Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 113
Filtrar
Más filtros

País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
Am J Med Genet A ; 194(4): e63477, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37969032

RESUMEN

Germline pathogenic variants in the RAS/mitogen-activated protein kinase (MAPK) signaling pathway are the molecular cause of RASopathies, a group of clinically overlapping genetic syndromes. RASopathies constitute a wide clinical spectrum characterized by distinct facial features, short stature, predisposition to cancer, and variable anomalies in nearly all the major body systems. With increasing global recognition of these conditions, the 8th International RASopathies Symposium spotlighted global perspectives on clinical care and research, including strategies for building international collaborations and developing diverse patient cohorts in anticipation of interventional trials. This biannual meeting, organized by RASopathies Network, was held in a hybrid virtual/in-person format. The agenda featured emerging discoveries and case findings as well as progress in preclinical and therapeutic pipelines. Stakeholders including basic scientists, clinician-scientists, practitioners, industry representatives, patients, and family advocates gathered to discuss cutting edge science, recognize current gaps in knowledge, and hear from people with RASopathies about the experience of daily living. Presentations by RASopathy self-advocates and early-stage investigators were featured throughout the program to encourage a sustainable, diverse, long-term research and advocacy partnership focused on improving health and bringing treatments to people with RASopathies.


Asunto(s)
Síndrome de Costello , Displasia Ectodérmica , Cardiopatías Congénitas , Neoplasias , Síndrome de Noonan , Humanos , Proteínas ras/genética , Sistema de Señalización de MAP Quinasas/genética , Síndrome de Costello/genética , Neoplasias/genética , Displasia Ectodérmica/genética , Síndrome de Noonan/genética , Cardiopatías Congénitas/genética
2.
Adv Exp Med Biol ; 1441: 761-775, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38884747

RESUMEN

Lesions of the semilunar valve and the aortic arch can occur either in isolation or as part of well-described clinical syndromes. The polygenic cause of calcific aortic valve disease will be discussed including the key role of NOTCH1 mutations. In addition, the complex trait of bicuspid aortic valve disease will be outlined, both in sporadic/familial cases and in the context of associated syndromes, such as Alagille, Williams, and Kabuki syndromes. Aortic arch abnormalities particularly coarctation of the aorta and interrupted aortic arch, including their association with syndromes such as Turner and 22q11 deletion, respectively, are also discussed. Finally, the genetic basis of congenital pulmonary valve stenosis is summarized, with particular note to Ras-/mitogen-activated protein kinase (Ras/MAPK) pathway syndromes and other less common associations, such as Holt-Oram syndrome.


Asunto(s)
Aorta Torácica , Válvula Aórtica , Humanos , Aorta Torácica/anomalías , Aorta Torácica/patología , Válvula Aórtica/anomalías , Válvula Aórtica/patología , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/patología , Enfermedad de la Válvula Aórtica Bicúspide/genética , Estenosis de la Válvula Pulmonar/genética , Mutación , Receptor Notch1/genética , Enfermedad de la Válvula Aórtica/genética , Enfermedades de las Válvulas Cardíacas/genética , Enfermedades de las Válvulas Cardíacas/patología , Calcinosis/genética , Calcinosis/patología , Enfermedades Hematológicas/genética , Enfermedades Hematológicas/patología , Enfermedades Vestibulares/genética , Enfermedades Vestibulares/patología
3.
Adv Exp Med Biol ; 1441: 505-534, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38884729

RESUMEN

Ventricular septal defects (VSDs) are recognized as one of the commonest congenital heart diseases (CHD), accounting for up to 40% of all cardiac malformations, and occur as isolated CHDs as well as together with other cardiac and extracardiac congenital malformations in individual patients and families. The genetic etiology of VSD is complex and extraordinarily heterogeneous. Chromosomal abnormalities such as aneuploidy and structural variations as well as rare point mutations in various genes have been reported to be associated with this cardiac defect. This includes both well-defined syndromes with known genetic cause (e.g., DiGeorge syndrome and Holt-Oram syndrome) and so far undefined syndromic forms characterized by unspecific symptoms. Mutations in genes encoding cardiac transcription factors (e.g., NKX2-5 and GATA4) and signaling molecules (e.g., CFC1) have been most frequently found in VSD cases. Moreover, new high-resolution methods such as comparative genomic hybridization enabled the discovery of a high number of different copy number variations, leading to gain or loss of chromosomal regions often containing multiple genes, in patients with VSD. In this chapter, we will describe the broad genetic heterogeneity observed in VSD patients considering recent advances in this field.


