Frontonasal dysplasia (FND) is a rare birth condition, marked by abnormalities in the head and facial development before a baby is born. Also referred to as median cleft face syndrome, people born with this condition often have features like widely spaced flat nasal bridges and eyes, as well as occasionally a split or cleft in the nose.¹ Having frontonasal dysplasia can have an impact on the development of individuals affecting both physical growth and cognitive abilities.¹ Understanding these developmental delays is crucial for providing effective treatment and family support, thereby improving the quality of life of affected people. 

Understanding frontonasal dysplasia

There are mainly 3 subtypes of frontonasal dysplasia, based on genetic origins and symptoms, each with different physical features and different degrees of severity.¹

Frontonasal dysplasia-1 (FND-1)

Individuals with FND-1 subtype frequently exhibit a range of physical features and health conditions such as:

• Hypertelorism or widely spaced eyes
• Vertical groove on the face 
• Flat or broad nose
• Small nostrils
• Widow's peak or V-shaped hairline 
• Swollen philtrum–swollen area between the nose and upper lip
• Ptosis or drooping eyelids
• Cleft palate 
• Frontal cutaneous lipoma–small, fatty lump that may appear on the forehead.
• Dermoid cyst–non-cancerous growth that often appears along the midline of the face.
• Heart defects (like tetralogy of Fallot)
• Underdeveloped chest muscles
• Clinodactyly and camptodactyly (bent or curved fingers)^1,2

Frontonasal dysplasia type 2 (FND-2)

FND-2 is characterised by a large skull defect and early fusion of a skull suture, which can impact brain growth and shape. Other key features in individuals with FND-2 include:

• Microphthalmia–small or underdeveloped eyes
• Blepharophimosis– drooping or narrowed eyelid openings
• Flat or depressed nasal bridge
• Cleft alae nasi–cleft in the sides of the nostrils 
• Hypertelorism
• Craniosynostosis– premature fusion of skull bones, 
• Total alopecia–little or no scalp hair
• Very little or missing eyebrows and eyelashes
• Skeletal abnormalities with varying severity
• Hypospadias–the opening of the urethra is not at the tip of the penis 
• Cryptorchidism–undescended testicles
• Partial absence of corpus callosum^1,2

Frontonasal dysplasia type 3 (FND-3)

The common traits seen in children with this type of FND are:

• Bilateral facial cleft
• Microphthalmia
• Cleft palate
• Coloboma
• Absence of eyebrows
• Sparse eyelashes
• Missing or very small ears^1,2

Causes of frontonasal dysplasia

Each type of FND is caused by mutations in specific genes. Mutations in the ALX3 gene produce FND-1, the ALX4 gene causes FND-2, and the ALX1 gene causes FND-3. FND-1 and FND-3 have a recessive pattern of inheritance, meaning that a child must inherit two copies of the faulty gene in order to show symptoms. However, since FND-2 is inherited in a dominant manner, the condition can be brought on by a single faulty copy of the gene. However, these genetic alterations can sometimes occur spontaneously and are not passed from parents.¹

The Impact of FND in cognitive and physical development 

Cognitive development

Cognitive development refers to the ability to think, learn, reason, and understand the world.. This includes the development of skills such as memory, problem-solving, language, and decision-making, starting from infancy through adulthood.^3,4 In people with frontonasal dysplasia, cognitive development can be affected or delayed, especially due to the craniofacial or skeletal abnormalities associated with the condition.² The most common cognitive developmental issues reported in people with FND include:

Corpus callosum agenesis

The structure that joins your brain's two hemispheres is called the corpus callosum. It is essential for the integration of sensory, motor, and cognitive processes. This structure is absent or underdeveloped in individuals with FND, which can result in different degrees of intellectual disability. Children, particularly FND1 and FND2, may experience mild to severe intellectual disability, which can impact their ability to develop skills such as speaking, learning, reasoning, and problem-solving.^2,5,6,7

Cerebellar vermis hypoplasia

Children with FND may have underdeveloped cerebellar vermis, the region of the brain that regulates balance and coordination, which can also lead to learning challenges and delayed cognitive milestones.²

