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Advances in DNA sequencing technologies, especially next-generation sequencing (NGS), which is the basis for whole-exome sequencing (WES) and whole-genome sequencing (WGS), have profoundly transformed immune-mediated rheumatic disease diagnosis. Recently, substantial cost reductions have facilitated access to these diagnostic tools, expanded the capacity of molecular diagnostics and enabled the pursuit of precision medicine in rheumatology. Understanding the fundamental principles of genetics and diversity in genetic variant classification is a crucial milestone in rheumatology. However, despite the growing availability of DNA sequencing platforms, a significant number of autoinflammatory diseases (AIDs), neuromuscular disorders, hereditary collagen diseases, and monogenic bone diseases remain unsolved, and variants of uncertain significance (VUS) pose a formidable challenge to addressing these unmet needs in the coming decades. This article aims to provide an overview of the clinical indications and interpretation of comprehensive genetic testing in the medical field, addressing the related complexities and implications.
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Testes Genéticos , Doenças Reumáticas , Humanos , Testes Genéticos/métodos , Doenças Reumáticas/genética , Doenças Reumáticas/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Reumatologia , Sequenciamento do Exoma , Doenças Neuromusculares/genética , Doenças Neuromusculares/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/diagnóstico , ReumatologistasRESUMO
BACKGROUND: Lactose tolerant test (LTT) is the most broadly used diagnostic test for lactose intolerance in Brazil, is an indirect, minimally invasive and a low-cost test that is widely available in primary care and useful in clinical practice. The C/T-13910 polymorphism in lactase persistence has been well characterized in Caucasian populations, but there are no studies evaluating the concordance between C/T-13910 polymorphism genotyping results and LTT results in Brazil, where the population is highly mixed. OBJECTIVE: We aimed to evaluate agreement between presence of C/T-13910 polymorphism genotyping and malabsorption in LTT results. METHODS: This is a retrospective analysis of a Brazilian population whose data were collected from a single laboratory database present in several Brazilian states. Results of individuals who underwent both genetic testing for lactose intolerance (C/T-13910 polymorphism genotyping) and an LTT from April 2016 until February 2019 were analysed to evaluate agreement between tests. Groups were classified according to age (<10-year-old (yo), 10-17 yo, ≥18 yo groups) and state of residence (São Paulo or Rio Grande do Sul). Results: Among the 404 patients evaluated, there was agreement between the genotyping and LTT results in 325 (80.4%) patients and discordance in 79 (19.6%) patients (k=0.42 -moderate agreement). Regarding the genotype, 47 patients with genotype C/C (lactase nonpersistence) had normal LTT results, and 32 with genotype C/T or T/T (indicating lactase persistence) had abnormal LTT results. Neither age nor state of residence (Rio Grande do Sul or São Paulo) affected the agreement between test results. CONCLUSION: Considering the moderate agreement between C/T-13910 polymorphism genotyping and LTT results (κ=0.42) in the Brazilian population, we hypothesize that an analysis of other polymorphisms could be a strategy to improve the agreement between genotyping and established tests and suggest that additional studies should focus on exploring this approach. BACKGROUND: ⢠Lactose intolerance is highly prevalent and may be implicated as a cofactor, or as a differential diagnosis, in many gastrointestinal conditions. BACKGROUND: ⢠The C/T-13910 polymorphism in lactase persistence is well characterized in Caucasian populations for lactase persistence. BACKGROUND: ⢠Concordance between genotyping and functional tests does not occur in all patients. BACKGROUND: ⢠Brazil has a highly mixed population and knowledge regarding presence of other polymorphisms is of importance in clarifying difficult cases.
