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1.
J Med Genet ; 56(10): 701-710, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31451536

RESUMO

BACKGROUND: The 15q11.2 deletion is frequently identified in the neurodevelopmental clinic. Case-control studies have associated the 15q11.2 deletion with neurodevelopmental disorders, and clinical case series have attempted to delineate a microdeletion syndrome with considerable phenotypic variability. The literature on this deletion is extensive and confusing, which is a challenge for genetic counselling. The aim of this study was to estimate the effect size of the 15q11.2 deletion and quantify its contribution to neurodevelopmental disorders. METHODS: We performed meta-analyses on new and previously published case-control studies and used statistical models trained in unselected populations with cognitive assessments. We used new (n=241) and previously published (n=150) data from a clinically referred group of deletion carriers. 15q11.2 duplications (new n=179 and previously published n=35) were used as a neutral control variant. RESULTS: The deletion decreases IQ by 4.3 points. The estimated ORs and respective frequencies in deletion carriers for intellectual disabilities, schizophrenia and epilepsy are 1.7 (3.4%), 1.5 (2%) and 3.1 (2.1%), respectively. There is no increased risk for heart malformations and autism. In the clinically referred group, the frequency and nature of symptoms in deletions are not different from those observed in carriers of the 15q11.2 duplication suggesting that most of the reported symptoms are due to ascertainment bias. CONCLUSIONS: We recommend that the deletion should be classified as 'pathogenic of mild effect size'. Since it explains only a small proportion of the phenotypic variance in carriers, it is not worth discussing in the developmental clinic or in a prenatal setting.

2.
Am J Hum Genet ; 103(2): 305-316, 2018 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-30057029

RESUMO

Next-generation sequencing combined with international data sharing has enormously facilitated identification of new disease-associated genes and mutations. This is particularly true for genetically extremely heterogeneous entities such as neurodevelopmental disorders (NDDs). Through exome sequencing and world-wide collaborations, we identified and assembled 20 individuals with de novo variants in FBXO11. They present with mild to severe developmental delay associated with a range of features including short (4/20) or tall (2/20) stature, obesity (5/20), microcephaly (4/19) or macrocephaly (2/19), behavioral problems (17/20), seizures (5/20), cleft lip or palate or bifid uvula (3/20), and minor skeletal anomalies. FBXO11 encodes a member of the F-Box protein family, constituting a subunit of an E3-ubiquitin ligase complex. This complex is involved in ubiquitination and proteasomal degradation and thus in controlling critical biological processes by regulating protein turnover. The identified de novo aberrations comprise two large deletions, ten likely gene disrupting variants, and eight missense variants distributed throughout FBXO11. Structural modeling for missense variants located in the CASH or the Zinc-finger UBR domains suggests destabilization of the protein. This, in combination with the observed spectrum and localization of identified variants and the lack of apparent genotype-phenotype correlations, is compatible with loss of function or haploinsufficiency as an underlying mechanism. We implicate de novo missense and likely gene disrupting variants in FBXO11 in a neurodevelopmental disorder with variable intellectual disability and various other features.

3.
Int J Pediatr Otorhinolaryngol ; 108: 208-212, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29605356

RESUMO

OBJECTIVE: Evaluation of clinical findings and audiological outcome after surgery in a Danish family with autosomal dominant facio-audio-symphalangism syndrome with stapes fixation, syndactyly and symphalangism. METHODS: Retrospective report on eight affected family members in a Danish family. Clinical investigation included X-ray, audiology and in one case video-recorded surgery. Main outcome measure was audiologic results after stapedectomy. Sanger DNA sequencing of NOG was performed on peripheral blood. RESULTS: Audiologic analysis showed that seven of eight affected family members had bilateral conductive hearing loss. Three patients were treated with stapedectomy, on one or both ears, due to fixation of stapes. All the affected members had syndactyly and symphalangism. A not previously reported mutation in the NOG gene (c.688_699del, p.Cys230_Cys232delins11) was found to segregate with the stapes fixation, syndactyly, and symphalangism. p.Cys230_Cysdelins11 was classified as likely pathogenic according to guidelines from the American College of Medical Genetics and Genomics. CONCLUSION: The clinical presentation of the reported mutation corresponds with previous case reports of families with NOG mutation. In this family, surgery with stapedectomy had lasting effect without renewed fixation of the stapes in a follow up period of 18 months-38 years.


