Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardio-facio-cutaneous (CFC) syndrome is a multiple congenital anomaly/mental retardation syndrome characterized by heart defects, a distinctive facial appearance, ectodermal abnormalities and mental retardation. Clinically, it overlaps with both Noonan syndrome and Costello syndrome, which are caused by mutations in two genes, PTPN11 and HRAS, respectively. Recently, we identified mutations in KRAS and BRAF in 19 of 43 individuals with CFC syndrome, suggesting that dysregulation of the RAS/RAF/MEK/ERK pathway is a molecular basis for CFC syndrome. The purpose of this study was to perform comprehensive mutation analysis in 56 patients with CFC syndrome and to investigate genotype-phenotype correlation. We analyzed KRAS, BRAF, and MAP2K1/2 (MEK1/2) in 13 new CFC patients and identified five BRAF and one MAP2K1 mutations in nine patients. We detected one MAP2K1 mutation in three patients and four new MAP2K2 mutations in four patients out of 24 patients without KRAS or BRAF mutations in the previous study [Niihori et al., 2006]. No mutations were identified in MAPK3/1 (ERK1/2) in 21 patients without any mutations. In total, 35 of 56 (62.5%) patients with CFC syndrome had mutations (3 in KRAS, 24 in BRAF, and 8 in MAP2K1/2). No significant differences in clinical manifestations were found among 3 KRAS-positive patients, 16 BRAF-positive patients, and 6 MAP2K1/2-positive patients. Wrinkled palms and soles, hyperpigmentation and joint hyperextension, which have been commonly reported in Costello syndrome but not in CFC syndrome, were observed in 30-40% of the mutation-positive CFC patients, suggesting a significant clinical overlap between these two syndromes.
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PMID:Molecular and clinical characterization of cardio-facio-cutaneous (CFC) syndrome: overlapping clinical manifestations with Costello syndrome. 1736 77

The RAS proteins and their downstream pathways play pivotal roles in cell proliferation, differentiation, survival and cell death, but their physiological roles in human development had remained unknown. Noonan syndrome, Costello syndrome, and cardio-facio-cutaneous (CFC) syndrome are autosomal dominant multiple congenital anomaly syndromes characterized by a distinctive facial appearance, heart defects, musculocutaneous abnormalities, and mental retardation. A variety of mutations in protein tyrosine phosphatase, non-receptor type 11(PTPN11) has been identified in 50% of Noonan patients. Specific mutations in PTPN11 have been identified in LEOPARD (multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) syndrome. In 2005, we discovered Harvey-RAS (HRAS) germline mutations in patients with Costello syndrome. This discovery provided a clue to identification of germline mutations in Kirsten-RAS (KRAS), BRAF and mitogen-activated protein kinase kinase 1 and 2 (MAP2K1/MAP2K2) in patients with CFC syndrome. These genes encode molecules in the RAS/RAF/MEK/extracellular signal-regulated kinase (ERK) pathway, leading to a new concept that clinically related disorders, i.e., Noonan, Costello, and CFC syndromes are caused by dysregulation of the RAS/mitogen activated protein kinase (MAPK) pathway. In the present review, we summarize mutations in HRAS, KRAS, BRAF, MAP2K1/2, and PTPN11, the phenotypes of patients with these mutations, the functional properties of mutants and animal models. Finally we suggest that disorders with mutations of molecules in the RAS/MAPK cascade (Noonan, LEOPARD, Costello, and CFC syndromes and neurofibromatosis type I) may be comprehensively termed "the RAS/MAPK syndromes." Details on mutations will be updated in the RAS/MAPK Syndromes Homepage (www.medgen.med.tohoku.ac.jp/RasMapk syndromes.html).
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PMID:The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. 1847 Sep 43

Noonan syndrome (NS) and cardio-facio-cutaneous (CFC) syndrome are autosomal dominant disorders characterized by heart defects, facial dysmorphism, ectodermal abnormalities, and mental retardation. There is a significant clinical overlap between NS and CFC syndrome, but ectodermal abnormalities and mental retardation are more frequent in CFC syndrome. Mutations in PTPN11 and KRAS have been identified in patients with NS and those in KRAS, BRAF and MAP2K1/2 have been identified in patients with CFC syndrome, establishing a new role of the RAS/MAPK pathway in human development. Recently, mutations in the son of sevenless gene (SOS1) have also been identified in patients with NS. To clarify the clinical spectrum of patients with SOS1 mutations, we analyzed 24 patients with NS, including 3 patients in a three-generation family, and 30 patients with CFC syndrome without PTPN11, KRAS, HRAS, BRAF, and MAP2K1/2 (MEK1/2) mutations. We identified two SOS1 mutations in four NS patients, including three patients in the above-mentioned three-generation family. In the patients with a CFC phenotype, three mutations, including a novel three amino-acid insertion, were identified in one CFC patient and two patients with both NS and CFC phenotypes. These three patients exhibited ectodermal abnormalities, such as curly hair, sparse eyebrows, and dry skin, and two of them showed mental retardation. Our results suggest that patients with SOS1 mutations range from NS to CFC syndrome.
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PMID:Clinical manifestations in patients with SOS1 mutations range from Noonan syndrome to CFC syndrome. 1865 Oct 97

