Introduction

Frontofacionasal dysplasia is a rare congenital disease that is largely characterised by physical craniofacial and ocular malformations. This disease is currently an active area of research with many aspects yet to be explored and understood.¹ While it can vary in severity, it also has many syndromes commonly associated with it. This article focuses on what frontofacionasal dysplasia is, as well as the syndromes that are often associated with it due to similar symptoms and manifestations.

Causes and risk factors of frontofacionasal dysplasia

It has been suggested that frontofacionasal dysplasia is an autosomal recessive disorder and is more common within children of parents who are blood related, also known as ‘consanguineous’ children. This is because the presence of the same autosomal recessive mutations in both parents is more likely, as they may originate from their common ancestor.¹ A child carrying one autosomal recessive gene for frontofacionasal dysplasia is a carrier; however, a child carrying two autosomal recessive genes will suffer from frontofacionasal dysplasia.

The greater the blood relation between two parents, the more likely it is that they both carry an autosomal recessive gene for the disease, meaning there is a greater chance for the disease's appearance.² The autosomal recessive genes associated with frontofacionasal dysplasia are not present in every human, because the associated genes are mutated. The exact genes correlated with frontofacionasal dysplasia are not fully understood, and more research is needed to draw a complete conclusion.³

Symptoms of frontofacionasal dysplasia

Due to the variability of the condition and the existence of symptoms similar to other, but potentially less severe, disorders, differential diagnosis is usually necessary in potential cases of frontofacionasal dysplasia. However, there are some distinguishing features such as S-shaped palpebral fissures (narrowing of the folds in upper and lower eyelids), missing parts of the eyelids, increased distance between eyes, and cleft lip or palate.^4,5 In these cases, patients tend to have skull malformations accompanied by ocular, nasal and facial defects.¹ Other more prevalent features include a broad head, an inability to close the eyes fully and abnormal alae nasi parts of the nose.⁶

Aside from these more prominent symptoms, a vast range of other features such as craniosynostosis, midface hypoplasia, microphthalmia (small eyeballs), widow’s peaks, benign forehead tumors and cyst formation around the eyes.¹ Each of these symptoms can have its impact on the patient, and these consequences may also need management. For example, cleft palate and lip have been associated with a greater incidence of missing and supernumerary teeth. However, the lack of a clear scientific root cause for frontofacionasal dysplasia indicates that more research is needed behind the specific biological mechanisms responsible for the disease. This also led to a clearer path towards a more effective treatment.⁷

Diagnosis of frontofacionasal dysplasia

Identifying frontofacionasal dysplasia usually depends on physical examinations, either prenatally or postnatally. Due to the congenital nature of the condition, traits such as cleft palate can be detected before birth using fetal ultrasounds.¹ This is useful because prenatal detection is optimal for improving clinical care for patients to organise prebirth multidisciplinary treatment.⁸

If prenatal detection is not possible, individuals undergo a physical examination of clinical manifestations to identify what abnormal features are present. MRIs, CT scans, and physical examinations can be used to identify the baby with potential frontofacionasal dysplasia if distinctive symptoms, such as S-shaped palpebral fissures and missing parts of the eyelids, are present.⁷

Treatment and management of frontofacionasal dysplasia

Frontofacionasal dysplasia’s symptoms are difficult to treat at once, simultaneously. Therefore, proper management of this disorder needs a variety of healthcare professionals to treat each symptom that may affect an individual.

For example, treating the distinct S-shaped palpebral fissures and missing parts of the eyelids present in frontofacionasal dysplasia requires an oculoplastic surgeon. However, treatment of the cleft lip and palate requires a maxillofacial surgeon. Thus, a multidisciplinary approach is necessary when the symptoms require varied surgical interventions.

As mentioned, the symptoms of frontofacionasal dysplasia can lead to other issues, such as supernumerary teeth, and to resolve these problems, specialists such as orthodontists are needed.⁷ Besides, new processes have been clinically tried to treat certain aspects of frontofacionasal dysplasia more effectively.

