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1.
BMC Med Genet ; 21(1): 239, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33261563

RESUMO

BACKGROUND: Early-onset chronic diarrhoea often indicates a congenital disorder. Mutation in diacylglycerol o-acyltransferase 1 (DGAT1) has recently been linked to early-onset chronic diarrhoea. To date, only a few cases of DGAT1 deficiency have been reported. Diarrhoea in those cases was severe and developed in the neonatal period or within 2 months after birth. CASE PRESENTATION: Here, we report a female patient with DGAT1 mutations with delayed-onset chronic diarrhoea. The patient had vomiting, hypoalbuminemia, hypertriglyceridemia, and failure to thrive at early infancy. Her intractable chronic diarrhoea occurred until she was 8 months of age. A compound heterozygous DGAT1 mutation was found in the patient, which was first found in the Chinese population. Her symptoms and nutrition status improved after nutritional therapy, including a fat restriction diet. CONCLUSIONS: This case expanded our knowledge of the clinical features of patients with DGAT1 mutations. Intractable diarrhoea with delayed onset could also be a congenital disorder.


Assuntos
Diacilglicerol O-Aciltransferase/genética , Diarreia/genética , Insuficiência de Crescimento/genética , Hipertrigliceridemia/genética , Hipoalbuminemia/genética , Mutação , Vômito/genética , Idade de Início , Sequência de Bases , Diacilglicerol O-Aciltransferase/deficiência , Diarreia/dietoterapia , Diarreia/metabolismo , Diarreia/fisiopatologia , Dieta com Restrição de Gorduras , Insuficiência de Crescimento/dietoterapia , Insuficiência de Crescimento/metabolismo , Insuficiência de Crescimento/fisiopatologia , Feminino , Expressão Gênica , Heterozigoto , Humanos , Hipertrigliceridemia/dietoterapia , Hipertrigliceridemia/metabolismo , Hipertrigliceridemia/fisiopatologia , Hipoalbuminemia/dietoterapia , Hipoalbuminemia/metabolismo , Hipoalbuminemia/fisiopatologia , Lactente , Índice de Gravidade de Doença , Vômito/dietoterapia , Vômito/metabolismo , Vômito/fisiopatologia
2.
Pediatrics ; 146(2)2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32709737

RESUMO

Establishing the diagnosis of hereditary fructose intolerance (HFI) remains difficult despite the availability of specific molecular genetic testing of the ALDOB gene. This is attributable, at least in part, to the lack of a specific and practical biomarker. We report the incidental diagnosis of HFI as a consequence of nontargeted genetic testing ordered for alternative indications in 5 patients, including 3 children and 2 adults. Two of the children were diagnosed with HFI after extensive evaluations that ultimately involved clinical or research exome sequencing. The third child was diagnosed with HFI during subsequent genetic testing of at-risk family members. Both adults learned to avoid fructose and remained asymptomatic of HFI before diagnosis. One was diagnosed with HFI during preconception, nontargeted expanded carrier screening. For the other, concern for HFI was initially raised by indeterminate direct-to-consumer genetic testing results. None of these patients presented with infantile acute liver failure or other acute decompensation. Our findings suggest that the emphasis of classic teaching on infantile liver failure after first exposure to fructose may be inadvertently increasing the likelihood of missing cases of HFI characterized by other manifestations. HFI is likely underdiagnosed and should be considered for patients with nonspecific findings as well as for individuals with significant aversion to sweets.


Assuntos
Intolerância à Frutose/diagnóstico , Adulto , Idoso , Doenças Assintomáticas , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Triagem e Testes Direto ao Consumidor , Nanismo/genética , Insuficiência de Crescimento/genética , Feminino , Preferências Alimentares , Intolerância à Frutose/genética , Frutose-Bifosfato Aldolase/genética , Frutas/efeitos adversos , Testes Genéticos , Humanos , Achados Incidentais , Infertilidade Feminina , Masculino , Cuidado Pré-Concepcional , Verduras/efeitos adversos , Sequenciamento Completo do Exoma
3.
BMC Neurol ; 20(1): 246, 2020 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-32546208