Assuntos
Ossos do Carpo/anormalidades , Proteínas de Transporte/genética , Deformidades Congênitas do Pé/cirurgia , Deformidades Congênitas da Mão/cirurgia , Perda Auditiva Condutiva/cirurgia , Cirurgia do Estribo/métodos , Estribo/anormalidades , Sinostose/cirurgia , Ossos do Tarso/anormalidades , Adolescente , Adulto , Idoso , Ossos do Carpo/cirurgia , Dinamarca , Feminino , Seguimentos , Deformidades Congênitas do Pé/genética , Deformidades Congênitas da Mão/genética , Perda Auditiva Condutiva/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prótese Ossicular/efeitos adversos , Linhagem , Fenótipo , Estudos Retrospectivos , Cirurgia do Estribo/efeitos adversos , Sindactilia/genética , Sinostose/genética , Ossos do Tarso/cirurgia , Resultado do Tratamento
4.
Orphanet J Rare Dis ; 13(1): 39, 2018 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-29506540

RESUMO

BACKGROUND: Pigmentary mosaicism is a term that describes varied patterns of pigmentation in the skin caused by genetic heterogeneity of the skin cells. In a substantial number of cases, pigmentary mosaicism is observed alongside extracutaneous abnormalities typically involving the central nervous system and the musculoskeletal system. We have compiled information on previous cases of pigmentary mosaicism aiming to optimize the handling of patients with this condition. Our study is based on a database search in PubMed containing papers written in English, published between January 1985 and April 2017. The search yielded 174 relevant and original articles, detailing a total number of 651 patients. RESULTS: Forty-three percent of the patients exhibited hyperpigmentation, 50% exhibited hypopigmentation, and 7% exhibited a combination of hyperpigmentation and hypopigmentation. Fifty-six percent exhibited extracutaneous manifestations. The presence of extracutaneous manifestations in each subgroup varied: 32% in patients with hyperpigmentation, 73% in patients with hypopigmentation, and 83% in patients with combined hyperpigmentation and hypopigmentation. Cytogenetic analyses were performed in 40% of the patients: peripheral blood lymphocytes were analysed in 48%, skin fibroblasts in 5%, and both analyses were performed in 40%. In the remaining 7% the analysed cell type was not specified. Forty-two percent of the tested patients exhibited an abnormal karyotype; 84% of those presented a mosaic state and 16% presented a non-mosaic structural or numerical abnormality. In patients with extracutaneous manifestations, 43% of the cytogenetically tested patients exhibited an abnormal karyotype. In patients without extracutaneous manifestations, 32% of the cytogenetically tested patients exhibited an abnormal karyotype. CONCLUSION: We recommend a uniform parlance when describing the clinical picture of pigmentary mosaicism. Based on the results found in this review, we recommend that patients with pigmentary mosaicism undergo physical examination, highlighting with Wood's light, and karyotyping from peripheral blood lymphocytes and skin fibroblasts. It is important that both patients with and without extracutaneous manifestations are tested cytogenetically, as the frequency of abnormal karyotype in the two groups seems comparable. According to the results only a minor part of patients, especially those without extracutaneous manifestations, are tested today reflecting a need for change in clinical practice.

