Asunto(s)
Síndrome de Costello , Neuroblastoma , Rabdomiosarcoma , Humanos , Neuroblastoma/patología , Neuroblastoma/complicaciones , Neuroblastoma/terapia , Síndrome de Costello/patología , Síndrome de Costello/genética , Síndrome de Costello/complicaciones , Rabdomiosarcoma/patología , Rabdomiosarcoma/complicaciones , Lactante , Masculino , Neoplasias Primarias Múltiples/patología , FemeninoRESUMEN
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)/genéticaRESUMEN
BACKGROUND: Costello syndrome (CS) is a cancer-predisposition disorder caused by germline pathogenic variants in HRAS. We conducted a systematic review using case reports and case series to characterise cancer risk in CS. METHODS: We conducted a systematic review to identify CS cases to create a retrospective cohort. We tested genotype-phenotype correlations and calculated cumulative incidence and hazard rates (HR) for cancer and cancer-free death, standardised incidence rates (SIR) and survival after cancer. RESULTS: This study includes 234 publications reporting 621 patients from 35 countries. Over nine percent had cancer, including rhabdomyosarcoma, bladder, and neuroblastoma. The rate of cancer and death associated with p.Gly12Ser were lower when compared to all other variants (P < 0.05). Higher mortality for p.Gly12Cys, p.Gly12Asp, p.Gly12Val and p.Gly60Val and higher malignancy rate for p.Gly12Ala were confirmed (P < 0.05). Cumulative incidence by age 20 was 13% (cancer) and 11% (cancer-free death). HR (death) was 3-4% until age 3. Statistically significant SIRs were found for rhabdomyosarcoma (SIR = 1240), bladder (SIR = 1971), and neuroblastoma (SIR = 60). Survival after cancer appeared reduced. CONCLUSIONS: This is the largest investigation of cancer in CS to date. The high incidence and SIR values found to highlight the need for rigorous surveillance and evidence-based guidelines for this high-risk population.
Asunto(s)
Síndrome de Costello , Neuroblastoma , Rabdomiosarcoma , Humanos , Síndrome de Costello/genética , Síndrome de Costello/patología , Estudios Retrospectivos , GenotipoRESUMEN
Costello syndrome (CS) is a rare genetic syndrome affecting multiple organs, generally caused by mutations of the HRAS gene, belonging to the RAS/MAPK genes family.A male patient with CS developed a painful pulsatile mass on the lateral side of the wrist. An initial ultrasonographic investigation confirmed the presence of a radial artery lesion, possibly an arterial aneurysm. On surgical resection, histological evaluation showed a tangle of vascular structures with variable calibre and abnormal wall histology. Immunohistochemical stainings revealed a very poor endothelial contribution to the central vascular wall structure. These histological observations led us to conclude we had managed an acute vascular malformation (VM) rupture, rather than a common arterial aneurysmal condition. Considering the molecular mechanisms regulated by RAS/MAPK genes, CS patients might have a higher risk of developing VMs and, in the presence of a pulsatile mass with acute onset, VM rupture should be considered.
Asunto(s)
Anomalías Cardiovasculares , Síndrome de Costello , Malformaciones Vasculares , Humanos , Masculino , Síndrome de Costello/genética , Síndrome de Costello/patología , Genes ras , Mutación , Malformaciones Vasculares/genéticaRESUMEN
Costello syndrome (CS) is caused by heterozygous HRAS germline mutations. Most patients share the HRAS variant p.Gly12Ser that is associated with a typical, homogeneous phenotype. Rarer pathogenic HRAS variants (e.g., p.Thr56Ile) were identified in individuals with attenuated CS phenotypes. The obvious phenotypical variability reflects different dysfunctional consequences of distinct HRAS variants. We report on two boys with the novel de novo HRAS variant c.466 C > T p.(Phe156Leu). Both had severe feeding difficulties, airway obstruction and developmental delay, which are typical findings in CS. They showed subtle facial and dermatologic features consistent with attenuated CS. They significantly differed in their musculoskeletal, cardiovascular and endocrinologic manifestations underscoring the clinical variability of individuals with identical, in particular rarer pathogenic HRAS variants. Functional studies revealed enhanced effector-binding, increased downstream signaling activation and impaired growth factor-induced signaling dynamics in cells expressing HRASPhe156Leu. Our data further illustrate the molecular and phenotypic variability of CS.