RESUMO

BACKGROUND: KMT2B-related dystonia is a recently described form of childhood onset dystonia that may improve with deep brain stimulation. Prior reports have focused on neurologic features including prominent bulbar involvement without detailing general health consequences that may result from orolingual dysfunction. We describe a family with novel KMT2B mutation with several members with failure to thrive to highlight this non-neurologic, but consequential impact of mutation in this gene. CASE PRESENTATION: We present a case of a 15-year old female who was admitted and evaluated for failure to thrive. On exam, she had severe speech dysfluency, limited ability to protrude the tongue, and generalized dystonia involving the oromandibular region, right upper and left lower extremity with left foot inversion contracture. The proband and her parents underwent whole genome sequencing. A previously undescribed variant, c.4960 T > C (p.Cys1654Arg), was identified in the KMT2B gene in the proband and mother, and this variant was subsequently confirmed in two maternal cousins, one with failure to thrive. Literature review identified frequent reports of prominent bulbar involvement but failure to thrive is rarely mentioned. CONCLUSION: Failure to thrive is a common pediatric clinical condition that has consequences for growth and development. In the presence of an abnormal neurologic exam, a search for a specific underlying genetic etiology should be pursued. With this case series, we highlight an unusual potentially treatable cause of failure to thrive, reinforce the importance of precise molecular diagnosis for patients with failure to thrive and an abnormal neurologic exam, and underscore the importance of cascade screening of family members.


Assuntos
Distúrbios Distônicos/genética , Insuficiência de Crescimento/genética , Histona-Lisina N-Metiltransferase/genética , Adolescente , Criança , Feminino , Humanos , Mutação , Linhagem
4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(5): 567-569, 2020 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-32335888

RESUMO

OBJECTIVE: To explore the genotype-phenotype correlation of Cardio-facio-cutaneous syndrome (CFCS) caused by MAP2K1 gene variants. METHODS: Genomic DNA was extracted from peripheral blood sample from a child patient and his parents. Whole exome sequencing (WES) was carried out for the patient. Suspected variant was verified by Sanger sequencing. RESULTS: The patient was a 1-year-8-month old Chinese male who manifested short stature, psychomotor retardation, relative macrocephaly, distinctive facial features, and congenital heart disease. WES test revealed a heterozygous missense c.389A>G (p.Tyr130Cys) variant in the MAP2K1 gene. Sanger sequencing has confirmed the variant as de novo. According to ACMG/AMP guidelines, the variant was classified as pathogenic. CONCLUSION: Compared with previously reported CFCS cases due to MAP2K1 variants. The patient showed obvious behavioral problems, good appetite and tricuspid regurgitation, which may to be novel features for CFCS.


Assuntos
Displasia Ectodérmica , Facies , Insuficiência de Crescimento , Variação Genética , Cardiopatias Congênitas , MAP Quinase Quinase 1 , China , Displasia Ectodérmica/genética , Insuficiência de Crescimento/genética , Estudos de Associação Genética , Cardiopatias Congênitas/genética , Heterozigoto , Humanos , Lactente , MAP Quinase Quinase 1/genética , Masculino , Mutação , Sequenciamento Completo do Exoma
5.
Am J Med Genet C Semin Med Genet ; 184(1): 73-80, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32022400

RESUMO

Noonan syndrome is a pleomorphic genetic disorder, in which a high percentage of affected individuals have cardiovascular involvement, most prevalently various forms of congenital heart disease (i.e., pulmonary valve stenosis, septal defects, left-sided lesions, and complex forms with multiple anomalies). Care includes attentiveness to several comorbidities, some directly impacting cardiac management (bleeding diatheses and lymphatic anomalies). More than 50% of patients with Noonan syndrome harbor PTPN11 pathogenic variation, which results in hyperactivation of RAS/mitogen-activated protein kinase signaling. Several other disease genes with similar biological effects have been uncovered for NS and phenotypically related disorders, collectively called the RASopathies. Molecular diagnosis with gene resequencing panels is now widely available, but phenotype variability and in some cases, subtlety, continues to make identification of Noonan syndrome difficult. Until genetic testing becomes universal for patients with congenital heart disease, alertness to Noonan syndrome's broad clinical presentations remains crucial. Genotype-phenotype associations for Noonan syndrome enable better prognostication for affected patients when a molecular diagnosis is established. We still lack Noonan syndrome-specific treatment; however, newly developed anticancer RAS pathway inhibitors could fill that gap if safety and efficacy can be established for indications such as pulmonary valve stenosis.