5.
Mol Genet Genomic Med ; 6(1): 121-125, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29243366

RESUMO

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder caused by mutations in ENG, ACVRL1, or SMAD4. Around 90% of HHT patients present with a heterozygous pathogenic genetic variation. Almost all cases of HHT have a family history. Very few cases are de novo or mosaicism. We describe a case with mutational mosaicism that would not be observed in the clinical routine when using Sanger sequencing or a NGS read coverage below app. 100. METHODS: DNA was extracted from peripheral blood leukocytes, and buccal swabs. The coding region, exon-intron boundaries, and the flanking sequences of the genes were sequenced by NGS. RESULTS: The proband had clinical HHT fulfilling the Curaçao criteria and genetic testing identified a frameshift mutation in ENG. The mother of the proband, also with clinical HHT, was found negative when analyzing DNA from blood for the familial mutation using Sanger sequencing. Analyzing her DNA by NGS HHT panel sequencing when extracted from both peripheral blood leukocytes, and cheek swabs, identified the familial ENG mutation at low levels. CONCLUSION: We provide evidence of ENG mutational mosaicism in an individual presenting with clinical HHT. These findings illustrate the importance of considering mutational mosaicism.


Assuntos
Endoglina/genética , Telangiectasia Hemorrágica Hereditária/genética , Receptores de Activinas Tipo II/genética , Adulto , Idoso , Sequência de Bases , Endoglina/fisiologia , Éxons , Feminino , Mutação da Fase de Leitura , Testes Genéticos , Humanos , Mosaicismo , Mutação , Linhagem , Proteína Smad4/genética , Telangiectasia Hemorrágica Hereditária/fisiopatologia
6.
Am J Hum Genet ; 101(6): 1013-1020, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29220673

RESUMO

Using trio whole-exome sequencing, we have identified de novo heterozygous pathogenic variants in GRIA4 in five unrelated individuals with intellectual disability and other symptoms. GRIA4 encodes an AMPA receptor subunit known as GluR4, which is found on excitatory glutamatergic synapses and is important for learning and memory. Four of the variants are located in the highly conserved SYTANLAAF motif in the transmembrane protein M3, and the fifth is in an extra-cellular domain. Molecular modeling of the altered protein showed that three of the variants in the SYTANLAAF motif orient toward the center of the pore region and most likely lead to disturbance of the gating mechanism. The fourth variant in the SYTANLAAF motif most likely results in reduced permeability. The variant in the extracellular domain potentially interferes with the binding between the monomers. On the basis of clinical information and genetic results, and the fact that other subunits of the AMPA receptor have already been associated with neurodevelopmental disorders, we suggest that pathogenic de novo variants in GRIA4 lead to intellectual disability with or without seizures, gait abnormalities, problems of social behavior, and other variable features.


Assuntos
Transtornos Neurológicos da Marcha/genética , Deficiência Intelectual/genética , Transtornos dos Movimentos/genética , Receptores de AMPA/genética , Convulsões/genética , Adolescente , Adulto , Pré-Escolar , Feminino , Humanos , Masculino , Modelos Moleculares , Comportamento Problema , Comportamento Social , Sequenciamento Completo do Exoma , Adulto Jovem
7.
Eur J Med Genet ; 60(2): 110-113, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27866049

RESUMO

Pathogenic germline mutations in ELN can be detected in patients with supravalvular aortic stenosis. The mutation might occur de novo or be inherited following an autosomal dominant pattern of inheritance. In this report we describe a three-generation family suffering from supravalvular aortic stenosis, various other arterial stenoses, sudden death, and intracranial aneurysms. A frameshift mutation in exon 12, not described before, was detected in the affected family members. This report emphasises the importance of family history, genetic counselling, and demonstrates the great variability in the phenotype within a single SVAS family.


Assuntos
Estenose Aórtica Supravalvular/genética , Elastina/genética , Aneurisma Intracraniano/genética , Adulto , Estenose Aórtica Supravalvular/fisiopatologia , Éxons/genética , Feminino , Mutação da Fase de Leitura , Aconselhamento Genético , Mutação em Linhagem Germinativa , Humanos , Aneurisma Intracraniano/fisiopatologia , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo
8.
Bone ; 92: 145-149, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27591150

