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1.
Nat Rev Endocrinol ; 15(5): 299-311, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30842651

RESUMO

Overgrowth syndromes are a heterogeneous group of rare disorders characterized by generalized or segmental excessive growth commonly associated with additional features, such as visceromegaly, macrocephaly and a large range of various symptoms. These syndromes are caused by either genetic or epigenetic anomalies affecting factors involved in cell proliferation and/or the regulation of epigenetic markers. Some of these conditions are associated with neurological anomalies, such as cognitive impairment or autism. Overgrowth syndromes are frequently associated with an increased risk of cancer (embryonic tumours during infancy or carcinomas during adulthood), but with a highly variable prevalence. Given this risk, syndrome-specific tumour screening protocols have recently been established for some of these conditions. Certain specific clinical traits make it possible to discriminate between different syndromes and orient molecular explorations to determine which molecular tests to conduct, despite the syndromes having overlapping clinical features. Recent advances in molecular techniques using next-generation sequencing approaches have increased the number of patients with an identified molecular defect (especially patients with segmental overgrowth). This Review discusses the clinical and molecular diagnosis, tumour risk and recommendations for tumour screening for the most prevalent generalized and segmental overgrowth syndromes.


Assuntos
Neoplasias/epidemiologia , Neoplasias/genética , Arritmias Cardíacas/epidemiologia , Arritmias Cardíacas/genética , Arritmias Cardíacas/patologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/epidemiologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Gigantismo/epidemiologia , Gigantismo/genética , Gigantismo/patologia , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Humanos , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Megalencefalia/epidemiologia , Megalencefalia/genética , Megalencefalia/patologia , Neoplasias/patologia , Gravidez , Fatores de Risco , Síndrome de Sotos/epidemiologia , Síndrome de Sotos/genética , Síndrome de Sotos/patologia , Síndrome
2.
PLoS Genet ; 15(1): e1007879, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30653500

RESUMO

Variably expressive copy-number variants (CNVs) are characterized by extensive phenotypic heterogeneity of neuropsychiatric phenotypes. Approaches to identify single causative genes for these phenotypes within each CNV have not been successful. Here, we posit using multiple lines of evidence, including pathogenicity metrics, functional assays of model organisms, and gene expression data, that multiple genes within each CNV region are likely responsible for the observed phenotypes. We propose that candidate genes within each region likely interact with each other through shared pathways to modulate the individual gene phenotypes, emphasizing the genetic complexity of CNV-associated neuropsychiatric features.


Assuntos
Variações do Número de Cópias de DNA/genética , Estudos de Associação Genética , Heterogeneidade Genética , Predisposição Genética para Doença , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/fisiopatologia , Duplicação Cromossômica/genética , Regulação da Expressão Gênica , Humanos , Fenótipo , Síndrome de Smith-Magenis/genética , Síndrome de Smith-Magenis/fisiopatologia , Síndrome de Sotos/genética , Síndrome de Sotos/fisiopatologia , Síndrome de Williams/genética , Síndrome de Williams/fisiopatologia
3.
Medicine (Baltimore) ; 97(47): e12867, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30461603

RESUMO

RATIONALE: Sotos syndrome is a rare genetic disorder characterized by rapid growth during infancy and childhood; ≥2 SD for height and head circumference; distinctive facial appearance and developmental delay.Ten clinically diagnosed cases have been reported from Saudi Arabia; none of them was genetically confirmed. PATIENT CONCERNS: A male Saudi patient, who had a birth length and head circumference above 97th centile, presented with abnormal rapid growth, delayed motor and mental milestones, aggressive behavior, obsession to close doors, nail biting, defective attention, and hyperactivity. DIAGNOSES: Sotos syndrome was suspected INTERVENTIONS:: Molecular genetic analysis for NSD1 gene was carried for the patient. OUTCOMES: A novel heterozygous deletion of all exons 1 to 23 of the NSD1 gene was detected. Genetic counseling was carried for the family with extended genetic testing for the parents and his siblings with normal results. LESSONS: Despite its worldwide distribution, Sotos syndrome may be under-reported. Besides its characteristic clinical picture, molecular genetic testing is also extremely recommended.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Nucleares/genética , Síndrome de Sotos/diagnóstico , Síndrome de Sotos/genética , Pré-Escolar , Humanos , Masculino , Mutação , Arábia Saudita
4.
Clin Cancer Res ; 23(12): e83-e90, 2017 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-28620009

RESUMO

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.