Assuntos
Insuficiência de Crescimento/diagnóstico , Cardiopatias Congênitas/diagnóstico , Síndrome de Noonan/diagnóstico , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/terapia , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/patologia , Insuficiência de Crescimento/terapia , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/terapia , Humanos , Mutação/genética , Síndrome de Noonan/complicações , Síndrome de Noonan/genética , Síndrome de Noonan/terapia , Fenótipo
7.
Gene ; 733: 144369, 2020 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-31972311

RESUMO

MAP2K1 encodes mitogen-activated protein kinase 1 (MEK1). Mutations in MAP2K1 lead to continuous activation of MEK/ERK signaling pathway, giving rise to cardio-facio-cutaneous syndrome (CFCS). However, the molecular mechanisms of abnormal activation of MEK/ERK signaling pathway and the role of autophagy, if any, in manifesting CFCS in MAP2K mutants remain unclear. Here, we report three Chinese children with CFCS having MAP2K1 pathogenic variants, identified by exome sequencing. They presented with dysmorphic facial features, seizures, psychomotor retardation, and short stature. Additionally, the third child showed pulmonary valve stenosis, multiple skeletal deformities, and osteoporosis. Whole exome sequencing revealed two heterozygous missense mutations in exon 3 of MAP2K1 (c.383G>T; p.Gly128Val and c.389A>G; p.Tyr130Cys), as well as a novel heterozygous missense variant (c.170A>T; p.Lys57Met) in exon 2 of MAP2K1. In SH-SY5Y cells, we identified, for the first time, that MAP2K1 mutations can activate the p-ERK-dependent cell cycle progression and autophagy, and cause CFCS. Our results extended the mutational spectrum of MAP2K1, examined the role of MEK1 protein in nerve cell functions, and demonstrated, for the first time, that autophagy may mediate the altered MAP2K1 function, leading to CFCS phenotypes.


Assuntos
Autofagia , Displasia Ectodérmica/patologia , Insuficiência de Crescimento/patologia , Cardiopatias Congênitas/patologia , MAP Quinase Quinase 1/genética , Mutação , Adulto , Apoptose , Ciclo Celular , Movimento Celular , Proliferação de Células , Criança , Displasia Ectodérmica/genética , Displasia Ectodérmica/metabolismo , Facies , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/metabolismo , Feminino , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/metabolismo , Humanos , Lactente , Sistema de Sinalização das MAP Quinases , Masculino , Fenótipo , Fosforilação , Células Tumorais Cultivadas
8.
Am J Med Genet A ; 182(1): 201-204, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31692235

RESUMO

Bohring-Opitz syndrome (BOS) has been described as a clinically recognizable genetic syndrome since 1999. Clinical diagnostic criteria were established in 2011 and include microcephaly, trigonocephaly, distinctive craniofacial dysmorphic features, facial nevus flammeus, failure to thrive, and severe developmental delays. The same year, different de novo heterozygous nonsense mutations in the ASXL1 were found in affected individuals. Since then, several cases have been reported confirming the association between this chromatin remodeling gene and BOS. Most affected individuals die in early childhood because of unexplained bradycardia, obstructive apnea, or pulmonary infections. Those that survive usually cannot walk independently and are nonverbal. Some have had success using walkers and braces in late childhood. While few are able to speak, many have been able to express basic needs using communication devices as well as gestures with associated basic vocalizations. In this article, we present a mild case of BOS with a de novo pathogenic mutation c.1720-2A>G (p.I574VfsX22) in ASXL1 detected on whole-exome sequencing and confirmed by functional analysis of the messenger RNA splicing pattern on the patient's fibroblasts. She has typical dysmorphic features and is able to run and walk independently as well as to communicate with basic sign language.


