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1.
Clin Dermatol ; 38(4): 455-461, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32972603

RESUMO

RASopathies are a group of disorders characterized by mutations in the RAS-MAPK pathway. RAS-MAP signaling plays a critical role in cell differentiation, proliferation, and survival. Germline mutations can result in distinctive syndromes, including Noonan syndrome, Costello syndrome, and neurofibromatosis type 1. Mosaic RASopathies can present as localized cutaneous lesions like epidermal nevi and nevus sebaceous, or more extensive conditions such as encephalocraniocutaneous lipomatosis. We review the heterogenous presentation of RAS mutations, discuss new targeted therapies, and highlight areas of uncertainty, including carcinogenesis risk and appropriate screening.


Assuntos
Síndrome de Costello/genética , Oftalmopatias/genética , Mutação em Linhagem Germinativa , Lipomatose/genética , Sistema de Sinalização das MAP Quinases/genética , Proteínas Monoméricas de Ligação ao GTP/genética , Síndromes Neurocutâneas/genética , Neurofibromatose 1/genética , Síndrome de Noonan/genética , Síndrome de Costello/diagnóstico , Síndrome de Costello/terapia , Oftalmopatias/diagnóstico por imagem , Oftalmopatias/terapia , Humanos , Lipomatose/diagnóstico por imagem , Lipomatose/terapia , Terapia de Alvo Molecular , Mutação , Síndromes Neurocutâneas/diagnóstico por imagem , Síndromes Neurocutâneas/terapia , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/terapia , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/terapia , Risco
3.
Arch Argent Pediatr ; 117(5): 330-337, 2019 10 01.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31560489

RESUMO

INTRODUCTION: RASopathies are a set of syndromes with phenotypic overlapping features caused by gene mutations involved in the RAS/MAPK pathway. They are autosomal dominantly inherited and share common clinical characteristics, including short stature, craniofacial dysmorphisms, congenital heart disease, ectodermal manifestations, and a higher risk for cancer. A molecular diagnosis is a key factor. OBJECTIVE: To identify PTPN11, SOS1, RAF1, BRAF, and HRAS mutations and compare the main clinical characteristics of patients with molecular confirmation. Population and methods. Children with a clinical diagnosis of RASopathy assessed between August 2013 and February 2017. RESULTS: Mutations were identified in 71 % (87/122) of patients. The molecular test confirmed diagnosis in 73 % of patients with Noonan syndrome. The most prevalent mutation was c.922A>G (p.Asn308Asp) in the PTPN11 gene. A previously undescribed variant in RAF1 was detected: c.1467G>>C (p.Leu489Phe). Cardiofaciocutaneous syndrome was confirmed in 67 % of cases with BRAF mutations. Costello syndrome and Noonan syndrome with multiple lentigines were confirmed in all cases. CONCLUSION: The confirmation of clinical diagnosis allowed for a more accurate differential diagnosis. The prevalence of PTPN11 (58 %), SOS1 (10 %), and RAF1 mutations (5 %) in children with Noonan syndrome, of PTPN11 mutations (100 %) in those with Noonan syndrome with multiple lentigines, of BRAF mutations (67 %) in those with cardiofaciocutaneous syndrome, and of HRAS mutations (100 %) in those with Costello syndrome was determined.


Assuntos
Síndrome de Costello/diagnóstico , Displasia Ectodérmica/diagnóstico , Insuficiência de Crescimento/diagnóstico , Cardiopatias Congênitas/diagnóstico , Síndrome de Noonan/diagnóstico , Adolescente , Argentina , Criança , Pré-Escolar , Síndrome de Costello/genética , Diagnóstico Diferencial , Displasia Ectodérmica/genética , Facies , Insuficiência de Crescimento/genética , Feminino , Cardiopatias Congênitas/genética , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Síndrome de Noonan/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína SOS1/genética , Adulto Jovem
4.
Am J Med Genet A ; 179(6): 940-947, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30854769

