RESUMEN
Cardio-facio-cutaneous (CFC) syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. It phenotypically overlaps with Noonan and Costello syndrome, which are caused by mutations in PTPN11 and HRAS, respectively. In 43 individuals with CFC, we identified two heterozygous KRAS mutations in three individuals and eight BRAF mutations in 16 individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway is a common molecular basis for the three related disorders.
Asunto(s)
Cara/anomalías , Cardiopatías Congénitas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas/genética , Anomalías Cutáneas/genética , Secuencia de Aminoácidos , Humanos , Discapacidad Intelectual/genética , Datos de Secuencia Molecular , Proteínas Proto-Oncogénicas p21(ras) , Valores de Referencia , Síndrome , Proteínas rasRESUMEN
Congenital cataracts are the most important cause of severe visual impairment in infants. Genetic factors contribute to the disease development and 29 genes are known to cause congenital cataracts. Identifying the genetic cause of congenital cataracts can be difficult because of genetic heterogeneity. V-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (MAF) encodes a basic region/leucine zipper transcription factor that plays a key role as a regulator of embryonic lens fiber cell development. MAF mutations have been reported to cause juvenile-onset pulverulent cataract, microcornea, iris coloboma, and other anterior segment dysgenesis. We report on six patients in a family who have congenital cataracts were identified MAF mutation by whole exome sequencing (WES). The heterozygous MAF mutation Q303L detected in the present family occurs in a well conserved glutamine residue at the basic region of the DNA-binding domain. All affected members showed congenital cataracts. Three of the six members showed microcornea and one showed iris coloboma. Congenital cataracts with MAF mutation exhibited phenotypically variable cataracts within the family. Review of the patients with MAF mutations supports the notion that congenital cataracts caused by MAF mutations could be accompanied by microcornea and/or iris coloboma. WES is a useful tool for detecting disease-causing mutations in patients with genetically heterogeneous conditions.
Asunto(s)
Pueblo Asiatico/genética , Catarata/congénito , Catarata/genética , Mutación Missense , Proteínas Proto-Oncogénicas c-maf/genética , Alelos , Secuencia de Aminoácidos , Catarata/diagnóstico , Preescolar , Análisis Mutacional de ADN , Exoma , Femenino , Estudios de Asociación Genética , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Japón , Masculino , Datos de Secuencia Molecular , Linaje , Fenotipo , Proteínas Proto-Oncogénicas c-maf/química , Alineación de SecuenciaRESUMEN
Wolf-Hirschhorn syndrome (WHS) is a contiguous gene deletion syndrome of the distal 4p chromosome, characterized by craniofacial features, growth impairment, intellectual disability, and seizures. Although genotype-phenotype correlation studies have previously been published, several important issues remain to be elucidated including seizure severity. We present detailed clinical and molecular-cytogenetic findings from a microarray and fluorescence in situ hybridization (FISH)-based genotype-phenotype analysis of 22 Japanese WHS patients, the first large non-Western series. 4p deletions were terminal in 20 patients and interstitial in two, with deletion sizes ranging from 2.06 to 29.42 Mb. The new Wolf-Hirschhorn syndrome critical region (WHSCR2) was deleted in all cases, and duplication of other chromosomal regions occurred in four. Complex mosaicism was identified in two cases: two different 4p terminal deletions; a simple 4p terminal deletion and an unbalanced translocation with the same 4p breakpoint. Seizures began in infancy in 33% (2/6) of cases with small (<6 Mb) deletions and in 86% (12/14) of cases with larger deletions (>6 Mb). Status epilepticus occurred in 17% (1/6) with small deletions and in 87% (13/15) with larger deletions. Renal hypoplasia or dysplasia and structural ocular anomalies were more prevalent in those with larger deletions. A new susceptible region for seizure occurrence is suggested between 0.76 and 1.3 Mb from 4 pter, encompassing CTBP1 and CPLX1, and distal to the previously-supposed candidate gene LETM1. The usefulness of bromide therapy for seizures and additional clinical features including hypercholesterolemia are also described.