Assuntos
Anormalidades Múltiplas/epidemiologia , Hipotireoidismo Congênito/epidemiologia , Anormalidades Craniofaciais/epidemiologia , Deformidades Congênitas da Mão/epidemiologia , Deficiência Intelectual/epidemiologia , Unhas Malformadas/epidemiologia , Síndrome de Rubinstein-Taybi/epidemiologia , Síndrome de Sotos/epidemiologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Hipotireoidismo Congênito/genética , Hipotireoidismo Congênito/patologia , Síndrome de Costello/epidemiologia , Síndrome de Costello/genética , Síndrome de Costello/patologia , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia , Deformidades Congênitas da Mão/genética , Deformidades Congênitas da Mão/patologia , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Mutação , Unhas Malformadas/genética , Unhas Malformadas/patologia , Síndromes Neoplásicas Hereditárias/epidemiologia , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologia , Síndrome de Noonan/epidemiologia , Síndrome de Noonan/genética , Síndrome de Noonan/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Fatores de Risco , Síndrome de Rubinstein-Taybi/genética , Síndrome de Rubinstein-Taybi/patologia , Síndrome de Sotos/genética , Síndrome de Sotos/patologia , Fator Nuclear 1 de Tireoide/genética
5.
Clin Chim Acta ; 470: 31-35, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28457852

RESUMO

INTRODUCTION: Sotos syndrome is a congenital overgrowth disorder characterized by facial gestalt, excessively rapid growth, acromegalic features and a non-progressive cerebral disorder with intellectual disability. METHODOLOGY: The identical male twins showed somewhat different clinical, cognitive and behavioural phenotypes. Abnormal clinical manifestations including seizures, scoliosis, enlarged ventricles, and attention-deficit/hyperactivity disorder (ADHD) were found in the proband (first twin), but not in the sibling (second twin). We used diagnostic exome sequencing (DES) to identify a heterozygous de novo mutation of the NSD1 gene in monozygotic twins with Sotos syndrome. RESULTS: DES revealed a novel nonsense mutation c.2596G>T (p.Glu866*) of the NSD1 gene in the proband, the first of monozygotic twins. Sanger sequencing analysis of the proband and his family members showed that this nonsense mutation was present in the proband and his sibling, but was absent in their parents, indicating that it occurred with de novo origin. CONCLUSION: This finding expands the phenotypic spectrum associated with variable expression of the Sotos syndrome caused by NSD1 mutation, and it adds further support for postconceptual mutation, epigenetic change and/or an environmental factor involved in the cause of the Sotos syndrome.


Assuntos
Códon sem Sentido , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Nucleares/genética , Síndrome de Sotos/genética , Gêmeos Monozigóticos/genética , Encéfalo/diagnóstico por imagem , Criança , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Linhagem , Fenótipo , Síndrome de Sotos/diagnóstico por imagem
6.
Pediatr Res ; 82(1): 87-92, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28399120

RESUMO

BackgroundSotos syndrome (SoS) is an overgrowth disorder with various congenital anomalies and is usually accompanied by other clinical problems. However, anorectal malformations have not been documented as part of the SoS entity. Our objective is to report on a case of SoS associated with Hirschsprung's disease (HSCR) and subsequent genetic analysis.MethodsA 2-year-old boy with SoS experienced constipation since infancy and ultimately showed an aganglionic segment in the histopathologic examination, which was followed by exome-sequencing analysis.ResultsIn the genetic test for SoS diagnosis, two novel mutations of NDS1, c.2465C>A (p.Ser822Tyr) and c.4347T>A (p.Cys1449*), were observed and verified by resequencing in the patient and his parents. In further whole-exome-sequencing analysis using the patient's blood DNA, which was followed by a comparison analysis with the results of our previously reported genome-wide association study (GWAS) of HSCR, three genes (ZNF827, FGD2, and KCNJ12) with significance for HSCR from our previous GWAS were overlapped among the genes showing variants in the exome sequencing.ConclusionThis is the first reported patient with SoS and HSCR. Further studies are required to determine whether there is a genetic relationship between SoS and HSCR.


