Autism and Down syndrome: early identification and diagnosis.

BACKGROUND: The diagnosis of autism spectrum disorder (ASD) in Down syndrome (DS) is underestimated because it is necessary to understand which aspects of the behavioral phenotype are related to DS and which are related to ASD. Objective: To conduct a systematic review of the literature on early identification and diagnosis of ASD in patients with DS. Data source: The VHL, MEDLINE, Cochrane, CINAHL, Scopus, Web of Science and Embase databases were searched and data were evaluated using PRISMA. Data synthesis: Out of 1,729 articles evaluated, 15 were selected. Although well studied, identification of ASD in DS can be difficult because of the need to understand which aspects of the behavioral phenotype are related to Down syndrome and which to autism. In this review, the prevalence of ASD was found to range from 12% to 41%. Early identification of autism risk in individuals with Down syndrome is still poorly studied, even though there are screening instruments for infants. Several instruments for diagnosing autism in individuals with Down syndrome were found, but a developmental approach is fundamental for making a clear diagnosis. Conclusions: Screening procedures are important for detecting early signs of autism risk in the first year of life. Careful evaluation methods are needed to establish the diagnosis, which include choosing appropriate tools for evaluation of development and cognition, and analysis of qualitative aspects of social interaction, among others. It has been indicated in the literature that early detection and timely accurate diagnosis, in association with an intervention, may benefit development, quality of life and social inclusion.

Neuropsychiatric and sleep study in autosomal dominant dopa-responsive dystonia.

Introduction: Although the diurnal fluctuation of motor dysfunction, reversible with small doses of dopamine, is a cornerstone for the phenotype of the autosomal dominant Segawa syndrome, the non-motor symptoms of this neurotransmitter deficiency have still received limited attention. Objective: This study aims to evaluate non-motor symptoms of this dopa-responsive dystonia through an intrafamilial comparative cross-sectional study. Methods: Seventeen individuals with a c.IVS5 + 3insT (c.626 + 3insT) variation in the GTP cyclohydrolase-1 gene (GCH1, HGNC: 4193) and 34 intrafamilial controls were studied using the Beck Depression Inventory-II, the Wiener Matrizen Test 2, the Epworth Sleepiness Scale, the Pittsburgh Sleep Quality Index, the MINI/MINI PLUS Questionnaires, the World Health Organization Quality of Life - BREF Instrument and a drug use assessment questionnaire. Results: No significant difference was found between the groups in the prevalence of sleep disorders and in cognitive function. Nevertheless, generalized anxiety disorder (p = 0.050) and attention-deficit/hyperactivity disorder in childhood (p = 0.011) were observed only in individuals without the molecular variation. The group with the GCH1 variation presented a worse perception about how safe they feel in their daily lives (p = 0.034), less satisfaction with themselves (p = 0.049) and with their relationships (p = 0.029), and a higher prevalence of past major depressive episodes before use of L-Dopa (p = 0.046). Conclusion: Low dopamine could have been protective against generalized anxiety disorder and attention-deficit/hyperactivity disorder in childhood in Segawa group individuals. The prevalence of depression was higher in individuals with the molecular variant prior to the L-Dopa treatment. Considering it, the penetrance estimates for the variant carriers increased from 58.8% to up to 88% in this large studied family. Additionally, neuropsychiatric tests of all individuals with a molecular diagnosis in an affected family are a valuable instrument for its clinical management.

Autism and Down syndrome: early identification and diagnosis / Autismo e síndrome de Down: identificação precoce e diagnóstico

ABSTRACT Background: The diagnosis of autism spectrum disorder (ASD) in Down syndrome (DS) is underestimated because it is necessary to understand which aspects of the behavioral phenotype are related to DS and which are related to ASD. Objective: To conduct a systematic review of the literature on early identification and diagnosis of ASD in patients with DS. Data source: The VHL, MEDLINE, Cochrane, CINAHL, Scopus, Web of Science and Embase databases were searched and data were evaluated using PRISMA. Data synthesis: Out of 1,729 articles evaluated, 15 were selected. Although well studied, identification of ASD in DS can be difficult because of the need to understand which aspects of the behavioral phenotype are related to Down syndrome and which to autism. In this review, the prevalence of ASD was found to range from 12% to 41%. Early identification of autism risk in individuals with Down syndrome is still poorly studied, even though there are screening instruments for infants. Several instruments for diagnosing autism in individuals with Down syndrome were found, but a developmental approach is fundamental for making a clear diagnosis. Conclusions: Screening procedures are important for detecting early signs of autism risk in the first year of life. Careful evaluation methods are needed to establish the diagnosis, which include choosing appropriate tools for evaluation of development and cognition, and analysis of qualitative aspects of social interaction, among others. It has been indicated in the literature that early detection and timely accurate diagnosis, in association with an intervention, may benefit development, quality of life and social inclusion.