Asunto(s)
Defectos del Tabique Interventricular , Humanos , Aberraciones Cromosómicas , Variaciones en el Número de Copia de ADN/genética , Predisposición Genética a la Enfermedad/genética , Defectos del Tabique Interventricular/genética , Mutación , Factores de Transcripción/genética
4.
Am J Med Genet A ; 191(8): 2074-2082, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37194190

RESUMEN

Costello syndrome is a clinically recognizable, severe neurodevelopmental disorder caused by heterozygous activating variants in HRAS. The vast majority of affected patients share recurring variants affecting HRAS codons 12 and 13 and a relatively uniform phenotype. Here, we report the unique and attenuated phenotype of six individuals of an extended family affected by the HRAS variant c.176C>T p.(Ala59Gly), which, to our knowledge, has never been reported as a germline variant in patients so far. HRAS Alanine 59 has been previously functionally investigated as an oncogenic hotspot and the p.Ala59Gly substitution was shown to impair intrinsic GTP hydrolysis. All six individuals we report share a phenotype of ectodermal anomalies and mild features suggestive of a RASopathy, reminiscent of patients with Noonan syndrome-like disorder with loose anagen hair. All six are of normal intelligence, none have a history of failure to thrive or malignancy, and they have no known cardiac or neurologic pathologies. Our report adds to the previous reports of patients with rare variants affecting amino acids located in the SWITCH II/G3 region of HRAS and suggests a consistent, attenuated phenotype distinct from classical Costello syndrome. We propose the definition of a new distinct HRAS-related RASopathy for patients carrying HRAS variants affecting codons 58, 59, 60.


Asunto(s)
Síndrome de Costello , Síndrome de Noonan , Humanos , Síndrome de Costello/genética , Síndrome de Costello/patología , Fenotipo , Síndrome de Noonan/genética , Síndrome de Noonan/patología , Insuficiencia de Crecimiento/genética , Insuficiencia de Crecimiento/patología , Mutación de Línea Germinal , Proteínas Proto-Oncogénicas p21(ras)/genética
5.
BMC Pediatr ; 23(1): 374, 2023 07 24.
Artículo en Inglés | MEDLINE | ID: mdl-37488489

RESUMEN

BACKGROUND: Costello syndrome (CS) is a rare genetic condition characterized by dysregulation of the signaling pathway, phenotypic alteration due to fetal macrosomia or growth retardation, facial abnormalities, loose skin, cardiovascular abnormalities, and a variable degree of intellectual disability. CASE PRESENTATION: We describe the case of a 20-month-old male patient with fetal macrosomia and polyhydramnios, presenting psychomotor development delay and growth limitation during the first months of life. CS was diagnosed at four months of age after detecting a variant of the HRAS gene c.35G > C (p.G12A). A clinical description of his condition was recorded throughout his life, including cardiovascular diseases, endocrine disorders, and recurrent infections. At 20 months of age, after presenting events of marked hypotonia and generalized seizures, brain magnetic resonance revealed symmetrical lesions of the infra- and supratentorial white matter in both cerebral hemispheres, which resulted in the diagnosis of cerebral leukodystrophy. The patient had a rapid and progressive deterioration that eventually led to death. CONCLUSIONS: This is the first report of a case of CS in Peru. In addition, this is a case that presented with multisystemic conditions culminating in leukodystrophy, which is a rare event according to the literature.


