Clinical and Genetic Spectrum of Filippi Syndrome: A Systematic Review of Published Case Reports and Case Series

Filippi syndrome is a very rare autosomal recessive craniodigital disorder primarily caused by mutations in the gene CKAP2L, characterized by syndactyly, microcephaly, growth retardation, distinctive craniofacial features, and intellectual disability. Because of its rarity and phenotypical overlap and related craniodigital disorders, its full clinical and genetic spectrum remains poorly defined. This systematic review aimed to synthesize the published literature on the clinical presentation, genetic findings, and reported management of Filippi syndrome and Filippi-like overlapping phenotypes.

We performed a systematic review in accordance with PRISMA 2020, searching in PubMed, Embase, and Web of Science from inception to June 2025 for case reports and series describing Filippi syndrome, clinically diagnosed classical Filippi syndrome, and Filippi-like overlapping phenotypes. Clinical, radiological, and genetic data were extracted descriptively.

Twenty-two studies comprising 43 reported patients were included. The most frequent findings were characteristic craniofacial dysmorphism, digital syndactyly, microcephaly, short stature or growth retardation, and neurodevelopmental impairment. CKAP2L was the principal implicated gene in molecularly confirmed cases, while a smaller number of reports described alternative genetic findings in patients with Filippi-like overlapping phenotypes. Additional manifestations included dental anomalies, skeletal abnormalities, neurologic involvement, cardiovascular defects, and genitourinary abnormalities. Reported management was mainly supportive and symptom-directed, including surgical correction of syndactyly and rehabilitative therapies.

Filippi syndrome has a broad and heterogenous clinical presentation centered on microcephaly, syndactyly, craniofacial dysmorphism, growth impairment, and developmental delay. Inclusion of Filippi-like overlapping phenotypes highlights both the diagnostic complexity and the need to distinguish CKAP2L-related disease from phenotypically similar entities. This review collates a broad overview of clinical and genetic observations, highlighting the necessity for a multidisciplinary approach to enhance management and outcome. Further studies will be needed to delineate genotype-phenotype correlation and standardize treatment guidelines.