Asunto(s)
Estudios de Asociación Genética , Hibridación Fluorescente in Situ , Análisis de Secuencia por Matrices de Oligonucleótidos , Síndrome de Wolf-Hirschhorn/diagnóstico , Síndrome de Wolf-Hirschhorn/genética , Adolescente , Pueblo Asiatico/genética , Niño , Preescolar , Aberraciones Cromosómicas , Bandeo Cromosómico , Facies , Femenino , Humanos , Hibridación Fluorescente in Situ/métodos , Lactante , Japón , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , FenotipoRESUMEN
It is debatable whether Hajdu-Cheney syndrome (HCS) and serpentine fibula-polycystic kidney syndrome (SFPKS) represent a single clinical entity with a variable degree of expression or two different entities, because both disorders share common clinical and radiological manifestations, including similar craniofacial characteristics, and defective bone mineralization. Since it was shown that heterozygous truncating mutations in NOTCH2 are responsible for both HCS and SFPKS, 37 patients with HCS and four patients with SFPKS are reported. To elucidate the clinical consequences of NOTCH2 mutations, we present detailed clinical information for seven patients with truncating mutations in exon 34 of NOTCH2, six with HCS and one with SFPKS. In addition, we review all the reported patients whose clinical manifestations are available. We found 13 manifestations including craniofacial features, acroosteolysis, Wormian bones, and osteoporosis in >75% of NOTCH2-positive patients. Acroosteolysis was observed in two patients with SFPKS and bowing fibulae were found in two patients with HCS. These clinical and molecular data would support the notion that HCS and SFPKS are a single disorder.
Asunto(s)
Síndrome de Hajdu-Cheney/diagnóstico por imagen , Receptor Notch2/genética , Adolescente , Adulto , Preescolar , Codón sin Sentido , Análisis Mutacional de ADN , Exones , Estudios de Asociación Genética , Síndrome de Hajdu-Cheney/genética , Humanos , Persona de Mediana Edad , Radiografía , Adulto JovenRESUMEN
Mutations in the components of the SWItch/sucrose nonfermentable (SWI/SNF)-like chromatin remodeling complex have recently been reported to cause Coffin-Siris syndrome (CSS), Nicolaides-Baraitser syndrome (NCBRS), and ARID1B-related intellectual disability (ID) syndrome. We detail here the genotype-phenotype correlations for 85 previously published and one additional patient with mutations in the SWI/SNF complex: four with SMARCB1 mutations, seven with SMARCA4 mutations, 37 with SMARCA2 mutations, one with an SMARCE1 mutation, three with ARID1A mutations, and 33 with ARID1B mutations. The mutations were associated with syndromic ID and speech impairment (severe/profound in SMARCB1, SMARCE1, and ARID1A mutations; variable in SMARCA4, SMARCA2, and ARID1B mutations), which was frequently accompanied by agenesis or hypoplasia of the corpus callosum. SMARCB1 mutations caused "classical" CSS with typical facial "coarseness" and significant digital/nail hypoplasia. SMARCA4 mutations caused CSS without typical facial coarseness and with significant digital/nail hypoplasia. SMARCA2 mutations caused NCBRS, typically with short stature, sparse hair, a thin vermillion of the upper lip, an everted lower lip and prominent finger joints. A SMARCE1 mutation caused CSS without typical facial coarseness and with significant digital/nail hypoplasia. ARID1A mutations caused the most severe CSS with severe physical complications. ARID1B mutations caused CSS without typical facial coarseness and with mild digital/nail hypoplasia, or caused syndromic ID. Because of the common underlying mechanism and overlapping clinical features, we propose that these conditions be referred to collectively as "SWI/SNF-related ID syndromes".