RESUMO

Microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1), or Taybi-Linder syndrome is characterized by distinctive skeletal dysplasia, severe intrauterine and postnatal growth retardation, microcephaly, dysmorphic features, and neurological malformations. It is an autosomal recessive disorder caused by homozygous or compound heterozygous mutations in the RNU4ATAC gene resulting in impaired function of the minor spliceosome. Here, we present the first report on bone morphology, bone density and bone microstructure in two adult MOPD1 patients and applied radiographs, dual energy X-ray absorptiometry, high-resolution peripheral quantitative computed tomography and biochemical evaluation. The MOPD1 patients presented with short stature, low BMI but normal macroscopic bone configuration. Bone mineral density was low. Compared to Danish reference data, total bone area, cortical bone area, cortical thickness, total bone density, cortical bone density, trabecular bone density and trabecular bone volume per tissue volume (BV/TV) were all low. These findings may correlate to the short stature and low body weight of the MOPD1 patients. Our findings suggest that minor spliceosome malfunction may be associated with altered bone modelling.


Assuntos
Densidade Óssea/genética , Nanismo/diagnóstico por imagem , Nanismo/genética , Retardo do Crescimento Fetal/diagnóstico por imagem , Retardo do Crescimento Fetal/genética , Microcefalia/diagnóstico por imagem , Microcefalia/genética , Mutação/genética , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/genética , RNA Nuclear Pequeno/genética , Spliceossomos/genética , Adolescente , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
Dis Colon Rectum ; 59(8): 751-7, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27384093

RESUMO

BACKGROUND: Juvenile polyps in the large bowel are rare but the most common type of polyp in children. The prevalence and incidence are unknown, and few studies exist on the occurrence in adults. They are considered not to harbor any malignant potential unless they are part of the hereditary juvenile polyposis syndrome. OBJECTIVE: We aimed to study the demographics of juvenile polyps in Denmark in a 20-year period from 1995 to 2015 in both adults and children. This is the first report on the occurrence, anatomic localization, and reoccurrence of these polyps in a whole population. DESIGN: Data from all of the patients who had been diagnosed with 1 or more juvenile polyp from January 1, 1995, until December 31, 2014, were obtained. SETTINGS: The study was conducted based on patients registered in the nationwide pathological register in Denmark, the Danish Pathology Data Bank. PATIENTS: We detected a total of 1772 patients who had 2108 juvenile polyps removed (male = 946; female = 826). MAIN OUTCOME MEASURES: We noted the sex, age, number, reoccurrence, and localization of polyps. RESULTS: Of the detected juvenile polyps ≈75% were detected in adults and ≈25% in children. Approximately 96% of the patients had a single juvenile polyp without reoccurrence, 1% fulfilled the diagnostic criteria for juvenile polyposis syndrome (more than 5 polyps), and 5% had multiple juvenile polyps (2-5 polyps). The incidence in the Danish population can be estimated to be between 1:45,000 and 1:65,000. LIMITATIONS: Miscoding or misclassification in the register cannot be ruled out. We only have data for the 20-year period, limiting the evaluation of reoccurrence, and no data for the endoscopic removal procedures. CONCLUSIONS: We conclude that juvenile polyps are rare, with the majority found in adults, and most often found as a single juvenile polyp. A subgroup of patients have juvenile polyposis syndrome, which requires follow-up.


Assuntos
Polipose Intestinal/congênito , Pólipos Intestinais/epidemiologia , Síndromes Neoplásicas Hereditárias/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Dinamarca/epidemiologia , Feminino , Seguimentos , Humanos , Incidência , Lactente , Polipose Intestinal/epidemiologia , Polipose Intestinal/patologia , Pólipos Intestinais/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias/patologia , Sistema de Registros , Estudos Retrospectivos , Adulto Jovem
10.
Scand J Gastroenterol ; 51(9): 1118-25, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27146957

