Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome

Authors: Schulz¹; Albrecht²; Arici³; van der Burgt,⁴; Buske⁵; Gillessen-Kaesbach; Heller⁶; Horn⁷; Hübner; Korenke⁸; König⁹; Kress¹⁰; Krüger¹¹; Meinecke¹²; Mücke¹³; Plecko; Rossier¹⁴; Schinzel¹⁵; Schulze¹⁶; Seemanova¹⁷; Seidel¹⁸; Spranger¹⁹; Tuysuz²⁰; Uhrig²¹; Wieczorek²; Kutsche; Zenker

Source: Clinical Genetics, Volume 73, Number 1, January 2008 , pp. 62-70(9)

Publisher: Blackwell Publishing

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Abstract:

Schulz AL, Albrecht B, Arici C, van der Burgt I, Buske A, Gillessen-Kaesbach G, Heller R, Horn D, Hübner CA, Korenke GC, König R, Kress W, Krüger G, Meinecke P, Mücke J, Plecko B, Rossier E, Schinzel A, Schulze A, Seemanova E, Seidel H, Spranger S, Tuysuz B, Uhrig S, Wieczorek D, Kutsche K, Zenker M. Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome.

Clin Genet 2008: 73: 62-70. © Blackwell Munksgaard, 2008

Cardio-facio-cutaneous (CFC) and Costello syndrome (CS) are congenital disorders with a significant clinical overlap. The recent discovery of heterozygous mutations in genes encoding components of the RAS-RAF-MAPK pathway in both CFC and CS suggested a similar underlying pathogenesis of these two disorders. While CFC is heterogeneous with mutations in BRAF, MAP2K1, MAP2K2 and KRAS, HRAS alterations are almost exclusively associated with CS. We carried out a comprehensive mutation analysis in 51 CFC-affected patients and 31 individuals with CS. Twelve different BRAF alterations were found in twenty-four patients with CFC (47.0%), two MAP2K1 mutations in five (9.8%) and two MAP2K2 sequence variations in three CFC-affected individuals (5.9%), whereas three patients had a KRAS alteration (5.9%). We identified four different missense mutations of HRAS in twenty-eight cases with CS (90.3%), while KRAS mutations were detected in two infants with a phenotype meeting criteria for CS (6.5%). In 14 informative families, we traced the parental origin of HRAS alterations and demonstrated inheritance of the mutated allele exclusively from the father, further confirming a paternal bias in the parental origin of HRAS mutations in CS. Careful clinical evaluation of patients with BRAF and MAP2K1/2 alterations revealed the presence of slight phenotypic differences regarding craniofacial features in MAP2K1- and MAP2K2-mutation positive individuals, suggesting possible genotype-phenotype correlations.

Keywords: B-RAF; CFC; CS; MEK1; MEK2; oncogene; RAS

Document Type: Research article

DOI: 10.1111/j.1399-0004.2007.00931.x

Affiliations: 1: Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany 2: Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany 3: Department of General Surgery, Akdeniz University Medical Faculty, Antalya, Turkey 4: Department of Human Genetics, University Medical Center, St Radboud, Nijmegen, The Netherlands 5: Medizinische Genetik, Berlin, Germany 6: Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany 7: Institut für Medizinische Genetik, Universitätsklinikum Charité, Medizinische Fakultät der Humboldt-Universität zu Berlin, Berlin, Germany 8: Zentrum für Kinder- und Jugendmedizin, Neuropädiatrie, Klinikum Oldenburg, Oldenburg, Germany 9: Institute of Human Genetics, University of Frankfurt/Main, Frankfurt/Main, Germany 10: Institute of Human Genetics, University of Würzburg, Würzburg, Germany 11: Medizinische Genetik, Kinder- und Jugendklinik, Universität Rostock, Rostock, Germany 12: Medizinische Genetik, Altonaer Kinderkrankenhaus, Hamburg, Germany 13: Medizinische Genetik, St Ingbert, Germany 14: Abteilung Humangenetik, Universitätsklinikum Ulm, Ulm, Germany 15: Institute of Medical Genetics, University of Zurich, Schwerzenbach, Switzerland 16: Department of Paediatrics, Odense University Hospital, Odense, Denmark 17: Institute of Biology and Medical Genetics, Charles University, University Hospital Prague, Prague, Czech Republic 18: Institute of Human Genetics, Ludwig-Maximilian University, Munich, Germany 19: Praxis für Humangenetik, Bremen, Germany 20: Department of Pediatric Genetics, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey 21: Institut für Humangenetik, Medizinische Universität Graz, Graz, Austria

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