Asunto(s)
Anomalías Cardiovasculares , Síndrome de Costello , Discapacidad Intelectual , Embarazo , Femenino , Humanos , Masculino , Lactante , Síndrome de Costello/complicaciones , Síndrome de Costello/diagnóstico , Síndrome de Costello/genética , Macrosomía Fetal , Genes ras , Discapacidad Intelectual/genética
6.
Pediatr Int ; 65(1): e15589, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37615376

RESUMEN

BACKGROUND: The RASopathies (Noonan syndrome [NS] and Costello syndrome [CS]) are rare disorders. Although these have been characterized, precise delineation of the differences in the spinal deformities associated with RASopathy has not been described. This study characterized the spinal deformities found in NS and CS and describes a strategy for the screening of scoliosis. METHODS: The clinical records and spinal X-rays of 35 consecutive NS and CS patients were reviewed. Spinal X-rays were assessed to define the presence and progression of scoliosis. Clinical records were examined to identify the risk factors associated with scoliosis. In addition, we investigated the association between clinical records and scoliosis using logistic regression analysis. RESULTS: Twenty-four patients with NS and 11 with CS were included. Nine patients with NS and five with CS showed scoliosis. The mean ± SD age at diagnosis was 12.6 ± 2.4 years in NS and 11.4 ± 2.5 years in CS (p = 0.55), and mean follow-up period was 4.8 ± 2.6 years and 6.3 ± 2.4 years (p = 0.42), respectively. The coronal angular deformity at final follow-up was 27.3 ± 8.5° in NS and 19.4 ± 6.9° in CS (p = 0.030) with a mean annual progression of 2.8 ± 1.1° in NS 1.0 ± 1.0° in CS (p = 0.030). Cardiac disease was present in eight out of nine patients with NS with concomitant scoliosis in NS, and significantly more than in CS (p = 0.007). PTPN11 significantly correlated with scoliosis (odds ratio 12.4 0.035, 95% confidence interval: 1.20-128.00). CONCLUSIONS: Spinal deformity in NS is more severe than in CS. This study identified a relationship between PTPN11 and scoliosis. Therefore, PTPN11 can be used for the screening of scoliosis.


Asunto(s)
Síndrome de Costello , Síndrome de Noonan , Escoliosis , Humanos , Escoliosis/diagnóstico por imagen , Escoliosis/epidemiología , Síndrome de Noonan/complicaciones , Síndrome de Noonan/diagnóstico , Estudios Retrospectivos
7.
Gen Dent ; 71(5): 46-52, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37595083

RESUMEN

Patients with a complex problem set involving multiple levels of altered structure challenge the clinician to develop an individualized, appropriate treatment plan. Dentofacial deficiency, occlusal problems, and loss of tooth structure require intervention to establish stability and regain function, speech, esthetics, and masticatory muscle comfort. The comprehensive examination must quantify each problem to specify the diagnosis for realistic treatment planning. The clinical case of a patient with Costello syndrome is presented to illustrate essential concepts in diagnosis and treatment of complex cases, including (1) Global Diagnosis of anterior esthetic relationships, (2) occlusal analysis with diagnostic casts verified in centric relation, (3) comprehensive restoration previewed with a diagnostic wax-up and removable acrylic resin overlay, (4) adhesive monobody composite resin onlays that preserve tooth structure, and (5) programmed occlusion, quantified with digital occlusal analysis, to ensure stability and comfort. Costello syndrome is a neurodevelopmental syndrome causing multisystem effects, including a distinctive craniofacial phenotype, cardiovascular disease, intellectual disability, growth hormone deficiency, and dental abnormalities such as delayed dental development, bruxism, and demineralized enamel lesions. In the present case, quantification of the patient's problem set allowed precise treatment planning that resulted in predictable restoration.


