Introduction

Overview of frontofacionasal dysplasia (FFND)

Definition and description of frontofacionasal dysplasia

The structure of the skull and the face is very complicated because they contain many organs and nerves, including the most important organ in the human body, which is the brain.¹

How the skull and face of the human develop while being an embryo is unique, as every part of them develops individually, and then they start to fuse, allowing the confined organs to grow.¹

When these parts fuse, they form facial and cranial midlines (an imaginary vertical line that divides the brain into equal left and right hemispheres). Any error that occurs during the development of any of the parts or the fusion will affect both midlines, leading to what is known as frontofacionasal dysplasia, which means frontal, nasal and facial defects. These defects affect the face and skull's shape, and the organs' functions.¹

Aetiology and genetic factors involved

Researchers have found that genetic factors are involved in causing frontofacionasal dysplasia. Six genes are linked to most types of this disorder. In addition, environmental factors are also involved in causing frontofacionasal dysplasia.¹

Significance of orofacial clefts

Definition of cleft lip and palate

Orofacial clefts mean a disturbance or break in the continuity of the natural facial feature, and the three most common orofacial clefts are:²

• Cleft palate, which involves the roof of the mouth
• Cleft lip, which includes the upper lip
• Cleft lip and palate

There are other forms of orofacial clefts, but these three are the most common in the world population, with a rate of one case to every 1000 births.²

In the United Kingdom (England, Wales and Northern Ireland), 21,865 children were recorded to be born with cleft lip and/or palate between 1 January 2000 and 31 December 2020.

Cleft palate was more commonly seen in babies, followed by cleft lip, unilateral cleft lip (one side of the lip is affected) and palate, and bilateral cleft lip (both sides of the lip are affected) and palate – the rarest type of orofacial cleft.

The development of the face and mouth occurs during the very early stages of pregnancy, where both the nasal cavity and the mouth are connected. Then the roof of the mouth (the palate) starts to fuse, separating the nasal cavity from the oral cavity.²

Individuals born with any of the three disorders – cleft palate, cleft lip, or cleft lip and palate – face many difficulties during feeding and speech. Surgeries and dental procedures are required to correct these defects.²

Individuals born with orofacial clefts have an increased rate of mental illness compared to others.²

Causative factors of orofacial clefts in frontofacionasal dysplasia

Genetic and environmental contributors

Genetic factors associated with FFND and cleft formation

Research has proven that genetics influences or contributes to the occurrence of cleft lip, cleft palate, or cleft lip and palate. However, despite multiple studies, the specific gene contributing to orofacial clefts has not been found.²

Studies have discovered the chances of familial inheritance of cleft lip and cleft palate. The chances of a child being born with a cleft lip to a first-degree relative of an individual with a cleft lip were 32 times higher than for those without. Furthermore, for cleft palates, the risk was 56 times higher than for those without a family history.²

This risk is reduced with the genetic distance (second-degree relatives and so on).²

Environmental risk factors

Environmental risk factors play an important role in orofacial clefts and frontofacionasal dysplasia occurrence.

• Smoking during pregnancy, especially in the first trimester, or being exposed to smoking can affect the development of the foetus and increase the risk of orofacial clefts by 6.1%²
• Consumption of alcohol has an effect as well, but not as much as smoking, unless it is consumed in large amounts over a short period²
• Some drugs may cause orofacial clefts or frontofacionasal dysplasia if they have anti-folate properties affecting the folic acid in the mother's body²
• Some environmental factors can positively affect orofacial clefts, like vitamin supplements (e.g., folic acid). They are considered a protective factor working on preventing the occurrence of these disorders²

Pathophysiology and clinical presentation

Developmental biology of orofacial clefts

Pathological mechanisms leading to cleft formation in FFND

• Orofacial clefts can happen due to chromosomal and genetic abnormalities and some syndromes, like Fryns syndrome (a syndrome with diaphragmatic defects), Meckel syndrome (a syndrome characterised by brain malformation and kidney defects), Treacher Collins syndrome (a disorder that affects the development of the head) and other syndromes³
• In addition, defects in genes that influence the mother’s ability to maintain a certain level of zinc concentration in the red blood cells and myoinositol can lead to orofacial clefts³ 
• Some environmental factors like smoking, drinking alcohol, deficiency of vitamins like B6 and B12, diabetes, and the age of the parents may cause orofacial clefts³
• Drugs can also play a role in the development of orofacial clefts, but it is not significant. Drugs like amoxicillin and phenytoin can cause cleft lip and palate, while a drug like carbamazepine can cause a posterior cleft palate³