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Intolerância à Lactose , Humanos , Criança , Teste de Tolerância a Lactose , Brasil , Intolerância à Lactose/diagnóstico , Intolerância à Lactose/genética , Genótipo , Estudos Retrospectivos , Lactase/genéticaRESUMO
BACKGROUND: Next-generation sequencing has had a significant impact on genetic disease diagnosis, but the interpretation of the vast amount of genomic data it generates can be challenging. To address this, the American College of Medical Genetics and Genomics and the Association for Molecular Pathology have established guidelines for standardized variant interpretation. In this manuscript, we present the updated Hospital Israelita Albert Einstein Standards for Constitutional Sequence Variants Classification, incorporating modifications from leading genetics societies and the ClinGen initiative. RESULTS: First, we standardized the scientific publications, documents, and other reliable sources for this document to ensure an evidence-based approach. Next, we defined the databases that would provide variant information for the classification process, established the terminology for molecular findings, set standards for disease-gene associations, and determined the nomenclature for classification criteria. Subsequently, we defined the general rules for variant classification and the Bayesian statistical reasoning principles to enhance this process. We also defined bioinformatics standards for automated classification. Our workgroup adhered to gene-specific rules and workflows curated by the ClinGen Variant Curation Expert Panels whenever available. Additionally, a distinct set of specifications for criteria modulation was created for cancer genes, recognizing their unique characteristics. CONCLUSIONS: The development of an internal consensus and standards for constitutional sequence variant classification, specifically adapted to the Brazilian population, further contributes to the continuous refinement of variant classification practices. The aim of these efforts from the workgroup is to enhance the reliability and uniformity of variant classification.
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Testes Genéticos , Variação Genética , Humanos , Estados Unidos , Mutação , Reprodutibilidade dos Testes , Teorema de Bayes , Genoma HumanoRESUMO
OBJECTIVE: To report the effectiveness of early molecular diagnosis in the clinical management of rare diseases, presenting 8 patients with 8p23.1DS who have clinical features that overlap the phenotypic spectrum of 22q11.2DS. STUDY DESIGN: This report is part of a previous study that aims to provide a precocious molecular diagnosis of the 22q11.2 deletion syndrome in 118 infants with congenital heart disease. To confirm the clinical diagnosis, patients underwent comparative genomic screening by the multiplex ligation-dependent probe amplification (MLPA) assay with the SALSA MLPA probemix kits P064-B2, P036-E1, P070-B2, P356-A1, and P250- B1. Subsequently, the patients performed the genomic microarray using the Infinium CytoSNP-850K BeadChip to confirm the deletion, determine the breakpoints of the deletion, and search for genomic copy number variations. RESULTS: MLPA performed with 3 different kits revealed the 8p23.1 typical deletion involving the PPP1R3B, MSRA, and GATA4 genes in the 5 patients. The array analysis was performed on these 5 patients and 3 other patients (8 patients) who also had clinical suspicion of 22q11 deletion (8 patients) allowed a precise definition of the breakpoints and excluded other genomic abnormalities. CONCLUSIONS: Cytogenomic screening was efficient in establishing a differential diagnosis and ruling out the presence of other concomitant syndromes. The clinical picture of the 8p23.1 deletion syndrome is challenging; however, cytogenomic tools can provide an exact diagnosis and help to clarify the genotype-phenotype complexity of these patients. Our reports underline the importance of early diagnosis and clinical follow-up of microdeletion syndromes.