RESUMO

Pain in individuals with RASopathies is a neglected topic in literature. In this article, we assessed prevalence and profile of pain in a sample of 80 individuals affected by RASopathies. The study sample included individuals with Noonan syndrome (N = 42), Costello syndrome (N = 17), and cardio-facio-cutaneous syndrome (N = 21). A set of standardized questionnaires and scales were administered (VAS/numeric scale, r-FLACC, Wang-Baker scale, NPSI, BPI, NCCPC-R) to detect and characterize acute and chronic pain and to study the influence of pain on quality of life (PEDs-QL, SF-36) and sleeping patterns (SDSC); revision of past medical history and multisystemic evaluation was provided. Available clinical data were correlated to the presence of pain. High prevalence of acute (44%) and chronic (61%) pain was documented in the examined sample. Due to age and intellectual disability, acute pain was localized in 18/35 individuals and chronic pain in 33/49. Muscle-skeletal and abdominal pain was more frequently reported. The intensity of acute and chronic pain interfered with daily activities in 1/3 of the sample. Pain negatively impacted on QoL and sleeping patterns. This work documents that pain is highly prevalent in RASopathies. Future studies including subjective and objective measures of pain are required to discriminate a somatosensory abnormality from an abnormal elaboration of painful stimuli at a central level.


Assuntos
Síndrome de Costello/complicações , Síndrome de Costello/epidemiologia , Displasia Ectodérmica/complicações , Displasia Ectodérmica/epidemiologia , Insuficiência de Crescimento/complicações , Insuficiência de Crescimento/epidemiologia , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/epidemiologia , Síndrome de Noonan/complicações , Síndrome de Noonan/epidemiologia , Dor/epidemiologia , Dor/etiologia , Adolescente , Adulto , Criança , Pré-Escolar , Síndrome de Costello/diagnóstico , Síndrome de Costello/etiologia , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/etiologia , Facies , Insuficiência de Crescimento/diagnóstico , Insuficiência de Crescimento/etiologia , Feminino , Marcadores Genéticos , Mutação em Linhagem Germinativa , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/etiologia , Humanos , Lactente , Masculino , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/etiologia , Dor/diagnóstico , Fenótipo , Prevalência , Vigilância em Saúde Pública , Inquéritos e Questionários , Adulto Jovem
5.
Br J Dermatol ; 180(1): 172-180, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30141192

RESUMO

BACKGROUND: Data on dermatological manifestations of cardiofaciocutaneous syndrome (CFCS) remain heterogeneous and almost without expert dermatological classification. OBJECTIVES: To describe the dermatological manifestations of CFCS; to compare them with the literature findings; to assess those discriminating CFCS from other RASopathies, including Noonan syndrome (NS) and Costello syndrome (CS); and to test for dermatological phenotype-genotype correlations. METHODS: We performed a 4-year, large, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Forty-five patients were enrolled. Hair abnormalities were ubiquitous, including scarcity or absence of eyebrows and wavy or curly hair in 73% and 69% of patients, respectively. Keratosis pilaris (KP), ulerythema ophryogenes (UO), palmoplantar hyperkeratosis (PPHK) and multiple melanocytic naevi (MMN; over 50 naevi) were noted in 82%, 44%, 27% and 29% of patients, respectively. Scarcity or absence of eyebrows, association of UO and PPHK, diffuse KP and MMN best differentiated CFCS from NS and CS. Oral acitretin may be highly beneficial for therapeutic management of PPHK, whereas treatment of UO by topical sirolimus 1% failed. No significant dermatological phenotype-genotype correlation was determined. CONCLUSIONS: A thorough knowledge of CFCS skin manifestations would help in making a positive diagnosis and differentiating CFCS from CS and NS.


Assuntos
Displasia Ectodérmica/diagnóstico , Insuficiência de Crescimento/diagnóstico , Cardiopatias Congênitas/diagnóstico , Acitretina/administração & dosagem , Administração Cutânea , Administração Oral , Adolescente , Criança , Pré-Escolar , Síndrome de Costello/diagnóstico , Diagnóstico Diferencial , Displasia Ectodérmica/tratamento farmacológico , Displasia Ectodérmica/genética , Facies , Insuficiência de Crescimento/tratamento farmacológico , Insuficiência de Crescimento/genética , Feminino , França , Estudos de Associação Genética , Cardiopatias Congênitas/tratamento farmacológico , Cardiopatias Congênitas/genética , Humanos , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 2/genética , Masculino , Mutação , Síndrome de Noonan/diagnóstico , Estudos Prospectivos , Proteínas Proto-Oncogênicas B-raf/genética , Sirolimo/administração & dosagem , Resultado do Tratamento , Adulto Jovem
8.
Eur J Dermatol ; 27(6): 641-645, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29165300