Clinical features

Typical presentation of cleft lip and palate in FFND

Children with a cleft lip, palate or both have significantly decreased quality of life. From birth, they suffer during feeding and swallowing due to the absence of the oral seal made by both the palate and the lip, in addition to the nasal regurgitation.³

They suffer from hearing difficulties because of the defective palate muscles. They also experience speech abnormalities from dental problems and a lack of nasal articulation.³

Studies on adolescents with orofacial clefts and other congenital abnormalities showed them to have a very low quality of life in comparison with adolescents who don't have any kind of malformation. They also suffer from stigma, which affects their psychological and mental health.³

Orofacial clefts are either:

• Syndromic, which means that they are associated with a certain syndrome
• Non-syndromic, which means that the individual is healthy but only suffers from orofacial clefts

Treatment approaches for orofacial clefts in FFND

Surgical interventions

Surgeons treat orofacial clefts by repairing and reconstructing the lip. Palatoplasty is the surgery done to close the palate and restore the oral seal.

Treating the orofacial clefts needs a group of specialists to work together – a surgeon, speech specialist, dentist, hearing specialist, orthodontist (teeth and jaw alignment specialist), and a paediatrician.³

Timing and types of surgical repair

• Palatal repair
  • The goal is to allow speech development, facial growth and velopharyngeal function (separating the mouth and the nose to allow proper speech and swallowing). To do this, the nasal, muscular, and oral mucosal layers must be sealed⁶
  • There are two techniques to repair the palatal cleft. The first is a one-stage technique where both the soft and hard palates are repaired at the same time. This technique has the advantage of helping in developing speech⁴
  • The second technique is a two-stage technique where the soft palate is repaired early, around nine and 12 months. The hard palate is repaired later on, at the stage of tooth development. This technique allows facial and maxillary (upper jawbone) growth
• Cleft lip repair
  • Usually, the lip repair is also accompanied by the correction of the nose position, which allows a symmetrical growth of the face
  • There are many techniques for lip repair, and surgery usually takes place between 12 months to 18 months of age

Multidisciplinary management

Role of plastic surgeons, orthodontists, speech therapists, and other specialists

Role of a speech therapist

As mentioned earlier, the child with orofacial clefts has difficulty with speech. Therefore, a speech specialist helps to rehabilitate speech and helps them pronounce and produce sounds correctly after surgery.⁵

Role of the audiologist

Due to the defects in the musculature of the palate, the child might have difficulty hearing or a hearing impairment. The child might also suffer from repeated infections, requiring an audiologist to prevent the infections and treat hearing loss.⁵

Role of the plastic surgeon

A plastic surgeon is needed to treat the clefts and allow symmetrical facial growth without leaving scars, or with minimal scarring, that does not negatively affect the aesthetics of the child.⁵

Role of the dentist

Children with orofacial clefts suffer from crowding of teeth, impacted teeth, delayed eruption of teeth and also missing teeth, which in turn affect the chewing of food and the quality of life.⁵

Role of the orthodontist

Orofacial clefts can affect the growth of both the lower (mandible) and upper (maxilla) jawbones, causing jaw misalignment (malocclusion), which affects the health of the jaw joints (temporomandibular joint or TMJ). An orthodontist is needed to treat these problems.⁵

Summary

Orofacial clefts are facial defects a child is born with due to a disturbance or failure in the fusion of tissues that should have occurred naturally during foetal development. Cleft palate, cleft lip, unilateral cleft lip (one side of the lip is affected) and palate, and bilateral cleft lip (both sides of the lip are affected) and palate are the types of orofacial clefts. Between 2000 and 2020, 21,865 children were born in the UK with orofacial clefts.

Genetic and environmental factors (e.g., smoking during pregnancy) cause orofacial clefts in frontofacionasal dysplasia. Orofacial syndrome can be syndromic, i.e., associated with other syndromes, or non-syndromic, as seen in otherwise healthy individuals. Orofacial clefts are treated surgically by a multidisciplinary group of specialists.