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Síndrome de DiGeorge , Cardiopatias Congênitas , Humanos , Deleção Cromossômica , Variações do Número de Cópias de DNA , Síndrome de DiGeorge/diagnóstico , Fenótipo , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genéticaAssuntos
Exoma , Doenças Raras , Brasil , Humanos , Doenças Raras/genética , Análise de Sequência de DNARESUMO
Hearing loss (HL) is a common sensory deficit in humans and represents an important clinical and social burden. We studied whole-genome sequencing data of a cohort of 2,097 individuals from the Brazilian Rare Genomes Project who were unaffected by hearing loss to investigate pathogenic and likely pathogenic variants associated with nonsyndromic hearing loss (NSHL). We found relevant frequencies of individuals harboring these alterations: 222 heterozygotes (10.59%) for sequence variants, 54 heterozygotes (2.58%) for copy-number variants (CNV), and four homozygotes (0.19%) for sequence variants. The top five most frequent genes and their corresponding combined allelic frequencies (AF) were GJB2 (AF = 1.57%), STRC (AF = 1%), OTOA (AF = 0.69%), TMPRSS3 (AF = 0.41%), and OTOF (AF = 0.29%). The most frequent sequence variant was GJB2:c.35del (AF = 0.72%), followed by OTOA:p. (Glu787Ter) (AF = 0.61%), while the most recurrent CNV was a microdeletion of 57.9 kb involving the STRC gene (AF = 0.91%). An important fraction of these individuals (n = 104; 4.96%) presented variants associated with autosomal dominant forms of NSHL, which may imply the development of some hearing impairment in the future. Using data from the heterozygous individuals for recessive forms and the Hardy-Weinberg equation, we estimated the population frequency of affected individuals with autosomal recessive NSHL to be 1:2,222. Considering that the overall prevalence of HL in adults ranges from 4-15% worldwide, our data indicate that an important fraction of this condition may be associated with a monogenic origin and dominant inheritance.
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Genomic studies may generate massive amounts of data, bringing interpretation challenges. Efforts for the differentiation of benign and pathogenic variants gain importance. In this article, we used segregation analysis and other molecular data to reclassify to benign or likely benign several rare clinically curated variants of autosomal dominant inheritance from a cohort of 500 Brazilian patients with rare diseases. This study included only symptomatic patients who had undergone molecular investigation with exome sequencing for suspected diseases of genetic etiology. Variants clinically suspected as the causative etiology and harbored by genes associated with highly-penetrant conditions of autosomal dominant inheritance underwent Sanger confirmation in the proband and inheritance pattern determination because a "de novo" event was expected. Among all 327 variants studied, 321 variants were inherited from asymptomatic parents. Considering segregation analysis, we have reclassified 51 rare variants as benign and 211 as likely benign. In our study, the inheritance of a highly penetrant variant expected to be de novo for pathogenicity assumption was considered as a non-segregation and, therefore, a key step for benign or likely benign classification. Studies like ours may help to identify rare benign variants and improve the correct interpretation of genetic findings.
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Pais , Doenças Raras , Brasil , Humanos , Mutação , Linhagem , Doenças Raras/genética , Sequenciamento do ExomaRESUMO
BACKGROUND: Several metabolic disorders follow an autosomal recessive inheritance pattern. Epidemiological information on these disorders is usually limited in developing countries. Our objective is to assess carrier frequencies of rare autosomal recessive metabolic diseases in a cohort of Brazilian patients that underwent molecular investigation with exome sequencing and estimate the overall frequency of these diseases using the Hardy-Weinberg equation. METHODS AND RESULTS: We reviewed the molecular findings of 320 symptomatic patients who had carrier status for recessive diseases actively searched. A total of 205 rare variants were reported in 138 different genes associated with metabolic diseases from 156 patients, which represents that almost half (48.8%) of the patients were carriers of at least one heterozygous pathogenic/likely pathogenic (P/LP) variant for rare metabolic disorders. Most of these variants are harbored by genes associated with multisystemic involvement. We estimated the overall frequency for rare recessive metabolic diseases to be 10.96/10,000 people, while the frequency of metabolic diseases potentially identified by newborn screening was estimated to be 2.93/10,000. CONCLUSIONS: This study shows the potential research utility of exome sequencing to determine carrier status for rare metabolic diseases, which may be a possible strategy to evaluate the clinical and social burden of these conditions at the population level and guide the optimization of health policies and newborn screening programs.
