Clinical and molecular analyses in 8 new craniofrontonasal syndrome families: revisiting the mild end of the phenotypic spectrum in females

Abstract

Objective: Craniofrontonasal syndrome (CFNS) is a rare X-linked disorder caused by EFN81 pathogenic variants. It is characterized by coronal synostosis, facial asymmetry, hypertelorism, bifid nasal tip, woolly hair, longitudinal nail ridging, and skeletal anomalies in heterozygous females. Hemizygous males paradoxically display a less severe phenotype. This study aims to further define the clinical and mutational spectrum of CFNS in 8 new families. Materials and Methods: Nine female and 2 male patients were included. After detailed phenotypic characterization, Sanger sequencing of EFN81 was performed, followed by deletion- duplication analysis of mutation-negative patients. Results: Universal findings in affected females included wide nasal bridge, hypertelorism, and nasal tip abnormalities. Clinical features were consistent with literature data in the majority, except for 2 females with a mild phenotype resembling hemizygous males. Rare or previously undescribed features included enlarged cisterna magna, nasolacrimal duct obstruction, mesoaxial polydactyly, small echogenic kidney, and hypoplastic labia minora in females, and metopic groove, columellar skin pit, and absent midline mustache hair in males. Genetic analyses identified 6 EFN81 variants, including a novel variant, heterozygous in females and hemizygous in males. One female patient with a classical CFNS phenotype had no identifiable EFN81 variant. Conclusion: This study of the largest CFNS cohort from T & uuml;rkiye expands the phenotypic spectrum in affected males and females and contributes to the genetic landscape of EFN81 variants. Two females of the cohort with a phenotype at the mildest end of the CFNS spectrum emphasize the importance of recognizing atypical CFNS presentations for timely diagnosis and accurate genetic counseling.