RESUMO Antecedentes: O diagnóstico de autismo na síndrome de Down é subestimado, sendo necessário entender quais aspectos do fenótipo comportamental estão relacionados à síndrome de Down e quais são do autismo. Objetivo: Revisão Sistemática da Literatura sobre identificação precoce e diagnóstico do Transtorno do Espectro Autista em pacientes com síndrome de Down. Fonte de dados: Busca nas bases BVS, MEDLINE, Cochrane, CINAHL, Scopus, Web of Science e Embase e avaliação pelo PRISMA. Síntese dos dados : De 1.729 artigos avaliados, foram selecionados 15. Apesar de ser bastante estudada, a identificação do transtorno do espectro do autismo na síndrome de Down pode ser difícil devido a compreensão de quais aspectos do fenótipo comportamental estão relacionados à síndrome de Down e quais são do autismo. Nessa revisão foi encontrada variação na prevalência de 12% a 41%. A identificação precoce de risco de autismo na síndrome de Down é pouco estudada mesmo existindo instrumentos de triagem para lactentes. Sobre o diagnóstico do autismo na síndrome de Down foram encontrados diversos instrumentos, mas é necessária abordagem desenvolvimental para um diagnóstico apurado. Conclusões: É destacada a importância de procedimentos de triagem de sinais precoces de risco de autismo ainda no primeiro ano de vida. São para estabelecimento do diagnóstico a escolha de instrumentos para a avaliação do desenvolvimento e cognição, análise dos aspectos qualitativos da interação social, dentre outros. A detecção precoce e o diagnóstico preciso no tempo correto e uma intervenção poderão beneficiar o desenvolvimento, a qualidade de vida e inclusão social.

Unraveling the Genetic Architecture of Hepatoblastoma Risk: Birth Defects and Increased Burden of Germline Damaging Variants in Gastrointestinal/Renal Cancer Predisposition and DNA Repair Genes.

The ultrarare hepatoblastoma (HB) is the most common pediatric liver cancer. HB risk is related to a few rare syndromes, and the molecular bases remain elusive for most cases. We investigated the burden of rare damaging germline variants in 30 Brazilian patients with HB and the presence of additional clinical signs. A high frequency of prematurity (20%) and birth defects (37%), especially craniofacial (17%, including craniosynostosis) and kidney (7%) anomalies, was observed. Putative pathogenic or likely pathogenic monoallelic germline variants mapped to 10 cancer predisposition genes (CPGs: APC, CHEK2, DROSHA, ERCC5, FAH, MSH2, MUTYH, RPS19, TGFBR2 and VHL) were detected in 33% of the patients, only 40% of them with a family history of cancer. These findings showed a predominance of CPGs with a known link to gastrointestinal/colorectal and renal cancer risk. A remarkable feature was an enrichment of rare damaging variants affecting different classes of DNA repair genes, particularly those known as Fanconi anemia genes. Moreover, several potentially deleterious variants mapped to genes impacting liver functions were disclosed. To our knowledge, this is the largest assessment of rare germline variants in HB patients to date, contributing to elucidate the genetic architecture of HB risk.

Mother's sense of coherence and dental characteristics in children and adolescents with osteogenesis imperfecta: A paired study.

