Overview 

Filippi syndrome is an autosomal recessive disorder characterised by short stature, microcephaly, syndactyly, intellectual disability, and facial dysmorphism with a bulging forehead, broad and prominent nasal bridge, and reduced alar flare.¹ Additional features include cryptorchidism, seizures, clinodactyly of the fifth finger, speech difficulty, vision problems, polydactyly and ectodermal abnormalities.

This condition is also known as Scott's craniodigital syndrome with mental retardation or type 1 syndactyly with microcephaly and mental retardation.²

Filippi syndrome is caused by mutations in the DNA. Genetic mutations mostly follow an inheritance pattern, suggesting they are passed on from parents to children or can develop during cell division. They can also be caused by viruses or external factors like ultraviolet (UV) rays.

Mutations in the CKAP2L gene can cause the syndrome. It means that a child must possess two copies of the defective gene, one from each biological parent, in order to be affected by the syndrome.²

Filippi syndrome is an uncommon genetic disorder that appears to affect people equally, regardless of gender. Since the disorder was first characterised in 1985 (G. Filippi), there have been around 30 cases documented in the medical literature, including affected siblings within certain families as well as individualistic cases.³ Symptoms of this condition may occur in newborns and infants.

Craniofacial features of Filippi syndrome

Microcephaly

Infants with this disorder may frequently demonstrate microcephaly, a condition in which the head circumference is smaller than expected for an infant's age and gender. Other features may include frontal bossing, long eyelashes, arched eyebrows and high hairline with thin hair.⁴ They also possess intellectual disability and speech delay. Seizures and impaired muscular function are other possible symptoms in severe cases. Though there is no treatment plan for microcephaly, early intervention with speech and occupational therapy can help a child's development and quality of life.⁵

Microcephaly depicted on an infant (Image from Wikimedia Commons)

Hypertelorism

In this condition, the space between the inner eye corners and between the pupils is greater than normal (widely spaced eyes). So, it will cause a rise in intercanthal distance (ICD), outer canthal distance (OCD), and interpupillary distance (IPD). When there is an increase in all three above-mentioned measurements over 95% from normal values, it is known as true orbital hypertelorism.⁶

Patient showing hypertelorism and broad nose features (Image from Wikimedia Commons)

Broad and prominent nasal bridge

Anterior location of the nasal root in comparison to the typical position for age causes a broad nasal bridge and underdeveloped alar flare. Since the orbits are placed widely apart, it will usually result in a broad nose.

Cleft lip and/or palate

Presence of split in the upper lip and/or roof of the mouth. They have difficulties speaking and eating. Treatment options include surgery which restores normal function and speech therapy for better communication.

Image showing the cleft palate of an infant (Image from Wikimedia Commons)

Other common craniofacial anomalies

Micrognathia 

It is a condition in which the jaw is undersized. Also called mandibular hypoplasia.

High-arched palate

It is an elevated roof of the mouth and is also known as high-vaulted palate (high-arched roof of the mouth). Micrognathia or a high-arched palate can also contribute to speech difficulties, making it hard for the tongue to move freely and produce certain sounds correctly.

Low-set ears

This type of low-set ears are characterised by the ear being placed two or more inches below the horizontal imaginary line as in the average population.³

Image of an infant having low-set ears (Image from Wikimedia Commons)

Pseudoproptosis

This occurs when the eye has a drooping anatomic appearance but no mass effect from a lesion that displaces the globe or any underlying pathology.⁶ In some patients, optic atrophy has been noted.⁷

Associated dental abnormalities

Delayed eruption of teeth

Tooth eruption is a physiological process which directly influences the proper development of the craniofacial complex. Individuals with Filippi syndrome show delayed teeth eruption.

Congenitally missing teeth

Congenital absence of bilateral lateral incisors and third molars was noted in this syndrome.^8,9 

Other features such as shortened crown root length, carious teeth and enlarged pulpal spaces were also seen in a particular case study.⁹

Diagnosis of craniofacial abnormalities

Clinical assessment

Physical examination: A thorough physical examination has to be done to diagnose Filippi syndrome, which is characterised by craniofacial abnormalities (microcephaly, hypertelorism, cleft lip/palate), skeletal abnormalities (syndactyly, or fused fingers), and other physical characteristics such as low-set ears, micrognathia or a high-arched palate.¹⁰

Also, any delay in the developmental cycle, intellectual disability, and other cognitive impairments have to be assessed. Evaluating the developmental delays will help us determine the child’s cognitive and motor skills.