Asunto(s)
Síndrome de Costello , Niño , Síndrome de Costello/genética , Síndrome de Costello/patología , Mutación de Línea Germinal , Heterocigoto , Humanos , Masculino , Fenotipo , Proteínas Proto-Oncogénicas p21(ras)/genética , Transducción de Señal/genéticaRESUMEN
Costello syndrome (CS) is a rare disorder caused by activating dominantly acting germline variants in the HRAS gene. CS is defined by a clinical phenotype characterized by a distinctive gestalt, multiple congenital anomalies, and increased risk to develop tumors. Hypoglycemia and hypercholesterolemia have been reported to occur in affected individuals, but the underlying molecular events remain to be characterized. Here, we provided data on glucose/lipid metabolism and amino acid profile of a large single-center cohort of individuals affected by CS to systematically assess the extent of metabolic dysregulation characterizing this disorder and optimize patient management.
Asunto(s)
Anomalías Múltiples , Síndrome de Costello , Hipoglucemia , Anomalías Múltiples/genética , Estudios de Cohortes , Síndrome de Costello/genética , Síndrome de Costello/patología , Humanos , Fenotipo , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
Costello syndrome (CS) is an autosomal dominant disorder caused by mutations in HRAS. Although CS patients have skeletal abnormalities, the role of mutated HRAS in bone development remains unclear. Here, we use CS induced pluripotent stem cells (iPSCs) undergoing osteogenic differentiation to investigate how dysregulation of extracellular matrix (ECM) remodeling proteins contributes to impaired osteogenesis. Although CS patient-derived iPSCs develop normally to produce mesenchymal stem cells (MSCs), the resulting CS MSCs show defective osteogenesis with reduced alkaline phosphatase activity and lower levels of bone mineralization. We found that hyperactivation of SMAD3 signaling during the osteogenic differentiation of CS MSCs leads to aberrant expression of ECM remodeling proteins such as MMP13, TIMP1, and TIMP2. CS MSCs undergoing osteogenic differentiation also show reduced ß-catenin signaling. Knockdown of TIMPs permits normal differentiation of CS MSCs into osteoblasts and enhances ß-catenin signaling in a RUNX2-independent manner. Thus, this study demonstrates that enhanced TIMP expression induced by hyperactivated SMAD3 signaling impairs the osteogenic development of CS MSCs via an inactivation of ß-catenin signaling.
Asunto(s)
Diferenciación Celular/genética , Síndrome de Costello/genética , Proteínas de la Matriz Extracelular/genética , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Mesenquimatosas/metabolismo , Osteogénesis/genética , Fosfatasa Alcalina/metabolismo , Calcificación Fisiológica/genética , Células Cultivadas , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Síndrome de Costello/metabolismo , Síndrome de Costello/patología , Proteínas de la Matriz Extracelular/metabolismo , Regulación de la Expresión Génica , Humanos , Osteoblastos/citología , Osteoblastos/metabolismo , Transducción de Señal/genética , Proteína smad3/genética , Proteína smad3/metabolismo , Inhibidor Tisular de Metaloproteinasa-1/genética , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
Costello syndrome (CS), characterized by a developmental delay and a failure to thrive, is also associated with an impaired lipid and energy metabolism. White adipose tissue is a central sensor of whole-body energy homeostasis, and HRAS hyperactivation may affect adipocyte differentiation and mature adipocyte homeostasis. An extremely useful tool for delineating in vitro intrinsic cellular signaling leading to metabolic alterations during adipogenesis is mouse embryonic fibroblasts, known to differentiate into adipocytes in response to adipogenesis-stimulating factors. Here, we describe in detail the isolation and maintenance of CS HRAS G12V mouse embryonic fibroblasts, their differentiation into adipocytes, and an assessment of adipocyte differentiation.