Asunto(s)
Bruxismo , Síndrome de Costello , Humanos , Resinas Compuestas/química , Incrustaciones , Relación Céntrica , Restauración Dental Permanente/métodos
8.
Hum Mutat ; 43(1): 3-15, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34618388

RESUMEN

Costello syndrome (CS) is an autosomal-dominant disorder characterized by distinctive facial features, hypertrophic cardiomyopathy, skeletal abnormalities, intellectual disability, and predisposition to cancers. Germline variants in HRAS have been identified in patients with CS. Intragenic HRAS duplications have been reported in three patients with a milder phenotype of CS. In this study, we identified two known HRAS variants, p.(Glu63_Asp69dup), p.(Glu62_Arg68dup), and one novel HRAS variant, p.(Ile55_Asp57dup), in patients with CS, including a patient with craniosynostosis. These intragenic duplications are located in the G3 domain and the switch II region. Cells expressing cDNA with these three intragenic duplications showed an increase in ELK-1 transactivation. Injection of wild-type or mutant HRAS mRNAs with intragenic duplications in zebrafish embryos showed significant elongation of the yolk at 11 h postfertilization, which was improved by MEK inhibitor treatment, and a variety of developmental abnormalities at 3 days post fertilization was observed. These results indicate that small in-frame duplications affecting the G3 domain and switch II region of HRAS increase the activation of the ERK pathway, resulting in developmental abnormalities in zebrafish or patients with CS.


Asunto(s)
Anomalías Múltiples , Síndrome de Costello , Anomalías Múltiples/genética , Animales , Síndrome de Costello/genética , Humanos , Sistema de Señalización de MAP Quinasas , Fenotipo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Pez Cebra/genética
9.
Am J Med Genet C Semin Med Genet ; 190(4): 452-458, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36541891

RESUMEN

RASopathies are rare genetic disorders caused by germline pathogenic variants in genes belonging to the RAS/MAPK pathway, which signals cell proliferation, differentiation, survival and death. The dysfunction of such signaling pathway causes syndromes with overlapping clinical manifestations. Skin and adnexal lesions are the cardinal clinical signs of RASopathies, such as cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, formerly known as LEOPARD syndrome, Costello syndrome, neurofibromatosis (NF1), Legius syndrome, Noonan-like syndrome with loose anagen hair (NSLH) and Noonan syndrome. As NF1, one of the most common RASopathies, described in 1882, has its clinical features well delineated, we will focus on the dermatological diagnosis, management and care of non-NF1 RASopathies, which are less known and more recently described. Dermatological manifestations are important clinical diagnostic elements that can aid differential diagnosis among RASopathies. They can affect dermis and epidermis, causing pigmented lesions (melanocytic nevi, café-au-lait spots, and lentigines), hyperkeratosis (keratosis pilaris, ulerythema ophryogenes, and palmoplantar keratosis) or hyperplasia. To date there are rare known links to malignancy, but oftentimes skin lesions require close attention because they can highly affect quality of life.


Asunto(s)
Síndrome de Costello , Enfermedad de Darier , Síndrome de Noonan , Humanos , Calidad de Vida , Proteínas ras/genética , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Síndrome de Noonan/terapia , Síndrome de Costello/diagnóstico , Síndrome de Costello/genética , Síndrome de Costello/terapia , Mutación
10.
Am J Med Genet C Semin Med Genet ; 190(4): 440-451, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36408797

RESUMEN

The cardiovascular phenotype associated with RASopathies has expanded far beyond the original descriptions of pulmonary valve stenosis by Dr Jaqueline Noonan in 1968 and hypertrophic cardiomyopathy by Hirsch et al. in 1975. Because of the common underlying RAS/MAPK pathway dysregulation, RASopathy syndromes usually present with a typical spectrum of overlapping cardiovascular anomalies, although less common cardiac defects can occur. The identification of the causative genetic variants has enabled the recognition of specific correlations between genotype and cardiac phenotype. Characterization and understanding of genotype-phenotype associations is not only important for counseling a family of an infant with a new diagnosis of a RASopathy condition but is also critical for their clinical prognosis with respect to cardiac disease, neurodevelopment and other organ system involvement over the lifetime of the patient. This review will focus on the cardiac manifestations of the most common RASopathy syndromes, the relationship between cardiac defects and causal genetic variation, the contribution of cardiovascular abnormalities to morbidity and mortality and the most relevant follow-up issues for patients affected by RAS/MAPK pathway diseases, with respect to cardiac clinical outcomes and management, in children and in the adult population.