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Doenças Metabólicas , Brasil/epidemiologia , Estudos de Coortes , Heterozigoto , Humanos , Recém-Nascido , Doenças Metabólicas/epidemiologia , Doenças Metabólicas/genética , Sequenciamento do ExomaRESUMO
Next-generation sequencing (NGS) has altered clinical genetic testing by widening the access to molecular diagnosis of genetically determined rare diseases. However, physicians may face difficulties selecting the best diagnostic approach. Our goal is to estimate the rate of possible molecular diagnoses missed by different targeted gene panels using data from a cohort of patients with rare genetic diseases diagnosed with exome sequencing (ES). For this purpose, we simulated a comparison between different targeted gene panels and ES: the list of genes harboring clinically relevant variants from 158 patients was used to estimate the theoretical rate of diagnoses missed by NGS panels from 53 different NGS panels from eight different laboratories. Panels presented a mean rate of missed diagnoses of 64% (range 14%-100%) compared to ES, representing an average predicted sensitivity of 36%. Metabolic abnormalities represented the group with highest mean of missed diagnoses (86%), while seizure represented the group with lowest mean (46%). Focused gene panels are restricted in covering select sets of genes implicated in specific diseases and they may miss molecular diagnoses of rare diseases compared to ES. However, their role in genetic diagnosis remains important especially for well-known genetic diseases with established genetic locus heterogeneity.
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Several Mendelian disorders follow an autosomal recessive inheritance pattern. Epidemiological information on many inherited disorders may be useful to guide health policies for rare diseases, but it is often inadequate, particularly in developing countries. We aimed to calculate the carrier frequencies of rare autosomal recessive Mendelian diseases in a cohort of Brazilian patients using whole exome sequencing (WES). We reviewed the molecular findings of WES from 320 symptomatic patients who had carrier status for recessive diseases. Using the Hardy-Weinberg equation, we estimated recessive disease frequencies (q2 ) considering the respective carrier frequencies (2pq) observed in our study. We calculated the sensitivity of carrier screening tests based on lists of genes from five different clinical laboratories that offer them in Brazil. A total of 425 occurrences of 351 rare variants were reported in 278 different genes from 230 patients (71.9%). Almost half (48.8%) were carriers of at least one heterozygous pathogenic/likely pathogenic variant for rare metabolic disorders, while 25.9% of epilepsy, 18.1% of intellectual disabilities, 15.6% of skeletal disorders, 10.9% immune disorders, and 9.1% of hearing loss. We estimated that an average of 67% of the variants would not have been detected by carrier screening panels. The combined frequencies of autosomal recessive diseases were estimated to be 26.39/10,000 (or ~0.26%). This study shows the potential research utility of WES to determine carrier status, which may be a possible strategy to evaluate the clinical and social burden of recessive diseases at the population level and guide the optimization of carrier screening panels.
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Deficiência Intelectual , Doenças Raras , Brasil/epidemiologia , Estudos de Coortes , Humanos , Sequenciamento do ExomaRESUMO
Rare diseases comprise a diverse group of conditions, most of which involve genetic causes. We describe the variable spectrum of findings and clinical impacts of exome sequencing (ES) in a cohort of 500 patients with rare diseases. In total, 164 primary findings were reported in 158 patients, representing an overall diagnostic yield of 31.6%. Most of the findings (61.6%) corresponded to autosomal dominant conditions, followed by autosomal recessive (25.6%) and X-linked (12.8%) conditions. These patients harbored 195 variants, among which 43.6% are novel in the literature. The rate of molecular diagnosis was considerably higher for prenatal samples (67%; 4/6), younger children (44%; 24/55), consanguinity (50%; 3/6), gastrointestinal/liver disease (44%; 16/36) and syndromic/malformative conditions (41%; 72/175). For 15.6% of the cohort patients, we observed a direct potential for the redirection of care with targeted therapy, tumor screening, medication adjustment and monitoring for disease-specific complications. Secondary findings were reported in 37 patients (7.4%). Based on cost-effectiveness studies in the literature, we speculate that the reports of secondary findings may influence an increase of 123.2 years in the life expectancy for our cohort, or 0.246 years/cohort patient. ES is a powerful method to identify the molecular bases of monogenic disorders and redirect clinical care.