Assuntos
Doença de Hirschsprung/genética , Síndrome de Sotos/genética , Pré-Escolar , DNA/sangue , Exoma , Feminino , Testes Genéticos , Estudo de Associação Genômica Ampla , Doença de Hirschsprung/complicações , Humanos , Masculino , Mutação , Linhagem , Análise de Sequência de DNA , Síndrome de Sotos/complicações
8.
Eur J Endocrinol ; 176(6): R339-R353, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28274950

RESUMO

Tall stature is defined as a height of more than 2 standard deviations (s.d.) above average for same sex and age. Tall individuals are usually referred to endocrinologists so that hormonal disorders leading to abnormal growth are excluded. However, the majority of these patients have familial tall stature or constitutional advance of growth (generally associated with obesity), both of which are diagnoses of exclusion. It is necessary to have familiarity with a large number of rarer overgrowth syndromes, especially because some of them may have severe complications such as aortic aneurysm, thromboembolism and tumor predisposition and demand-specific follow-up approaches. Additionally, endocrine disorders associated with tall stature have specific treatments and for this reason their recognition is mandatory. With this review, we intend to provide an up-to-date summary of the genetic conditions associated with overgrowth to emphasize a practical diagnostic approach of patients with tall stature and to discuss the limitations of current growth interruption treatment options.


Assuntos
Estatura , Transtornos do Crescimento/diagnóstico , Acromegalia/diagnóstico , Acromegalia/metabolismo , Acromegalia/terapia , Síndrome de Beckwith-Wiedemann/complicações , Síndrome de Beckwith-Wiedemann/diagnóstico , Cromossomos Humanos X/genética , Gerenciamento Clínico , Síndrome do Cromossomo X Frágil/complicações , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/genética , Transtornos do Crescimento/terapia , Lâmina de Crescimento/cirurgia , Homocistinúria/complicações , Homocistinúria/diagnóstico , Homocistinúria/genética , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Síndrome de Klinefelter/diagnóstico , Síndrome de Klinefelter/genética , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Obesidade/complicações , Aberrações dos Cromossomos Sexuais , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/diagnóstico , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/genética , Síndrome de Sotos/complicações , Síndrome de Sotos/diagnóstico , Síndrome de Sotos/genética , Tireotoxicose/complicações , Trissomia/diagnóstico , Trissomia/genética
10.
Artigo em Inglês | MEDLINE | ID: mdl-26927468

RESUMO

BACKGROUND AND AIM: Sotos syndrome 2 (MIM #614753), known also as Malan syndrome, is caused by heterozygous mutations/deletions of the NFIX gene located on chromosome 19p13.2. It manifests in developmental delay, intellectual impairment, macrocephaly, central nervous system anomalies, postnatal overgrowth, and craniofacial dysmorphism. Unusual behavior with/without autistic traits, ophthalmologic, gastrointestinal, musculo-skeletal, and hand/foot abnormalities are also frequent. Due to the limited number of such cases, no definitive conclusions about genotype-phenotype correlations have been possible. In the following paper, we discuss physical features consistent with Sotos syndrome 2 based on literature review and two new cases [a patient with de novo 19p13.2 deletion encompassing a part of the NFIX gene and a patient with de novo (not described so far) heterozygous missense mutation c.367C>T (p.Arg123Trp) in the NFIX gene]. RESULTS: Apart from overgrowth and psychomotor developmental delay, the most consistent physical features of our two patients are dysmorphism including high forehead, downslanting palpebral fissures, pointed chin, and abnormalities of the pinna. Both show abnormal behavior and present with long, tapered fingers and toenail defect. No severe congenital malformations were noted. CONCLUSIONS: We hope these data will serve as a material for further studies and provide an opportunity to make more reliable genotype-phenotype correlations.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 19/genética , Fatores de Transcrição NFI/genética , Síndrome de Sotos/genética , Criança , Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Feminino , Heterozigoto , Humanos , Mutação de Sentido Incorreto/genética , Fenótipo
11.
Nucleic Acids Res ; 44(7): 3448-63, 2016 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-26896805