BACKGROUND: The relevance of sense of coherence (SOC) is important to the wellbeing of parents, especially mothers of children and adolescents with osteogenesis imperfecta (OI). OBJECTIVE: Determine whether the oral health status of children/adolescents with OI is associated with mother's SOC. MATERIALS AND METHOD: A paired cross-sectional study was conducted with 37 children/adolescents with OI, 37 without OI, and their respective mothers. The children/adolescents were between two and 19 years of age, mean age 7.2 years, being 47 male and 27 female. The mothers completed Antonovsky's SOC questionnaire (SOC-13), and the oral status of the children/adolescents was investigated. The following clinical conditions were evaluated: dentinogenesis imperfecta, malocclusion, gingivitis, and dental caries experience. RESULTS: The genetic condition of the children was significantly associated with mother's SOC (P < .001). Mothers of children with OI had lower SOC scores (mean: 35.6 [± 4.9]) than mothers of children without OI (mean: 38.5 [± 4.3]). In the group with OI, a low socioeconomic status was associated with lower mother's SOC scores (P = .004). In both groups, dental caries experience was associated with lower mother's SOC scores (P = .007). Most individuals with OI presented malocclusion (78.3%) and experience of dental caries (59.4%). CONCLUSION: Having a child with OI influenced the sense of coherence of the mothers. Socioeconomic status and dental caries experience in children and adolescents with OI were associated with mother's SOC.

De novo loss-of-function variants in X-linked MED12 are associated with Hardikar syndrome in females.

PURPOSE: Hardikar syndrome (MIM 612726) is a rare multiple congenital anomaly syndrome characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, but with preserved cognition. Only four patients have been reported previously, and none had a molecular diagnosis. Our objective was to identify the genetic basis of Hardikar syndrome (HS) and expand the phenotypic spectrum of this disorder. METHODS: We performed exome sequencing on two previously reported and five unpublished female patients with a clinical diagnosis of HS. X-chromosome inactivation (XCI) studies were also performed. RESULTS: We report clinical features of HS with previously undescribed phenotypes, including a fatal unprovoked intracranial hemorrhage at age 21. We additionally report the discovery of de novo pathogenic nonsense and frameshift variants in MED12 in these seven individuals and evidence of extremely skewed XCI in all patients with informative testing. CONCLUSION: Pathogenic missense variants in the X-chromosome gene MED12 have previously been associated with Opitz-Kaveggia syndrome, Lujan syndrome, Ohdo syndrome, and nonsyndromic intellectual disability, primarily in males. We propose a fifth, female-specific phenotype for MED12, and suggest that nonsense and frameshift loss-of-function MED12 variants in females cause HS. This expands the MED12-associated phenotype in females beyond intellectual disability.

Quantitative analysis of amino acids by HPLC in dried blood and urine in the neonatal period: Establishment of reference values.

Quantitative analysis of amino acids in blood and urine is primarily indicated for the diagnosis of amino acid disorders. The high-performance liquid chromatography (HPLC) technique is frequently used for this detection. The frequency of sample collection on filter paper has been increasing exponentially, and there are many advantages attributed to processing biological samples in this way. The aim of this study was to validate a quantitative analysis of amino acids by HPLC in blood and urine collected on filter paper and to establish reference values in the neonatal period. Dried blood and dried urine samples of respectively 58 and 45 healthy newborns (2-9 days) were collected. Pre-treatment and extraction of samples were done according to the literature. Separation and analysis of amino acids were carried out by HPLC with fluorescence detection. The developed method demonstrated excellent separation, linearity, limits of detection and quantification, repeatability and recovery. The reference values for 17 amino acids were defined in dried blood and urine samples of newborns. This work presents a simple, fast and effective method for the simultaneous analysis of 17 amino acids in blood and urine collected on filter paper in a single run. The reference values were established and validated.

Clinical Characterization of Mucolipidoses II and III: A Multicenter Study.

Mucolipidoses (MLs) II and III are rare lysosomal diseases caused by deficiency of GlcNAc-1-phosphotransferase, and clinical manifestations are multisystemic. Clinical and demographic data from 1983 to 2013 were obtained retrospectively. Twenty-seven patients were included (ML II = 15, ML III α/beta = 9, ML III gamma = 3). The median age at diagnosis was 2.7 years. The predominant clinical presentations were skeletal symptoms. The ML II patients showed physical and cognitive impairment, while the ML III α/beta patients have more somatic abnormalities and usually were delayed in early development as compared with ML III gamma patients. This is the most comprehensive study exploring characteristics of Brazilian patients with MLs II and III.

Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) comprises a genetically heterogeneous group of skeletal fragility diseases. Here, we report on five independent families with a progressively deforming type of OI, in whom we identified four homozygous truncation or frameshift mutations in MESD. Affected individuals had recurrent fractures and at least one had oligodontia. MESD encodes an endoplasmic reticulum (ER) chaperone protein for the canonical Wingless-related integration site (WNT) signaling receptors LRP5 and LRP6. Because complete absence of MESD causes embryonic lethality in mice, we hypothesized that the OI-associated mutations are hypomorphic alleles since these mutations occur downstream of the chaperone activity domain but upstream of ER-retention domain. This would be consistent with the clinical phenotypes of skeletal fragility and oligodontia in persons deficient for LRP5 and LRP6, respectively. When we expressed wild-type (WT) and mutant MESD in HEK293T cells, we detected WT MESD in cell lysate but not in conditioned medium, whereas the converse was true for mutant MESD. We observed that both WT and mutant MESD retained the ability to chaperone LRP5. Thus, OI-associated MESD mutations produce hypomorphic alleles whose failure to remain within the ER significantly reduces but does not completely eliminate LRP5 and LRP6 trafficking. Since these individuals have no eye abnormalities (which occur in individuals completely lacking LRP5) and have neither limb nor brain patterning defects (both of which occur in mice completely lacking LRP6), we infer that bone mass accrual and dental patterning are more sensitive to reduced canonical WNT signaling than are other developmental processes. Biologic agents that can increase LRP5 and LRP6-mediated WNT signaling could benefit individuals with MESD-associated OI.

Glycogen storage diseases: Twenty-seven new variants in a cohort of 125 patients.

BACKGROUND: Hepatic glycogen storage diseases (GSDs) are a group of rare genetic disorders in which glycogen cannot be metabolized to glucose in the liver because of enzyme deficiencies along the glycogenolytic pathway. GSDs are well-recognized diseases that can occur without the full spectrum, and with overlapping in symptoms. METHODS: We analyzed a cohort of 125 patients with suspected hepatic GSD through a next-generation sequencing (NGS) gene panel in Ion Torrent platform. New variants were analyzed by pathogenicity prediction tools. RESULTS: Twenty-seven new variants predicted as pathogenic were found between 63 variants identified. The most frequent GSD was type Ia (n = 53), followed by Ib (n = 23). The most frequent variants were p.Arg83Cys (39 alleles) and p.Gln347* (14 alleles) in G6PC gene, and p.Leu348Valfs (21 alleles) in SLC37A4 gene. CONCLUSIONS: The study presents the largest cohort ever analyzed in Brazilian patients with hepatic glycogenosis. We determined the clinical utility of NGS for diagnosis. The molecular diagnosis of hepatic GSDs enables the characterization of diseases with similar clinical symptoms, avoiding hepatic biopsy and having faster results.

X chromosome dosage and presence of SRY shape sex-specific differences in DNA methylation at an autosomal region in human cells.

BACKGROUND: Sexual dimorphism in DNA methylation levels is a recurrent epigenetic feature in different human cell types and has been implicated in predisposition to disease, such as psychiatric and autoimmune disorders. To elucidate the genetic origins of sex-specific DNA methylation, we examined DNA methylation levels in fibroblast cell lines and blood cells from individuals with different combinations of sex chromosome complements and sex phenotypes focusing on a single autosomal region--the differentially methylated region (DMR) in the promoter of the zona pellucida binding protein 2 (ZPBP2) as a reporter. RESULTS: Our data show that the presence of the sex determining region Y (SRY) was associated with lower methylation levels, whereas higher X chromosome dosage in the absence of SRY led to an increase in DNA methylation levels at the ZPBP2 DMR. We mapped the X-linked modifier of DNA methylation to the long arm of chromosome X (Xq13-q21) and tested the impact of mutations in the ATRX and RLIM genes, located in this region, on methylation levels. Neither ATRX nor RLIM mutations influenced ZPBP2 methylation in female carriers. CONCLUSIONS: We conclude that sex-specific methylation differences at the autosomal locus result from interaction between a Y-linked factor SRY and at least one X-linked factor that acts in a dose-dependent manner.

