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


METHODS
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.
Ismael
I
Ejarque
José M
JM
Millán-Salvador
Silvestre
S
Oltra
José V
JV
Pesudo-Martínez
Magdalena
M
Beneyto
Hospital La Fe, 46009 Valencia, Espana.
Antonio
A
Pérez-Aytés
D000328:Adult; D001139:Arnold-Chiari Malformation / Q000209:etiology* / Q000601:surgery; D002648:Child; D019299:Decompression, Surgical; D005091:Exons; D005260:Female; D006801:Humans; D044542:LEOPARD Syndrome / Q000150:complications / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology; D020125:Mutation, Missense; D009634:Noonan Syndrome / Q000150:complications* / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D017354:Point Mutation; D011247:Pregnancy; D011248:Pregnancy Complications / Q000235:genetics; D011296:Prenatal Diagnosis; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D016283:Proto-Oncogene Proteins p21(ras)