Asunto(s)
Adipocitos/patología , Diferenciación Celular , Síndrome de Costello/patología , Modelos Animales de Enfermedad , Fibroblastos/patología , Mutación , Proteínas Proto-Oncogénicas p21(ras)/fisiología , Adipocitos/metabolismo , Adipogénesis , Animales , Síndrome de Costello/genética , Síndrome de Costello/metabolismo , Embrión de Mamíferos/metabolismo , Embrión de Mamíferos/patología , Femenino , Fibroblastos/metabolismo , Homeostasis , Técnicas In Vitro , Masculino , Ratones , Ratones NoqueadosRESUMEN
BACKGROUND: Costello syndrome (CS, OMIM 218040) is a rare congenital disorder caused by mutations in HRAS. Previous studies reported that approximately 80% of patients with CS share the same pathogenic variant in HRAS gene in c.34G> A (p.G12S). Here, we report a CS patient with c.34G> A (p.G12D) variant in HRAS gene and she presented with special manifestation. METHODS AND RESULTS: We describe a 31-year-old female patient who presented with distinctive facial appearance, intellectual disability, dental abnormalities, hyperkeratosis of palmer and planter, loose skin at birth, papillomata on the face and nipples. The whole-exome sequencing (WES) technology provided by Haotian Biotechnology (China) confirmed p.G12D variant in HRAS gene. To elucidate the typical features of CS with p.G12D variant, we further reviewed these previously reported cases and found that patients with G12D variant died within three months after birth due to multiple organ failure. They had the typical facial characteristics, failure to thrive, skin and cardiac abnormalities, and gene testing confirmed the diagnosis of CS. CONCLUSION: To the best of our knowledge, this is the first article to report a patient with a p.G12D variant that had special but mild manifestation. Moreover, this report and literature review casts new light on the clinical features of p.G12D variant.
Asunto(s)
Síndrome de Costello/genética , Fenotipo , Proteínas Proto-Oncogénicas p21(ras)/genética , Adulto , Síndrome de Costello/patología , Femenino , Heterocigoto , Humanos , Mutación Missense , Piel/patologíaRESUMEN
Senescence is a biological process that induces a permanent cell cycle arrest and a specific gene expression program in response to various stressors. Following studies over the last few decades, the concept of senescence has evolved from an antiproliferative mechanism in cancer (oncogene-induced senescence) to a critical component of physiological processes associated with embryonic development, tissue regeneration, ageing and its associated diseases. In somatic cells, oncogenic mutations in RAS-MAPK pathway genes are associated with oncogene-induced senescence and cancer, while germline mutations in the same pathway are linked to a group of monogenic developmental disorders generally termed RASopathies. Here, we consider that in these disorders, senescence induction may result in opposing outcomes, a tumour protective effect and a possible contributor to a premature ageing phenotype identified in Costello syndrome, which belongs to the RASopathy group. In this review, we will highlight the role of senescence in organismal homeostasis and we will describe the current knowledge about senescence in RASopathies. Additionally, we provide a perspective on examples of experimentally characterised RASopathy mutations that, alone or in combination with various stressors, may also trigger an age-dependent chronic senescence, possibly contributing to the age-dependent worsening of RASopathy pathophenotype and the reduction of lifespan.