Asunto(s)
Displasia Ectodérmica , Cardiopatías Congénitas , Síndrome de Noonan , Humanos , Síndrome de Noonan/genética , Síndrome de Noonan/diagnóstico , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/diagnóstico , Insuficiencia de Crecimiento/genética , Insuficiencia de Crecimiento/diagnóstico , Proteínas ras/genética , Displasia Ectodérmica/genética , Mutación
11.
Am J Med Genet C Semin Med Genet ; 190(4): 414-424, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36428239

RESUMEN

RASopathies comprise a group of clinically overlapping developmental disorders caused by genetic variations affecting components or modulators of the RAS-MAPK signaling cascade, which lead to dysregulation of signal flow through this pathway. Noonan syndrome and the less frequent, clinically related disorders, Costello syndrome, cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, and Noonan syndrome-like disorder with loose anagen hair are part of the RASopathy spectrum and share a recognizable pattern of multisystem involvement. This review describes the "Noonan syndrome-like" phenotype as a common phenotypic signature of generalized developmental RAS pathway dysregulation. Distinctive features of the different entities are revisited against the background of the understanding of underlying genetic alterations and genotype correlations, which has evolved rapidly during the past 20 years, thereby leading to suggestions regarding the nosology of RASopathies.


Asunto(s)
Síndrome de Costello , Cardiopatías Congénitas , Síndrome de Noonan , Humanos , Síndrome de Noonan/genética , Cardiopatías Congénitas/genética , Síndrome de Costello/genética , Insuficiencia de Crecimiento/genética , Mutación
12.
Clin Genet ; 101(4): 454-458, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35038173

RESUMEN

Costello syndrome (CS) is a rare disorder affecting development and growth characterized by cancer predisposition and caused by mutations in HRAS proto-oncogene. Somatic HRAS mutations drive bladder carcinogenesis. The aim of this study was to analyze prevalence and histological characterization of bladder cancer (BC) in a cohort of patients with CS to help clinicians plan effective management strategies. This study included 13 patients above 10 years of age with molecular diagnosis of CS. Screening cystoscopies (31 total procedures) were performed to exclude BC. Any lesion was analyzed through cold-cup biopsy or trans-urethral resection of the bladder. According to histology, patients were followed-up with urinalysis and abdominal ultrasound yearly, and cystoscopies every 12-24 months. During study enrollment, bladder lesions (often multifocal) were detected in 11/13 patients. Histological analysis documented premalignant lesions in 90% of cystoscopies performed, epithelial dysplasia in 71%, and papillary urothelial neoplasm of low-malignant potential in 19%. BC G1/low grade (Ta) were removed in 10%. Overall, 76% of patients showed a bladder lesion at first cystoscopy. The present findings document that individuals with CS aged 10 years and older have high prevalence of bladder lesions (premalignant/malignant), highlighting the importance of personalized screening protocols.


Asunto(s)
Síndrome de Costello , Neoplasias de la Vejiga Urinaria , Niño , Toma de Decisiones Clínicas , Síndrome de Costello/diagnóstico , Síndrome de Costello/epidemiología , Síndrome de Costello/genética , Femenino , Humanos , Masculino , Mutación , Prevalencia , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/epidemiología , Neoplasias de la Vejiga Urinaria/genética
13.
Am J Med Genet A ; 188(4): 1280-1286, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34964243

RESUMEN

Costello syndrome (CS) is an autosomal dominant disorder caused by pathogenic variants in HRAS. Craniosynostosis is a known feature of other RASopathies (Noonan and cardiofaciocutaneous syndromes) but not CS. We describe four individuals with CS and craniosynostosis and present a summary of all previously reported individuals with craniosynostosis and RASopathy.


