Infantile epileptic spasms syndrome in children with cardiofaciocutanous syndrome: Clinical presentation and associations with genotype

Daniel L. Kenney-Jung, Dante J. Rogers, Samuel J. Kroening, Abigail L. Zatkalik, Ashley E. Whitmarsh, Amy E. Roberts, Martin Zenker, Maria Luigia Gambardella, Ilaria Contaldo, Chiara Leoni, Roberta Onesimo, Giuseppe Zampino, Marco Tartaglia, Domenica I. Battaglia, Elizabeth I. Pierpont

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Gene variants that dysregulate signaling through the RAS-MAPK pathway cause cardiofaciocutaneous syndrome (CFCS), a rare multi-system disorder. Infantile epileptic spasms syndrome (IESS) and other forms of epilepsy are among the most serious complications. To investigate clinical presentation, treatment outcomes, and genotype–phenotype associations in CFCS patients with IESS, molecular genetics and clinical neurological history were reviewed across two large clinical research cohorts (n = 180). IESS presented in 18/180 (10%) cases, including 16 patients with BRAF variants and 2 with MAP2K1 variants. Among IESS patients with BRAF variants, 16/16 (100%) had sequence changes affecting the protein kinase domain (exons 11–16), although only 57% of total BRAF variants occurred in this domain. Clinical onset of spasms occurred at a median age of 5.4 months (range: 1–24 months). Among 13/18 patients whose IESS resolved with anti-seizure medications, 10 were treated with ACTH and/or vigabatrin. A substantial majority of CFCS patients with IESS subsequently developed other epilepsy types (16/18; 89%). In terms of neurodevelopmental outcomes, gross motor function and verbal communication were more limited in patients with a history of IESS compared to those without IESS. These findings can inform clinical neurological care guidelines for CFCS and development of relevant pre-clinical models for severe epilepsy phenotypes.

Original languageEnglish (US)
Pages (from-to)501-509
Number of pages9
JournalAmerican Journal of Medical Genetics, Part C: Seminars in Medical Genetics
Volume190
Issue number4
DOIs
StatePublished - Dec 2022

Bibliographical note

Funding Information:
We appreciate the support of the CFCS community, families, and advocacy groups. The completion of this research was made possible by funding from CFC International's Lillian's Legacy Grant, a microgrant from the Rare Disease Foundation, and support by AISC—Associazione Italiana Sindromi Costello e Cardiofaciocutanea. Martin Zenker received funding from the German Ministry of Education and Research (BMBF), project titles GeNeRARe (FKZ 01GM1902A) and NSEuroNet (FKZ 01GM1921A). Marco Tartaglia received funding from AIRC (IG 21614) and EJP‐RD (NSEuroNet). Martin Zenker, Giuseppe Zampino, and Marco Tartaglia are members of the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN‐ITHACA (EU Framework Partnership Agreement ID: 3HP‐HP‐FPA ERN‐01‐2016/739516). Support for Elizabeth I. Pierpont was provided by the National Institutes of Health's National Center for Advancing Translational Sciences grants KL2TR002492 and by the University of Minnesota Department of Pediatrics. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding Information:
We appreciate the support of the CFCS community, families, and advocacy groups. The completion of this research was made possible by funding from CFC International's Lillian's Legacy Grant, a microgrant from the Rare Disease Foundation, and support by AISC—Associazione Italiana Sindromi Costello e Cardiofaciocutanea. Martin Zenker received funding from the German Ministry of Education and Research (BMBF), project titles GeNeRARe (FKZ 01GM1902A) and NSEuroNet (FKZ 01GM1921A). Marco Tartaglia received funding from AIRC (IG 21614) and EJP-RD (NSEuroNet). Martin Zenker, Giuseppe Zampino, and Marco Tartaglia are members of the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA (EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516). Support for Elizabeth I. Pierpont was provided by the National Institutes of Health's National Center for Advancing Translational Sciences grants KL2TR002492 and by the University of Minnesota Department of Pediatrics. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2022 The Authors. American Journal of Medical Genetics Part C: Seminars in Medical Genetics published by Wiley Periodicals LLC.

Keywords

  • BRAF
  • KRAS
  • MAP2K1
  • MAP2K2
  • RASopathies
  • seizures

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