Asunto(s)
Envejecimiento Prematuro/metabolismo , Envejecimiento/metabolismo , Proliferación Celular , Senescencia Celular , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas ras/metabolismo , Factores de Edad , Envejecimiento/genética , Envejecimiento/patología , Envejecimiento Prematuro/genética , Envejecimiento Prematuro/patología , Animales , Diferenciación Celular , Síndrome de Costello/genética , Síndrome de Costello/metabolismo , Síndrome de Costello/patología , Displasia Ectodérmica/genética , Displasia Ectodérmica/metabolismo , Displasia Ectodérmica/patología , Facies , Insuficiencia de Crecimiento/genética , Insuficiencia de Crecimiento/metabolismo , Insuficiencia de Crecimiento/patología , Predisposición Genética a la Enfermedad , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/metabolismo , Cardiopatías Congénitas/patología , Humanos , Mutación , Síndrome de Noonan/genética , Síndrome de Noonan/metabolismo , Síndrome de Noonan/patología , Fenotipo , Transducción de Señal , Proteínas ras/genéticaRESUMEN
Costello syndrome is an autosomal dominant disorder that is caused by germline HRAS mutations. Patients with Costello syndrome present craniofacial abnormalities, cardiac defects, and cancer predisposition, as well as skin abnormalities, including papillomas, keratosis pilaris, and eczematous dermatitis. However, the mechanisms underlying the dermatological abnormalities remain unclear. Here, we demonstrated that knock-in mice expressing an Hras G12S mutation (HrasG12S/+ mice) are susceptible to develop atopic dermatitis (AD)-like skin lesions, including eczema, pruritus, elevated serum IgE levels, acanthosis, and the infiltration of mast cells, basophils, and type-2 innate lymphoid cells in the dermis, after stimulation with house dust mite allergens (Dermatophagoides farinae, Dfb). Reduced skin barrier function, increased proliferation of phosphorylated ERK (p-ERK)-positive epidermal cells, and increased Th2-type cytokines as well as epithelial cell-derived cytokines, including IL-33, were observed in the skin tissue of HrasG12S/+ mice compared with Hras+/+ mice. Cultured HrasG12S/+ keratinocytes exhibited increased IL-33 expression after Dfb stimulation. PD0325901, an MEK inhibitor, ameliorated AD-like symptoms in HrasG12S/+ mice, showing decreased proliferation of p-ERK-positive epidermal cells and decreased expression of IL-33. Our findings indicate that the epidermis of HrasG12S/+ mice stimulated by Dfb strongly induced IL-33 expression and type-2 innate lymphoid cells, resulting in AD-like skin lesions. These results suggest that the epidermis of HrasG12S/+ mice are prone to development of eczematous dermatitis stimulated with house dust mite allergens.
Asunto(s)
Síndrome de Costello/genética , Dermatitis Atópica/genética , Dermatitis Atópica/parasitología , Mutación/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Pyroglyphidae/fisiología , Animales , Benzamidas/farmacología , Proliferación Celular/efectos de los fármacos , Síndrome de Costello/complicaciones , Síndrome de Costello/patología , Citocinas/metabolismo , Dermatitis Atópica/complicaciones , Dermatitis Atópica/patología , Difenilamina/análogos & derivados , Difenilamina/farmacología , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Oído/patología , Epidermis/efectos de los fármacos , Epidermis/parasitología , Epidermis/patología , Mediadores de Inflamación/metabolismo , Interleucina-33/metabolismo , Masculino , Ratones Endogámicos C57BL , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Modelos Biológicos , Inhibidores de Proteínas Quinasas/farmacología , Prurito/complicaciones , Prurito/patología , Pyroglyphidae/efectos de los fármacosRESUMEN
Specific activating missense HRAS variants cause Costello syndrome (CS), a RASopathy with recognizable facial features. The majority of these dominant disease causing variants affect the glycine residues in position 12 or 13. A clinically suspected CS diagnosis can be confirmed through identification of a dominant pathogenic HRAS variant. A novel HRAS variant predicting p.(Glu62_Arg68dup) was identified in an individual with hypertrophic cardiomyopathy, Chiari 1 malformation and ectodermal findings consistent with a RASopathy. Functional studies showed that the p.Glu62_Arg68dup alteration affects HRAS interaction with effector protein PIK3CA (catalytic subunit of phosphoinositide 3-kinase) and the regulator neurofibromin 1 (NF1) GTPase-activating protein (GAP). HRASGlu62_Arg68dup binding with effectors rapidly accelerated fibrosarcoma (RAF1), RAL guanine nucleotide dissociation stimulator (RALGDS) and phospholipase C1 (PLCE1) was enhanced. Accordingly, p.Glu62_Arg68dup increased steady-state phosphorylation of MEK1/2 and ERK1/2 downstream of RAF1, whereas AKT phosphorylation downstream of PI3K was not significantly affected. Growth factor stimulation revealed that expression of HRASGlu62_Arg68dup abolished the HRAS' capacity to modulate downstream signaling. Our data underscore that different qualities of dysregulated HRAS-dependent signaling dynamics determine the clinical severity in CS.