RESUMO

Cardio-facio-cutaneous syndrome (CFC), Noonan syndrome (NS), and Costello syndrome are a group of diseases that belong to the RASopathies. The syndromes share clinical features making diagnosis a challenge. To investigate the phenotype and genotype of a 10-year-old Iraqi girl with overlapping features of CFC, NS, and Costello syndromes, with additional features of ectodermal dysplasia. DNA was examined by exome sequencing and protein expression by immunohistochemistry. Exome sequencing identified a mutation in the SOS1 gene and a de novo deletion in the FOXI2 gene which was neither present in the international databases, nor in 400 chromosomes from the same population. Based on immunohistochemical staining, FOXI2 was identified in the basal cell layer of the skin and overlapped with the expression of P63, a major player in ectodermal dysplasia. We therefore suggest screening for FOXI2 mutation in the setting of ectodermal features that are not associated with genes known to contribute to ectodermal dysplasia.


Assuntos
Displasia Ectodérmica/genética , Mutação , Criança , Síndrome de Costello/diagnóstico , Síndrome de Costello/genética , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/patologia , Facies , Insuficiência de Crescimento/diagnóstico , Insuficiência de Crescimento/genética , Feminino , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Humanos , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Proteína SOS1 , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética
9.
Am J Med Genet A ; 173(4): 1109-1114, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28328122

RESUMO

De novo germline mutations in HRAS cause Costello syndrome, with >95% of the mutations causing Costello syndrome affecting amino acid position 12 (p.Gly12) or 13 (p.Gly13). We report on a patient with de novo missense mutation causing an amino acid change at codon 146 of HRAS, c.436G > C:p.Ala146Pro, who presented with subtle dysmorphic features, failure to thrive, global developmental delay, and hypertrophic obstructive cardiomyopathy. Mutations affecting codon 146 are observed in <1% of patients with Costello syndrome. From literature search, there were only two other patients reported with mutations involving the same location. We summarized and updated their findings, and discussed evidence to show that these patients with less obvious signs of Costello syndrome may not necessarily run a more benign clinical course.


Assuntos
Cardiomiopatia Hipertrófica/genética , Síndrome de Costello/genética , Deficiências do Desenvolvimento/genética , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas p21(ras)/genética , Substituição de Aminoácidos , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/patologia , Pré-Escolar , Síndrome de Costello/diagnóstico , Síndrome de Costello/patologia , Análise Mutacional de DNA , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/patologia , Expressão Gênica , Humanos , Masculino
10.
Clin Genet ; 92(3): 332-337, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28139825

RESUMO

Costello syndrome (CS) is caused by heterozygous germline HRAS mutations. Most patients share the HRAS mutation c.34G>A (p.Gly12Ser) associated with the typical, relatively homogeneous phenotype. Rarer mutations occurred in individuals with an attenuated phenotype. Although many disease-associated HRAS alterations trigger constitutive activation of HRAS-dependent signalling pathways, additional pathological consequences exist. An infant with failure-to-thrive and hypertrophic cardiomyopathy had a novel de novo HRAS mutation (c.179G>T; p.Gly60Val). He showed subtle dysmorphic findings consistent with attenuated CS and died from presumed cardiac cause. Functional studies revealed that amino acid change p.Gly60Val impairs HRAS binding to effectors PIK3CA, phospholipase C1, and RAL guanine nucleotide dissociation stimulator. In contrast, interaction with effector rapidly accelerated fibrosarcoma (RAF) and regulator NF1 GTPase-activating protein was enhanced. Importantly, expression of HRAS p.Gly60Val in HEK293 cells reduced growth factor sensitivity leading to damped RAF-MAPK and phosphoinositide 3-kinases-AKT signalling response. Our data support the idea that a variable range of dysregulated HRAS-dependent signalling dynamics, rather than static activation of HRAS-dependent signal flow, may underlie the phenotypic variability in CS.


