Introduction

Brief overview of frontonasal dysplasia (FND)

Frontonasal dysplasia (FND) is a rare developmental defect considered as a sporadic condition that primarily affects the face and head region of the body, often resulting in abnormal development of the forehead, nose, and nasal passages.
The condition ranges in severity from a mild form with minimal clinical features to a severe form that includes clefts and involvement of the central nervous system (CNS). FND has been reported either on its own (non-syndromic) or in conjunction with other serious abnormalities (syndromic).^1,2

Pathophysiology of frontonasal dysplasia

The embryological basis of this syndrome ( FND) originates before the embryo reaches a crown-rump length of 28 mm. During the third week of gestation, two thickened ectodermal areas, known as olfactory areas (early embryonic structures that develop into the sense of smell), develop under the forebrain in the front wall of the stomodeum, on either side of the frontonasal prominence. These areas become pits, called olfactory pits, which divide the frontonasal prominence into a medial and two lateral nasal processes as the surrounding tissue grows. FND arises from improper remodelling of the nasal capsule, causing the fronto-naso-ethmoidal complex to remain in its foetal form. Research suggests that a decrease in 6 migrating neural crest cells leads to these developmental defects.³

The development of frontonasal anomalies is influenced by a combination of genetic predispositions and environmental factors.⁴ Genetic factors include spontaneous mutations (random natural DNA changes) or inherited patterns that affect critical signalling pathways in embryonic development.
Although frontonasal dysplasia occurs as an isolated condition in some cases, it is often associated with a range of other syndromes and systemic abnormalities. These associated conditions can affect the central nervous system, skeletal system, and other organ systems. Understanding the associated syndromes is vital for diagnosis, management, and counselling, as they can include a wide range of other clinical features and systemic impacts.

Clinical features of frontonasal dysplasia 

FND is diagnosed clinically based on the presence of at least two specific characteristics.³

Common craniofacial anomalies are : 

• Hypertelorism (wide-set eyes) 
• Broad nasal bridge 
• Cleft lip and palate 
• Widened philtrum 
• Widow’s peak frontal hairline
• Missing or underdeveloped nasal tip
• Skull malformations

Central nervous system involvement

Other associated physical abnormalities

One of the most well-known signs is the nasal cleft, which can vary from a slight widening of the nasal tip to a split in the nose. This may result in narrowed nostrils leading to airway obstruction and breathing difficulties.⁵

When any of these clinical features manifest, the physical characteristics of FND are often noticeable and identified at birth. The resulting facial abnormalities can adversely impact psychosocial well-being and overall quality of life.⁵

Frontonasal dysplasia syndromes

They include:

• FND1 (caused by ALX3 mutations) 
• FND2 (caused by ALX4 mutations) 
• FND3 (caused by ALX1 mutations)

FND has been categorised into frontonasal dysplasia 1(FND1), frontonasal dysplasia 2 (FND2), and frontonasal dysplasia (FND3), based on the responsible genes, with each displaying varying degrees of distinct phenotypes. These forms are caused by mutations in the ALX3, ALX4, and ALX1 genes, respectively.⁶ These genes are involved in craniofacial development, and mutations can lead to the defective formation of midfacial structures. The mode of inheritance for frontonasal dysplasia could be either autosomal recessive or autosomal dominant.⁷

Frontonasal dysplasia type-2 (FND2) is primarily characterised by malformations of the skull and facial skeleton: this condition results from a mutation in the ALX4 gene.⁶ This type of frontonasal dysplasia is characterised by a significant skull defect and early fusion of the coronal suture (coronal craniosynostosis). Notable features include widely spaced eyes (ocular hypertelorism), a markedly flattened nasal bridge, and variations in hair growth. Affected individuals may experience total alopecia, normal hair, or unusual facial hair growth (facial hypertrichosis).

FND type 3 (FND3) is an extremely severe variant of FND. Mutation of the ALX1 (Aristaless homeodomain 1) gene can lead to severe clinical manifestations.⁸ Frontonasal dysplasia-3 is characterised by the absence of eyes (anophthalmia) or unusually small eyes (microphthalmia), along with low-set, backward-rotated ears.

Diagnosis and differential diagnosis

Clinical assessment

The diagnosis of frontonasal dysplasia usually involves a combination of clinical assessments and advanced imaging methods. A comprehensive physical examination aims to detect distinct facial features, which can offer immediate indications of FND. This condition is diagnosed shortly after birth (neonatal period).