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Exoma , Doenças Raras , Criança , Estudos de Coortes , Consanguinidade , Exoma/genética , Feminino , Humanos , Gravidez , Doenças Raras/diagnóstico , Doenças Raras/genética , Sequenciamento do ExomaRESUMO
Fish species exhibit substantial variation in the degree of genetic differentiation between sex chromosome pairs, and therefore offer the opportunity to study the full range of sex chromosome evolution. We used restriction-site associated DNA sequencing (RAD-seq) to study the sex chromosomes of Characidium gomesi, a species with conspicuous heteromorphic ZW/ZZ sex chromosomes. We screened 9863 single-nucleotide polymorphisms (SNPs), corresponding to ~1 marker/100 kb distributed across the genome for sex-linked variation. With this data set, we identified 26 female-specific RAD loci, putatively located on the W chromosome, as well as 148 sex-associated SNPs showing significant differentiation (average FST=0.144) between males and females, and therefore in regions of more recent divergence between the Z and W chromosomes. In addition, we detected 25 RAD loci showing extreme heterozygote deficiency in females but which were in Hardy-Weinberg equilibrium in males, consistent with degeneration of the W chromosome and therefore female hemizygosity. We validated seven female-specific and two sex-associated markers in a larger sample of C. gomesi, of which three localised to the W chromosome, thereby providing useful markers for sexing wild samples. Validated markers were evaluated in other populations and species of the genus Characidium, this exploration suggesting a rapid turnover of W-specific repetitive elements. Together, our analyses point to a complex origin for the sex chromosome of C. gomesi and highlight the utility of RAD-seq for studying the composition and evolution of sex chromosomes systems in wild populations.
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Caraciformes/genética , Evolução Molecular , Cromossomos Sexuais/genética , Animais , Sequência Conservada/genética , Feminino , Genoma , Masculino , Sequências Repetitivas de Ácido Nucleico/genética , Análise de Sequência de DNARESUMO
BACKGROUND: Breast cancer is the most common among women worldwide, and ovarian cancer is the most difficult gynecological tumor to diagnose and with the lowest chance of cure. Mutations in BRCA1 and BRCA2 genes increase the risk of ovarian cancer by 60% and breast cancer by up to 80% in women. Molecular tests allow a better orientation for patients carrying these mutations, affecting prophylaxis, treatment, and genetic counseling. RESULTS: Here, we evaluated the performance of a panel for BRCA1 and BRCA2, using the Ion Torrent PGM (Life Technologies) platform in a customized workflow and multiplex ligation-dependent probe amplification for detection of mutations, insertions, and deletions in these genes. We validated the panel with 26 samples previously analyzed by Myriad Genetics Laboratory, and our workflow showed 95.6% sensitivity and 100% agreement with Myriad reports, with 85% sensitivity on the positive control sample from NIST. We also screened 68 clinical samples and found 22 distinct mutations. CONCLUSIONS: The selection of a robust methodology for sample preparation and sequencing, together with bioinformatics tools optimized for the data analysis, enabled the development of a very sensitive test with high reproducibility. We also highlight the need to explore the limitations of the NGS technique and the strategies to overcome them in a clinically confident manner.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Mutação , Neoplasias Ovarianas/genética , Análise de Sequência de DNA/métodos , Fluxo de Trabalho , Neoplasias da Mama/patologia , Biologia Computacional/métodos , Feminino , Humanos , Neoplasias Ovarianas/patologia , Análise de Sequência de DNA/instrumentaçãoRESUMO
OBJECTIVES: To estimate the frequency of metabolic syndrome (MetS) in a daily urology practice and to determine its association with lower urinary tract symptoms (LUTS) and erectile dysfunction (ED). MATERIAL AND METHODS: A retrospective study was conducted. Data from all male patients aged ≥40 years who attended our outpatient urology clinic from 2010 to 2011 was collected. Prevalence of MetS was determined, and LUTS and ED were assessed. A logistic model was used to determine possible associations, controlling for confounders and interaction factors. RESULTS: A total of 616 patients were included. MetS was observed in 43.8% (95% CI 39.6-48.3). The bivariate model showed an association between MetS and LUTS (p<0.01), but not between MetS and ED. The logistic model showed an association between MetS and the International Prostate Symptom Score (IPSS), while controlling for other variables. Patients exhibiting moderate LUTS had a greater risk for MetS than patients with mild LUTS (OR 1.83, 95% CI 1.14-2.94). After analyzing for individual components of MetS, positive associations were found between diabetes and severe LUTS (OR 1.3, 95% CI 1.24-7.1), and between diabetes and ED (OR 2.57, 95% CI 1.12-5.8). CONCLUSION: This study was able to confirm an association between MetS and LUTS, but not for ED. Specific components such as diabetes were associated to both. Geographical differences previously reported in the literature might account for these findings. Given that MetS is frequent among urological patients, it is advisable that urologists actively screen for it.
