Isolated hereditary congenital ptosis can be caused by defects of craniofacial development

Ptosis is an ophthalmological condition describing abnormal drooping of the upper eyelid, which can be congenital or acquired. It may be idiopathic, but various etiologies are now recognized related to myogenic, aponeuretic, mechanical, posttraumatic and synkinetic causes. Familial forms include Isolated Hereditary Congenital Ptosis (IHCP) which demonstrates an autosomal dominant inheritance pattern. In this study, we investigated 12 multiplex IHCP families. Exome sequencing was performed for all affected and selected unaffected family members. In addition, linkage analysis and CNV analysis were performed using genome wide SNP data from a subset of the families (Illumina OmniExpress array). Using this approach, we identified three novel variants, none annotated in EXAC, in three unrelated Italian families in three different genes previously identified as being important for craniofacial development. Pedigree UU diagnosed with mild form of unilateral ptosis, harbors a novel FGFR2 variant (c.760C>T, p.H254Y). Mutations in this gene are associated with syndromic craniosynostosis. Individuals in Pedigree IQ had variable expression of the ptosis phenotype, ranging from mild to severe. Exome data of this family revealed a novel missense variant, c.379G>A p.A127T in the Helix-Loop-Helix domain of TWIST1, which is typically associated with a variable and sometimes severe form familial craniosynostosis syndrome, Saethre-Chotzen syndrome; no symptoms of craniosynostosis were reported by the referring clinician. Lastly, Pedigree TQ was diagnosed with severe congenital bilateral ptosis suggestive of a diagnosis of blepharophimosis, ptosis and epicanthus inversus syndrome (BPES). CNV analysis revealed the presence of a heterozygous deletion on the short arm of chromosome 2 (chr2:45024863-43300029), segregating with the affection status, that removes the entire gene SIX2 A deletion with similar breakpoints also removing the entirety of SIX2 was recently reported in a novel form of frontonasal dysplasia with features overlapping the clinical presentation of our family. These data expand the phenotype of known craniosynostosis genes and indicate that the presence of ptosis should alert clinicians to the possibility of variants in genes which may be more commonly associated with severe forms of craniofacial developmental disorders