Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio‐facio‐cutaneous syndrome from Costello syndrome

Abstract

Because Cardio-facio-cutaneous (CFC) syndrome has significant phenotypic overlap with Costello syndrome, it may be difficult to establish the diagnosis on a clinical basis. The recent discoveries of germline HRAS mutations in patients with Costello syndrome and mutations in BRAF, MEK1, and MEK2 in CFC syndrome uncovered the biologic mechanism for the shared phenotypic findings based on the close interaction of the affected gene products within the MAP kinase pathway. We evaluated a series of patients who were either clinically diagnosed with Costello syndrome, or in whom the diagnoses of both Costello and CFC syndromes were considered. After excluding mutations in HRAS, we identified eight changes in BRAF and five in MEK1. Five mutations are novel, and all changes occurred de novo among those triads tested. A review of the clinical abnormalities showed important differences between patients with either a BRAF or MEK1 mutation, and those previously reported with an HRAS mutation. Statistical significance was achieved, despite the relatively small number of patients with BRAF and MEK1 mutations reported here, for polyhydramnios, growth hormone deficiency and the presence of more than one papilloma, which were less common in CFC compared to HRAS mutation positive patients. Although both CFC and Costello syndrome are characterized by cardiac abnormalities in about three-fourths of patients, the pattern of congenital heart defects (CHD), hypertrophic cardiomyopathy (HCM), and tachycardia differs somewhat. CHD, especially pulmonic stenosis associated with a secundum-type atrial septal defect, are more common in CFC than Costello syndrome (P = 0.02). Atrial tachycardia is less frequent in CFC patients with BRAF or MEK1 mutations, compared to Costello syndrome patients with HRAS mutation (P = 0.04). Chaotic atrial rhythm or multifocal atrial tachycardia was observed only in Costello syndrome. Malignant tumors have been viewed as characteristic for Costello syndrome due to HRAS mutations, however, we report here on a MEK1 mutation in a patient with a malignant tumor, a hepatoblastoma. Although this indicates that the presence of a tumor is not specific for Costello syndrome with HRAS mutation, it is noteworthy that the tumor histology differs from those commonly seen in Costello syndrome. Based on these clinical differences we suggest that patients with BRAF and MEK mutations should be diagnosed with CFC syndrome, and the diagnosis of Costello syndrome be reserved for patients with HRAS mutations.

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.…”

Costello syndrome: a Ras/mitogen activated protein kinase pathway syndrome (rasopathy) resulting from HRAS germline mutations

“…Failure to identify an HRAS mutation in an individual with a phenotype thought to be typical for Costello syndrome can result from either (1) the rare occurrence of low level of somatic mosaicism for the HRAS disease-causing mutation in the tested tissue [11][12][13][14] or (2) the more common presence of a mutation in another gene, consistent with a diagnosis of CFC syndrome 15,16 or another disorder of the Ras/MAPK pathway. 17 In the early series, the 10-15% of individuals suspected of having Costello syndrome who lacked an HRAS mutation were later found to have CFC syndrome.…”

“…17 In the early series, the 10-15% of individuals suspected of having Costello syndrome who lacked an HRAS mutation were later found to have CFC syndrome. 15,16 molecular genetic pathogenesis HRAS is a well-known proto-oncogene, and aberrant activation is often found in sporadic somatic tumors; it is thus not surprising to see the increased cancer incidence in individuals with a germline HRAS mutation. The work performed by Kerr et al 18 showing loss of heterozygosity for 11p15.5 in rhabdomyosarcoma from individuals with Costello syndrome suggests that loss of the wild-type allele is the second hit in tumor development.…”

HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome

“…The number of fatal cases was 5/138 patients with p.G12S, 4/6 with p.G12C, 3/17 with p.G12A, 3/4 with p.G12D, 2/2 with p.G12V, 1/1 with p.G12E and 1/1 with p.E63K. 3,[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] The mortality of patients with p.G12C or p.G12D was significantly higher than that of the patients with the more common p.G12S (P¼0.026 by Fisher's exact test). Previous studies have shown that the p.G12V substitution has the highest transformative potential (p.G12V4p.G12A, p.G12S, p.G12C, p.G12D4p.G13D) and is the most frequently found mutation in human tumors.…”

“…3 It has been suggested that the CS diagnosis should be applied only to patients with a mutation in HRAS because of the high risk of malignancies associated with HRAS mutations and the relative homogeneity of the CS phenotype. 4 A total of 14 HRAS missense mutations and one duplication mutation have been reported in 185 patients with CS 3,[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] or congenital myopathy with excess of muscle spindles. 24 Most of these mutations have previously been reported as somatic and oncogenic mutations in various tumors.…”