Asunto(s)
Síndrome de Costello/genética , Duplicación de Gen , Proteínas Proto-Oncogénicas p21(ras)/genética , Preescolar , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Síndrome de Costello/patología , Células HEK293 , Humanos , Sistema de Señalización de MAP Quinasas , Masculino , Neurofibromina 1/metabolismo , Fenotipo , Unión Proteica , Proteínas Proto-Oncogénicas p21(ras)/metabolismoAsunto(s)
Síndrome de Costello/genética , Síndrome de Costello/patología , Predisposición Genética a la Enfermedad/epidemiología , Nevo Pigmentado/patología , Neoplasias Cutáneas/genética , Proteínas ras/genética , Adolescente , Adulto , Distribución por Edad , Niño , Síndrome de Costello/diagnóstico , Femenino , Heterocigoto , Humanos , Incidencia , Masculino , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Nevo Pigmentado/epidemiología , Nevo Pigmentado/genética , Pronóstico , Enfermedades Raras , Distribución por Sexo , Transducción de Señal/genética , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/patologíaRESUMEN
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/genéticaRESUMEN
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 JovenRESUMEN
RASopathies are a group of phenotypically overlapping disorders that arise from dysregulation of the RAS/MAPK pathway. These disorders include Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome, and neurofibromatosis-Type 1. While somatic mutations in the three human Ras genes (KRAS, HRAS, and NRAS) are a common finding in a variety of cancers, germline mutations in each of the these genes cause developmental RASopathy phenotypes with mutations in specific genes typically correlating with specific phenotypes. We present the case of a germline heterozygous NRAS mutation producing a severe phenotype involving embryonal rhabdomyosarcoma, severe intellectual disability, and numerous melanocytic nevi in addition to more typical manifestations of Noonan syndrome. Additionally, the specific p.G12R NRAS mutation in this case is a common somatic mutation in cancer cells, and analysis of previously reported NRAS-RASopathy cases suggests that mutations at traditionally oncogenic codons are associated with elevated cancer risk not present with mutations at other sites.