RESUMO

OBJECTIVE: A subgroup of patients with hamartomatous polyps in the GI tract has a hereditary Hamartomatous Polyposis Syndrome with an increased risk of cancer. The distinction between patients with one or few polyps and patients with a syndrome can be difficult. A pathogenic germline mutation can be detected in a majority of HPS patients. This study investigates whether patients with one or few hamartomatous polyps could have a syndrome based on genetic screening of relevant genes. METHODS: We designed a gene panel including 26 hamartomatous polyposis-associated genes. Using targeted Next Generation Sequencing, DNA samples from 77 patients with 84 hamartomatous polyps were sequenced. The detected germline variants were classified into pathogenicity classes. RESULTS: We detected several germline variants, among them three in ENG, two in BMPR1A, one in PTEN, and one in SMAD4. Although some of the detected variants have been reported previously none could be definitely pathogenic or likely pathogenic. CONCLUSIONS: Our study points towards that genetic testing for the Hamartomatous Polyposis Syndromes in patients with one or few polyps does not improve diagnostics, however we illustrate that the clinical significance of genetic variants can be difficult to interpret. A family history of polyps, cancer, or extraintestinal findings or a minimum of 3-5 polyps seems to be relevant information to include before genetic testing.


Assuntos
Síndrome de Peutz-Jeghers/complicações , Síndrome de Peutz-Jeghers/diagnóstico , Síndrome de Peutz-Jeghers/genética , Pólipos/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/genética , Criança , Pré-Escolar , Neoplasias do Colo/diagnóstico , Dinamarca , Endoglina/genética , Feminino , Testes Genéticos , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/genética , Estudos Retrospectivos , Proteína Smad4/genética , Adulto Jovem
11.
Ugeskr Laeger ; 177(32): V12140755, 2015 Aug 03.
Artigo em Dinamarquês | MEDLINE | ID: mdl-26321587

RESUMO

Noonan syndrome is part of the group of RASopathies caused by germ line mutations in genes involved in the RAS/MAPK pathway. There is substantial phenotypic overlap among the RASopathies. Diagnosis of Noonan syndrome is often based on clinical features including dysmorphic facial features, short stature and congenital heart disease. Rapid advances in sequencing technology have made molecular genetic analyses a helpful tool in diagnosing and distinguishing Noonan syndrome from other RASopathies.


Assuntos
Síndrome de Noonan/diagnóstico , Humanos , Sistema de Sinalização das MAP Quinases , Síndrome de Noonan/genética , Síndrome de Noonan/patologia , Síndrome de Noonan/fisiopatologia , Proteínas ras/fisiologia
12.
Microvasc Res ; 99: 118-26, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25892364

RESUMO

UNLABELLED: Hereditary hemorrhagic telangiectasia (HHT), the most common inherited vascular disorder, is predominantly caused by mutations in ENG and ACVRL1, which are part of the transforming growth factor beta (TGF-ß) signaling pathway. HHT is characterized by the presence of mucocutaneous telangiectases and arteriovenous malformations in visceral organs, primarily the lungs, brain and liver. The most common symptom in HHT is epistaxis originating from nasal telangiectasia, which can be difficult to prevent and can lead to severe anemia. The clinical manifestations of HHT are extremely variable, even within family members, and the exact mechanism of how endoglin and ALK1 haploinsufficiency leads to HHT manifestations remains to be identified. OBJECTIVES: The purpose of this study was to detect significantly differentially regulated genes in HHT, and try to elucidate the pathways and regulatory mechanisms occurring in the affected tissue of HHT patients, in order to further characterize this disorder and hypothesize on how telangiectases develop. By microarray technology (Agilent G3 Human GE 8x60), we performed global gene expression profiling of mRNA transcripts from HHT nasal telangiectasial (n = 40) and non-telangiectasial (n = 40) tissue using a paired design. Comparing HHT telangiectasial and non-telangiectasial tissue, significantly differentially expressed genes were detected using a paired t-test. Gene set analysis was performed using GSA-SNP. In the group of ENG mutation carriers, we detected 67 differentially expressed mRNAs, of which 62 were down-regulated in the telangiectasial tissue. Gene set analysis identified the gene ontology (GO) terms vasculogenesis, TGF-ß signaling, and Wnt signaling as differentially expressed in HHT1. Altered Wnt signaling might be related to HHT pathogenesis and a greater understanding of this may lead to the discovery of therapeutic targets in HHT.