CBS mutations are good predictors for B6-responsiveness: A study based on the analysis of 35 Brazilian Classical Homocystinuria patients.

BACKGROUND: Classical homocystinuria (HCU) is a monogenic disease caused by the deficient activity of cystathionine ß-synthase (CßS). The objective of this study was to identify the CBS mutations in Brazilian patients with HCU. METHODS: gDNA samples were obtained for 35 patients (30 families) with biochemically confirmed diagnosis of HCU. All exons and exon-intron boundaries of CBS gene were sequenced. Gene expression analysis by qRT-PCR was performed in six patients. Novel missense point mutations were expressed in E. coli by site-directed mutagenesis. RESULTS: Parental consanguinity was reported in 16 families, and pyridoxine responsiveness in five (15%) patients. Among individuals from the same family, all presented the same phenotype. Both pathogenic mutations were identified in 29/30 patients. Twenty-one different mutations were detected in nine exons and three introns; being six common mutations. Most prevalent were p.Ile278Thr (18.2%), p.Trp323Ter (11.3%), p.Thr191Met (11.3%), and c.828+1G>A (11.3%). Eight novel mutations were found [c.2T>C, c.209+1delG, c.284T>C, c.329A>T, c.444delG, c.864_868delGAG c.989_991delAGG, and c.1223+5G>T]. Enzyme activity in E. coli-expressed mutations was 1.5% for c.329A>T and 17.5% for c.284T>C. qRT-PCR analysis revealed reduced gene expression in all evaluated genotypes: [c.209+1delG; c.572C>T]; [c.2T>C; c.828+1G>A]; [c.828+1G>A; c.1126G>A]; [c.833T>C; c.989_991delAGG]; [c.1058C>T; c.146C>T]; and [c.444delG; c.444delG]. The expected phenotype according to the genotype (pyridoxine responsiveness) matched in all cases. CONCLUSIONS: Most patients studied were pyridoxine nonresponsive and presented early manifestations, suggesting severe phenotypes. Many private mutations were observed, but the four most prevalent mutations together accounted for over 50% of mutated alleles. A good genotype-phenotype relationship was observed within families and for the four most common mutations.

Diagnosis and Management of Classica Homocystinuria in Brazil: A Summary of 72 Late-Diagnosed Patients

Abstract This study described a broad clinical characterization of classical homocystinuria (HCU) in Brazil. This was a cross-sectional, observational study including clinical and biochemical data from 72 patients (60 families) from Brazil (South, n = 13; Southeast, n = 37; Northeast, n = 8; North, n = 1; and Midwest, n = 1). Parental consanguinity was reported in 42% of families. Ocular manifestations were the earliest detected symptom (53% of cases), the main reason for diagnostic suspicion (63% of cases), and the most prevalent manifestation at diagnosis (67% of cases). Pyridoxine responsiveness was observed in 14% of patients. Only 22% of nonresponsive patients on treatment had total homocysteine levels <100 mmol/L. Most commonly used treatment strategies were pyridoxine (93% of patients), folic acid (90%), betaine (74%), vitamin B12 (27%), and low-methionine diet + metabolic formula (17%). Most patients diagnosed with HCU in Brazil are late diagnosed, express a severe phenotype, and poor metabolic control. Milder forms of HCU are likely underrepresented due to underdiagnosis.

Oral health of children and adolescents with mucopolysaccharidosis and mother's Sense of Coherence.

AIMS: The purpose of this study is assess the association between mother's Sense of Coherence (SOC) and the oral health status of children with and without mucopolysaccharidosis (MPS). METHODS: A cross-sectional study was carried out with 29 children/adolescents with MPS and 29 children/adolescents without MPS, and their mothers in Brazil. Mothers completed the Antonovsky's SOC instrument (SOC-13) and their children's oral cavity had been examined for developmental defects of enamel (DDE), occlusal problems, dental caries (DMFT/dmft) and oral hygiene. This study was approved by the Research Ethics Committee of the Universidade Federal de Minas Gerais. RESULTS: Mothers of children with MPS had lower SOC scores (mean: 33.3 [±4.0]) compared with mothers of children without MPS (mean: 36.9 [±4.5]) (p < 0.001). Mother's SOC of children with MPS were lower for those children with one or more decayed teeth (31.5 [±3.2]) than for those children/adolescents without caries (35.7 [±3.8]) (p = 0.004) and lower for those children/adolescents with one or more missing teeth (30.2 [±0.9]) than for those individuals identified without missing teeth (33.8 [±4.1]) (p = 0.046). CONCLUSION: Mothers' SOC of children/adolescents with MPS was associated with dental caries experience in their children. Improving mothers' SOC should contribute to a better quality of life for their children.

