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Expanding the phenotype for the recurrent p.Ala391Glu variant in FGFR3: Beyond crouzon syndrome and acanthosis nigricans.
Mol Genet Genomic Med. 2019 06; 7(6):e656.MG

Abstract

BACKGROUND

Craniosynostosis, or premature fusion of the skull sutures, is a group of disorders that can present in isolation (nonsyndromic) or be associated with other anomalies (syndromic). Delineation of syndromic craniosynostosis is confounded due to phenotypic overlap, variable expression as well as molecular heterogeneity. We report on an infant who presented at birth with multisuture synostosis, turribrachycephaly, midface hypoplasia, beaked nose, low set ears, a high palate and short squat appearing thumbs, and great toes without deviation. The additional MRI findings of choanal stenosis and a Chiari I malformation suggested a diagnosis of Pfeiffer syndrome. First tier molecular testing did not reveal a pathogenic variant.

METHODS

Whole exome sequencing on DNA samples from the proband and her unaffected parents was utilized to delineate the variant causative for the Pfeiffer syndrome diagnosis.

RESULTS

On whole exome sequencing, a de novo NM_000142.4:c.1428C>A missense variant causing a p.Ala391Glu amino acid change in FGFR3 has been identified. The p.Ala391Glu change has been predominantly identified in patients with Crouzon syndrome with acanthosis nigricans.

CONCLUSIONS

This finding illustrates the first reported case of a child with an overlap with Pfeiffer syndrome to have the p.Ala391Glu variant.

Authors+Show Affiliations

Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia.Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia.Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia.Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia.Department of Psychiatry, SUNY Downstate Medical Center, Brooklyn, New York.Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, Virginia. Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia.Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia.

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31016899

Citation

Rymer, Karen, et al. "Expanding the Phenotype for the Recurrent p.Ala391Glu Variant in FGFR3: Beyond Crouzon Syndrome and Acanthosis Nigricans." Molecular Genetics & Genomic Medicine, vol. 7, no. 6, 2019, pp. e656.
Rymer K, Shiang R, Hsiung A, et al. Expanding the phenotype for the recurrent p.Ala391Glu variant in FGFR3: Beyond crouzon syndrome and acanthosis nigricans. Mol Genet Genomic Med. 2019;7(6):e656.
Rymer, K., Shiang, R., Hsiung, A., Pandya, A., Bigdeli, T., Webb, B. T., & Rhodes, J. (2019). Expanding the phenotype for the recurrent p.Ala391Glu variant in FGFR3: Beyond crouzon syndrome and acanthosis nigricans. Molecular Genetics & Genomic Medicine, 7(6), e656. https://doi.org/10.1002/mgg3.656
Rymer K, et al. Expanding the Phenotype for the Recurrent p.Ala391Glu Variant in FGFR3: Beyond Crouzon Syndrome and Acanthosis Nigricans. Mol Genet Genomic Med. 2019;7(6):e656. PubMed PMID: 31016899.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Expanding the phenotype for the recurrent p.Ala391Glu variant in FGFR3: Beyond crouzon syndrome and acanthosis nigricans. AU - Rymer,Karen, AU - Shiang,Rita, AU - Hsiung,Anting, AU - Pandya,Arti, AU - Bigdeli,Tim, AU - Webb,Bradley T, AU - Rhodes,Jennifer, Y1 - 2019/04/23/ PY - 2018/08/23/received PY - 2019/02/28/revised PY - 2019/03/01/accepted PY - 2019/4/25/pubmed PY - 2020/6/24/medline PY - 2019/4/25/entrez KW - FGFR3 KW - Crouzon KW - Pfeiffer KW - craniosynostosis SP - e656 EP - e656 JF - Molecular genetics & genomic medicine JO - Mol Genet Genomic Med VL - 7 IS - 6 N2 - BACKGROUND: Craniosynostosis, or premature fusion of the skull sutures, is a group of disorders that can present in isolation (nonsyndromic) or be associated with other anomalies (syndromic). Delineation of syndromic craniosynostosis is confounded due to phenotypic overlap, variable expression as well as molecular heterogeneity. We report on an infant who presented at birth with multisuture synostosis, turribrachycephaly, midface hypoplasia, beaked nose, low set ears, a high palate and short squat appearing thumbs, and great toes without deviation. The additional MRI findings of choanal stenosis and a Chiari I malformation suggested a diagnosis of Pfeiffer syndrome. First tier molecular testing did not reveal a pathogenic variant. METHODS: Whole exome sequencing on DNA samples from the proband and her unaffected parents was utilized to delineate the variant causative for the Pfeiffer syndrome diagnosis. RESULTS: On whole exome sequencing, a de novo NM_000142.4:c.1428C>A missense variant causing a p.Ala391Glu amino acid change in FGFR3 has been identified. The p.Ala391Glu change has been predominantly identified in patients with Crouzon syndrome with acanthosis nigricans. CONCLUSIONS: This finding illustrates the first reported case of a child with an overlap with Pfeiffer syndrome to have the p.Ala391Glu variant. SN - 2324-9269 UR - https://wwww.unboundmedicine.com/medline/citation/31016899/Expanding_the_phenotype_for_the_recurrent_p_Ala391Glu_variant_in_FGFR3:_Beyond_crouzon_syndrome_and_acanthosis_nigricans_ L2 - https://doi.org/10.1002/mgg3.656 DB - PRIME DP - Unbound Medicine ER -