Assuntos
Receptores de Activinas Tipo II/genética , Antígenos CD/genética , Perfilação da Expressão Gênica , Receptores de Superfície Celular/genética , Telangiectasia Hemorrágica Hereditária/genética , Malformações Arteriovenosas/genética , Biópsia , Análise por Conglomerados , Endoglina , Saúde da Família , Feminino , Genótipo , Humanos , Masculino , Mutação , Mucosa Nasal/patologia , Hibridização de Ácido Nucleico , Análise de Componente Principal , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo
13.
Eur J Hum Genet ; 23(10): 1423-6, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25604854

RESUMO

Following the implementation of high-throughput sequencing legal and ethical issues are discussed intensively. The management of incidental findings (IFs) in a research setting have been investigated but there is a lack of literature concerning research participant's perspective. The aim of this study was to investigate whether research participants want disclosure of IFs and what kind of IFs they want to know about. One hundred and twenty-seven research participants in a study of gastrointestinal polyps were informed about whole-exome sequencing and the risk of IFs. They were asked to decide whether they (A) wanted disclosure of IFs no matter whether the variants were associated with a non-treatable or non-preventable condition, (B) wanted disclosure of variants associated with treatable or preventable conditions or (C) wanted no disclosure at all. Participants who wanted disclosure of all the IFs (A) accounted for the majority (n=78), 45 of the participants only wanted disclosure of variants, which could lead to surveillance or treatment (B) and 4 participants did not want IFs to be disclosed at all (C). The study showed that almost all research participants wanted disclosure of at least some types of IFs.


Assuntos
Pesquisa Biomédica/ética , Variação Genética/genética , Sequenciamento de Nucleotídeos em Larga Escala/ética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Pesquisa Biomédica/métodos , Revelação/ética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Achados Incidentais , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Ugeskr Laeger ; 176(25A)2014 Dec 15.
Artigo em Dinamarquês | MEDLINE | ID: mdl-25497626

RESUMO

Two girls suffering from early-onset epileptic encephalopathy are described. Both girls had changes involving the gene CDKL5. They both had seizures in the first weeks of life and normal EEG interictally. Both developed infantile spasms and severe developmental defect. The epilepsy was difficult to treat.


Assuntos
Mutação , Proteínas Serina-Treonina Quinases/genética , Síndrome de Rett/genética , Espasmos Infantis/genética , Anticonvulsivantes/uso terapêutico , Síndromes Epilépticas , Feminino , Humanos , Recém-Nascido , Síndrome de Rett/diagnóstico , Síndrome de Rett/dietoterapia , Síndrome de Rett/tratamento farmacológico , Espasmos Infantis/diagnóstico , Espasmos Infantis/dietoterapia , Espasmos Infantis/tratamento farmacológico
15.
Ugeskr Laeger ; 176(7A): V05130280, 2014 Feb 10.
Artigo em Dinamarquês | MEDLINE | ID: mdl-25347558

RESUMO

Hereditary palmoplantar keratoderma comprises a heterogenous group of genodermatoses. The clinical spectrum of palmoplantar keratoderma can range from pure skin thickening, restricted to palmoplantar skin to complex conditions with dental anomalies, eye symptoms, deafness, cardiac disease and cancer. The classification of hereditary palmoplantar keratoderma has been complicated. In recent years the molecular genetic background has been clarified for an increasing number of palmoplantar keratodermas, which makes it possible to make a more accurate diagnosis.


Assuntos
Ceratodermia Palmar e Plantar , Humanos , Ceratodermia Palmar e Plantar/diagnóstico , Ceratodermia Palmar e Plantar/genética , Ceratodermia Palmar e Plantar/patologia
16.
Ugeskr Laeger ; 176(44)2014 Oct 27.
Artigo em Dinamarquês | MEDLINE | ID: mdl-25354001

RESUMO

Juvenile polyposis syndrome is an autosomal dominant polyposis syndrome. It is characterized by predisposition to multiple juvenile polyps in the gastrointestinal tract and is associated with an increased risk of colorectal and ventricular cancer. Patients and at risk family members should be offered surveillance. This article discusses clinical features and surveillance based on the current literature.