Asunto(s)
Síndrome de Costello , Craneosinostosis , Displasia Ectodérmica , Síndrome de Noonan , Síndrome de Costello/diagnóstico , Síndrome de Costello/genética , Craneosinostosis/diagnóstico , Craneosinostosis/genética , Facies , Insuficiencia de Crecimiento , Humanos
14.
Am J Med Genet A ; 188(6): 1915-1927, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35266292

RESUMEN

RASopathies are a group of genetic disorders that are caused by genes that affect the canonical Ras/mitogen-activated protein kinase (MAPK) signaling pathway. Despite tremendous progress in understanding the molecular consequences of these genetic anomalies, little movement has been made in translating these findings to the clinic. This year, the seventh International RASopathies Symposium focused on expanding the research knowledge that we have gained over the years to enhance new discoveries in the field, ones that we hope can lead to effective therapeutic treatments. Indeed, for the first time, research efforts are finally being translated to the clinic, with compassionate use of Ras/MAPK pathway inhibitors for the treatment of RASopathies. This biannual meeting, organized by the RASopathies Network, brought together basic scientists, clinicians, clinician scientists, patients, advocates, and their families, as well as representatives from pharmaceutical companies and the National Institutes of Health. A history of RASopathy gene discovery, identification of new disease genes, and the latest research, both at the bench and in the clinic, were discussed.


Asunto(s)
Síndrome de Costello , Síndrome de Noonan , Síndrome de Costello/genética , Humanos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Síndrome de Noonan/genética , Transducción de Señal , Proteínas ras/genética , Proteínas ras/metabolismo
15.
Am J Med Genet A ; 188(2): 422-430, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34913244

RESUMEN

Costello syndrome (CS) is a neurodevelopmental disorder with a distinctive musculoskeletal phenotype and reduced bone mineral density (BMD) caused by activating de novo mutations in the HRAS gene. Herein, we report the results of a prospective study evaluating the efficacy of a 4-year vitamin D supplementation on BMD and bone health. A cohort of 16 individuals ranging from pediatric to adult age with molecularly confirmed CS underwent dosages of bone metabolism biomarkers (serum/urine) and dual-energy X-ray absorptiometry (DXA) scans to assess bone and body composition parameters. Results were compared to age-matched control groups. At baseline evaluation, BMD was significantly reduced (p ≤ 0.05) compared to controls, as were the 25(OH)vitD levels. Following the 4-year time interval, despite vitamin D supplementation therapy at adequate dosages, no significant improvement in BMD was observed. The present data confirm that 25(OH)vitD and BMD parameters are reduced in CS, and vitamin D supplementation is not sufficient to restore proper BMD values. Based on this evidence, routine monitoring of bone homeostasis to prevent bone deterioration and possible fractures in adult patients with CS is highly recommended.


Asunto(s)
Síndrome de Costello , Absorciometría de Fotón , Densidad Ósea , Huesos , Niño , Síndrome de Costello/complicaciones , Síndrome de Costello/genética , Estudios de Seguimiento , Homeostasis , Humanos , Estudios Prospectivos , Vitamina D/uso terapéutico
16.
Ultrasound Obstet Gynecol ; 60(4): 487-493, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35397126

