FGFR3 – Crouzon syndrome-acanthosis nigricans syndrome

Crouzon syndrome with acanthosis nigricans (CAN) is a craniosynostosis syndrome characterized by classic Crouzon facies and cutaneous hyperpigmentation and papillomatous lesions. CAN is caused by a specific heterozygous point mutation in FGFR3, distinguishing it from classic FGFR2-mediated Crouzon syndrome. The hallmark features include craniosynostosis (HP:0001363), midface retrusion (HP:0011800), ocular proptosis (HP:0000520), choanal atresia (HP:0000453), hydrocephalus (HP:0000238) and early-onset acanthosis nigricans (HP:0000956) often accompanied by bilateral choanal atresia (HP:0004502).

Genetic evidence for FGFR3 involvement in CAN is robust. A series of 35 published cases first highlighted the recurrent c.1172C>A (p.Ala391Glu) substitution in FGFR3 in individuals presenting with CAN (35 probands) (PMID:20199409). A subsequent radiographic study of six additional patients confirmed the same heterozygous transmembrane domain variant (six probands) (PMID:11426459). Across these reports, the variant has been consistently de novo or familial with autosomal dominant inheritance and is absent from population databases.

Inheritance is autosomal dominant, with no additional segregating affected relatives reported beyond the probands. The key pathogenic variant is c.1172C>A (p.Ala391Glu), which alters the transmembrane domain of FGFR3, mimicking achondroplasia-type activation but driving the distinct CAN phenotype.

Functional studies of FGFR3 transmembrane and kinase domain mutations demonstrate that substitutions at analogous residues (e.g., p.Gly380Arg, p.Lys650Glu) induce ligand-independent receptor dimerization and constitutive kinase activation. While the specific p.Ala391Glu variant has not been directly assayed in vitro, its proximity to known activating sites supports a mechanism of constitutive FGFR3 activation leading to aberrant craniofacial ossification and epidermal proliferation.

No conflicting reports have been identified disputing the FGFR3 p.Ala391Glu association with CAN. The phenotype is highly specific, with craniosynostosis preceding dermatologic changes, and radiographic “achondroplasia-like” skeletal features further support the diagnosis before skin findings emerge.

In conclusion, FGFR3 c.1172C>A (p.Ala391Glu) is definitively associated with Crouzon syndrome with acanthosis nigricans. Molecular testing for this variant enables early and accurate diagnosis, informs recurrence risk, and guides multidisciplinary management including neurosurgical and dermatologic interventions.

References

• Pediatric dermatology • 2010 • A newborn with acanthosis nigricans: can it be Crouzon syndrome with acanthosis nigricans? PMID:20199409
• American journal of medical genetics • 2001 • Subtle radiographic findings of achondroplasia in patients with Crouzon syndrome with acanthosis nigricans due to an Ala391Glu substitution in FGFR3. PMID:11426459
• Dermatology reports • 2023 • Crouzon syndrome with acanthosis nigricans: a case report and literature review. PMID:37397405

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