Asunto(s)
GTP Fosfohidrolasas/genética , Predisposición Genética a la Enfermedad , Proteínas de la Membrana/genética , Rabdomiosarcoma Embrionario/genética , Proteínas ras/genética , Adolescente , Niño , Síndrome de Costello/genética , Síndrome de Costello/patología , Displasia Ectodérmica/genética , Displasia Ectodérmica/patología , Facies , Insuficiencia de Crecimiento/genética , Insuficiencia de Crecimiento/patología , Femenino , Mutación de Línea Germinal/genética , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/patología , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Neurofibromatosis 1/genética , Neurofibromatosis 1/patología , Síndrome de Noonan/genética , Síndrome de Noonan/patología , Fenotipo , Rabdomiosarcoma Embrionario/patología , Adulto JovenRESUMEN
RASopathies are a group of genetic disorders due to dysregulation of the RAS-MAPK signaling pathway, which is important in regulating cell growth, proliferation, and differentiation. These include Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), cardiofaciocutaneous (CFC) syndrome, and Costello syndrome (CS), clinical manifestations include growth retardation, developmental delay, cardiac defects, and specific dysmorphic features. There were abundant publications describing the genotype and phenotype from the Western populations. However, detailed study of RASopathies in Chinese population is lacking. We present here the largest cohort of RASopathies ever reported in Chinese populations, detailing the mutation spectrum and clinical phenotypes of these patients. The Clinical Genetic Service, Department of Health, and Queen Mary Hospital are tertiary referral centers for genetic disorders in Hong Kong. We retrospectively reviewed all the genetically confirmed cases of RASopathies, including NS, NSML, CFC syndrome, and CS, over the past 29 years (from 1989 to 2017). Analyses of the mutation spectrum and clinical phenotypes were performed. One hundred and ninety-one ethnic Chinese patients with genetically confirmed RASopathies were identified, including 148 patients with NS, 23 NSML, 12 CFC syndrome, and eight CS. We found a lower incidence of hypertrophic cardiomyopathy in individuals with NSML (27.3%), and NS caused by RAF1 mutations (62.5%). Another significant finding was for those NS patients with myeloproliferative disorder, the mutations fall within Exon 3 of PTPN11 but not only restricted to the well-known hotspots, that is, p.Asp61 and p.Thr731, which suggested that re-evaluation of the current tumor surveillance recommendation maybe warranted.
Asunto(s)
Mutación , Fenotipo , Proteínas ras/genética , Síndrome de Costello/genética , Síndrome de Costello/patología , Displasia Ectodérmica/genética , Displasia Ectodérmica/patología , Facies , Insuficiencia de Crecimiento/genética , Insuficiencia de Crecimiento/patología , Femenino , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/patología , Hong Kong , Humanos , Síndrome LEOPARD/genética , Síndrome LEOPARD/patología , Sistema de Señalización de MAP Quinasas/genética , Masculino , Síndrome de Noonan/genética , Síndrome de Noonan/patología , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Estudios RetrospectivosRESUMEN
RASopathies are a group of heterogeneous conditions caused by germline mutations in RAS/MAPK signalling pathway genes. With next-generation sequencing (NGS), sequencing capacity is no longer a limitation to molecular diagnosis. Instead, the rising number of variants of unknown significance (VUSs) poses challenges to clinical interpretation and genetic counselling. We investigated the potential of an integrated pipeline combining NGS and the functional assessment of variants for the diagnosis of RASopathies. We included 63 Chinese patients with RASopathies that had previously tested negative for PTPN11 and HRAS mutations. In these patients, we performed a genetic analysis of genes associated with RASopathies using a multigene NGS panel and Sanger sequencing. For the VUSs, we evaluated evidence from genetic, bioinformatic and functional data. Twenty disease-causing mutations were identified in the 63 patients, providing a primary diagnostic yield of 31.7%. Four VUSs were identified in five patients. The functional assessment supported the pathogenicity of the RAF1 and RIT1 VUSs, while the significance of two VUSs in A2ML1 remained unclear. In summary, functional analysis improved the diagnostic yield from 31.7% to 36.5%. Although technically demanding and time-consuming, a functional genetic diagnostic analysis can ease the clinical translation of these findings to aid bedside interpretation.