Cardio-facio-cutaneous syndrome (CFCS) is a rare disease characterized by mental retardation, facial dysmorphisms, ectodermal abnormalities, heart defects and developmental delay. CFCS is genetically heterogeneous and mutations in the KRAS, BRAF, MAP2K1 (MEK1) and MAP2K2 (MEK2) genes, encoding for components of the RAS-mitogen activated protein kinase (MAPK) signaling pathway, have been identified in up to 90% of cases. Here we screened a cohort of 33 individuals with CFCS for MEK1 and MEK2 gene mutations to further explore their molecular spectrum in this disorder, and to analyze genotype-phenotype correlations. Three MEK1 and two MEK2 mutations were detected in six patients. Two missense MEK1 (L42F and Y130H) changes and one in-frame MEK2 (K63_E66del) deletion had not been reported earlier. All mutations were localized within exon 2 or 3. Together with the available records, the present data document that MEK1 mutations are relatively more frequent than those in MEK2, with exons 2 and 3 being mutational hot spots in both genes. Mutational analysis of the affected MEK1 and MEK2 exons did not reveal occurrence of mutations among 75 patients with Noonan syndrome, confirming the low prevalence of MEK gene defects in this disorder. Clinical review of known individuals with MEK1/MEK2 mutations suggests that these patients show dysmorphic features, ectodermal abnormalities and cognitive deficit similar to what was observed in BRAF-mutated patients and in the general CFCS population. Conversely, congenital heart defects, particularly mitral valve and septal defects, and ocular anomalies seem to be less frequent among MEK1/MEK2 mutation-positive patients.
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PMID:Spectrum of MEK1 and MEK2 gene mutations in cardio-facio-cutaneous syndrome and genotype-phenotype correlations. 1915 72

Noonan syndrome (NS) and related disorders are autosomal dominant disorders characterized by heart defects, facial dysmorphism, ectodermal abnormalities, and mental retardation. The dysregulation of the RAS/MAPK pathway appears to be a common molecular pathogenesis of these disorders: mutations in PTPN11, KRAS, and SOS1 have been identified in patients with NS, those in KRAS, BRAF, MAP2K1, and MAP2K2 in patients with CFC syndrome, and those in HRAS mutations in Costello syndrome patients. Recently, mutations in RAF1 have been also identified in patients with NS and two patients with LEOPARD (multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) syndrome. In the current study, we identified eight RAF1 mutations in 18 of 119 patients with NS and related conditions without mutations in known genes. We summarized clinical manifestations in patients with RAF1 mutations as well as those in NS patients withPTPN11, SOS1, or KRAS mutations previously reported. Hypertrophic cardiomyopathy and short stature were found to be more frequently observed in patients with RAF1 mutations. Mutations in RAF1 were clustered in the conserved region 2 (CR2) domain, which carries an inhibitory phosphorylation site (serine at position 259; S259). Functional studies revealed that the RAF1 mutants located in the CR2 domain resulted in the decreased phosphorylation of S259, and that mutant RAF1 then dissociated from 14-3-3, leading to a partial ERK activation. Our results suggest that the dephosphorylation of S259 is the primary pathogenic mechanism in the activation of RAF1 mutants located in the CR2 domain as well as of downstream ERK.
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PMID:Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation. 2005 57

Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomaly/mental retardation syndrome characterized by a distinctive facial appearance, ectodermal abnormalities, and heart defects. Clinically, it overlaps with both Noonan syndrome and Costello syndrome. Mutations in KRAS, BRAF, and MAP2K1/2 (MEK1/2) have been identified in patients with CFC syndrome. BRAF mutations are involved in more than 80% of CFC syndrome patients, and we have reported earlier that 2 CFC patients with BRAF mutations developed acute lymphoblastic leukemia. Here we report a boy with CFC syndrome who developed non-Hodgkin lymphoma. At 2 months of age, he developed pneumonia with pleurisy and was diagnosed as having non-Hodgkin lymphoma (precursor T-cell lymphoblastic lymphoma) by cytopathologic examination of the pleural fluid. He was suspected of having Noonan syndrome because of his facial appearance, webbed neck, and cubitus valgus. Precursor T-cell lymphoblastic lymphoma was treated by the TCCSG NHL 94-04 protocol. At 9 years of age, he was clinically reevaluated and diagnosed as having CFC syndrome because of his distinctive facial appearance, multiple nevi, and moderate mental retardation. Sequencing analysis showed a germline p.A246P (c.736G>C) mutation in BRAF reported earlier in CFC syndrome. Molecular diagnosis and careful observation should be considered in children with CFC syndrome.
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PMID:Non-hodgkin lymphoma in a patient with cardiofaciocutaneous syndrome. 2052 44