Asunto(s)
Anomalías Múltiples/genética , Ensamble y Desensamble de Cromatina/genética , Cara/anomalías , Deformidades Congénitas del Pie/genética , Deformidades Congénitas de la Mano/genética , Hipotricosis/genética , Discapacidad Intelectual/genética , Micrognatismo/genética , Cuello/anomalías , Factores de Transcripción/genética , Proteínas Cromosómicas no Histona/genética , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Facies , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Mutación , Proteínas Nucleares/genética , Proteína SMARCB1 , SíndromeRESUMEN
15q24 deletion syndrome is a recently-described chromosomal disorder, characterized by developmental delay, growth deficiency, distinct facial features, digital abnormalities, loose connective tissue, and genital malformations in males. To date, 19 patients have been reported. We report on a 13-year-old boy with this syndrome manifesting childhood myelodysplastic syndrome (MDS). He had characteristic facial features, hypospadias, and mild developmental delay. He showed neutropenia and thrombocytopenia for several years. At age 13 years, bone marrow examination was performed, which showed a sign suggestive of childhood MDS: mild dysplasia in the myeloid, erythroid, and megakaryocytic cell lineages. Array comparative genomic hybridization (array CGH) revealed a de novo 3.4 Mb 15q24.1q24.3 deletion. Although MDS has not been described in patients with the syndrome, a boy was reported to have acute lymphoblastic leukemia (ALL). The development of MDS and hematological malignancy in the syndrome might be caused by the haploinsufficiency of deleted 15q24 segment either alone or in combination with other genetic abnormalities in hematopoietic cells. Further hematological investigation is recommended to be beneficial if physical and hematological examination results are suggestive of hematopoietic disturbance in patients with the syndrome.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 15 , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Adolescente , Hibridación Genómica Comparativa , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/patología , Humanos , Hipospadias/diagnóstico , Hipospadias/patología , Hibridación Fluorescente in Situ , Linfocitos/citología , Masculino , Síndromes Mielodisplásicos/diagnóstico , Neutropenia/diagnóstico , Neutropenia/patología , Trombocitopenia/diagnóstico , Trombocitopenia/patologíaRESUMEN
The proband was a male fetus who died at 18 weeks of gestation. The fetus had growth retardation, hydrocephalus, exophthalmos, and micrognathia. The placental villus was not available. We performed interphase fluorescence in situ hybridization (FISH) using buccal cells of the fetus. The FISH using centromere specific probes for chromosome 7, 8 and 18, and RB1 gene (13q14)-specific probe showed three signals for each chromosome. The sex chromosome composition was XXY by FISH using centromere-specific probes for X and Y chromosomes. Thus, the fetus was diagnosed with triploidy syndrome. This report suggested that interphase FISH using buccal cells is useful for examining chromosomal abnormalities in intrauterine fetal death when placental villus is not available.
Asunto(s)
Aberraciones Cromosómicas/embriología , Muerte Fetal/etiología , Hibridación in Situ/métodos , Mucosa Bucal/citología , Mucosa Bucal/embriología , Triploidía , Adulto , Vellosidades Coriónicas , Cromosomas Humanos/genética , Femenino , Asesoramiento Genético , Humanos , Masculino , Embarazo , SíndromeRESUMEN
LEOPARD syndrome (LS), generally caused by heterozygous mutations in the PTPN11 gene, is a rare autosomal-dominant multiple congenital anomaly condition, characterized by skin, facial, and cardiac abnormalities. Prognosis appears to be related to the type of structural, myocardial, and arrhythmogenic cardiac disease, especially hypertrophic cardiomyopathy (HCM). We report on a woman with LS and a novel Gln510His mutation in PTPN11, who had progressive HCM with congestive heart failure and nonsustained ventricular tachycardia, successfully treated with implantable cardioverter defibrillator (ICD). Comparing our patient to the literature suggests that specific mutations at codon 510 in PTPN11 (Gln510Glu, Gln510His, but not Gln510Pro) might be a predictor of fatal cardiac events in LS. Molecular risk stratification and careful evaluations for an indication of ICD implantation are likely to be beneficial in managing patients with LS and HCM.
Asunto(s)
Cardiomiopatía Hipertrófica/terapia , Desfibriladores Implantables , Síndrome LEOPARD/genética , Síndrome LEOPARD/patología , Síndrome LEOPARD/terapia , Mutación Missense/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Adulto , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/patología , Análisis Mutacional de ADN , Cartilla de ADN/genética , Femenino , HumanosRESUMEN
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.
Asunto(s)
Mutación , Síndrome de Noonan/genética , Proteínas Proto-Oncogénicas c-raf/genética , Serina/genética , Proteínas 14-3-3/metabolismo , Animales , Cardiomiopatías/genética , Facies , Humanos , Ratones , Modelos Genéticos , Células 3T3 NIH , Fosforilación , Unión Proteica , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genéticaRESUMEN
We describe two patients with Pallister-Hall syndrome (PHS) with genital abnormalities: a female with hydrometrocolpos secondary to vaginal atresia and a male with micropenis, hypoplastic scrotum, and bilateral cryptorchidism. Nonsense mutations in GLI3 were identified in both patients. Clinical and molecular findings of 12 previously reported patients who had GLI3 mutations and genital abnormalities were reviewed. Genital features in the male patients included hypospadias, micropenis, and bifid or hypoplastic scrotum, whereas all the females had hydrometrocolpos and/or vaginal atresia. No hotspot for GLI3 mutations has been found. The urogenital and anorectal abnormalities associated with PHS might be related to dysregulation of SHH signaling caused by GLI3 mutations rather than hormonal aberrations. We recommend that clinical investigations of genital abnormalities are considered in patients with PHS, even those without hypopituitarism.