Learning difficulties

Children with FND may experience varying degrees of learning difficulties as a result of abnormalities in their brain structure. Developmental delays in a kid with FND may affect the child's capacity to carry out tasks that are suitable for their age. For instance, a 12-year-old child with FND is able to do tasks equivalent to those of a 7-year-old.⁵

Mental Retardation

Mental retardation in FND can greatly affect the cognitive development of an individual. For instance, a study conducted on 10 Brazilian male children with FND revealed that all exhibited severe mental retardation. This can contribute to significant delays in cognitive development and overall intellectual function.⁶

Apart from these, some children experience seizures and convulsions, which can further impact cognitive development and require ongoing medical management. Moreover, many children show delays in overall neuropsychological development, with difficulties in both cognitive and motor skills, requiring additional support to meet developmental milestones. In severe cases of FND, children may not acquire language skills, indicating profound cognitive impairment and the need for specialised communication support. People with milder cases of frontonasal dysplasia may not be diagnosed with the condition right away because the changes in their faces are not as obvious at first. But as these features become more noticeable over time, they may harm a person's mental health by affecting their self-esteem.^6,8

Physical development delays

Physical development delays are common in people with FND. For instance, many kids with FND take longer than expected to reach motor milestones like sitting up, crawling, or walking. This may be the result of neurological problems, underdeveloped muscles, skeletal abnormalities, or craniofacial abnormalities.⁵

Craniofacial abnormalities–Some of the most common craniofacial abnormalities that can affect a child’s physical development include:

• Cranium bifidum occultum
• Craniosynostosis which can affect the shape of the head and brain development.
• Underdeveloped upper jaw bones^2,5,7

Skeletal abnormalities –This can affect the physical development of children with some facing significant issues with their bones. Common skeletal anomalies in FND patients that contribute to delayed physical development are thoracolumbar scoliosis (curvature of the spine), curved tibiae, short halluces (big toes), and club foot. Additionally, limb anomalies like mildly short limbs, hyperextensible joints, and 5th finger clinodactyly (curvature of the little finger)⁷.

Hypotonia– Reduced muscle tone, known as hypotonia, can contribute to delays in motor development, making it difficult for children to develop the strength and coordination needed for movement.

Clumsiness and coordination issues– Some children exhibit clumsiness in movements, which is a sign of balance problems and makes the delay in motor skill development even worse.⁵

Physical growth variability–While some kids develop normally, others exhibit growth setbacks, especially when it comes to weight and height. A delay in physical growth is indicated by some children's growth measurements, which are below the third percentile for their age.⁶ Moreover, some people may have feeding difficulties, which were likely related to their craniofacial abnormalities and developmental delays.^2,6

Genital hypoplasia–Some people with FND have genital hypoplasia or a delayed or underdevelopment of external genital organs.⁶

Vision and hearing problems–Strabismus, ptosis, and iris coloboma are some conditions that can contribute to visual abnormalities in affected individuals.⁶

Management and treatment strategies 

The management and treatment plan for developmental delays and related issues are determined by how extended or severe the physical traits are.

Surgery

Surgery can be performed to correct the craniofacial abnormalities (eg. cleft lip, split nose, etc.). However, when a child with the condition gets older, more procedures can be required in some situations. For instance, to correct craniosynostosis, a minimally invasive suturectomy surgery is usually performed. It is followed by helmet therapy for younger patients or an open operation for older children. Surgical correction for a cleft nose is usually performed when they are 1 or 2 years old and is often followed by revision surgeries and possibly a rhinoplasty during adolescence.^1,9

Genetic counseling

If you or someone in your family is affected by FND, genetic counselling is beneficial. For infants and kids with this illness, a team approach that includes specialised social, educational, as well as medical services may be beneficial.¹

Summary

Frontonasal dysplasia is a rare congenital condition marked by facial and head abnormalities.

This condition can cause significant cognitive developmental delays, including intellectual disabilities, mental retardation, and learning difficulties, which can impact language, problem-solving, and reasoning abilities.

Physical development is also delayed due to craniofacial and skeletal abnormalities and underdeveloped muscles, leading to issues like delayed motor milestones and growth setbacks.

Management of this condition mainly includes surgical correction of facial defects, genetic counselling, as well as a multidisciplinary approach in order to support developmental needs and improve the quality of life.