FGF10 – Lacrimo-auriculo-dento-digital syndrome

Lacrimo-auriculo-dento-digital (LADD) syndrome is an autosomal dominant congenital anomaly disorder characterized by aplasia or hypoplasia of lacrimal and salivary glands, cup-shaped ears, hearing loss, dental defects, and digital anomalies. Heterozygous loss-of-function variants in FGF10 disrupt terminal branching of glandular and pulmonary epithelia via the TBX4-FGF10-FGFR2 signaling axis.

Multiple distinct FGF10 pathogenic alleles have been identified across unrelated families. A nonsense variant c.190G>T (p.Gly64Ter) was reported in a LADD pedigree, and a 12 158 bp deletion removing two FGF10 exons segregated in seven affected individuals ([PMID:16630169]; [PMID:33967277]). Segregation in multi-generational cohorts supports an autosomal dominant haploinsufficiency mechanism.

Functional assays demonstrate that LADD-associated FGF10 mutants severely impair FGF10–FGFR2b binding and downstream ERK phosphorylation, consistent with in vitro studies of paracrine signaling loss ([PMID:17682060]). Mouse models harboring Fgf10 splice or missense mutations recapitulate gland hypoplasia and ocular surface defects, including Harderian gland atrophy and slit-eye phenotypes ([PMID:19407009]; [PMID:15972105]).

No conflicting evidence has emerged to dispute the FGF10–LADD association, although phenotypic expressivity varies, likely due to modifier loci. Additional splice-site and missense variants in aplasia of lacrimal and salivary glands (ALSG) further define a continuous FGF10-related clinical spectrum.

Integration of genetic and experimental data yields a Strong ClinGen‐level association. Inclusion of FGF10 in diagnostic gene panels for congenital lacrimal and salivary gland disorders enables targeted management and genetic counseling. Key take-home: FGF10 haploinsufficiency reliably underlies LADD syndrome and should be systematically tested in relevant clinical presentations.

References

• Clinical Genetics • 2006 • LADD syndrome is caused by FGF10 mutations. PMID:16630169
• European Journal of Human Genetics • 2022 • Deletion of the last two exons of FGF10 in a family with LADD syndrome and pulmonary acinar hypoplasia. PMID:33967277
• Molecular and Cellular Biology • 2007 • Lacrimo-auriculo-dento-digital syndrome is caused by reduced activity of the fibroblast growth factor 10 (FGF10)-FGF receptor 2 signaling pathway. PMID:17682060
• Investigative Ophthalmology & Visual Science • 2009 • A new Fgf10 mutation in the mouse leads to atrophy of the harderian gland and slit-eye phenotype in heterozygotes: a novel model for dry-eye disease? PMID:19407009
• BMC Developmental Biology • 2005 • FGF10/FGFR2b signaling plays essential roles during in vivo embryonic submandibular salivary gland morphogenesis. PMID:15972105

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