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Disfunção Erétil/epidemiologia , Sintomas do Trato Urinário Inferior/epidemiologia , Síndrome Metabólica/epidemiologia , Adulto , Idoso , Causalidade , Colômbia/epidemiologia , Comorbidade , Fatores de Confusão Epidemiológicos , Diabetes Mellitus Tipo 2/epidemiologia , Disfunção Erétil/etiologia , Humanos , Sintomas do Trato Urinário Inferior/etiologia , Masculino , Pessoa de Meia-Idade , Ambulatório Hospitalar/estatística & dados numéricos , Prevalência , Estudos Retrospectivos , Fumar/epidemiologia , UrologiaRESUMO
OBJECTIVE: To describe the most prominent clinical features of a cohort of patients with oculo-auriculo-vertebral (OAV) dysplasia in Brazil. METHOD: A review of medical records of patients with diagnosis of OAV from 1990 to 2010 was performed in a medical genetics center. RESULTS: 41 patients were included in the study. Their average age at diagnosis was 2y 10mo (34,4±48,8 months) and the female proportion was 53.7%. Mean maternal age at patient's birth was 28.5y (min: 17, max: 46y) for mothers and 31.4y (min: 21, max: 51y) for fathers. Most patients (97.5%) had auricular involvement, with facial manifestation in 90.2%, spinal in 65.9%, ocular in 53.7%, 36.6% with cardiovascular involvement, 29.3% urogenital, and 17% of the cases with central nervous system (CNS) involvement. The classic OAV triad was present in only 34%. All patients except one had concomitant problems in other organs or systems. CONCLUSION: Since the diagnosis of OAV dysplasia relies only on a comprehensive medical evaluation, it is imperative that clinicians be aware of the most common presentation of the syndrome. Once suspected, every patient should undergo a complete medical evaluation of multiple systems including complementary exams. Treatment of these patients is based on surgical correction of malformations and rehabilitation.
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Síndrome de Goldenhar/epidemiologia , Síndrome de Goldenhar/patologia , Brasil/epidemiologia , Pré-Escolar , Orelha/anormalidades , Anormalidades do Olho , Face/anormalidades , Feminino , Síndrome de Goldenhar/fisiopatologia , Humanos , Masculino , Prontuários Médicos , Estudos Retrospectivos , Distribuição por Sexo , Coluna Vertebral/anormalidadesRESUMO
SUMMARY Objective: To describe the most prominent clinical features of a cohort of patients with oculo-auriculo-vertebral (OAV) dysplasia in Brazil. Method: A review of medical records of patients with diagnosis of OAV from 1990 to 2010 was performed in a medical genetics center. Results: 41 patients were included in the study. Their average age at diagnosis was 2y 10mo (34,4±48,8 months) and the female proportion was 53.7%. Mean maternal age at patient’s birth was 28.5y (min: 17, max: 46y) for mothers and 31.4y (min: 21, max: 51y) for fathers. Most patients (97.5%) had auricular involvement, with facial manifestation in 90.2%, spinal in 65.9%, ocular in 53.7%, 36.6% with cardiovascular involvement, 29.3% urogenital, and 17% of the cases with central nervous system (CNS) involvement. The classic OAV triad was present in only 34%. All patients except one had concomitant problems in other organs or systems. Conclusion: Since the diagnosis of OAV dysplasia relies only on a comprehensive medical evaluation, it is imperative that clinicians be aware of the most common presentation of the syndrome. Once suspected, every patient should undergo a complete medical evaluation of multiple systems including complementary exams. Treatment of these patients is based on surgical correction of malformations and rehabilitation.