Assuntos
Síndrome de Costello/diagnóstico , Síndrome de Costello/genética , Mutação , Fenótipo , Proteínas Proto-Oncogênicas p21(ras)/genética , Alelos , Substituição de Aminoácidos , Autopsia , Linhagem Celular , Síndrome de Costello/metabolismo , Evolução Fatal , Estudos de Associação Genética , Genótipo , Humanos , Lactente , Masculino , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Transdução de Sinais
11.
Clin Dysmorphol ; 26(2): 83-90, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28027064

RESUMO

Costello syndrome (CS) is a rare congenital disorder from the group of RASopathies, characterized by a distinctive facial appearance, failure to thrive, cardiac and skin anomalies, intellectual disability, and a predisposition to neoplasia. CS is associated with germline mutations in the proto-oncogene HRAS, a small GTPase from the Ras family. In this study, a molecular and clinical analysis was carried out in eight Polish patients with the Costello phenotype. A molecular test showed two known heterozygous mutations in the first coding exon of the gene in seven patients: p.G12S (n=4) and p.G12A (n=3), and a novel pathogenic variant p.G60V in one child with an unusually severe, lethal course of the syndrome. In addition, a fatal course of CS was present in one patient with the p.G12A mutation and in another with p.G12S, there was a co-occurrence of Turner syndrome because of the distal Xp deletion. A severe clinical manifestation with a lethal outcome in an individual with p.G60V in HRAS and contrary observations of an attenuated phenotype in CS patients with other mutations at glycine-60 residue may suggest that the nature of the substituted amino acid plays a significant role in the clinical variability observed in some CS cases.


Assuntos
Síndrome de Costello/diagnóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Adolescente , Criança , Pré-Escolar , Síndrome de Costello/genética , Evolução Fatal , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto , Fenótipo , Polônia
12.
Am J Med Genet A ; 170(10): 2570-7, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27155212

RESUMO

Noonan, Cardio-facio-cutaneous, and Costello syndromes are disorders of the Ras/MAPK pathway that share many clinical features. This observational and anthropometric study was conducted to describe the key facial features of each syndrome in order to improve discrimination between the three conditions, particularly in young children where diagnosis is most challenging. Direct measurement of the head and face was used to enhance diagnostic accuracy, and identify the most unusual or specific dimensions. The Noonan syndrome cohort included 123 individuals, aged 6 months to 41 years. There were 20 children and adolescents with Cardio-facio-cutaneous syndrome, and 28 individuals with Costello syndrome, aged 1-32 years. The facial phenotypes of these syndromes, particularly Noonan syndrome, are well-described but objective data have not been published in peer-reviewed literature. In this study, subjective observations, in the main, were validated by anthropometry with one exception. In individuals with Costello syndrome, mouth width was normal, thus the impression of wide mouth is likely due to full lips or the mouth being viewed in relation to a narrow lower face. When the three conditions were compared objectively, syndrome-specific pattern profiles showed high concordance in early life. At older ages, Cardio-facio-cutaneous syndrome was distinguished by increased width of the mid/lower face, and reduced growth of maxillary and mandibular dimensions was noted in both Noonan and Costello syndromes. Despite substantial similarities in face shape in older individuals with these two conditions, bulbous nasal tip, full lips, and an apparently wide mouth in those with Costello Syndrome facilitate discrimination from Noonan syndrome. © 2016 Wiley Periodicals, Inc.


Assuntos
Síndrome de Costello/diagnóstico , Displasia Ectodérmica/diagnóstico , Facies , Insuficiência de Crescimento/diagnóstico , Cardiopatias Congênitas/diagnóstico , Síndrome de Noonan/diagnóstico , Adolescente , Adulto , Fatores Etários , Pesos e Medidas Corporais , Criança , Pré-Escolar , Síndrome de Costello/genética , Síndrome de Costello/metabolismo , Diagnóstico Diferencial , Displasia Ectodérmica/genética , Displasia Ectodérmica/metabolismo , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/metabolismo , Feminino , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/metabolismo , Humanos , Lactente , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Síndrome de Noonan/genética , Síndrome de Noonan/metabolismo , Fenótipo , Transdução de Sinais , Adulto Jovem , Proteínas ras/metabolismo
13.
Am J Med Genet A ; 170(7): 1849-57, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27102959