Assuntos
Neoplasias Gastrointestinais/etiologia , Polipose Intestinal/complicações , Síndromes Neoplásicas Hereditárias/complicações , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/genética , Procedimentos Clínicos , Mutação em Linhagem Germinativa , Humanos , Polipose Intestinal/congênito , Polipose Intestinal/diagnóstico , Polipose Intestinal/genética , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologia , Fatores de Risco , Proteína Smad4/genética , Telangiectasia Hemorrágica Hereditária/diagnóstico , Telangiectasia Hemorrágica Hereditária/genética
17.
Ugeskr Laeger ; 176(44)2014 Oct 27.
Artigo em Dinamarquês | MEDLINE | ID: mdl-25354002

RESUMO

Germ line mutations in SMAD4 can cause both juvenile polyposis syndrome and hereditary haemorrhagic telangiectasia syndrome. In this case we present a 37-year-old man with a frameshift mutation in SMAD4. The patient had multiple polyps in the gastrointestinal tract and was diagnosed with colon cancer at the age of 21 and gastro-oesophageal junction cancer at the age of 37. Furthermore the patient had telangiectasias and recurrent epistaxis.


Assuntos
Polipose Intestinal/genética , Síndromes Neoplásicas Hereditárias/genética , Proteína Smad4/genética , Telangiectasia Hemorrágica Hereditária/genética , Adulto , Carcinoma de Células em Anel de Sinete/etiologia , Carcinoma de Células em Anel de Sinete/genética , Carcinoma de Células em Anel de Sinete/cirurgia , Epistaxe/genética , Mutação da Fase de Leitura , Neoplasias Gastrointestinais/etiologia , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/cirurgia , Mutação em Linhagem Germinativa , Humanos , Polipose Intestinal/complicações , Polipose Intestinal/congênito , Masculino , Síndromes Neoplásicas Hereditárias/complicações , Telangiectasia Hemorrágica Hereditária/complicações
18.
Orphanet J Rare Dis ; 9: 101, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-25022750

RESUMO

Hamartomatous Polyposis Syndromes (HPS) are genetic syndromes, which include Peutz-Jeghers syndrome, Juvenile polyposis syndrome, PTEN hamartoma tumour syndrome (Cowden Syndrom, Bannayan-Riley-Ruvalcaba and Proteus Syndrome) as well as hereditary mixed polyposis syndrome. Other syndromes such as Gorlin Syndrome and multiple endocrine neoplasia syndrome 2B are sometimes referred to as HPS. HPS is characterized by the development of hamartomatous polyps in the gastrointestinal tract as well as several extra-intestinal findings such as dermatological and dysmorphic features or extra-intestinal cancer. The syndromes are rare and inherited in an autosomal dominant manner.The diagnosis of HPS has traditionally been based on clinical criteria, but can sometimes be difficult as the severity of symptoms range considerably from only a few symptoms to very severe cases - even within the same family. De novo cases are also frequent. However, because of the discovery of several associated germline-mutations as well as the rapid development in genetics it is now possible to use genetic testing more often in the diagnostic process. Management of the syndromes is different for each syndrome as extra-intestinal symptoms and types of cancers differs.Clinical awareness and early diagnosis of HPS is important, as affected patients and at-risk family members should be offered genetic counselling and surveillance. Surveillance in children with HPS might prevent or detect intestinal or extra-intestinal complications, whereas in adulthood surveillance is recommended due to an increased risk of cancer e.g. intestinal cancer or breast cancer.


