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FGFR3 encodes a tyrosine kinase receptor in the FGF pathway and has been implicated in autosomal dominant Lacrimo-Auriculo-Dento-Digital (LADD) syndrome (MONDO:0007872). LADD is characterized by aplasia or hypoplasia of lacrimal and salivary ducts, low cup-shaped ears, hearing loss and dental anomalies. Heterozygous FGFR3 variants were first identified in multiple LADD families, establishing a direct gene–disease link (PMID:16501574). The inheritance pattern is autosomal dominant, with variable expressivity and incomplete penetrance of craniofacial and digital features. Clinical diagnosis relies on recognition of the constellation of ocular, auricular and dental signs, prompting targeted FGFR3 sequencing. Early genetic confirmation guides management of tear-duct obstruction, hearing impairment and dental hypoplasia.
Case reports include a novel missense variant, c.1882G>A (p.Asp628Asn), in an Iranian family, co-segregating with LADD features across affected members (PMID:28483234). A 12-year-old index case and her relatives exhibited cup-shaped ears, hearing loss and taurodontism corresponding to FGFR3 mutation carriage. Sporadic presentations have also been documented, underscoring the need to consider FGFR3 screening even in isolated cases. These reports expand the phenotypic spectrum and affirm the variant’s pathogenicity.
In a multi-family study, heterozygous FGFR3 mutations were detected in four unrelated LADD kindreds, with missense changes clustering in the tyrosine kinase domain (PMID:16501574). The affected residues are highly conserved and predicted to disrupt downstream FGF signaling. No loss-of-function or splice variants have been reported in LADD, emphasizing the predominance of dominant-negative or gain-of-function mechanisms. Recurrent and private variants demonstrate both founder and de novo events, with no clear population-specific allele frequency data available.
The inheritance mode is autosomal dominant. Segregation analysis in the Iranian pedigree revealed one additional affected relative, confirming co-segregation of the c.1882G>A change with disease. Overall, at least five unrelated probands (including the Iranian family and three LADD kindreds) have been reported with FGFR3 missense mutations ([PMID:28483234]; [PMID:16501574]). The variant spectrum comprises exclusively missense substitutions in the kinase domain, consistent with a dominant effect on receptor function.
Mechanistically, LADD-associated FGFR3 variants cluster in the activation loop and juxtamembrane regions, likely perturbing ligand binding or kinase auto-inhibition. Although direct functional assays in LADD are lacking, analogies to FGFR3 dysregulation in skeletal dysplasias support a model of aberrant FGF signaling leading to glandular hypoplasia and craniofacial anomalies. No rescue or animal models have yet been described for LADD, and downstream signaling effects remain to be elucidated.
In summary, heterozygous FGFR3 missense variants are established as a moderate‐strength cause of autosomal dominant LADD syndrome. Genetic testing for FGFR3 should be considered in individuals with lacrimal duct aplasia, cup-shaped ears, hearing loss and dental anomalies to confirm diagnosis and guide multidisciplinary care. Early molecular confirmation enables targeted management of ocular, auditory and dental complications.
Gene–Disease AssociationModerateHeterozygous FGFR3 missense variants reported in at least five unrelated LADD probands ([PMID:28483234]; [PMID:16501574]) with segregation and consistent clinical phenotypes Genetic EvidenceModerateFive FGFR3 variants across four families; autosomal dominant inheritance; segregation in one kindred Functional EvidenceLimitedNo direct functional assays in LADD; variants predicted to alter kinase activity and FGF signaling by analogy to skeletal dysplasias |