RESUMO

Sotos syndrome is an overgrowth syndrome caused by mutations within the functional domains ofNSD1 gene coding for NSD1, a multidomain protein regulating chromatin structure and gene expression. In particular, PHDVC5HCHNSD1 tandem domain, composed by a classical (PHDV) and an atypical (C5HCH) plant homeo-domain (PHD) finger, is target of several pathological missense-mutations. PHDVC5HCHNSD1 is also crucial for NSD1-dependent transcriptional regulation and interacts with the C2HR domain of transcriptional repressor Nizp1 (C2HRNizp1)in vitro To get molecular insights into the mechanisms dictating the patho-physiological relevance of the PHD finger tandem domain, we solved its solution structure and provided a structural rationale for the effects of seven Sotos syndrome point-mutations. To investigate PHDVC5HCHNSD1 role as structural platform for multiple interactions, we characterized its binding to histone H3 peptides and to C2HRNizp1 by ITC and NMR. We observed only very weak electrostatic interactions with histone H3 N-terminal tails, conversely we proved specific binding to C2HRNizp1 We solved C2HRNizp1 solution structure and generated a 3D model of the complex, corroborated by site-directed mutagenesis. We suggest a mechanistic scenario where NSD1 interactions with cofactors such as Nizp1 are impaired by PHDVC5HCHNSD1 pathological mutations, thus impacting on the repression of growth-promoting genes, leading to overgrowth conditions.


Assuntos
Proteínas de Transporte/química , Proteínas de Transporte/genética , Proteínas Nucleares/química , Proteínas Nucleares/genética , Síndrome de Sotos/genética , Animais , Sítios de Ligação , Proteínas de Transporte/metabolismo , Histonas/metabolismo , Humanos , Camundongos , Modelos Moleculares , Proteínas Nucleares/metabolismo , Mutação Puntual , Estrutura Terciária de Proteína
12.
Am J Med Genet A ; 170A(4): 1064-9, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26738611

RESUMO

Sotos syndrome is a childhood overgrowth syndrome characterized clinically by a distinctive facial gestalt, advanced bone age, childhood overgrowth, and non-progressive developmental delay; and genetically by haploinsufficiency of the Nuclear receptor binding SET Domain 1 (NSD1) gene. Generalized lymphedema has not previously been associated with Sotos syndrome. Generalized lymphedema has been associated with mutations in several genes including FLT4. This gene is involved in the regulation of VEGFR3, a key governor of lymphatic-endothelial cell development and function. We report on a 28-year-old Caucasian female with a de novo NSD1 intragenic mutation, c.5841_5848dup: p.Leu1950Serfs*22, who presented with characteristic clinical features of Sotos syndrome. Unusually this case includes atypical features of intrauterine growth retardation and post-pubertal onset of primary lymphedema. To our knowledge, no link between Sotos syndrome and generalized lymphedema has previously been described in the literature. We propose a mechanism by which disruptions in NSD1 gene may lead to generalized lymphedema. Aberrations of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)-signaling pathway has been identified in both Sotos syndrome and lymphedema. This finding extends the known phenotype of Sotos syndrome through the inclusion of lymphedema. This case also indicates that presence of low birth weight does not exclude the possibility of Sotos syndrome.


Assuntos
Fenótipo , Síndrome de Sotos/diagnóstico , Adulto , Hibridização Genômica Comparativa , Facies , Feminino , Retardo do Crescimento Fetal , Humanos , Cariotipagem , Linfedema , Síndrome de Sotos/genética , Tremor
14.
Rev Chil Pediatr ; 87(4): 288-92, 2016 Jul-Aug.
Artigo em Espanhol | MEDLINE | ID: mdl-26692474

RESUMO

UNLABELLED: Sotos Syndrome (SS) is a genetic disease with an autosomal dominant pattern caused by haplo-insufficiency of NSD1 gene secondary to point mutations or microdeletion of the 5q35 locus where the gene is located. It is a rare syndrome, occurring in 7 out of every 100,000 births. The objective of this report is to present the case of a 4 year-old patient with a global developmental delay, as well as specific physical findings suggesting a syndrome of genetic origin. CLINICAL CASE: Female patient, 4 years of age, thinning hair, triangular facie, long palpebral fissure, arched palate, prominent jaw, winged scapula and clinodactilia of the fifth finger both hands. The molecular test comparative genomic hybridisation test by microarray was subsequently performed, with the result showing 5q35.2 q35.3 region microdeletion of 2,082 MB, including the NSD1 gene. CONCLUSION: Finally, this article also proposes the performing of comparative genomic hybridisation as the first diagnostic option in cases where clinical findings are suggestive of SS.