RESUMO

Costello syndrome (CS) is a multisystem disorder caused by heterozygous germline mutations in the HRAS proto-oncogene. Respiratory system complications have been reported in individuals with CS, but a comprehensive description of the full spectrum and incidence of respiratory symptoms in these patients is not available. Here, we report the clinical course of four CS patients with respiratory complications as a major cause of morbidity. Review of the literature identified 56 CS patients with descriptions of their neonatal course and 17 patients in childhood/adulthood. We found that in the neonatal period, respiratory complications are seen in approximately 78% of patients with transient respiratory distress reported in 45% of neonates. Other more specific respiratory diagnoses were reported in 62% of patients, the majority of which comprised disorders of the upper and lower respiratory tract. Symptoms of upper airway obstruction were reported in CS neonates but were more commonly diagnosed in childhood/adulthood (71%). Analysis of HRAS mutations and their respiratory phenotype revealed that the common p.Gly12Ser mutation is more often associated with transient respiratory distress and other respiratory diagnoses. Respiratory failure and dependence on mechanical ventilation occurs almost exclusively with rare mutations. In cases of prenatally diagnosed CS, the high incidence of respiratory complications in the neonatal period should prompt anticipatory guidance and development of a postnatal management plan. This may be important in cases involving rarer mutations. Furthermore, the high frequency of airway obstruction in CS patients suggests that otorhinolaryngological evaluation and sleep studies should be considered. © 2016 Wiley Periodicals, Inc.


Assuntos
Síndrome de Costello/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Anormalidades do Sistema Respiratório/genética , Síndrome de Costello/complicações , Síndrome de Costello/diagnóstico , Síndrome de Costello/fisiopatologia , Feminino , Mutação em Linhagem Germinativa , Humanos , Recém-Nascido , Masculino , Fenótipo , Gravidez , Anormalidades do Sistema Respiratório/complicações , Anormalidades do Sistema Respiratório/diagnóstico , Anormalidades do Sistema Respiratório/fisiopatologia
14.
Am J Med Genet A ; 170(6): 1433-8, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26888048

RESUMO

We report a 10-year-old girl presenting with severe neonatal hypertrophic cardiomyopathy (HCM), feeding difficulties, mildly abnormal facial features, and progressive skeletal muscle symptoms but with normal cognitive development. Targeted oligonucleotide-selective sequencing of 101 cardiomyopathy genes revealed the genetic diagnosis, and the mutation was verified by Sanger sequencing in the patient and her parents. To offer insights into the potential mechanism of patient mutation, protein structural analysis was performed using the resolved structure of human activated HRAS protein with bound GTP analogue (PDB id 5P21) in Discovery Studio 4.5 (Dassault Systèmes Biovia, San Diego, CA). The patient with hypertrophic cardiomyopathy and normal cognitive development was diagnosed with an HRAS mutation c.173C>T (p.T58I), a milder variant of Costello syndrome affecting a highly conserved amino acid, threonine 58. Our analysis suggests that the p.G12 mutations slow GTP hydrolysis rendering HRAS unresponsive to GTPase activating proteins, and resulting in permanently active state. The p.T58I mutation likely affects binding of guanidine-nucleotide-exchange factors, thereby promoting the active state but also allowing for slow inactivation. Patients with the HRAS mutation c.173C>T (p.T58I) might go undiagnosed because of the milder phenotype compared with other mutations causing Costello syndrome. We expand the clinical and molecular picture of the rare HRAS mutation by reporting the first case in Europe and the fourth case in the literature. Our protein structure analysis offers insights into the mechanism of the mildly activating p.T58I mutation. © 2016 Wiley Periodicals, Inc.