Assuntos
Síndrome de Peutz-Jeghers/diagnóstico , Humanos , Síndrome de Peutz-Jeghers/fisiopatologia
19.
J Lipid Res ; 55(6): 1165-72, 2014 06.
Artigo em Inglês | MEDLINE | ID: mdl-24771866

RESUMO

A new mechanism for formation of 7-ketocholesterol was recently described involving cytochrome P-450 (CYP)7A1-catalyzed conversion of 7-dehydrocholesterol into 7-ketocholesterol with cholesterol-7,8-epoxide as a side product. Some patients with cerebrotendinous xanthomatosis (CTX) and all patients with Smith-Lemli-Opitz syndrome (SLO) have markedly increased levels of 7-dehydrocholesterol in plasma and tissues. In addition, the former patients have markedly upregulated CYP7A1. We hypothesized that these patients may produce 7-ketocholesterol from 7-dehydrocholesterol with formation of cholesterol-7,8-epoxide as a side product. In accord with this hypothesis, two patients with CTX were found to have increased levels of 7-ketocholesterol and 7-dehydrocholesterol, as well as a significant level of cholesterol-7,8-epoxide. The latter steroid was not detectable in plasma from healthy volunteers. Downregulation of CYP7A1 activity by treatment with chenodeoxycholic acid reduced the levels of 7-ketocholesterol in parallel with decreased levels of 7-dehydrocholesterol and cholesterol-7,8-epoxide. Three patients with SLO were found to have markedly elevated levels of 7-ketocholesterol as well as high levels of cholesterol-7,8-epoxide. The results support the hypothesis that 7-dehydrocholesterol is a precursor to 7-ketocholesterol in SLO and some patients with CTX.


Assuntos
Desidrocolesteróis/sangue , Cetocolesteróis/sangue , Síndrome de Smith-Lemli-Opitz/sangue , Xantomatose Cerebrotendinosa/sangue , Adolescente , Adulto , Criança , Colesterol 7-alfa-Hidroxilase/biossíntese , Colesterol 7-alfa-Hidroxilase/genética , Regulação para Baixo , Feminino , Regulação Enzimológica da Expressão Gênica , Humanos , Cetocolesteróis/genética , Síndrome de Smith-Lemli-Opitz/genética , Síndrome de Smith-Lemli-Opitz/patologia , Xantomatose Cerebrotendinosa/genética , Xantomatose Cerebrotendinosa/patologia
20.
PLoS One ; 9(3): e90272, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24603890

RESUMO

Hereditary Haemorrhagic Telangiectasia (HHT) is an autosomal dominantly inherited vascular disease characterized by the presence of mucocutaneous telangiectasia and arteriovenous malformations in visceral organs. HHT is predominantly caused by mutations in ENG and ACVRL1, which both belong to the TGF-ß signalling pathway. The exact mechanism of how haploinsufficiency of ENG and ACVRL1 leads to HHT manifestations remains to be identified. As long non-coding RNAs (lncRNAs) are increasingly recognized as key regulators of gene expression and constitute a sizable fraction of the human transcriptome, we wanted to assess whether lncRNAs play a role in the molecular pathogenesis of HHT manifestations. By microarray technology, we profiled lncRNA transcripts from HHT nasal telangiectasial and non-telangiectasial tissue using a paired design. The microarray probes were annotated using the GENCODE v.16 dataset, identifying 4,810 probes mapping to 2,811 lncRNAs. Comparing HHT telangiectasial tissue with HHT non-telangiectasial tissue, we identified 42 lncRNAs that are differentially expressed (q<0.001). Using GREAT, a tool that assumes cis-regulation, we showed that differently expressed lncRNAs are enriched for genomic loci involved in key pathways concerning HHT. Our study identified lncRNAs that are aberrantly expressed in HHT telangiectasia and indicates that lncRNAs may contribute to regulate protein-coding loci in HHT. These results suggest that the lncRNA component of the transcriptome deserves more attention in HHT. A deeper understanding of lncRNAs and their role in telangiectasia formation possesses potential for discovering therapeutic targets in HHT.


Assuntos
Perfilação da Expressão Gênica , Análise de Sequência com Séries de Oligonucleotídeos/métodos , RNA Longo não Codificante/genética , Telangiectasia Hemorrágica Hereditária/genética , Receptores de Activinas Tipo II/genética , Adulto , Antígenos CD/genética , Análise por Conglomerados , Endoglina , Feminino , Ontologia Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , RNA Longo não Codificante/classificação , Receptores de Superfície Celular/genética , Telangiectasia Hemorrágica Hereditária/patologia , Adulto Jovem
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