Assuntos
Craniossinostoses/genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Proteínas Repressoras/genética , Criança , Pré-Escolar , Códon sem Sentido/genética , Craniossinostoses/patologia , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/patologia , Feminino , Humanos , Deficiência Intelectual/patologia , Mutação/genética , Fenótipo
9.
Am J Med Genet A ; 182(1): 195-200, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31697451

RESUMO

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.


Assuntos
GTP Fosfo-Hidrolases/genética , Predisposição Genética para Doença , Proteínas de Membrana/genética , Rabdomiossarcoma Embrionário/genética , Proteínas ras/genética , Adolescente , Criança , Síndrome de Costello/genética , Síndrome de Costello/patologia , Displasia Ectodérmica/genética , Displasia Ectodérmica/patologia , Facies , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/patologia , Feminino , Mutação em Linhagem Germinativa/genética , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Neurofibromatose 1/genética , Neurofibromatose 1/patologia , Síndrome de Noonan/genética , Síndrome de Noonan/patologia , Fenótipo , Rabdomiossarcoma Embrionário/patologia , Adulto Jovem
10.
Indian Pediatr ; 56(9): 792-794, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31638014

RESUMO

BACKGROUND: Bainbridge-Ropers syndrome is a rare autosomal dominant genetic disorder. CASE CHARACTERISTICS: A 26-day-old neonate presented with feeding difficulties, excessive sleeping, and hirsutism over forehead and lumbosacral skin. OUTCOME: Whole-exome sequencing identified a novel nonsense mutation. MESSAGE: We report a novel mutation in a Chinese neonate with Bainbridge-Ropers syndrome.


Assuntos
Códon sem Sentido , Anormalidades Craniofaciais/diagnóstico , Distúrbios do Sono por Sonolência Excessiva/diagnóstico , Hipotonia Muscular/diagnóstico , Transtornos Psicomotores/diagnóstico , Fatores de Transcrição/genética , Anormalidades Craniofaciais/genética , Distúrbios do Sono por Sonolência Excessiva/genética , Insuficiência de Crescimento/diagnóstico , Insuficiência de Crescimento/genética , Feminino , Marcadores Genéticos , Hirsutismo/diagnóstico , Hirsutismo/genética , Humanos , Recém-Nascido , Hipotonia Muscular/genética , Transtornos Psicomotores/genética , Síndrome
11.
J Mol Med (Berl) ; 97(11): 1557-1566, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31529142

RESUMO

The VARS2 gene encodes a mitochondrial valyl-transfer RNA synthetase which is used in mitochondrial translation. To date, several patients with VARS2 pathogenic variants have been described in the literature. These patients have features of lactic acidosis with encephalomyopathy. We present a case of an infant with lactic acidosis, failure to thrive, and severe primary pulmonary hypertension who was found to be a compound heterozygote for two novel VARS2 variants (c.1940C>T, p.(Thr647Met) and c.2318G>A, p.(Arg773Gln)). The patient was treated with vitamin supplements and a carbohydrate-restricted diet. The lactic acidosis and failure to thrive resolved, and he showed good growth and development. Functional studies and molecular analysis employed a yeast model system and the VAS1 gene (yeast homolog of VARS2). VAS1 genes harboring either one of two mutations corresponding to the two novel variants in the VARS2 gene, exhibited partially reduced function in haploid yeast strains. A combination of both VAS1 variant alleles in a diploid yeast cell exhibited a more significant decrease in oxidative metabolism-dependent growth and in the oxygen consumption rate (reminiscent of the patient who carries two mutant VARS2 alleles). Our results demonstrate the pathogenicity of the biallellic novel VARS2 variants. KEY MESSAGES: • A case of an infant who is a compound heterozygote for two novel VARS2 variants. • This infant displayed lactic acidosis, failure to thrive, and pulmonary hypertension. • Treatment of the patient with a carbohydrate-restricted diet resulted in good growth and development. • Studies with the homologous yeast VAS1 gene showed reduced function of corresponding single mutant in haploid yeast strains. • A combination of both VAS1 variant alleles in diploid yeast exhibited a more significant decrease in function, thereby confirming the pathogenicity of the biallellic novel VARS2 variants.