Assuntos
Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/genética , Síndrome de Costello/diagnóstico , Síndrome de Costello/genética , Mutação , Fenótipo , Proteínas Proto-Oncogênicas p21(ras)/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Alelos , Biomarcadores , Análise Mutacional de DNA , Ecocardiografia , Estudos de Associação Genética , Testes Genéticos , Genótipo , Humanos , Recém-Nascido , Masculino , Radiografia Torácica , Índice de Gravidade de Doença
15.
Ital J Pediatr ; 42: 10, 2016 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-26812928

RESUMO

BACKGROUND: Costello syndrome is a rare syndrome of multiple congenital anomalies. The typical clinical traits include dysmorphic craniofacial features, skin hyperpigmentation and excess, feeding difficulties leading to severe postnatal growth retardation, short stature, joint hypermobility, and delayed psychomotor development. Additionally, Costello syndrome may present with an increased incidence of congenital heart disease, hypertrophic cardiomyopathy, and increased risk of both benign and malignant tumors. Furthermore, cases of patients with endocrine disorders such as adrenal insufficiency and endogenous growth hormone deficiency have also been documented. CASE PRESENTATION: We present a patient with Costello syndrome who has been successfully treated with recombinant human growth hormone (rhGH) for almost 4 years. CONCLUSIONS: The possibility of growth hormone (GH) treatment can be considered in cases of documented GH deficiency in patients with Costello syndrome, but only under close oncologic and cardiologic supervision.


Assuntos
Síndrome de Costello/diagnóstico , Síndrome de Costello/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos
16.
Am J Med Genet A ; 170(3): 559-64, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26572961

RESUMO

Costello syndrome (CS) entails a cancer predisposition and is caused by activating HRAS mutations, typically arising de novo in the paternal germline. Hypoglycemia is common in CS neonates. A previously reported individual with the rare HRAS p.Gln22Lys had hyperinsulinemic hypoglycemia. Autopsy showed a discrete pancreatic nodule. The morphologic and immunohistochemistry findings, including loss of p57(Kip2) protein, were identical to a focal lesion of congenital hyperinsulinism, however, no KCNJ11 or ABCC8 mutation was identified and germline derived DNA showed no alternation of the maternal or paternal 11p15 alleles. Here we report paternal uniparental disomy (pUPD) within the lesion, similar to the pUPD11p15.5 in Beckwith-Wiedemann syndrome (BWS). The similar extent of the pUPD suggests a similar mechanism driving hyperinsulinemia in both conditions. After coincidental somatic LOH and pUPD, the growth promoting effects of the paternally derived HRAS mutation, in combination with the increased function of the adjacent paternally expressed IGF2, may together result in clonal expansion. Although this somatic LOH within pancreatic tissue resulted in hyperinsulinism, similar LOH in mesenchymal cells may drive embryonal rhabdomyosarcoma (ERMS). Interestingly, biallelic IGF2 expression has been linked to rhabdomyosarcoma tumorigenesis and pUPD11 occurred in all 8 ERMS samples from CS individuals. Somatic KRAS and HRAS mutations occur with comparable frequency in isolated malignancies. Yet, the malignancy risk in CS is notably higher than in Noonan syndrome with a KRAS mutation. It is conceivable that HRAS co-localization with IGF2 and the combined effect of pUPD 11p15.5 on both genes contributes to the oncogenic potential.


Assuntos
Síndrome de Beckwith-Wiedemann/genética , Hiperinsulinismo Congênito/genética , Síndrome de Costello/genética , Impressão Genômica , Hipoglicemia/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Dissomia Uniparental/genética , Substituição de Aminoácidos , Sequência de Bases , Síndrome de Beckwith-Wiedemann/diagnóstico , Síndrome de Beckwith-Wiedemann/patologia , Cromossomos Humanos Par 11/química , Células Clonais , Hiperinsulinismo Congênito/diagnóstico , Hiperinsulinismo Congênito/patologia , Síndrome de Costello/diagnóstico , Síndrome de Costello/patologia , Evolução Fatal , Humanos , Hipoglicemia/diagnóstico , Hipoglicemia/patologia , Lactente , Padrões de Herança , Fator de Crescimento Insulin-Like II/genética , Perda de Heterozigosidade , Masculino , Dados de Sequência Molecular , Pâncreas/metabolismo , Pâncreas/patologia , Dissomia Uniparental/diagnóstico , Dissomia Uniparental/patologia
17.
Neuroradiol J ; 28(3): 254-8, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26246091

