Rapidly Progressive Multisutural Craniosynostosis in a Patient With Jackson-Weiss Syndrome and a De Novo FGFR2 Pathogenic Variant

Abstract

Little is currently known about the mechanisms by which pathogenic variants of FGFR2 produce changes in the FGFR protein and influence the clinical presentation of affected individuals. We report on a patient with a de novo pathogenic variant of FGFR2 and a phenotype consistent with Jackson-Weiss syndrome who presented with delayed, rapidly progressive multisutural craniosynostosis and associated medical complications. Using 3-dimensional modeling of the FGFR protein, we provide evidence that this variant resulted in abnormal dimerization and constitutive activation of FGFR, leading to the Jackson-Weiss phenotype. Knowledge regarding the correlation between genotype and phenotype of persons with FGFR2-related craniosynostosis has the potential to allow for anticipation of medical complications, institution of early treatment, and improved clinical outcomes.

Keywords

Jackson-Weiss syndrome syndromic craniosynostosis FGFR2

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References

Bagheri-Fam

Ono

Zhao

Ryan

Lai

Katsura

Rossello

Koopman

Scherer

et al. FGFR2 mutation in 46, XY sex reversal with craniosynostosis. Hum Mol Genet. 2015;24(23):6699–6710.

Cohen

. Jackson-Weiss syndrome. Am J Med Genet. 2001;100(4):325–329.

Copeland

Hoffman

Tsitouras

Jeevan

Drake

Forrest

. Clinical significance of venous anomalies in syndromic craniosynostosis. Plast Reconstr Surg Glob Open. 2018;6(1):e1613.

Fernandes

MBL

Maximino

Perosa

Abramides

DVM

Passos-Bueno

Yacubian-Fernandes

. Apert and Crouzon syndromes-cognitive development, brain abnormalities, and molecular aspects. Am J Med Genet. 2016;170(6):1532–1537.

Jackson

Weiss

Reynolds

Forman

Peterson

. Craniosynostosis, midfacial hypoplasia and foot abnormalities: an autosomal dominant phenotype in a large Amish kindred. J Pediatr. 1976;88(6):963–968.

Yang

Tianyi

Lei

. The C342R mutation in FGFR2 causes Crouzon syndrome with elbow deformity. J Craniofac Surg. 2015;26(2):584–586.

Passos-Bueno

Serti

AAL

Richieri-Costa

Alonso

LSG

Zatz

Alonso

Zatz

Alonso

Brunoni

Ribeiro

. Description of a new mutation and characterization of FGFR1, FGFR2, and FGFR3 mutations among Brazilian patients with syndromic craniosynostoses. Am J Med Genet. 1998;78(3):237–2341.

Reardon

Smith

Honour

Hindmarsh

Das

Rumsby

Nelson

Malcolm

Adès

Sillence

. Evidence for digenic inheritance in some cases of Antley-Bixler syndrome? J Med Genet. 2000;37(1):26–32.

Reardon

Winter

Rutland

Pulleyn

Jones

Malcolm

. Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome. Nat Genet. 1994;8(1):98–103.

10.

Robin

Falk

Haldeman-Englert

. FGFR-related craniosynostosis syndromes [Internet]. In: Adam

Ardinger

Pagon

Bean

Wallace

Stephens

Amemiya

, eds. GeneReviews. Seattle (WA): University of Washington, Seattle; 2011. Retrieved from: https://www.ncbi.nlm.nih.gov/books/NBK1455/. Accessed August 27, 2018.

11.

Runyan

Alperovich

Massie

Paek

Cohen

Staffenberg

Flores

Taylor

. Minor suture fusion in syndromic craniosynostosis. Plast Reconstr Surg. 2017;140(3):434e–445e.

12.

Sarabipour

Hristova

. Mechanism of FGF receptor dimerization and activation. Nat Commun. 2016a;7:10262.

13.

Sarabipour

Hristova

. Pathogenic cysteine removal mutations in FGFR extracellular domains stabilize receptor dimers and perturb the TM dimer structure. J Mol Biol. 2016b;428(20):3903–3910.

14.

Tartaglia

Di Rocco

Lajeunie

Valeri

Velardi

Battaglia

. Jackson-Weiss syndrome: identification of two novel FGFR2 missense mutations shared with Crouzon and Pfeiffer craniosynostotic disorders. Hum Genet. 1997;101(1):47–50.