RESUMEN

OBJECTIVE: To investigate the diagnostic yield of clinical whole-genome sequencing (WGS) in prenatally diagnosed non-immune hydrops fetalis (NIHF). METHODS: This was a retrospective study of 23 fetuses with prenatally diagnosed NIHF, negative for trisomies and copy-number variants, referred for analysis by WGS with an in-silico panel of 281 genes associated with hydrops fetalis. Due to identification of a high proportion of causative variants in the HRAS gene in the main cohort, Sanger sequencing of HRAS was performed in a replication cohort, consisting of 24 additional fetuses with NIHF that were negative for trisomies and copy-number variants and had not undergone WGS. RESULTS: Of the 23 fetuses in the main cohort, a molecular diagnosis was achieved in 12 (52.2%). Pathogenic or likely pathogenic variants were identified in seven genes: HRAS (n = 5), RIT1 (n = 2), FOXP3 (n = 1), GLB1 (n = 1), MAP2K1 (n = 1), PTPN11 (n = 1) and RASA1 (n = 1). The inheritance pattern of the 12 causative variants was autosomal dominant in 10 cases (HRAS, MAP2K1, PTPN11, RASA1, RIT1), autosomal recessive in one (GLB1) and X-linked recessive in one (FOXP3). Of the 24 fetuses in the replication cohort, a pathogenic variant in HRAS was identified in one, resulting in an overall frequency of causative HRAS variants of 12.8% (6/47) in our two cohorts. CONCLUSIONS: We demonstrate a diagnostic yield of 52% with clinical WGS in NIHF using an in-silico panel of 281 genes. However, the high diagnostic yield may be attributed to the small sample size and possible over-representation of severe phenotypes in the included fetuses. Bearing in mind that chromosomal abnormalities were excluded in our cohorts, a detection rate of up to 75% is possible in prenatally diagnosed NIHF when WGS analysis includes calling of chromosomal aberrations. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.


Asunto(s)
Hidropesía Fetal , Trisomía , Aberraciones Cromosómicas , Femenino , Factores de Transcripción Forkhead/genética , Humanos , Hidropesía Fetal/diagnóstico , Hidropesía Fetal/genética , Embarazo , Estudios Retrospectivos , Secuenciación Completa del Genoma , Proteína Activadora de GTPasa p120/genética
17.
Ann Oncol ; 31(7): 873-883, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32240795

RESUMEN

Somatic mutations in RAS and related pathway genes such as NF1 have been strongly implicated in the development of cancer while also being implicated in a diverse group of developmental disorders named the 'RASopathies', including neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), Costello syndrome (CS), cardiofaciocutaneous syndrome (CFC), and capillary malformation-arteriovenous syndrome (CM-AVM). It remains unclear why (i) there is little overlap in mutational subtype between Ras-driven malignancies associated with sporadic disease and those associated with the RASopathy syndromes, and (ii) RASopathy-associated cancers are usually of different histological origin to those seen with sporadic mutations of the same genes. For instance, germline variants in KRAS and NRAS are rarely found at codons 12, 13 or 61, the most common sites for somatic mutations in sporadic cancers. An exception is CS, where germline variants in codons 12 and 13 of HRAS occur relatively frequently. Given recent renewed drug interest following early clinical success of RAS G12C and farnesyl transferase inhibitors, an improved understanding of this relationship could help guide targeted therapies for both sporadic and germline cancers associated with the Ras pathway.


Asunto(s)
Síndrome de Costello , Neoplasias , Síndrome de Noonan , Células Germinativas/metabolismo , Humanos , Mutación , Neoplasias/genética , Proteínas ras/genética
18.
Am J Med Genet A ; 182(1): 130-136, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31680412

RESUMEN

Costello syndrome (CS) is an autosomal-dominant condition caused by activating missense mutations in HRAS. There is little literature describing health concerns specific to adults with CS. Parents of individuals with CS need to know what to anticipate as their children age. We surveyed a group of 20 adults and older adolescents with CS regarding their medical concerns and lifestyle characteristics. We identified several previously undescribed actionable medical concerns in adults with CS. First, the high prevalence of anxiety in this cohort indicates that screening for anxiety is warranted since this is a treatable condition that can have a significant impact on quality of life. Second, adults with CS should be monitored for progressive contractures or other problems that could decrease mobility. This is especially important in a population that seems to have increased risk for osteopenia. Finally, the lack of cancer diagnoses in adulthood is of interest, although the cohort is too small to draw definitive conclusions about cancer risk in adults with CS. Ongoing follow-up of the current cohort of adults with CS is necessary to delineate progressive medical and physical problems, which is essential for providing targeted management recommendations and anticipatory guidance to families.