RESUMO

This study aimed to assess changes in the posterior cranial fossa (PCF) to shed light on the mechanism of cerebellar herniation in children with Costello syndrome (CS) and posterior fossa crowding. We performed a morphovolumetric PCF analysis on brain magnetic resonance imaging (MRI) in seven children with CS (mean age 31 ± 16 months) comparing the MRI scans with those of seven age-matched healthy subjects.PCF volume (PCFV), PCF brain volume (PCFBV) and cerebellar volume (CeV) were assessed on axial T2-weighted MRI. Morphometric parameters (diameters of the foramen magnum, tentorial angle, basiocciput, supraocciput, basisphenoid and exocciput lengths) were measured on sagittal T1-weighted MRI. The volume of the cerebrospinal fluid (CSF) spaces was calculated as PCFV minus PCFBV.Five out of seven CS children showed tonsillar herniation in the upper cervical canal; no child had hydrocephalus but three out of seven children showed ventriculomegaly. In addition, the PCFV/PCFBV ratio, PCFV, CSF spaces volume, basiocciput, basisphenoid and exocciput lengths and latero-lateral and antero-posterior diameters of the foramen magnum were significantly reduced, whereas no significant changes were found in supraocciput length, PCFBV, CeV or hindbrain volume. The volumetric reduction of the PCF due to bony posterior fossa hypoplasia is a predisposing factor for developing cerebellar tonsillar herniation through the foramen magnum in children with CS. The altered anatomy of the foramen magnum and upward expansion of the PCF secondary to an increased tentorial slope serves to explain the possible mechanism of cerebellar herniation in patients with CS.


Assuntos
Cerebelo/patologia , Síndrome de Costello/diagnóstico , Fossa Craniana Posterior/patologia , Encéfalo/patologia , Estudos de Casos e Controles , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Tamanho do Órgão
18.
Hautarzt ; 66(4): 225-8, 2015 Apr.
Artigo em Alemão | MEDLINE | ID: mdl-25722179

RESUMO

An 18-year-old female with palmoplantar keratoderma, hyperhidrosis, facial verruciform papillomatosis, coarse face, growth retardation and developmental delay presented to our outpatient clinic. A diagnosis of Costello syndrome was made, and genetic counseling and a molecular genetic analysis were initiated. By this means, a heterozygous missense mutation in exon 2 of the HRAS gene, designated c.34G > A (p.Gly12Ser), was detected, confirming the clinical diagnosis. Costello syndrome belongs to the group of clinically and genetically heterogeneous RASopathies with cutaneous symptoms. Collectively, the RASopathies are caused by mutations in different genes, which lead to dysregulation of the RAS/MAPK (mitogen-activated protein kinase) signaling pathway. This signaling route regulates the delicate balance between cell proliferation and differentiation, and plays an important role in embryogenesis and carcinogenesis. In the RASopathies with cutaneous symptoms, overlapping clinical findings may hamper making an accurate diagnosis. Therefore, a molecular genetic analysis may be useful, as in the patient described here.


Assuntos
Síndrome de Costello/diagnóstico , Síndrome de Costello/genética , Testes Genéticos/métodos , Sistema de Sinalização das MAP Quinases/genética , Dermatopatias/diagnóstico , Dermatopatias/genética , Adolescente , Diagnóstico Diferencial , Feminino , Humanos , Avaliação de Sintomas/métodos
19.
Klin Padiatr ; 227(1): 45-7, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25062109

RESUMO

Costello syndrome is a rare congenital disease with typical craniofacial and musculoskeletal features, cutaneous lesions, cardiac defects and cancer susceptibility. Affected patients show severe feeding difficulties for the first years of life and developmental delay. We present the case of a patient, in whom fetal tachycardia, polyhdramnios and physical characteristics led to an early diagnosis of Costello syndrome. Based on this patient we describe challenges and problems of therapeutic management of infants with Costello syndrome.


Assuntos
Síndrome de Costello/diagnóstico , Síndrome de Costello/genética , Diagnóstico Precoce , Proteínas Proto-Oncogênicas p21(ras)/genética , Adulto , Flutter Atrial/diagnóstico , Flutter Atrial/genética , Eletrocardiografia , Feminino , Seguimentos , Triagem de Portadores Genéticos , Mutação em Linhagem Germinativa , Humanos , Recém-Nascido , Mutação de Sentido Incorreto , Gravidez , Processamento de Sinais Assistido por Computador , Transdução de Sinais/genética , Ultrassonografia Pré-Natal
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