Assuntos
Insuficiência de Crescimento/genética , Insuficiência de Crescimento/metabolismo , Antígenos HLA/genética , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/metabolismo , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Valina-tRNA Ligase/genética , Alelos , Sequência de Aminoácidos , Heterozigoto , Humanos , Lactente , Masculino , Mutação/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Análise de Sequência de DNA
12.
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
13.
Eur J Obstet Gynecol Reprod Biol ; 240: 232-241, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31336229

RESUMO

Antenatal diagnosis of cardio-facio-cutaneous syndrome: prenatal characteristics and contribution of fetal facial dysmorphic signs in utero. This paper is a case study and review of literature. "RASopathies" is the term coined for a group of genetic diseases that share modulation inside the MAPKinase pathway. Mutations inside the coding sequence of any of these genes may be responsible for the upregulation of the RAS pathway, leading on the clinical level to Type 1 Neurofibromatosis (NF1), Noonan syndrome (NS), Costello syndrome (CS), Multiple Lentigines, Loose Anagen Hair syndrome, Cardio-Facio-Cutaneous syndrome (CFCS), and, more recently, Legius syndrome. While the postnatal presentation of this group is well-known, prenatal findings are less well recognized. The presence of a RASopathy during the prenatal period can be suspected on account of non-specific abnormalities: polyhydramnios, cystic hygroma or high nuchal translucency, macrosomia with proportionate short long bones, macrocephaly, renal, lymphatic, or cardiac defects. The current case report underlines the characteristic dysmorphic facial features on 3D-ultrasound (hypertelorism, down-slanting palpebral fissures, a long and marked philtrum, and low-set posteriorly rotated ears) that allow for a "RASopathy" to be postulated. After detecting a copy number variation (CNV) absence on a CGH array, we performed a RASopathy gene panel analysis, which identified a so-far unreported heterozygous de novo mutation in the BRAF gene (namely NM_004333.4 : c.1396 G > C ; p.Gly466Arg). Genetic counseling has, therefore, focused on the diagnosis of a RASopathy and predictable phenotype of CFCS, a distinct entity characterized by an increased risk of intellectual disability and early-onset feeding problems. We suggest that a more detailed prenatal facial evaluation should be performed in fetuses presenting high nuchal thickness, heart defects, or unusual findings, along with the absence of a CNV on a CGH array. Due to the dysmorphic facial features, targeted RASopathy genes are presumed to likely to be responsible for NS, CFCS, and CS.


Assuntos
Displasia Ectodérmica/diagnóstico por imagem , Insuficiência de Crescimento/diagnóstico por imagem , Cardiopatias Congênitas/diagnóstico por imagem , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Variações do Número de Cópias de DNA , Displasia Ectodérmica/genética , Facies , Insuficiência de Crescimento/genética , Feminino , Cardiopatias Congênitas/genética , Humanos , Gravidez , Diagnóstico Pré-Natal , Ultrassonografia Pré-Natal
14.
Mol Cells ; 42(6): 441-447, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31250618

RESUMO

RAS gene mutations are frequently found in one third of human cancers. Affecting approximately 1 in 1,000 newborns, germline and somatic gain-of-function mutations in the components of RAS/mitogen-activated protein kinase (RAS/MAPK) pathway has been shown to cause developmental disorders, known as RASopathies. Since RAS-MAPK pathway plays essential roles in proliferation, differentiation and migration involving developmental processes, individuals with RASopathies show abnormalities in various organ systems including central nervous system. The frequently seen neurological defects are developmental delay, macrocephaly, seizures, neurocognitive deficits, and structural malformations. Some of the defects stemmed from dysregulation of molecular and cellular processes affecting early neurodevelopmental processes. In this review, we will discuss the implications of RAS-MAPK pathway components in neurodevelopmental processes and pathogenesis of RASopathies.