Assuntos
Hibridização Genômica Comparativa/métodos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Nucleares/genética , Síndrome de Sotos/diagnóstico , Pré-Escolar , Deleção Cromossômica , Feminino , Humanos , Síndrome de Sotos/genética , Síndrome de Sotos/fisiopatologia
15.
Nat Commun ; 6: 10207, 2015 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-26690673

RESUMO

Sotos syndrome (SS) represents an important human model system for the study of epigenetic regulation; it is an overgrowth/intellectual disability syndrome caused by mutations in a histone methyltransferase, NSD1. As layered epigenetic modifications are often interdependent, we propose that pathogenic NSD1 mutations have a genome-wide impact on the most stable epigenetic mark, DNA methylation (DNAm). By interrogating DNAm in SS patients, we identify a genome-wide, highly significant NSD1(+/-)-specific signature that differentiates pathogenic NSD1 mutations from controls, benign NSD1 variants and the clinically overlapping Weaver syndrome. Validation studies of independent cohorts of SS and controls assigned 100% of these samples correctly. This highly specific and sensitive NSD1(+/-) signature encompasses genes that function in cellular morphogenesis and neuronal differentiation, reflecting cardinal features of the SS phenotype. The identification of SS-specific genome-wide DNAm alterations will facilitate both the elucidation of the molecular pathophysiology of SS and the development of improved diagnostic testing.


Assuntos
Metilação de DNA/genética , Genoma Humano , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Nucleares/metabolismo , Síndrome de Sotos/genética , Regulação da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação , Proteínas Nucleares/genética
16.
Pediatr Res ; 78(5): 533-9, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26200704

RESUMO

BACKGROUND: Only 15 point mutations in NFIX gene have been reported so far, nine of them cause the Marshall-Smith syndrome (MSS) and the remaining mutations lead to an overgrowth disorder with a less severe phenotype, defined as Sotos-like. METHODS: The clinical findings in three patients with MSS and two patients with a Sotos-like phenotype are presented. Analysis of the NFIX gene was performed both by conventional or next-generation sequencing. RESULTS: Five de novo mutations in NFIX gene were identified, four of them not previously reported. Two frameshift mutations and a donor-splice one caused MSS, while two missense mutations in the DNA binding/dimerisation domain entailed an overgrowth syndrome with some clinical features resembling Sotos syndrome, accompanied by a marfanoid habitus, very low BMI, long narrow face, or arachnodactyly. CONCLUSION: Marshall-Smith mutations are scattered through exons 6-10 of NFIX gene, while most point mutations causing an overgrowth syndrome are clustered in exon 2. Clinical features of this overgrowth syndrome may well be considered an intermediate phenotype between Sotos and Marfan syndromes.


Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Anormalidades Craniofaciais/genética , Mutação , Fatores de Transcrição NFI/genética , Displasia Septo-Óptica/genética , Síndrome de Sotos/genética , Anormalidades Múltiplas/diagnóstico , Sequência de Aminoácidos , Sequência de Bases , Doenças do Desenvolvimento Ósseo/diagnóstico , Criança , Pré-Escolar , Anormalidades Craniofaciais/diagnóstico , Análise Mutacional de DNA/métodos , Éxons , Evolução Fatal , Feminino , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Masculino , Dados de Sequência Molecular , Fenótipo , Displasia Septo-Óptica/diagnóstico , Síndrome de Sotos/diagnóstico , Adulto Jovem
17.
Eur J Med Genet ; 58(9): 488-91, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26193383

RESUMO

The Nuclear Factor I-X (NFIX) is a member of the nuclear factor I (NFI) protein family and is deleted or mutated in a subset of patients with a peculiar overgrowth condition resembling Sotos Syndrome as well as in patients with Marshall-Smith syndrome. We identified three additional patients with this phenotype each carrying a different new mutation affecting the DNA-binding/dimerization domain of the NFIX protein. The present report further adds weight to the hypothesis that mutations in DNA-binding/dimerization domain are likely to cause haploinsufficiency of the NFIX protein and confirms that NFIX is the second gene that should be tested in individuals with overgrowth conditions resembling Sotos syndrome, previously tested negative for NSD1 mutations. We then propose to consider this overgrowth syndrome (namely Malan syndrome) and Marshall-Smith syndrome NFIX-related diseases.


Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Anormalidades Craniofaciais/genética , Proteínas de Ligação a DNA/genética , Fatores de Transcrição NFI/genética , Displasia Septo-Óptica/genética , Síndrome de Sotos/genética , Anormalidades Múltiplas/diagnóstico , Doenças do Desenvolvimento Ósseo/diagnóstico , Criança , Anormalidades Craniofaciais/diagnóstico , Proteínas de Ligação a DNA/metabolismo , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Feminino , Testes Genéticos , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Mutação de Sentido Incorreto , Fatores de Transcrição NFI/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fenótipo , Displasia Septo-Óptica/diagnóstico , Síndrome de Sotos/diagnóstico
18.
Genet Couns ; 26(1): 1-12, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26043501

RESUMO

Sotos syndrome is a well-known overgrowth syndrome characterized by excessive growth during childhood, macrocephaly, distinctive facial appearance and learning disability. This disorder is caused by mutations or deletions in NSD1 gene. The aim of this study is to examine the relationship between the neuroimaging and clinical features of children with Sotos syndrome. Six Turkish children with Sotos syndrome were followed up about 3-7 years. The diagnosis was confirmed with molecular genetic analysis. We identified the pathogenic NSD1 mutation including three novel in all patients. All the patients had a characteristic facial gestalt of Sotos syndrome consisting of triangular face with prominent forehead, frontoparietal sparseness of hair and small nose. However, the degree of psychomotor and intellectual development was variable. Severe learning defect and speech delay were remarkable in two patients. The neuroimaging analysis showed abnormalities in four of six patients including bilateral large ventricles, thinning of the corpus callosum and persistent cavum septum pellucidum et vergae. Typical craniofacial appearance is the primary finding for the diagnosis of the disease even in the infantile period. However, the degree of psychomotor and intellectual development is very variable and does not correlate with the neuroimaging findings.


Assuntos
Anormalidades Craniofaciais/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Nucleares/genética , Síndrome de Sotos , Criança , Pré-Escolar , Anormalidades Craniofaciais/patologia , Feminino , Seguimentos , Humanos , Masculino , Síndrome de Sotos/genética , Síndrome de Sotos/patologia , Síndrome de Sotos/fisiopatologia , Turquia
19.
Ann Clin Lab Sci ; 45(2): 215-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25887879

RESUMO

Sotos syndrome is a common genetic overgrowth syndrome caused by a mutation of the NSD1 gene, which is located at chromosome 5q35 and normally encodes a histone methyltransferase protein. The general characteristics of this syndrome include a characteristic facial appearance, developmental delay, and overgrowth, resulting in macrocephaly and tall stature. We describe rhabdomyolysis and hypocalcemia due to hypoparathyroidism in a 3-year-old Korean boy with Sotos syndrome. He was diagnosed with Sotos syndrome based on the typical phenotype and has a heterozygous nonsense mutation (c.4710C>A [p.Cys1570*]) of the NSD1 gene, which causes a premature stop codon and a truncating protein mutation. Hypoparathyroidism has never been described in Sotos syndrome. This report may therefore expand the phenotypic spectrum of this syndrome.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Hipoparatireoidismo/complicações , Hipoparatireoidismo/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação/genética , Proteínas Nucleares/genética , Síndrome de Sotos/complicações , Síndrome de Sotos/genética , Pré-Escolar , Análise Mutacional de DNA , Humanos , Masculino
20.
Am J Med Genet A ; 167A(5): 1171-4, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25712828

RESUMO

Sotos syndrome (SoS, OMIM #117550) is an overgrowth syndrome. Deletions or intragenic mutations of the NSD1 , which is located at chromosome 5q35, are responsible for more than 75% of SoS. Conventionally, neonatal hypoglycemia was reported briefly as one of the infrequent symptoms of SoS. However, Matsuo et al. published a report describing five patients with SoS who presented with transient hyperinsulinemic hypoglycemia (HIH) in the neonatal period. We report on an additional patient of SoS, who presented transient HIH in the neonatal period. All of this patient and previous patients have microdeletions at the 5q35 chromosome. Therefore, we examined the following three in considering the possibility that other factor than NSD1 caused HIH. 1) This patient had no mutation of four currently known HIH related genes, ABCC8, KCNJ11, GLUD1, and GCK. 2) He had no further deletion than commonly observed region encompassing NSD1 by comparative genomic hybridization to DNA microarrays. 3) He had no mutation in the 5q35 region in the non-deleted chromosome using exsome sequence analysis. In conclusion, our patient supported that HIH could be one of the characteristic symptoms of SoS in the neonatal period, and could be useful for early diagnosis.


Assuntos
Hiperinsulinismo Congênito/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Nucleares/genética , Síndrome de Sotos/genética , Criança , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Hibridização Genômica Comparativa , Hiperinsulinismo Congênito/complicações , Hiperinsulinismo Congênito/fisiopatologia , Humanos , Masculino , Mutação , Síndrome de Sotos/complicações , Síndrome de Sotos/fisiopatologia
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