FGFR2 – Lacrimo-Auriculo-Dento-Digital Syndrome

Lacrimo-Auriculo-Dento-Digital (LADD) syndrome is a rare congenital disorder characterised by hypoplasia or aplasia of the lacrimal and salivary systems, cup-shaped ears, hearing loss and dental anomalies. It follows an autosomal-dominant inheritance pattern and has been linked to heterozygous mutations in FGFR2, FGFR3 and FGF10.

Genetic studies have identified heterozygous missense variants in the tyrosine kinase domain of FGFR2 in at least 8 probands across multiple unrelated families ([PMID:19863897]; [PMID:16501574]; [PMID:30992102]; [PMID:32715658]). Co-segregation of these variants with LADD clinical features was noted in 3 additional affected relatives ([PMID:32715658]).

The variant spectrum in FGFR2 for LADD includes primarily missense changes affecting the kinase domain, exemplified by c.1547C>T (p.Ala516Val) ([PMID:32715658]). No recurrent or founder alleles have been reported.

Mechanistically, FGFR2 missense variants alter receptor conformation and FGF ligand binding, leading to aberrant FGF signaling during craniofacial and glandular development. Dedicated functional assays in LADD-specific models are limited, but the mutations are predicted to disrupt kinase activity.

No conflicting studies have been reported; all available data consistently support FGFR2’s role in LADD syndrome.

Overall, autosomal-dominant FGFR2 missense variants present strong genetic evidence and limited functional evidence for causation of LADD syndrome. Recognition of this gene–disease association informs molecular diagnosis, genetic counselling and multidisciplinary management.

Key take-home: Heterozygous FGFR2 kinase-domain missense variants cause autosomal-dominant LADD syndrome, providing a clear molecular target for genetic testing and diagnosis.

References

• European archives of paediatric dentistry • 2009 • Case report: Presentation of lacrimo-auriculodento-digital (LADD) syndrome in a young female patient. PMID:19863897
• Nature genetics • 2006 • Mutations in different components of FGF signaling in LADD syndrome. PMID:16501574
• Journal of dentistry for children • 2019 • Orodental Findings in Patients with Lacrimo-Auriculo-Dento-Digital Syndrome. PMID:30992102
• Molecular genetics & genomic medicine • 2020 • Lacrimo-auriculo-dento-digital syndrome: A novel mutation in a Korean family and review of literature. PMID:32715658

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