Asunto(s)
Síndrome de Costello/genética , Displasia Ectodérmica/genética , Insuficiencia de Crecimiento/genética , Cardiopatías Congénitas/genética , Neurofibromatosis 1/genética , Síndrome de Noonan/genética , Proteínas Proto-Oncogénicas c-raf/genética , Proteínas ras/genética , Adolescente , Animales , Bioensayo , Niño , Preescolar , Biología Computacional , Síndrome de Costello/patología , Displasia Ectodérmica/patología , Facies , Insuficiencia de Crecimiento/patología , Femenino , Expresión Génica , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Mutación de Línea Germinal , Cardiopatías Congénitas/patología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , MAP Quinasa Quinasa 1/genética , Masculino , Mutación Missense , Neurofibromatosis 1/patología , Síndrome de Noonan/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteína SOS1/genética , Pez Cebra , alfa-Macroglobulinas/genéticaRESUMEN
In October 2016, the American Association for Cancer Research held a meeting of international childhood cancer predisposition syndrome experts to evaluate the current knowledge of these syndromes and to propose consensus surveillance recommendations. Herein, we summarize clinical and genetic aspects of RASopathies and Sotos, Weaver, Rubinstein-Taybi, Schinzel-Giedion, and NKX2-1 syndromes as well as specific metabolic disorders known to be associated with increased childhood cancer risk. In addition, the expert panel reviewed whether sufficient data exist to make a recommendation that all patients with these disorders be offered cancer surveillance. For all syndromes, the panel recommends increased awareness and prompt assessment of clinical symptoms. Patients with Costello syndrome have the highest cancer risk, and cancer surveillance should be considered. Regular physical examinations and complete blood counts can be performed in infants with Noonan syndrome if specific PTPN11 or KRAS mutations are present, and in patients with CBL syndrome. Also, the high brain tumor risk in patients with L-2 hydroxyglutaric aciduria may warrant regular screening with brain MRIs. For most syndromes, surveillance may be needed for nonmalignant health problems. Clin Cancer Res; 23(12); e83-e90. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.
Asunto(s)
Anomalías Múltiples/epidemiología , Hipotiroidismo Congénito/epidemiología , Anomalías Craneofaciales/epidemiología , Deformidades Congénitas de la Mano/epidemiología , Discapacidad Intelectual/epidemiología , Uñas Malformadas/epidemiología , Síndrome de Rubinstein-Taybi/epidemiología , Síndrome de Sotos/epidemiología , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Neoplasias Encefálicas/epidemiología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Hipotiroidismo Congénito/genética , Hipotiroidismo Congénito/patología , Síndrome de Costello/epidemiología , Síndrome de Costello/genética , Síndrome de Costello/patología , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/patología , Deformidades Congénitas de la Mano/genética , Deformidades Congénitas de la Mano/patología , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Mutación , Uñas Malformadas/genética , Uñas Malformadas/patología , Síndromes Neoplásicos Hereditarios/epidemiología , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/patología , Síndrome de Noonan/epidemiología , Síndrome de Noonan/genética , Síndrome de Noonan/patología , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Factores de Riesgo , Síndrome de Rubinstein-Taybi/genética , Síndrome de Rubinstein-Taybi/patología , Síndrome de Sotos/genética , Síndrome de Sotos/patología , Factor Nuclear Tiroideo 1/genéticaRESUMEN
RASopathies comprise a group of disorders clinically characterized by short stature, heart defects, facial dysmorphism, and varying degrees of intellectual disability and cancer predisposition. They are caused by germline variants in genes encoding key components or modulators of the highly conserved RAS-MAPK signalling pathway that lead to dysregulation of cell signal transmission. Germline changes in the genes encoding members of the RAS subfamily of GTPases are rare and associated with variable phenotypes of the RASopathy spectrum, ranging from Costello syndrome (HRAS variants) to Noonan and Cardiofaciocutaneous syndromes (KRAS variants). A small number of RASopathy cases with disease-causing germline NRAS alterations have been reported. Affected individuals exhibited features fitting Noonan syndrome, and the observed germline variants differed from the typical oncogenic NRAS changes occurring as somatic events in tumours. Here we describe 19 new cases with RASopathy due to disease-causing variants in NRAS. Importantly, four of them harbored missense changes affecting Gly12, which was previously described to occur exclusively in cancer. The phenotype in our cohort was variable but well within the RASopathy spectrum. Further, one of the patients (c.35G>A; p.(Gly12Asp)) had a myeloproliferative disorder, and one subject (c.34G>C; p.(Gly12Arg)) exhibited an uncharacterized brain tumour. With this report, we expand the genotype and phenotype spectrum of RASopathy-associated germline NRAS variants and provide evidence that NRAS variants do not spare the cancer-associated mutation hotspots.