Arnold-Chiari malformation in Noonan syndrome and other syndromes of the RAS/MAPK pathway

Autores de IIS La Fe

• Ismael Ejarque Domenech

  Autor

• 

  José María Millán Salvador

  Autor

• Juan Silvestre Oltra Soler

  Autor

• Magdalena Beneyto Juan

  Autor

• Antonio Pérez Aytes

  Autor

Participantes ajenos a IIS La Fe

• Pesudo-Martínez JV

Grupos

• 

  Biomedicina Molecular, Celular y Genómica

• Investigación Traslacional en Genética

• Perinatología

Abstract

Introduction. Noonan syndrome (NS) and other syndromes with a similar phenotype, such as LEOPARD, cardiofaciocutaneous, Costello and Legius, are associated to mutations in genes included in the RAS/MAPK pathway (RASopathies), which is an important signalling pathway related to cell proliferation. Tonsillar descent into the upper cervical spinal canal, known as Arnold-Chiari malformation (ACM), has been reported in patients with NS and this has led some researchers to suggest that ACM could be part of the phenotypic spectrum of NS. We report two cases of NS and ACM. Case reports. Case 1: 29-year-old female with Noonan phenotype who underwent surgery at the age of nine years due to pulmonary valve stenosis. At the age of 27, she presented symptomatic ACM that required surgical decompression. She presented the c.922A>G (N308D) mutation in the gene PTPN that belongs to the RAS/MAPK pathway. Case 2: a 10-year-old female with Noonan phenotype and asymptomatic ACM detected in magnetic resonance imaging of the brain. She was a carrier of the c.923A>G (N308S) mutation in gene PTPN11. Conclusions. Six patients with this association have been found in the literature, four with the Noonan phenotype and two with LEOPARD. Our two patients provide supplementary evidence that backs up the hypothesis by which ACM would be part of the phenotypic spectrum of NS. The small number of reported cases of patients with this association does not allow us to draw up recommendations about when and how often neuroimaging studies should be performed; a careful neurological examination, however, should be included in the anticipatory health guidelines in syndromes involving the RAS/MAPK pathway.

Keywords

• Arnold-Chiari malformation; LEOPARD syndrome; Noonan syndrome; PTPN11; RAS/MAPK pathway; RASopathies