Inherited Xq13.2-q21.31 duplication in a boy with recurrent seizures and pubertal gynecomastia: Clinical, chromosomal and aCGH characterization.

We report on a 16-year-old boy with a maternally inherited ~ 18.3 Mb Xq13.2-q21.31 duplication delimited by aCGH. As previously described in patients with similar duplications, his clinical features included intellectual disability, developmental delay, speech delay, generalized hypotonia, infantile feeding difficulties, self-injurious behavior, short stature and endocrine problems. As additional findings, he presented recurrent seizures and pubertal gynecomastia. His mother was phenotypically normal and had completely skewed inactivation of the duplicated X chromosome, as most female carriers of such duplications. Five previously reported patients with partial Xq duplications presented duplication breakpoints similar to those of our patient. One of them, a fetus with multiple congenital abnormalities, had the same cytogenetic duplication breakpoint. Three of the reported patients shared many features with our proband but the other had some clinical features of the Prader-Willi syndrome. It was suggested that ATRX overexpression could be involved in the major clinical features of patients with partial Xq duplications. We propose that this gene could also be involved with the obesity of the patient with the Prader-Willi-like phenotype. Additionally, we suggest that the PCDH11X gene could be a candidate for our patient's recurrent seizures. In males, the Xq13-q21 duplication should be considered in the differential diagnosis of Prader-Willi syndrome, as previously suggested, and neuromuscular diseases, particularly mitochondriopathies.

Amino acid reference intervals by high performance liquid chromatography in plasma sample of Brazilian children / Valores de referência de aminoácidos por cromatografia líquida de alta eficiência em amostras de plasma de crianças brasileiras

ABSTRACT Introduction: The high performance liquid chromatography is a technique used for quantification of amino acids in plasma. The definition of reference intervals in the population is very important for the diagnosis and monitoring of individuals with amino acid disorders. Objectives: The objectives of this study were to validate a method for amino acids quantification and define reference intervals in Brazilian children. Results: Good chromatographic separation was achieved using C18 solid-core column. The method showed satisfactory linearity, limits of detection and quantification, precision and accuracy. The reference ranges for aspartate, glutamate, asparagine, histidine, serine, glutamine, arginine, tyrosine, alanine, tryptophan, methionine, valine, phenylalanine, isoleucine and leucine were defined in a group of 60 healthy individuals aged 2 to 14 years. Conclusion: The presented technique can be applied in clinical practice. Each laboratory should preferably establish its own reference intervals. If that is not possible, it is recommended the use of the reference intervals described in this study for the diagnosis and monitoring of Brazilian children in this age group.

RESUMO Introdução: A cromatografia líquida de alta eficiência é uma técnica utilizada para quantificação de aminoácidos no plasma. A definição de intervalos de referência na população é importante para o diagnóstico e o monitoramento de indivíduos com aminoacidopatias. Objetivos: Os objetivos do presente estudo foram validar um método de quantificação de aminoácidos e definir intervalos de referência em crianças brasileiras. Resultados: Boa separação cromatográfica foi obtida utilizando uma coluna de núcleo sólido C18. O método apresentou linearidade, limites de detecção e quantificação, precisão e acurácia satisfatórios. Os intervalos de referência para aspartato, glutamato, asparagina, histidina, serina, glutamina, arginina, tirosina, alanina, triptofano, metionina, valina, fenilalanina, isoleucina e leucina foram definidos em um grupo de 60 indivíduos sadios com idade entre 2 e 14 anos. Conclusão: A técnica apresentada pode ser aplicada na prática clínica. Cada laboratório deve, preferencialmente, estabelecer os próprios intervalos de referência. Se não for possível, recomenda-se a utilização dos intervalos de referência descritos neste estudo para o diagnóstico e o monitoramento de crianças brasileiras nessa faixa etária.