These processes reduce the risks involved by being less invasive than traditional surgery treatments and a faster option. By slowly improving upon current procedures, treating frontofacionasal dysplasia can become even safer and more efficient.⁹

Syndromic associations with frontofacionasal dysplasia

Frontofacionasal dysplasia has multiple syndromes associated with it that share similar abnormalities and manifestations, as well as the causes linked to genetic mutations.

Frontofacionasal dysplasia and holoprosencephaly

Holoprosencephaly is often confused with frontofacionasal dysplasia due to similar craniofacial abnormalities. It is a birth defect that causes the developing fetus’ brain to not fully separate into its right and left halves. These right and left hemispheres further divide into different parts which are important for the brain to process information and perform actions simultaneously. If it does not have this proper division, there are numerous neurological and physical issues, resulting from midline facial defects, which range in severity and symptoms, similar to frontofacionasal dysplasia. There are three major types of holoprosencephaly. Alobar holoprosencephaly is the most severe, which is when the baby’s brain has not divided into two halves at all and is therefore associated with severe facial deformities. Semilobar holoprosencephaly is when the baby’s brain has partially divided into two halves and usually only has a dividing line between the two at the back of the brain. Lobar holoprosencephaly is the least severe and is when the baby’s brain has almost fully separated into the two halves but there is an incomplete division of the two. The most common symptoms of holoprosencephaly include cleft lips and palates, developmental delays, small or large heads, single eyes, small eyeballs, flattened nose, closely spaced eyes and other facial abnormalities.¹⁰ As shown, many of these overlap with those associated with frontofacionasal dysplasia. Causes of holoprosencephaly include genetic syndromes and mutations of certain genes, once again similar to frontofacionasal dysplasia.

Frontofacionasal dysplasia and oculo-auriculo-vertebral spectrum

Oculo-auriculo-vertebral spectrum (OAVS) is a congenital disorder characterised by craniofacial deformities. The majority of these deformations occur in the eyes, mouth, including lips, tongue and palate, ear and spine.^11,12 Internal organs, such as the heart, kidneys, and central nervous system, may also be involved. There is a spectrum of symptoms associated, which range from facial symmetry to facial deformations and internal organ effects.¹¹

Approximately 60% of manifestations occur on only one side of the body, but can occur on both sides in around 10%-33% of people.¹² There may also be developmental delays. Unfortunately, management and treatment of OAVS can prove challenging due to the varying levels of severity in abnormalities.¹¹ In most cases, OAVS appears randomly; however, some family histories suggest autosomal inheritance.¹² Above lists several aspects that may also be associated with frontofacionasal dysplasia, including the craniofacial anomalies and midline defects.

Frontofacionasal dysplasia and Treacher Collins syndrome

Treacher Collins syndrome (TCS) is a rare genetic disorder characterised by distinctive malformations of the head or face. These may include an underdeveloped skull, facial structure, cheekbones, palate, and mouth. Other manifestations can include palpebral fissures (downward slanting of the upper and lower eyelids), anomalies in ear structure, a small head and psychomotor delay. The severity once again varies between individuals, with some going undiagnosed and others with life-threatening complications. It is also caused by variations and mutations in various genes.¹³ This disorder also shows similarities with frontofacionasal dysplasia.

Summary

To summarise, frontofacionasal dysplasia is a rare but complex congenital disorder that most likely arises from specific gene mutations. The condition is marked by a wide variety of clinical manifestations, some overlap with other craniofacial disorders, making accurate diagnosis challenging. This complexity necessitates a comprehensive, multidisciplinary approach to treatment, where various specialists are involved with treating the typically severe symptoms associated with the disorder. Given the variability in presentation, more research is essential to fully understand the genetic causes and mechanisms at play, which could lead to more precise and effective interventions. While current treatment efforts focus on managing the physical symptoms through surgical interventions, the future of managing frontofacionasal dysplasia lies in the advancement of medical technologies. However, much work remains to be done to utilise these early-stage technologies and procedures as reliable treatment options. The refinement of these approaches is critical, as they offer hope for improving the quality of life for individuals affected by this challenging condition.