Assuntos
Transtornos do Neurodesenvolvimento/genética , Proteínas ras/genética , Síndrome de Costello/genética , Displasia Ectodérmica/genética , Facies , Insuficiência de Crescimento/genética , Cardiopatias Congênitas/genética , Humanos , Recém-Nascido , Neoplasias/metabolismo , Neurofibromatose 1/genética , Nevo Sebáceo de Jadassohn/genética , Síndrome de Noonan/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-raf/genética , Proteína SOS1/genética , Transdução de Sinais/genética
15.
BMJ Case Rep ; 12(6)2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31217210

RESUMO

A 7-year-8-month-old boy with cardiofaciocutaneous syndrome caused by the D638E mutation of the B-Raf proto-oncogene (BRAF) presented with new-onset seizures. He was incidentally found to have advanced Tanner staging on physical examination. Hormonal testing revealed pubertal levels of gonadotropins and sex steroid hormones. On brain imaging, a lack of visualisation of the posterior pituitary bright spot was observed, in addition to mild thinning of the corpus callosum and the lateral gyri of the cerebellar hemispheres. A diagnosis of idiopathic central precocious puberty was made and the patient was started on leuprolide depot treatment. Pituitary hormone testing revealed hyperprolactinemia for which the patient did not receive treatment as he was asymptomatic. During a subsequent hospital admission for seizures, the patient was diagnosed with transient central diabetes insipidus for which he required treatment with a desmopressin infusion.


Assuntos
Diabetes Insípido Neurogênico/tratamento farmacológico , Displasia Ectodérmica/diagnóstico , Insuficiência de Crescimento/diagnóstico , Cardiopatias Congênitas/diagnóstico , Proteínas Proto-Oncogênicas B-raf/genética , Puberdade Precoce/diagnóstico , Convulsões/tratamento farmacológico , Antineoplásicos Hormonais/uso terapêutico , Criança , Desamino Arginina Vasopressina/uso terapêutico , Diabetes Insípido Neurogênico/fisiopatologia , Displasia Ectodérmica/tratamento farmacológico , Displasia Ectodérmica/genética , Displasia Ectodérmica/fisiopatologia , Facies , Insuficiência de Crescimento/tratamento farmacológico , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/fisiopatologia , Cardiopatias Congênitas/tratamento farmacológico , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/fisiopatologia , Hemostáticos/uso terapêutico , Humanos , Leuprolida/uso terapêutico , Masculino , Puberdade Precoce/tratamento farmacológico , Puberdade Precoce/genética , Puberdade Precoce/fisiopatologia , Convulsões/fisiopatologia , Resultado do Tratamento
16.
BMC Med Genet ; 20(1): 98, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164167

RESUMO

BACKGROUND: X-linked Adrenal Hypoplasia Congenita (AHC) is a rare cause of primary adrenal insufficiency due to mutations in the NR0B1 gene, causing a loss of function of the nuclear receptor protein DAX-1. Adrenal insufficiency usually appears in the first 2 months of life, but can sometimes emerge during childhood. Hypogonadotropic Hypogonadism is often associated later in life and patients may develop azoospermia. We describe an unusual onset of AHC started with isolated hypoaldosteronism as first and only sign of the disease. CASE PRESENTATION: A 18-days-old newborn presented with failure to thrive and feeding difficulties. Blood tests showed severe hyponatremia, hyperkalemia and hypochloremia. Renin was found over the measurable range and aldosterone was low whereas cortisol level was normal with a slightly increased ACTH. In the suspicion of Primary Hypoaldosteronism, correction of plasmatic electrolytes and replacement therapy with Fludrocortisone were promptly started. The subsequent evidence of low plasmatic and urinary cortisol and increased ACTH required the start of Hydrocortisone replacement therapy and it defined a clinical picture of adrenal insufficiency. Genetic analysis demonstrated a novel mutation in the DAX-1 gene leading to the diagnosis of AHC. CONCLUSIONS: AHC onset may involve the aldosterone production itself, miming an isolated defect of aldosterone synthesis. NR0B1/DAX-1 mutations should be considered in male infants presenting with isolated hypoaldosteronism as first sign of adrenal insufficiency.


