FGFR1 – Septo-optic Dysplasia

Heterozygous FGFR1 alterations have been reported in four unrelated patients with septo-optic dysplasia, including one Japanese female with a large ∼8.5 Mb deletion encompassing FGFR1 and three patients harboring missense/splice variants (p.Ser450Phe, c.336C>T (p.Thr112Thr), c.1447C>T (p.Pro483Ser)) (PMID:23657145, PMID:22319038). The inheritance is autosomal dominant, consistent with a haploinsufficiency mechanism. Overall, gene-disease validity is classified as Limited based on a total of 4 probands, absence of segregation data, and limited functional characterization.

In vitro assays demonstrate that the p.Ser450Phe and p.Pro483Ser substitutions impair FGFR1 signaling through reduced receptor activation and altered ligand affinity, while two other variants (p.Val102Ile, p.Ser107Leu) behave as benign polymorphisms (PMID:23657145, PMID:22319038). These findings support a mechanism of FGFR1 haploinsufficiency disrupting anterior midline forebrain and pituitary development, manifesting as septo-optic dysplasia with central hypothyroidism (HP:0011787). FGFR1 mutation screening is recommended in patients with septo-optic dysplasia to guide endocrine evaluation and management.

References

• Endocrine journal | 2013 | Submicroscopic deletion involving the fibroblast growth factor receptor 1 gene in a patient with combined pituitary hormone deficiency. PMID:23657145
• The Journal of clinical endocrinology and metabolism | 2012 | Genetic overlap in Kallmann syndrome, combined pituitary hormone deficiency, and septo-optic dysplasia. PMID:22319038

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