Imaging studies

Imaging studies, such as ultrasound, MRI, and CT, can be invaluable for assessing the internal structures of the face and brain, helping to identify any associated anomalies or complications.⁹

Genetic screening and identification of mutant genes

Genetic testing may also be suggested for certain patients to determine if there is an underlying genetic syndrome contributing to the observed features, especially if there are associated anomalies.^1,10

Syndromes commonly associated with frontonasal dysplasia

Opitz G/BBB Syndrome

Opitz G/BBB syndrome (MID1-OS) is defined by distinct facial features, including hypertelorism, a prominent forehead, a widow's peak, a broad nasal bridge, and upturned nostrils. It is also associated with genitourinary abnormalities such as hypospadias, cryptorchidism, and a hypoplastic or bifid scrotum, along with laryngotracheoesophageal defects.¹¹ Opitz G/BBB Syndrome and Frontonasal Dysplasia both involve facial anomalies such as hypertelorism and abnormalities in the nasal region.

Tessier cleft /syndrome 

The cause of this condition is unknown. Tessier cleft is a collection of conditions that cause severe facial defects or clefts in the bones and soft tissues of the face.

Oculoauriculovertebral spectrum (Goldenhar Syndrome)

Oculoauriculovertebral Spectrum (OAVS) is often associated with frontonasal dysplasia, resulting in a rare disorder known as Oculoauriculofrontonasal syndrome (OAFNS).^12,13 

The oculo-auriculo-vertebral spectrum is a complex developmental disorder primarily characterized by ear anomalies, hemifacial microsomia, epibulbar dermoids, and vertebral abnormalities.^14,15

Holoprosencephaly (HPE) spectrum

It is caused by the failure of the prosencephalon to properly divide along the midline. Holoprosencephaly (HPE) is classified into three types: alobar, semilobar, and lobar.¹⁶ 

Clinical features can vary in severity and presence depending on the HPE subtype. They include facial abnormalities such as cyclopia (a single central eye), synophthalmia (two eyes fused at the midline), hypotelorism (closely spaced eyes), absence of the nose with a proboscis, a small nose with a single nostril, anophthalmia or microphthalmia, an absent nasal septum, and clefts of the lip and palate. Additionally, motor deficits like limb spasticity, axial hypotonia, and dystonia, as well as cognitive impairments.

Apert syndrome

Apert syndrome (AS) is a rare genetic condition marked by craniosynostosis, acrocephaly, and syndactyly of the hands and feet, often accompanied by abnormalities in other organs. The mutations in the Fibroblast growth factor receptor 2 gene (FGFR2) are responsible for the development of the condition.¹⁷

Craniofrontonasal syndrome (CFNS)

Craniofrontonasal syndrome is a rare X-linked disorder that exhibits an unusual inheritance pattern, where heterozygous females display more severe symptoms than hemizygous males. Affected females typically present with features such as coronal craniosynostosis, frontal bossing, hypertelorism, a depressed nasal bridge, bifid nose, craniofacial asymmetry, down-slanting palpebral fissures, frizzy hair, syndactyly, and ridged fingernails.¹⁸

Management and treatment

Effectively managing frontonasal dysplasia and its related syndromes necessitates a collaborative approach, engaging specialists such as craniofacial surgeons, neurosurgeons, ophthalmologists, and geneticists. The primary aim of treatment is to address the functional and cosmetic issues caused by craniofacial and neurological abnormalities, with the overall objective of enhancing the quality of life for those affected.

Multidisciplinary approach

Surgical interventions

Surgical correction is often the primary intervention for the craniofacial anomalies associated with frontonasal dysplasia. Reconstructive surgery can help restore facial shape and reduce psychological stress.⁵

Genetic counselling and supportive care 

Affected people and their families may benefit from genetic counselling. For babies and children with, a team approach may be helpful and might involve specific healthcare, educational, and social interventions.

Summary

Frontonasal dysplasia is a complex craniofacial malformation often associated with various other syndromes and systemic abnormalities. The genetic and embryological basis of FND underscores the complexity of craniofacial development, with mutations in several key genes contributing to the characteristic craniofacial defects.

 Syndromes such as Oculoauriculovertebral Spectrum, Apert Syndrome, Holoprosencephaly, and Craniofrontonasal Syndrome highlight the diverse phenotypic spectrum of FND and associated conditions. 

The management of frontonasal dysplasia requires a multidisciplinary approach, addressing craniofacial abnormalities. Early diagnosis and intervention are critical for improving affected individuals' prognosis and quality of life. Genetic counselling and supportive therapies also play a crucial role in the management of FND and its associated syndromes.