Family history: A detailed familial history has to be taken to know about their genetic background especially if there is a history of Filippi syndrome or other genetic diseases in the family. 

Imaging studies

Radiography or imaging studies can be done to check for malformations of the craniofacial and skeletal abnormalities. Computed Tomography imaging (CT) or Magnetic Resonance Imaging (MRI) can be used to identify the skeletal defects.⁸

Other investigations include an orthopantomogram (OPG) to check for congenitally missing teeth, a lateral and posteroanterior (PA) view of the skull for dentofacial abnormalities and hand-wrist X-rays or skeletal X-rays for identifying the bony union of fingers/toes and a delay in the developmental bone age.⁴

Genetic testing

Although an initial assessment can be done, a diagnosis can be confirmed only after genetic testing. Genetic testing can be done through mutational analysis, karyotyping, Fluorescent In Situ Hybridization (FISH) analysis for the subtelomeric regions, Array-Comparative Genomic Hybridization (array-CGH) and Sanger Sequencing.⁴

These genetic assays can detect homozygous or heterozygous mutations and indicate co-segregation with disease phenotypes. Hence, the mutated CKAP2L gene assures the diagnosis of Filippi syndrome.

Management and treatment

As of now, Filippi syndrome does not have an exact treatment protocol. The affected children are treated based on their symptoms. Initially, the parents have to be properly addressed regarding this condition and its effect on the child, making sure they are informed and aware of the treatment options.

Multidisciplinary approach

A team of specialists, including paediatricians, geneticists, neurologists, orthodontists, plastic surgeons, and speech therapists engages in collaboration to develop a detailed treatment strategy. Every child's treatment is customised based on the specific symptoms and severity of their syndrome.

Surgical interventions

Cleft lip surgery is performed in the first few months of birth and cleft palate surgery can be performed between 6 and 18 months of age. The procedure involves bridging a gap in the lip and/or palate to improve feeding, speech development, and facial appearance.¹¹

Syndactyly release surgery: During surgery, an incision is made to separate the joined fingers or toes and then rebuilt using skin grafts.¹² This surgery is not mandatory for all the affected individuals as it is advised only based on the severity of syndactyly when it impairs normal daily activities.

Craniofacial surgery: Surgical interventions can help to modify certain craniofacial abnormalities. In this surgery, part of the bone or excessive skin is removed from the central area to correct hypertelorism. Reduced or underdeveloped nasal flare can also be corrected by reconstructing the orofacial region using cartilage grafts.¹³

Orthodontic and restorative treatment

Dental malocclusion can be corrected using orthodontic braces or by combining orthodontic treatment with surgical advancement to correct mandibular hypoplasia.

Carious teeth can be restored using many restorative techniques and counselling has to be given to the parents for maintaining proper oral hygiene.

Supportive therapies

Speech therapy: Children with this syndrome often have a cleft palate, which can lead to excessive nasal tone in speech, articulation difficulties and an inability to produce certain sounds.¹⁴ So providing speech therapy at a young age helps them to communicate. 

The importance of early intervention

If there is a known family history or if both parents are carriers of the genetic mutation associated with the CKAP2L gene, early or prenatal genetic testing can be done to ensure appropriate treatment. Carrier screening, amniocentesis or non-invasive prenatal testing can be done to determine if both parents carry the CKAP2L gene mutation.⁴ 

Summary

Filippi syndrome is a rare genetic disorder, and only around 30 people are affected worldwide, continuous research and clinical studies have to be done in the field of gene mutation. This will help to find the founder effect of this syndrome so that treatment plans can be achieved. With continued advancements and research, the future promises even better outcomes for those living with this genetic disorder. Thus, combining medical and clinical studies with genetic counselling can greatly enhance the quality of life for affected children.