Assuntos
Receptor Nuclear Órfão DAX-1/genética , Hipoadrenocorticismo Familiar/genética , Hipoaldosteronismo/genética , Mutação , Insuficiência Adrenal/etiologia , Insuficiência Adrenal/genética , Insuficiência de Crescimento/etiologia , Insuficiência de Crescimento/genética , Humanos , Hipoadrenocorticismo Familiar/complicações , Hipoaldosteronismo/etiologia , Recém-Nascido , Masculino
17.
Horm Res Paediatr ; 91(4): 223-240, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31195397

RESUMO

Based on a recent Dutch national guideline, we propose a structured stepwise diagnostic approach for children with growth failure (short stature and/or growth faltering), aiming at high sensitivity for pathologic causes at acceptable specificity. The first step is a detailed clinical assessment, aiming at obtaining relevant clinical clues from the medical history (including family history), physical examination (emphasising head circumference, body proportions and dysmorphic features) and assessment of the growth curve. The second step consists of screening: a radiograph of the hand and wrist (for bone age and assessment of anatomical abnormalities suggestive for a skeletal dysplasia) and laboratory tests aiming at detecting disorders that can present as isolated short stature (anaemia, growth hormone deficiency, hypothyroidism, coeliac disease, renal failure, metabolic bone diseases, renal tubular acidosis, inflammatory bowel disease, Turner syndrome [TS]). We advise molecular array analysis rather than conventional karyotyping for short girls because this detects not only TS but also copy number variants and uniparental isodisomy, increasing diagnostic yield at a lower cost. Third, in case of diagnostic clues for primary growth disorders, further specific testing for candidate genes or a hypothesis-free approach is indicated; suspicion of a secondary growth disorder warrants adequate further targeted testing.


Assuntos
Determinação da Idade pelo Esqueleto , Variações do Número de Cópias de DNA , Insuficiência de Crescimento , Hormônio do Crescimento Humano , Cariotipagem , Dissomia Uniparental , Criança , Pré-Escolar , Insuficiência de Crescimento/sangue , Insuficiência de Crescimento/diagnóstico , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/patologia , Feminino , Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/deficiência , Humanos , Masculino
18.
Acta Derm Venereol ; 99(9): 789-796, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31037311

RESUMO

Desmoplakin (DSP) and Desmoglein 1 (DSG1) variants result in skin barrier defects leading to erythroderma, palmoplantar keratoderma and variable [AQ4] other features. Some DSG1 variant carriers present with SAM syndrome (Severe dermatitis, multiple Allergies, Metabolic wasting) and a SAM-like phenotype has been reported in 4 subjects with different heterozygous DSP variants. We report here a patient with a novel DSP spectrin region (SR) 6 variant c.1756C>T, p.(His586Tyr), novel features of brain lesions and severe recurrent mucocutaneous herpes simplex virus infections, with a favourable response to ustekinumab. Through a review of reported cases of heterozygous variants in DSP SR6 (n = 15) and homozygous or compound heterozygous variants in DSG1 (n = 12) and SAM-like phenotype, we highlight phenotypic variability. Woolly hair, nail abnormalities and cardiomyopathy characterize patients with DSP variants, while elevated immunoglobulin E and food allergies are frequent in patients with DSG1 variants. Clinicians should be aware of the diverse manifestations of desmosomopathies.


Assuntos
Encefalopatias/genética , Dermatite Esfoliativa/genética , Desmoplaquinas/genética , Insuficiência de Crescimento/genética , Variação Genética , Herpes Simples/genética , Ictiose/genética , Encefalopatias/diagnóstico por imagem , Pré-Escolar , Dermatite Esfoliativa/diagnóstico , Dermatite Esfoliativa/tratamento farmacológico , Fármacos Dermatológicos/uso terapêutico , Insuficiência de Crescimento/diagnóstico , Predisposição Genética para Doença , Herpes Simples/diagnóstico , Herpes Simples/virologia , Humanos , Ictiose/diagnóstico , Ictiose/tratamento farmacológico , Lactente , Recém-Nascido , Masculino , Fenótipo , Índice de Gravidade de Doença , Resultado do Tratamento , Ustekinumab/uso terapêutico
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