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Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype-phenotype relationships and overlap with Costello syndrome.

ABSTRACT: Cardio-facio-cutaneous (CFC) syndrome, Noonan syndrome (NS), and Costello syndrome (CS) are clinically related developmental disorders that have been recently linked to mutations in the RAS/MEK/ERK signalling pathway. This study was a mutation analysis of the KRAS, BRAF, MEK1 and MEK2 genes in a total of 130 patients (40 patients with a clinical diagnosis of CFC, 20 patients without HRAS mutations from the French Costello family support group, and 70 patients with NS without PTPN11 or SOS1 mutations). BRAF mutations were found in 14/40 (35%) patients with CFC and 8/20 (40%) HRAS-negative patients with CS. KRAS mutations were found in 1/40 (2.5%) patients with CFC, 2/20 (10%) HRAS-negative patients with CS and 4/70 patients with NS (5.7%). MEK1 mutations were found in 4/40 patients with CFC (10%), 4/20 (20%) HRAS-negative patients with CS and 3/70 (4.3%) patients with NS, and MEK2 mutations in 4/40 (10%) patients with CFC. Analysis of the major phenotypic features suggests significant clinical overlap between CS and CFC. The phenotype associated with MEK mutations seems less severe, and is compatible with normal mental development. Features considered distinctive for CS were also found to be associated with BRAF or MEK mutations. Because of its particular cancer risk, the term "Costello syndrome" should only be used for patients with proven HRAS mutation. These results confirm that KRAS is a minor contributor to NS and show that MEK is involved in some cases of NS, demonstrating a phenotypic continuum between the clinical entities. Although some associated features appear to be characteristic of a specific gene, no simple rule exists to distinguish NS from CFC easily.

SUBMITTER: Nava C

PROVIDER: S-EPMC2652823 | biostudies-literature | 2007 Dec

REPOSITORIES: biostudies-literature

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Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype-phenotype relationships and overlap with Costello syndrome.

Nava Caroline C Hanna Nadine N Michot Caroline C Pereira Sabrina S Pouvreau Nathalie N Niihori Tetsuya T Aoki Yoko Y Matsubara Yoichi Y Arveiler Benoit B Lacombe Didier D Pasmant Eric E Parfait Béatrice B Baumann Clarisse C Héron Delphine D Sigaudy Sabine S Toutain Annick A Rio Marlène M Goldenberg Alice A Leheup Bruno B Verloes Alain A Cavé Hélène H

Journal of medical genetics 20070817 12

Cardio-facio-cutaneous (CFC) syndrome, Noonan syndrome (NS), and Costello syndrome (CS) are clinically related developmental disorders that have been recently linked to mutations in the RAS/MEK/ERK signalling pathway. This study was a mutation analysis of the KRAS, BRAF, MEK1 and MEK2 genes in a total of 130 patients (40 patients with a clinical diagnosis of CFC, 20 patients without HRAS mutations from the French Costello family support group, and 70 patients with NS without PTPN11 or SOS1 mutat ...[more]

PMID: 17704260

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Project description:Backgroundcardio-facio-cutaneous syndrome is a rare genetic disorder affecting less than 900 people in the world. It is mainly characterized by craniofacial, dermatologic and cardiac defects, but also gastroenterological symptoms may be present, ranging from feeding difficulties to gastroesophageal reflux and constipation.In this report we describe a case of this syndrome characterized by severe feeding and growth difficulties, with a particular focus on the management of gastroenterological complications.Case presentationthe patient was a caucasian male affected by Cardio-Facio-Cutaneous syndrome who presented feeding difficulties already a few hours after birth. These symptoms worsened in the following months and lead to a complete growth arrest and malnutrition. He was first treated with a nasogastric tube placement. Subsequently, a laparoscopic Nissen fundoplication and a laparoscopic Stamm gastrostomy were performed. The child was fed with nocturnal enteral nutrition and diurnal oral and enteral nutrition. Eventually the patient resumed feeding validly and regained adequate growth.Conclusionthis paper aims to bring to light a complex rare syndrome that infrequently comes to the attention of the pediatricians and whose diagnosis is not always straightforward. We also highlight the possible complications under a gastroenterologic point of view. Our contribution can be helpful to the pediatrician in the first diagnostic suspect of this syndrome. In particular, it is worth highlighting that -in an infant with Noonan-like features- symptoms like suction or swallowing problems, vomiting and feeding difficulties should orient towards the diagnosis of a Cardio-facio-cutaneous syndrome. It is also important to stress that its related gastroenterological issues may lead to severe growth failure and therefore the role of the gastroenterologist is key to manage supplemental feeding and to establish whether a nasogastric or gastrostomic tube placement is necessary.

Dataset Information

Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype-phenotype relationships and overlap with Costello syndrome.

Publications

Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype-phenotype relationships and overlap with Costello syndrome.

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