Asunto(s)
Anomalías Múltiples/genética , Síndrome de Pallister-Hall/diagnóstico , Anomalías Urogenitales/diagnóstico , Anomalías Urogenitales/genética , Niño , Preescolar , Codón sin Sentido , ADN/genética , ADN/aislamiento & purificación , Exones , Femenino , Mutación del Sistema de Lectura , Genes Dominantes , Heterocigoto , Humanos , Factores de Transcripción de Tipo Kruppel/genética , Masculino , Proteínas del Tejido Nervioso/genética , Técnicas de Amplificación de Ácido Nucleico , Reacción en Cadena de la Polimerasa , Proteína Gli3 con Dedos de ZincRESUMEN
We present the clinical and radiological findings of seven patients with a seemingly new variant of Desbuquois dysplasia (DBQD) and emphasize the radiographic findings in the hand. All cases showed remarkably accelerated carpal bone ages in childhood, but none of the patients had an accessory ossification center distal to the second metacarpal, or thumb anomalies, instead, there was shortness of one or all metacarpals, with elongated appearance of phalanges, resulting in nearly equal length of the second to fifth fingers. The two sibs followed for 20 years showed narrowing and fusion of the intercarpal joints with age and ultimately, precocious degenerative arthritis. The changes in the feet were similar to those of the hands, with advanced tarsal bone ages, shortness of the metatarsals and elongation of the second and third toes. Other radiographic findings were narrowness of the intervertebral disc spaces resulting in precocious degenerative spondylosis and progressive scoliosis. The femoral neck was short and thick and showed a persistent enlargement of the lesser trochanter with a high-riding, bulbous greater trochanter that became more prominent with age. Molecular testing of the diastrophic dysplasia sulfate transporter (DTDST) gene was performed on six patients and no mutations were detected. This radiographic and clinical observation further adds to the evidence that there may be subtypes of DBQD. Long-term follow-up showed that severe precocious osteoarthritis of the hand and spine is a major manifestation of this specific variant.
Asunto(s)
Determinación de la Edad por el Esqueleto , Enfermedades del Desarrollo Óseo/diagnóstico por imagen , Huesos del Carpo/diagnóstico por imagen , Falanges de los Dedos de la Mano/anomalías , Falanges de los Dedos de la Mano/diagnóstico por imagen , Huesos del Metacarpo/anomalías , Huesos del Metacarpo/diagnóstico por imagen , Adolescente , Adulto , Enfermedades del Desarrollo Óseo/complicaciones , Huesos del Carpo/anomalías , Niño , Preescolar , Femenino , Deformidades Congénitas del Pie/complicaciones , Deformidades Congénitas del Pie/diagnóstico por imagen , Deformidades Congénitas de la Mano/complicaciones , Deformidades Congénitas de la Mano/diagnóstico por imagen , Humanos , Rodilla/anomalías , Rodilla/diagnóstico por imagen , Masculino , Pelvis/anomalías , Pelvis/diagnóstico por imagen , Hermanos , Columna Vertebral/anomalías , Columna Vertebral/diagnóstico por imagen , Adulto JovenRESUMEN
We report on a girl with early onset Huntington disease (HD). Her initial symptoms at 2 years of age included oral motor dysfunction and gait disturbance. Magnetic resonance imaging of the head revealed severe atrophy of both the vermis and the cerebellar cortex in addition to the common findings of basal ganglia including the caudate nuclei, putamen, and globus pallidus. Molecular analysis showed 160 CAG repeats in the HD gene. This mutation was inherited from her mother who was also affected, with a HD CAG expansion of 60 repeats. Cerebellar symptoms should be considered as a manifestation of early onset HD.
Asunto(s)
Cerebelo/patología , Enfermedad de Huntington/genética , Enfermedad de Huntington/patología , Edad de Inicio , Anticipación Genética , Atrofia , Secuencia de Bases , Preescolar , Cartilla de ADN/genética , Femenino , Humanos , Proteína Huntingtina , Imagen por Resonancia Magnética , Madres , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , Expansión de Repetición de TrinucleótidoRESUMEN
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).
Asunto(s)
Enfermedades Genéticas Congénitas/metabolismo , Sistema de Señalización de MAP Quinasas , Proteínas ras/genética , Animales , Humanos , SíndromeRESUMEN
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.