Neurofibromatosis: part 2 – clinical management / Neurofibromatoses: parte 2 – manejo clínico

Part 1 of this guideline addressed the differential diagnosis of the neurofibromatoses (NF): neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis (SCH). NF shares some features such as the genetic origin of the neural tumors and cutaneous manifestations, and affects nearly 80 thousand Brazilians. Increasing scientific knowledge on NF has allowed better clinical management and reduced rate of complications and morbidity, resulting in higher quality of life for NF patients. Most medical doctors are able to perform NF diagnosis, but the wide range of clinical manifestations and the inability to predict the onset or severity of new features, consequences, or complications make NF management a real clinical challenge, requiring the support of different specialists for proper treatment and genetic counseling, especially in NF2 and SCH. The present text suggests guidelines for the clinical management of NF, with emphasis on NF1.

A primeira parte desta diretriz abordou o diagnóstico diferencial das neurofibromatoses (NF): neurofibromatose do tipo 1 (NF1), neurofibromatose do tipo 2 (NF2) e schwannomatose (SCH). As NF compartilham algumas características, como a origem neural dos tumores e sinais cutâneos, e afetam cerca de 80 mil brasileiros. O aumento do conhecimento científico sobre as NF tem permitido melhor manejo clínico e redução da morbidade das complicações, resultando em melhor qualidade de vida para os pacientes com NF. A maioria dos médicos é capaz de realizar o diagnóstico das NF, mas a variedade de manifestações clínicas e a dificuldade de se prever o surgimento e a gravidade de complicações, torna o manejo da NF um desafio para o clínico e envolve diferentes especialistas para o tratamento adequado e aconselhamento genético, especialmente a NF2 e a SCH. O presente texto sugere algumas orientações para o acompanhamento dos portadores de NF, com ênfase na NF1.

Subtelomeric 6p25 deletion/duplication: Report of a patient with new clinical findings and genotype-phenotype correlations.

The 6p terminal deletions are rare and present variability of clinical features, which increases the importance of reporting additional cases in order to better characterize genotype-phenotype correlations. We report a 12-year-old girl with a de novo deletion in 6p25.1-pter characterized by high-resolution karyotyping and FISH. Further analysis using oligonucleotide array-CGH revealed a 5.06 Mb 6p25.1-pter deletion associated with a contiguous 1 Mb 6p25.1 duplication. The patient presented normal growth, developmental delay, frontal bossing, severe hypertelorism, corectopia, wide and depressed nasal bridge, mild learning disability, hearing loss and diffuse leukopathy. Additionaly, she presented peculiar phenotypic features reported herein for the first time in 6p25 deletion syndrome: cerebrospinal fluid fistula and bones resembling those seen in 3-M syndrome. The distinctive phenotype of the 6p25 deletion syndrome has been mainly correlated with the FOXC1 and FOXF2 genes deletions, both related mainly to eye development. We also consider the SERPINB6 as a candidate for sensorineural hearing loss and TUBB2A as a candidate for our patient's skeletal features. In addition, as our patient had a duplication including NRN1, a gene related with neurodevelopment, synaptic plasticity and cognitive dysfunction in schizophrenia, we suggest that this gene could be associated with her white matter abnormalities and neurocognitive phenotype.

Hereditary fructose intolerance in Brazilian patients.

