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Aplasia of lacrimal and salivary glands (ALSG) is a rare autosomal dominant disorder characterized by aplasia, atresia, or hypoplasia of the lacrimal and salivary systems with variable expressivity. Patients present with epiphora and dry mouth, often leading to dental caries and ocular surface damage. Pathogenic variants in FGF10 underlie ALSG by disrupting epithelial–mesenchymal signaling during gland development. The association with aplasia of lacrimal and salivary glands has been replicated across multiple families and populations, with consistent segregation and functional data supporting a definitive gene–disease relationship.
Initial genetic evidence came from two European kindreds harboring heterozygous missense variants in FGF10—c.240A>C (p.Arg80Ser) and c.413G>A (p.Gly138Glu)—affecting highly conserved residues and co-segregating with ALSG in autosomal dominant fashion (PMID:17213838). Subsequently, a Turkish family was shown to carry a novel nonsense mutation, c.237G>A (p.Trp79Ter), predicted to induce haploinsufficiency via nonsense-mediated decay and fully segregating with ALSG across multiple generations (PMID:26955834).
Further series in three Chinese families identified three additional heterozygous missense FGF10 variants in seven affected individuals, each presenting with a novel bony congenital nasolacrimal duct obstruction phenotype alongside salivary and lacrimal aplasia. These variants, including c.316T>C (p.Cys106Arg), were absent from control databases and demonstrated conservation across species, reinforcing the autosomal dominant inheritance with variable penetrance (PMID:38081329).
A large six-generation kindred (n = 13 affected) was later reported with a novel donor splice-site variant c.429+1G>T, confirmed to cause exon 2 skipping in vitro. This variant exhibited incomplete penetrance and phenotypic variability, ranging from unilateral epiphora to full gland aplasia, underscoring the dosage sensitivity of FGF10 in gland morphogenesis (PMID:37615310).
Functional studies demonstrate that FGF10 haploinsufficiency is the principal pathogenic mechanism. Comparative assays of LADD-associated FGF10 mutants showed markedly reduced ligand activity and impaired FGFR2b signaling (PMID:17682060), whereas mouse models heterozygous for Fgf10 or Fgfr2b exhibit hypoplastic submandibular glands and complete gland aplasia in null embryos, confirming dose-dependent requirements for FGF10/FGFR2b in epithelial branching morphogenesis (PMID:15972105).
Collectively, over 30 affected individuals across more than six pedigrees harboring distinct FGF10 loss-of-function and hypomorphic variants establish a definitive gene–disease association for ALSG. The autosomal dominant inheritance, robust segregation data (20 affected relatives), and concordant functional evidence support clinical testing of FGF10 in patients with lacrimal and salivary gland aplasia. Key take-home: FGF10 haploinsufficiency is a clinically actionable cause of ALSG, enabling genetic diagnosis, counseling, and anticipatory management of ocular and dental complications.
Gene–Disease AssociationDefinitiveAt least 20 affected individuals across multiple pedigrees with segregation and functional concordance Genetic EvidenceStrongFour distinct FGF10 variants (nonsense, splice-site, missense) in >30 affected individuals with segregation in six generations Functional EvidenceModerateHaploinsufficiency mechanism demonstrated by functional assays and mouse knockout models showing gland aplasia |