Introduction

Filippi syndrome, which is an autosomal recessive genetic disorder, is characterised by abnormal physical development and intellectual disability, affecting a patient’s quality of life. Fewer than 1000 people in the US are diagnosed with this disease. Although it is classified as a rare disease, there has been progressive research aimed at expanding our understanding of Filippi syndrome, including diagnostic approaches, therapeutic strategies, and research progress.^1,2

Etiology and genetic basis

Genetic mutations associated with Filippi Syndrome 

Filippi syndrome is an autosomal recessive genetic disorder. The mutation responsible for the manifestation of this disease affects the CKAP2L gene. This syndrome will only be expressed if an individual inherits two mutated genes. If an individual inherits one normal gene and one mutated gene, they will be a carrier with no symptoms. If both parents are heterozygous for this mutated gene, there is a 25% probability that the offspring will inherit Filippi syndrome although both parents are healthy individuals.¹ The loss-of-function mutation of the CKAP2L gene results in the defect of a protein named cytoskeleton-associated protein-2-like, found on the centrosome and the mitotic spindle which plays an important role in chromosome organisation and segregation in the cell cycle. Based on mice studies, it has been found that this protein is needed in cell division of neural progenitors.³ Mutations of this gene is associated with the symptoms of Filippi syndrome like growth retardation and intellectual disability.⁴

Clinical manifestations

Physical characteristics

Symptoms of Filippi syndrome vary between affected individuals and may start to appear before, at or after birth.¹ Patients experience growth retardation, particularly concerning the head and facial (craniofacial) area. One of the most common symptoms would be a smaller-than-normal head circumference; this is known as microcephaly. Patients may also have a high forehead, small lower jaw, or distinct nose bridge. Furthermore, limb abnormalities are commonly presented by patients. For example, a 4-year-old male patient with Filippi syndrome had fingers that were webbed or fused, which is known as syndactyly, due to fusion of the skin or bones of the digits. The severity of syndactyly varies between individuals. Some patients may also have unusually short digits known as brachydactyly due to the abnormal development of the digits’ bones.⁵

Neurological and developmental features 

Patients with Filippi syndrome often experience intellectual disability of different severities, which leads to impaired cognitive abilities. Intellectual disability is defined as having an IQ score of below 70. This encompasses delayed language and speech development as well as learning difficulties.⁵ Besides intellectual disability, patients may have limited joint mobility and motor function issues due to the associated genetic mutations.¹

Diagnostic approaches

Clinical examination and family history analysis 

Previously, patients with Filippi syndrome were diagnosed based on their distinctive features or phenotype such as the syndactyly of the third and fourth finger, the syndactyly of certain toes and severe physical disability. As we are aware about the inheritance pattern of Filippi syndrome, family history analysis was also commonly used to predict the risk of offspring or children developing this disease based on the genotype of both parents.⁶ However, it is not the most accurate method as the symptoms often overlap with that of other diseases like Scott craniodigital syndrome where distinctive craniofacial features and abnormal formations of the digits are present. Patients with blephronasofacial syndrome also have intellectual disabilities.⁷

Genetic sequencing and imaging techniques 

Today, genetic analysis is performed to diagnose patients with Filippi syndrome due to its higher accuracy. An example would be using chromosomal microarray analysis (CMA) to detect chromosomal deletions or duplications associated with the disease; these mutations are often too small to be detected by other genetic testing methods like karyotyping and fluorescence in situ hybridisation (FISH). CMA is used to diagnose diseases related to developmental delay and intellectual disability.⁶

Since previous studies have demonstrated variants in CKAP2L in Filippi syndrome patients, whole-genome sequencing has also been used to identify them.⁸ Alternatively, variations of the mutated gene can be analysed using Sanger sequencing to assess the risk of the gene bring inherited by the next generation. Besides genetic sequencing, imaging techniques like MRI and CT scans can be used to reveal detailed information about craniofacial structures, brain morphology, and limb deformities.⁶

Management and treatment

Current treatment options 

Treatments are aimed at combating the symptoms of patients with Filippi syndrome. For individuals experiencing craniofacial abnormalities, surgery is an option for them to correct the formation of the craniofacial bones, but this will depend on the severity of the physical deformities.⁷ 

Therapies are also a conventional treatment, and it usually has to be given at an early stage. They can range from physical therapy to speech therapy, especially among children with Filippi syndrome. Thus, supportive therapy and symptomatic treatment are the only current available options.⁵

Advances in treatment strategies – gene therapy 

Gene therapy is a concept that is not new to the healthcare industry. It aims to replace defective parts of a DNA with a normal gene to treat genetic diseases. There have been many clinical trials ongoing for the development of gene therapy for rare neurological and neurodevelopmental disorders like spinal muscular atrophy (SMA) and Huntington’s disease.⁹ 

Gene therapy can be delivered to the target site via in vivo methods using different delivery systems like virus or lipid nanoparticles. Genetic modification can also occur outside of the body via ex vivo methods before the modified cells are returned to the patient’s body. However, we can expect more novel gene therapies to be approved and made available in the clinical setting in the near future.¹⁰

Challenges and future directions

Current challenges in treating Filippi Syndrome

Clinical trials and drug development remain a significant challenge for rare genetic diseases like Filippi Syndrome, mainly because of the high costs of research, development and manufacturing. There is also a small patient population, so there is a very low demand for gene therapies. It is not an attractive investment, given that the return is low. There is also competition from cheaper alternative treatment options like stem cell transplantation, making gene therapy or other interventions not accessible to patients from lower socio-economic backgrounds. Nevertheless, there are some potential solutions to combat the high development and manufacturing costs of gene therapies. Technological solutions like increased automation and high competitions driving down costs can be applied.¹⁰

Future research directions 

In order to propel the development of gene therapies for rare genetic disorders, different stakeholders need to work together to bring about changes to the drug development and authorisation process. This will allow increased accessibility of gene therapies to patients who will benefit from them significantly. This is important to ensure that the needs of those affected are met despite the small patient population.¹⁰

Summary

Overall, Filippi Syndrome is an extremely rare genetic disorder that often appears at birth (congenital). Symptoms and their severity can vary between individuals. Treatment options will depend on the symptoms experienced. Although there are interventions which aim to adjust physical deformities, neurological complications are more difficult to treat. In the near future, we can expect more breakthroughs in the treatment of Filippi Syndrome using various technologies such as gene therapy. With more extensive research, we can improve the diagnosis, management and treatment of this disease.