Loss of Fibroblast Growth Factor Signaling Causes LADD Syndrome

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Autosomal dominant lacrimo-auriculo-dento-digital (LADD) syndrome (OMIM 149730), also called Levy-Hollister syndrome, is characterized by multiple congenital anomalies primarily affecting lacrimal glands and ducts, salivary ducts, ears, teeth, and distal limb segments. It has been mapped to 3 different genes whose products belong to fibroblast growth factor (FGF) signaling pathways in the respective developing tissues.

To begin, linkage analysis of DNA samples from 3 large LADD families identified a region of chromsosome 10q26 containing critical genetic interval that was narrowed to 6.2 Mb in size. The gene encoding FGF receptor 2 (FGFR2), which resides in this region, was considered a strong candidate for mutations. For example, disruption of Fgfr2 in mice causes limb and digital malformations; and Fgfr2 is thought to regulate submandibular gland morphogenesis in mice. Sequencing FGFR2 in the LADD families revealed a heterozygous mutation predicted to substitute threonine for alanine at amino acid residue 648 that segregated with the LADD syndrome in 2 of the families. A 3-bp deletion that led to substitution of a highly conserved arginine residue at position 649 and loss of a neighboring aspartic acid residue was detected in the third family. Another FGFR2 mutation was detected in a sporadic case of LADD.

Realizing that gain-of-function mutations of FGFR2 are typically associated with craniosynostosis and other features quite distinct from LADD syndrome, ie, Pfeiffer, Crouzon, Apert and other craniosynostosis syndromes, the investigators speculated that the LADD mutations result in loss of FGFR2 function, Indeed, the LADD mutations map to activation or catalytic loop of the receptor’s tyrosine kinase domain, where alterations might be expected to disturb the enzymatic activity of the receptor.

Armed with this information, they searched for potential loss-of-function mutations of other FGF receptors (FGFR1, 3 and 4) and of 2 known ligands of FGFR2 (FGF8 and FGF10). Their analysis revealed mutations that segregated with the LADD syndrome of FGF10 in one family and of FGFR3 in another family. The authors speculate that the FGF10 mutation might have a dominant negative effect on FGFR signaling; the FGFR3 mutation maps to the tyrosine kinase domain of the receptor and like the FGFR2 mutations might be associated with loss of receptor function.

The authors conclude that LADD syndrome is genetically heterogeneous and may reflect loss of FGF signals that are propagated by FGF10 and FGFR2 and FGFR3 in regions affected in the syndrome. They acknowledge that they offer no experimental evidence for this hypothesis.

Rohmann E, Brunner HG, Kayserili H, et al. Mutations in different components of FGF signaling in LADD syndrome. Nat Genet. 2006;38:414–417.

Clinical findings, pedigrees and mutations in FGFR2, FGFR3 and FGF10 in LADD syndrome. (a-i) Phenotypic characteristics of LADD patients from different families: (a,d) LADD-Ala, III-2; (b) LADD-Ala, III-1; (c) LADD-Ist, II-5 and III-4; (e) LADD-Be, II-1; (f) LADD-Nij, III-4; (g,h) LADD-Nij, II-3; (l) LADD-Bo, II-4. (a-f) Photographs show facial appearance and typical ear anomalies in LADD patients. Digital anomalies included hypoplastic (g), absent (h) and bifid (i) thumbs. (j-o) Pedigrees of LADD families. Family name, gene involved and identified mutation are given in the gray box on top of each pedigree. Symbols: +, mutation present; -, mutation absent. Filled black symbols indicate affected individuals; filled gray symbols in the LADD-Bo family represent individuals who were probably affected but for whom a detailed clinical description is lacking. (p) Schematic model of FGFR2 and FGFR3. The locations of different mutations are marked by red dots on the receptor or ligand (FGF10). The intracellular tyrosine kinase domains of FGFR2 and FGFR3 are shown in orange.

Editor’s Comment

This paper is intriguing not because it shows genetic heterogeneity within a single clinical entity, but because it offers a potential explanation underscoring that developmental disorders like metabolic disorders involve pathways and networks, not just single genes. It follows that future therapeutic approaches for such conditions should also be targeted at relevant pathways and networks rather than just at products of single mutant genes.

William A. Horton, MD

Last Updated: 04/30/2008