FGFR1 – Encephalocraniocutaneous Lipomatosis

Encephalocraniocutaneous lipomatosis (ECCL) is a rare mosaic RASopathy characterized by unilateral nevus psiloliparus, ocular choristomas, and central nervous system lipomas often complicated by pilocytic astrocytoma. Somatic activating variants in FGFR1 underlie ECCL and drive constitutive MAPK pathway signaling.

Genetic evidence supports FGFR1 involvement in at least six unrelated probands (PMID:29683947), each harboring postzygotic missense mutations. Mosaic FGFR1 c.1966A>G (p.Lys656Glu) was detected in two children with ECCL and pilocytic astrocytoma (PMID:29683947, PMID:37486073). Recurrent mosaic c.1638C>G and c.1638C>A (p.Asn546Lys) were independently reported in three additional individuals (PMID:31173478, PMID:31649234), and a prenatal case confirmed a postzygotic FGFR1 alteration in classic ECCL features (PMID:34547955). No germline segregation has been observed.

The variant spectrum in ECCL is limited to recurrent tyrosine-kinase domain missense substitutions. All reported alleles—c.1966A>G (p.Lys656Glu) and c.1638C>G/A (p.Asn546Lys)—function as gain-of-function mutations with enhanced ligand-independent autophosphorylation and downstream MAPK activation.

Functional concordance is demonstrated by in vitro kinase assays and clinical stability of brain lesions on MEK inhibitor therapy. Trametinib treatment yielded tumor size stabilization in a patient with mosaic FGFR1 p.Lys656Glu (PMID:29683947). Sensitive droplet digital PCR assays confirm low-level mosaicism in blood and skin, improving diagnostic yield (PMID:31173478).

No conflicting evidence has been reported that refutes FGFR1 mosaic variants as the molecular basis of ECCL. Early functional studies of FGFR1 splice variants and receptor dynamics further corroborate the critical role of FGFR1 signaling in tissue development and tumorigenesis.

Together, genotype–phenotype correlations, mechanistic in vitro data, and therapeutic responses support a Strong clinical validity for FGFR1 in ECCL. Molecular testing for FGFR1 activating variants is essential for definitive diagnosis, risk stratification for brain tumor development, and consideration of targeted MEK inhibition.

Key take-home: Mosaic activating FGFR1 mutations definitively underlie ECCL and inform targeted management.

References

• Journal of pediatric hematology/oncology • 2018 • Encephalocraniocutaneous Lipomatosis. PMID:29683947
• American journal of medical genetics. Part A • 2019 • Sensitive detection of FGFR1 N546K mosaic mutation in patient with encephalocraniocutaneous lipomatosis and pilocytic astrocytoma. PMID:31173478
• The American journal of case reports • 2019 • Giant Ocular Lipodermoid Cyst in Encephalocraniocutaneous Lipomatosis: Surgical Treatment and Genetic Analysis. PMID:31649234
• Pediatric and developmental pathology • 2022 • Expending the Phenotypic Spectrum of Encephalocraniocutaneous Lipomatosis: About a Prenatal Case With Complete Autopsy. PMID:34547955
• Pediatric dermatology • 2024 • Next generation sequencing aids diagnosis and management in a case of encephalocraniocutaneous lipomatosis. PMID:37486073

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