Identification of a novel pathogenic variant in CKAP2L and literature review in a child with Filippi syndrome and congenital talipes equinovarus

Abstract

Filippi syndrome (MIM #272440), one of the craniodigital syndromes, is a rare genetic entity with autosomal recessive inheritance and characterized by pre‐ and postnatal growth retardation, microcephaly, distinctive facial appearance, developmental delay/intellectual disability, and variable syndactylies of the fingers and toes. In this report, a further female patient of Filippi syndrome who additionally had a unilateral congenital talipes equinovarus (CTEV), a feature not previously recorded, is described. Genetic testing revealed a novel homozygous frameshift pathogenic variant (c.552_555delCAAA, p.Asn184Lysfs*8) in CKAP2L and thus confirmed the diagnosis of Filippi syndrome. We hope that the newly recognized feature (CTEV) will contribute to expand the clinical spectrum of this extremely rare condition. In view of the paucity of reported cases, the full spectrum of clinical findings of Filippi syndrome necessitates obviously further affected individuals/pedigrees delineation in order to elucidate the etiological and phenotypic aspects of this orphan disease appropriately.

Expansion of the neurodevelopmental phenotypic spectrum of CKAP2L‐related Filippi syndrome to include an adolescent male with normal intellect

“…All diseasecausing variants in CKAP2L that have been reported to date are biallelic loss of function changes, as was the case in our patient. With the exception of one pathogenic variant reported in each of exons 1 and 2, the remainder of the reported variants seem to cluster within exon 4 (Capecchi et al, 2018;Hussain et al, 2014;Karakaya et al, 2021;Sabir et al, 2019). Our patient's variant, however, lies further downstream in the splice acceptor site of exon 7 out of 9.…”

“…Despite its rarity, the unique pattern of syndactyly of the hands and feet observed in this disorder is a helpful diagnostic handle, making this a recognizable syndrome. The neurodevelopmental phenotype of Filippi syndrome seems to encompass a wide range, with many individuals described as having moderate or severe ID, and yet a handful of others described as having milder delays (Karakaya et al, 2021). Our patient expands this phenotypic range even further, as the first individual that we are aware of with Filippi syndrome and a normal intellectual outcome.…”

“…To the Editor, Fillippi syndrome is characterized by developmental delay, poor growth, microcephaly, a characteristic pattern of hand and foot syndactyly, and distinctive facial features. Karakaya et al described in 2021 an infant with unilateral talipes equinovarus in addition to the typical features of Filippi syndrome in their article-"Identification of a novel pathogenic variant in CKAP2L and literature review in a child with Filippi syndrome and congenital talipes equinovarus" (Karakaya et al, 2021)." The authors also present a literature review of the clinical features of 13 individuals with Filippi syndrome secondary to confirmed biallelic CKAP2L variants.…”

Filippi Syndrome: A Lesser Reported Craniodigital Syndrome with Unique Features

“…Table 1 summarizes all the cases of Filippi syndrome reported to date worldwide. [1,2,4,8,9,[12][13][14][15][16][17][18][19][20][21][22][23][24] Management of Filippi syndrome is often individualized, and a multidisciplinary approach is required, which may include surgical correction of syndactyly of fingers and toes, speech therapy, and treatment of seizure disorders. [9] Diagnostic modalities such as MRI of the brain, electroencephalography, hand wrist radiography, and various metabolic tests like arginine challenge test facilitate the diagnosis.…”

Prognostic significance of CKAP2L expression in patients with clear cell renal cell carcinoma

“…However, mutations in this gene are linked to spindle organization defects, such as mitotic spindle defects, lagging chromosomes, and chromatin bridges ( Hussain et al, 2014 ; Capecchi et al, 2018 ). This is evident from the fact that mutations in this gene are linked with Filippi syndrome, in which symptoms such as growth defects, microcephaly, intellectual disability, facial feature defects, and syndactyly are developed ( Karakaya et al, 2021 ). In addition, CKAP2L has been reported to be associated with disease progression and prognosis in a variety of tumors, including non-small-cell lung cancer, glioblastoma, hepatocellular carcinoma, and colorectal cancer ( Xiong et al, 2019 ; Li et al, 2020 ; Wang and He, 2020 ; Feng et al, 2021 ).…”