Asunto(s)
Ansiedad/epidemiología , Síndrome de Costello/epidemiología , Neoplasias/epidemiología , Proteínas Proto-Oncogénicas p21(ras)/genética , Adolescente , Adulto , Ansiedad/complicaciones , Ansiedad/genética , Ansiedad/patología , Enfermedades Óseas Metabólicas/epidemiología , Enfermedades Óseas Metabólicas/genética , Enfermedades Óseas Metabólicas/patología , Niño , Síndrome de Costello/complicaciones , Síndrome de Costello/genética , Síndrome de Costello/patología , Femenino , Humanos , Masculino , Neoplasias/complicaciones , Neoplasias/genética , Neoplasias/patología , Fenotipo , Calidad de Vida , Adulto Joven
19.
Am J Med Genet A ; 182(3): 597-606, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31825160

RESUMEN

The RASopathies are a group of genetic disorders that result from germline pathogenic variants affecting RAS-mitogen activated protein kinase (MAPK) pathway genes. RASopathies share RAS/MAPK pathway dysregulation and share phenotypic manifestations affecting numerous organ systems, causing lifelong and at times life-limiting medical complications. RASopathies may benefit from precision medicine approaches. For this reason, the Sixth International RASopathies Symposium focused on exploring precision medicine. This meeting brought together basic science researchers, clinicians, clinician scientists, patient advocates, and representatives from pharmaceutical companies and the National Institutes of Health. Novel RASopathy genes, variants, and animal models were discussed in the context of medication trials and drug development. Attempts to define and measure meaningful endpoints for treatment trials were discussed, as was drug availability to patients after trial completion.


Asunto(s)
Enfermedades Genéticas Congénitas/genética , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Proteínas ras/genética , Enfermedades Genéticas Congénitas/patología , Mutación de Línea Germinal/genética , Humanos , Transducción de Señal/genética
20.
Am J Med Genet A ; 182(4): 866-876, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31913576

RESUMEN

RASopathies caused by germline pathogenic variants in genes that encode RAS pathway proteins. These disorders include neurofibromatosis type 1 (NF1), Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC), and Costello syndrome (CS), and others. RASopathies are characterized by heterogenous manifestations, including congenital heart disease, failure to thrive, and increased risk of cancers. Previous work led by the NCI Pediatric Oncology Branch has altered the natural course of one of the key manifestations of the RASopathy NF1. Through the conduct of a longitudinal cohort study and early phase clinical trials, the MEK inhibitor selumetinib was identified as the first active therapy for the NF1-related peripheral nerve sheath tumors called plexiform neurofibromas (PNs). As a result, selumetinib was granted breakthrough therapy designation by the FDA for the treatment of PN. Other RASopathy manifestations may also benefit from RAS targeted therapies. The overall goal of Advancing RAS/RASopathy Therapies (ART), a new NCI initiative, is to develop effective therapies and prevention strategies for the clinical manifestations of the non-NF1 RASopathies and for tumors characterized by somatic RAS mutations. This report reflects discussions from a February 2019 initiation meeting for this project, which had broad international collaboration from basic and clinical researchers and patient advocates.


Asunto(s)
Síndrome de Costello/terapia , Displasia Ectodérmica/terapia , Insuficiencia de Crecimiento/terapia , Cardiopatías Congénitas/terapia , Terapia Molecular Dirigida , Mutación , Neurofibromatosis 1/terapia , Síndrome de Noonan/terapia , Proteínas ras/antagonistas & inhibidores , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/genética , Síndrome de Costello/genética , Síndrome de Costello/patología , Displasia Ectodérmica/genética , Displasia Ectodérmica/patología , Facies , Insuficiencia de Crecimiento/genética , Insuficiencia de Crecimiento/patología , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/patología , Humanos , Colaboración Intersectorial , National Cancer Institute (U.S.) , Neurofibromatosis 1/genética , Neurofibromatosis 1/patología , Síndrome de Noonan/genética , Síndrome de Noonan/patología , Informe de Investigación , Transducción de Señal , Estados Unidos , Proteínas ras/genética
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA