposure to teratogens 

Teratogens are compounds that affect fetal growth during pregnancy. The most common teratogenic compounds are alcohol, smoke, the use of certain drugs or medications, and infection with infectious agents like rubella. These compounds have been shown to have a negative impact on fetal growth and some craniofacial features, although research is still going on in this area.⁴

Deficiency of certain nutritional factors like folic acid, vitamin B12, or some multivitamins during pregnancy can lead to many birth defects, such as neural tube defects, microcephaly, etc. Although the role of these nutrients is not established directly in the development of frontofacionasal dysplasia, but considering their importance in cell division and early fetal growth during pregnancy, the adequate supply of these nutrients is essential for a healthy pregnancy and proper fetal development.⁴

FAQs

What is the life expectancy of someone with frontonasal dysplasia?

The life expectancy of someone with frontonasal dysplasia depends on several conditions, such as the type and severity of symptoms or whether the affected person has other conditions related to development, access to relevant medical care, and awareness of family and timely medical interventions. A person with mild symptoms and better access to healthcare and management can have a normal life expectancy compared to a person with mild symptoms but poor access to healthcare. A person with severe symptoms and associated complications can have overall poor health and relatively short life expectancy, irrespective of medical care. Hence, the life expectancy in frontonasal dysplasia depends on the individual's conditions.

How do you treat frontonasal dysplasia?

There is no complete treatment or cure for frontonasal dysplasia, however, the necessary medical care and surgical intervention can significantly improve a person’s quality of life.

How rare is frontonasal dysplasia?

Frontonasal dysplasia is a rare genetic disorder, and it has an occurrence of less than 1 in every 1,000,000 live births.

What are the features of frontonasal dysplasia?

The main features of frontonasal dysplasia are wide-set eyes, a broad nasal bridge, absence of nose tip, facial cleft affecting the upper lip or palate and/or nose, and other deformities related to facial structures.

What happens if frontonasal dysplasia goes untreated?

The treatment of frontonasal dysplasia often involves corrective cosmetic surgeries to improve facial appearances, surgeries to improve breathing-related difficulties, feeding, speech, and vision-related issues, dental procedures to improve dental alignment, and hearing problems etc. The occurrence of these associated conditions depends on the severity of frontonasal dysplasia, and if left untreated, it can harm the day-to-day life of an affected individual and can even be life-threatening in some cases. As this condition affects facial appearances, a person affected with this condition can have difficulties in social interactions due to fear of bullying, social exclusion, and lower self-esteem, which can have a long-term psychological impact.

Is dysplasia painful?

Having dysplasia itself is not painful, but the associated complications can make a person’s life challenging, considering the medical care, surgical interventions needed for management of this condition, other difficulties like breathing, vision, dental issues, feeding problems, and a higher risk of infections due to structural deformities.

Is dysplasia considered a disability?

Considering dysplasia as a disability depends on the severity of symptoms related to dysplasia. If a person has severe symptoms of the condition and it impacts his/her ability to do everyday tasks such as feeding, moving around, communicating, then it can be considered a disability. However, if the symptoms are mild and only affect the appearance of certain facial features and do not limit their function, then it may not be considered a disability. Additionally, the definition of disability depends on legal definitions and social context, which can vary across countries and their respective laws..

Does dysplasia run in families?

Dysplasia can run in families if the parents are affected or carriers. But the causes of dysplasia are diverse; it can be inherited in an autosomal recessive, autosomal dominant, complex inheritance pattern, and sometimes even random mutations can occur in genes leading to dysplasia.

Is dysplasia a Tumour?

No, it is not a tumour.

Is dysplasia terminal?

It can be terminal if the symptoms are severe and proper medical care is not provided timely.

Does dysplasia need surgery?

Yes, some corrective surgeries might be necessary depending on the severity of symptoms. Such as improving facial appearances, breathing, jaw alignment for better feeding, eye surgery for improved vision, etc.

Are cleft noses genetic?

Cleft noses can have a genetic basis, but some cases of cleft noses can also arise due to environmental factors such as smoking during pregnancy, use of certain medications, alcohol use, and deficiency of certain nutrients such as folic acid.

Summary

The aetiology of frontofacionasal dysplasia is complex, and a lot is still unknown about this disorder. This disorder shares features with many craniofacial syndromes and shows a spectrum of clinical features ranging from mild to severe. Advanced molecular techniques of next-generation sequencing, such as whole-genome sequencing, whole-exome sequencing, can help to discover new genetic mutations associated with frontofacionasal dysplasia.