Bony Congenital Nasolacrimal Duct Obstruction: A Novel Phenotype of Aplasia of Lacrimal and Major Salivary Glands

Abstract

PurposeAplasia of lacrimal and salivary gland (ALSG) is a syndromic disorder characterized by aplasia of lacrimal and salivary systems. Reported ophthalmic manifestations of ALSG include aplasia of lacrimal glands, punctal agenesis, lacrimal sac mucocele and membranous congenital nasolacrimal duct obstruction (CNLDO). Bony CNLDO, a rare cause of congenital epiphora, has not been associated with any syndromic disorder. This study investigated the relationship between genetic mutations and bony CNLDO in three Chinese families with ALSG. DesignSingle-center observational case study. ParticipantsThree Chinese families with bony CNLDO including 7 affected and 9 healthy family members. MethodsSlit-lamp ophthalmic examination, comprehensive physical examination, orbital Computed Tomography (CT), cervicofacial Magnetic Resonance Imaging (MRI), audiometry and whole exome sequencing on periphery blood were performed. Variants were cross-referenced with 1000 control genomes and various population databases. Pathologic variants were identified using bioinformatic tools. Main Outcome MeasuresClinical examination, diagnostic imaging, whole exome sequencing and bioinformatic analysis findings. ResultsAffected patients had decreased tear production on Schimer I Test and reduced tear break-up time. Bony CNLDO was observed on computed tomography, showing unilateral or bilateral bony termination at the middle or terminal segment of the nasolacrimal canal. Cervicofacial MRI showed aplasia or absence of lacrimal, parotid and submandibular glands. Physical examination revealed normal ears, digits and facial morphology. Audiometry and dental assessment were conducted on the pediatric patients and yielded normal results. The clinical characteristic of patients aligned with diagnosis of ALSG. Genomic analysis revealed three novel heterozygous missense mutations of Fgf10 gene: c.316T>C, c.327C>G, c.332T>G. The inheritance pattern was autosomal dominant with variable penetrance. These variants were not observed in 1000 control chromosomes and population databases. These variant positions were also shown to be highly conversed across various animal species. Mutated genes and proteins were predicted as “deleterious” with most computational models with a few suggesting they may be “benign”. ConclusionsBony CNLDO was identified as a novel phenotype of ALSG implicated by missense mutations of highly conserved residues in the Fgf10 gene. These cases broadened our knowledge of Fgf10-related phenotypes and prompt clinicians to consider syndromic associations in patients with bony CNLDO.