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.

Spectrum of MEK1 and MEK2 gene mutations in cardio-facio-cutaneous syndrome and genotype–phenotype correlations

“…Consistent with the available records, 2 -4,16 -18,20 -22 these data indicate that MEK1 and MEK2 gene mutations 4 Niihori et al, 2 Nava et al, 16 Narumi et al, 3 Yoon et al, 20 Armour et al, 22 Gripp et al, 21 Schulz et al, 17 As facial dysmorphisms are not reported among Armour and Allanson's cohort, we compared the MEK-mutated CFCS cohort with our unpublished clinical data of 17 CFC BRAF-mutated positive patients. MEK1 and MEK2 mutations in CFC syndrome ML Dentici et al underlie a significant fraction of CFCS, accounting for approximately 20% of cases.…”

“…These results are in disagreement with earlier studies pointing to a lower prevalence of hypertelorism among MEK1/MEK2 mutation-positive patients (73%) than of those with BRAF mutation (91%). 16 Cryptorchidism has been described in the five male patients heterozygous for a MEK1/MEK2 mutation, although additional observations are necessary to support this association.…”

“…Until now, mutations in the MEK1 and MEK2 genes have been detected in 58 patients with CFCS, and in three patients exhibiting a phenotype apparently fitting NS. 16 Although these findings would be suggestive of phenotypic heterogeneity, the clinical features associated with mutations in the MEK1 and MEK2 genes have not been delineated exhaustively. The presence of normal cognitive abilities in a minor percentage of individuals seems to suggest that MEK1/MEK2 mutation-positive patients show a milder clinical phenotype than what is observed in patients with BRAF mutations or in the general CFCS population.…”

SOS1 and PTPN11 mutations in five cases of Noonan syndrome with multiple giant cell lesions

“…Birth prevalence is estimated between 1/1000 and 1/2500. Mutations in PTPN11 5 are reported in about 50% of cases, SOS1 6,7 in 10 -20%, RAF1 8 and KRAS, 9 both in less than 5%, Rare patients with BRAF, MEK1, or MEK2 may exhibit an NS phenotype, 10 although most of them have CFC syndrome.…”

Congenital Heart Disease: In Search of Remedial Etiologies

“…In patients with Down, Marfan, or Noonan Syndromes, there is increasing evidence that genes encoding nodal signaling kinases like FAK/AKTkt/PI3K, RAS, MEKK/ ERK1/2, PTPN11, etc., are likely candidates for CHD if they are mutated or overexpressed [2][3][4]. Such genes are not usually lethal (as there exist molecular or functional redundancies), yet as indicated for syndromic heart defects, they have potential to change functional behaviors in progenitor cells that normally mold and remodel the simple tubular heart into a four-chambered organ.…”