Asunto(s)
Anomalías Múltiples/genética , Cardiopatías Congénitas/genética , Síndrome de Noonan/genética , Síndrome de Noonan/fisiopatología , Proteína SOS1/genética , Adulto , Niño , Preescolar , Análisis Mutacional de ADN , Familia , Femenino , Cardiopatías Congénitas/complicaciones , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/fisiopatología , Humanos , Lactante , Masculino , Mutación/fisiología , Síndrome de Noonan/diagnóstico , Linaje , SíndromeRESUMEN
Cardio-facio-cutaneous (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, which are caused by mutations in 2 genes that encode molecules of the RAS/MAPK (mitogen activated protein kinase) pathway (PTPN11 and HRAS, respectively). Recently, mutations in KRAS, BRAF, and MEK1/2 have been identified in patients with CFC syndrome. Somatic mutations in KRAS and BRAF have been identified in various tumors. In contrast, the association with malignancy has not been noticed in CFC syndrome. Here we report a 9-year-old boy diagnosed with CFC syndrome and acute lymphoblastic leukemia. Sequencing analysis of the entire coding region of KRAS and BRAF showed a de novo germline BRAF E501G (1502A-->G) mutation. Molecular diagnosis and careful observations should be considered in children with CFC syndrome because they have germline mutations in proto-oncogenes and might develop malignancy.
Asunto(s)
Anomalías Múltiples/genética , Anomalías Craneofaciales/genética , Mutación de Línea Germinal/genética , Cardiopatías Congénitas/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Proto-Oncogénicas B-raf/genética , Anomalías Cutáneas/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/terapia , Niño , Anomalías Craneofaciales/diagnóstico , Anomalías Craneofaciales/terapia , Análisis Citogenético/métodos , Cara/anomalías , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/terapia , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Discapacidad Intelectual/terapia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Proto-Oncogenes Mas , Análisis de Secuencia de ADN/métodos , Anomalías Cutáneas/diagnóstico , Anomalías Cutáneas/terapia , SíndromeRESUMEN
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.
Asunto(s)
Anomalías Múltiples/genética , Discapacidad Intelectual/genética , MAP Quinasa Quinasa 1/genética , MAP Quinasa Quinasa 2/genética , Proteínas Proto-Oncogénicas B-raf/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/epidemiología , Estudios de Casos y Controles , Anomalías Craneofaciales/diagnóstico , Anomalías Craneofaciales/epidemiología , Anomalías Craneofaciales/genética , Análisis Mutacional de ADN , Diagnóstico Diferencial , Genotipo , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/epidemiología , Cardiopatías Congénitas/genética , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/epidemiología , Epidemiología Molecular , Fenotipo , Transducción de Señal , Anomalías Cutáneas/diagnóstico , Anomalías Cutáneas/epidemiología , Anomalías Cutáneas/genética , Síndrome , Proteínas ras/metabolismoAsunto(s)
Atrofia/complicaciones , Ganglios Basales/patología , Encefalopatías/diagnóstico , Encefalopatías/patología , Cerebelo/patología , Síndrome de Down/complicaciones , Síndrome de Down/patología , Dantroleno/uso terapéutico , Síndrome de Down/diagnóstico , Síndrome de Down/tratamiento farmacológico , Síndrome de Down/genética , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Relajantes Musculares Centrales/uso terapéutico , Fenotipo , Resultado del TratamientoRESUMEN
Autosomal-dominant, nonsyndromic hearing impairment is clinically and genetically heterogeneous. We encountered a large Japanese pedigree in which nonsyndromic hearing loss was inherited in an autosomal-dominant fashion. A genome-wide linkage study indicated linkage to the DFNA2 locus on chromosome 1p34. Mutational analysis of KCNQ4 encoding a potassium channel revealed a novel one-base deletion in exon 1, c.211delC, which generated a profoundly truncated protein without transmembrane domains (p.Q71fsX138). Previously, six missense mutations and one 13-base deletion, c.211_223del, had been reported in KCNQ4. Patients with the KCNQ4 missense mutations had younger-onset and more profound hearing loss than patients with the 211_223del mutation. In our current study, 12 individuals with the c.211delC mutation manifested late-onset and pure high-frequency hearing loss. Our results support the genotype-phenotype correlation that the KCNQ4 deletions are associated with later-onset and milder hearing impairment than the missense mutations. The phenotypic difference may be caused by the difference in pathogenic mechanisms: haploinsufficiency in deletions and dominant-negative effect in missense mutations.