RESUMO Objetivo: descrever os principais achados clínicos de uma coorte de pacientes com a displasia óculo-aurículo-vertebral (OAV). Método: revisão de prontuários médicos dos pacientes com diagnóstico de OAV no período de 1990 a 2010, acompanhados em um centro de genética médica. Resultados: foram incluídos no estudo 41 pacientes. A média de idade ao diagnóstico foi de 2 anos e 10 meses (34,4±48,8 meses) e a proporção de pacientes do sexo feminino foi de 53,7%. A média de idade dos pais ao nascimento do paciente foi de 28,5±6,9 anos para as mães e 31,4±7,4 anos para os pais. A maioria dos indivíduos (97,5%) possuía acometimento auricular, 90,2% tinham manifestações faciais, 65,9%, vertebrais, 53,7%, oculares, 36,6%, cardiovasculares, 29,3%, urogenitais e 17%, no sistema nervoso central. Além disso, 34% dos pacientes apresentavam a tríade clássica óculo-aurículo-vertebral, e todos os pacientes exceto um apresentavam concomitantemente problemas em outros órgãos ou sistemas. Conclusão: já que o diagnóstico desta entidade é eminentemente clínico, é imprescindível que os médicos das mais diversas especialidades conheçam os achados mais frequentes na OAV. Diante de um paciente com suspeita diagnóstica, deve ser realizada avaliação detalhada de outros órgãos, tanto clínica como por meio de exames complementares. O tratamento é baseado na correção cirúrgica das malformações e na reabilitação.
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Humanos , Masculino , Feminino , Síndrome de Goldenhar/patologia , Síndrome de Goldenhar/epidemiologia , Coluna Vertebral/anormalidades , Brasil/epidemiologia , Anormalidades do Olho , Prontuários Médicos , Estudos Retrospectivos , Distribuição por Sexo , Orelha/anormalidades , Face/anormalidades , Síndrome de Goldenhar/fisiopatologiaAssuntos
Doença de Fabry/patologia , Adolescente , Adulto , Angioceratoma/etiologia , Angioceratoma/patologia , Biópsia , Doença de Fabry/complicações , Doença de Fabry/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Sistema de Registros , Neoplasias Cutâneas/etiologia , Adulto JovemRESUMO
OBJECTIVES: Noonan and Noonan-related syndromes are common autosomal dominant disorders with neuro-cardio-facial-cutaneous and developmental involvement. The objective of this article is to describe the most relevant tegumentary findings in a cohort of 41 patients with Noonan or Noonan-related syndromes and to detail certain aspects of the molecular mechanisms underlying ectodermal involvement. METHODS: A standard questionnaire was administered. A focused physical examination and a systematic review of clinical records was performed on all patients to verify the presence of tegumentary alterations. The molecular analysis of this cohort included sequencing of the following genes in all patients: PTPN1, SOS1, RAF1, KRAS, SHOC2 and BRAF. RESULTS: The most frequent tegumentary alterations were xeroderma (46%), photosensitivity (29%), excessive hair loss (24%), recurrent oral ulcers (22%), curly hair (20%), nevi (17%), markedly increased palmar and plantar creases (12%), follicular hyperkeratosis (12%), palmoplantar hyperkeratosis (10%), café-au-lait spots (10%) and sparse eyebrows (7%). Patients with mutations in PTPN11 had lower frequencies of palmar and plantar creases and palmar/plantar hyperkeratosis compared with the other patients. CONCLUSIONS: We observed that patients with mutations in genes directly involved in cell proliferation kinase cascades (SOS1, BRAF, KRAS and RAF1) had a higher frequency of hyperkeratotic lesions compared with patients with mutations in genes that have a more complex interaction with and modulation of cell proliferation kinase cascades (PTPN11).