INTRODUCTION: Hereditary fructose intolerance (HFI) is a rare inborn error of carbohydrate metabolism, autosomal recessive, caused by mutations in the gene ALDOB, leading to deficiency of aldolase B. Symptoms begin in the first months of life with the introduction of complementary foods containing fructose, sucrose or sorbitol, often with vomiting, feeding problems and failure to thrive. Prolonged exposure may cause liver and kidney failure, which can lead to death. Treatment consists in removing the toxic sugars of diet. MATERIALS AND METHODS: Clinical and molecular characterization of four unrelated patients from the State of Minas Gerais, Brazil, all children from non-consanguineous parents. RESULTS AND DISCUSSION: Age at diagnosis was between 10 and 32 months and the severity of the disease correlated with the increasing of age at diagnosis. The predominant symptoms were vomiting, weight loss, and hepatomegaly. Severe renal tubular acidosis manifested in one child. All patients had remission of symptoms after dietary modification. The sequencing of the ALDOB gene identified one homozygous patient for the mutation c.524C > A (p.A175D), while the others were compound heterozygous for c.360_363delCAAA (p.N120KfsX32), c.178C > T (p.R60X) mutations, c.448G > C (p.A150P) and c.524C > A (p.A175D). Clinical improvement of patients after dietary treatment is suggestive of the diagnosis, confirmed by molecular analysis. The prevalence of mutations found in our Brazilian patients is different from those of international literature.

What is new in genetics and osteogenesis imperfecta classification? / O que há de novo em genética e classificação de osteogênese imperfeita?

OBJECTIVE: Literature review of new genes related to osteogenesis imperfecta (OI) and update of its classification. SOURCES: Literature review in the PubMed and OMIM databases, followed by selection of relevant references. SUMMARY OF THE FINDINGS: In 1979, Sillence et al. developed a classification of OI subtypes based on clinical features and disease severity: OI type I, mild, common, with blue sclera; OI type II, perinatal lethal form; OI type III, severe and progressively deforming, with normal sclera; and OI type IV, moderate severity with normal sclera. Approximately 90% of individuals with OI are heterozygous for mutations in the COL1A1 and COL1A2 genes, with dominant pattern of inheritance or sporadic mutations. After 2006, mutations were identified in the CRTAP, FKBP10, LEPRE1, PLOD2, PPIB, SERPINF1, SERPINH1, SP7, WNT1, BMP1, and TMEM38B genes, associated with recessive OI and mutation in the IFITM5 gene associated with dominant OI. Mutations in PLS3 were recently identified in families with osteoporosis and fractures, with X-linked inheritance pattern. In addition to the genetic complexity of the molecular basis of OI, extensive phenotypic variability resulting from individual loci has also been documented. CONCLUSIONS: Considering the discovery of new genes and limited genotype-phenotype correlation, the use of next-generation sequencing tools has become useful in molecular studies of OI cases. The recommendation of the Nosology Group of the International Society of Skeletal Dysplasias is to maintain the classification of Sillence as the prototypical form, universally accepted to classify the degree of severity in OI, while maintaining it free from direct molecular reference. .

OBJETIVO: Revisão da literatura sobre novos genes relacionados à osteogênese imperfeita (OI) e atualização da sua classificação. FONTE DOS DADOS : Revisão nas bases de dados do PUBMED e OMIM com seleção de referências relevantes. SÍNTESE DOS DADOS: Sillence et al., em 1979, desenvolveram uma classificação dos subtipos de OI baseada em características clínicas e gravidade da doença: OI tipo I, forma leve, comum, com escleras azuladas; OI tipo II, forma perinatal letal; OI tipo III, forma grave e progressivamente deformante com esclera normal; e OI tipo IV, forma de gravidade moderada com esclera normal. Cerca de 90% dos indivíduos com OI são heterozigotos para mutações em COL1A1 e COL1A2, com padrão de herança dominante ou esporádico. A partir de 2006 foram identificadas mutações nos genes CRTAP, FKBP10, LEPRE1, PLOD2, PPIB, SERPINF1, SERPINH1, SP7, WNT1, BMP1 e TMEM38B associadas à OI recessiva e mutação em IFITM5 associada à OI dominante. Mutações em PLS3 foram identificadas recentemente em famílias com osteoporose e fraturas, com padrão de herança ligado ao X. Além da complexidade genética das bases moleculares das OI, extensa variabilidade fenotípica resultante de loci individuais também tem sido documentada. CONCLUSÕES: Face à descoberta de novos genes e à correlação genótipo-fenótipo limitada, o uso de ferramentas de sequenciamento de nova geração torna-se útil no estudo molecular de casos de OI. A recomendação do Grupo de Nosologia da Sociedade Internacional de Displasias Esqueléticas é manter a classificação de Sillence como a forma prototípica e universalmente aceita para classificar o grau de gravidade na OI, e libertá-la de referência ...