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Síndrome de Noonan/patologia , Dermatopatias/patologia , Pele/patologia , Adolescente , Adulto , Criança , Pré-Escolar , MAP Quinases Reguladas por Sinal Extracelular/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Síndrome de Noonan/genética , Estudos Prospectivos , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Fatores Sexuais , Dermatopatias/genética , Inquéritos e Questionários , Adulto JovemRESUMO
OBJECTIVES: Noonan and Noonan-related syndromes are common autosomal dominant disorders with neuro-cardio-facial-cutaneous and developmental involvement. The objective of this article is to describe the most relevant tegumentary findings in a cohort of 41 patients with Noonan or Noonan-related syndromes and to detail certain aspects of the molecular mechanisms underlying ectodermal involvement. METHODS: A standard questionnaire was administered. A focused physical examination and a systematic review of clinical records was performed on all patients to verify the presence of tegumentary alterations. The molecular analysis of this cohort included sequencing of the following genes in all patients: PTPN1, SOS1, RAF1, KRAS, SHOC2 and BRAF. RESULTS: The most frequent tegumentary alterations were xeroderma (46%), photosensitivity (29%), excessive hair loss (24%), recurrent oral ulcers (22%), curly hair (20%), nevi (17%), markedly increased palmar and plantar creases (12%), follicular hyperkeratosis (12%), palmoplantar hyperkeratosis (10%), café-au-lait spots (10%) and sparse eyebrows (7%). Patients with mutations in PTPN11 had lower frequencies of palmar and plantar creases and palmar/plantar hyperkeratosis compared with the other patients. CONCLUSIONS: We observed that patients with mutations in genes directly involved in cell proliferation kinase cascades (SOS1, BRAF, KRAS and RAF1) had a higher frequency of hyperkeratotic lesions compared with patients with mutations in genes that have a more complex interaction with and modulation of cell proliferation kinase cascades (PTPN11). .
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Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Síndrome de Noonan/patologia , Dermatopatias/patologia , Pele/patologia , MAP Quinases Reguladas por Sinal Extracelular/genética , Mutação , Síndrome de Noonan/genética , Estudos Prospectivos , /genética , Fatores Sexuais , Inquéritos e Questionários , Dermatopatias/genéticaRESUMO
OBJECTIVE: Prader-Willi Syndrome is a common etiology of syndromic obesity that is typically caused by either a paternal microdeletion of a region in chromosome 15 (microdeletions) or a maternal uniparental disomy of this chromosome. The purpose of this study was to describe the most significant clinical features of 35 Brazilian patients with molecularly confirmed Prader-Willi syndrome and to determine the effects of growth hormone treatment on clinical outcomes. METHODS: A retrospective study was performed based on the medical records of a cohort of 35 patients diagnosed with Prader-Willi syndrome. The main clinical characteristics were compared between the group of patients presenting with microdeletions and the group presenting with maternal uniparental disomy of chromosome 15. Curves for height/length, weight and body mass index were constructed and compared between Prader-Willi syndrome patients treated with and without growth hormone to determine how growth hormone treatment affected body composition. The curves for these patient groups were also compared with curves for the normal population. RESULTS: No significant differences were identified between patients with microdeletions and patients with maternal uniparental disomy for any of the clinical parameters measured. Growth hormone treatment considerably improved the control of weight gain and body mass index for female patients but had no effect on either parameter in male patients. Growth hormone treatment did not affect height/length in either gender. CONCLUSION: The prevalence rates of several clinical features in this study are in agreement with the rates reported in the literature. Additionally, we found modest benefits of growth hormone treatment but failed to demonstrate differences between patients with microdeletions and those with maternal uniparental disomy. The control of weight gain in patients with Prader-Willi syndrome is complex and does not depend exclusively on growth hormone treatment.