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Septo-optic dysplasia (SOD) syndrome is a rare congenital disorder characterized by a classic triad of optic nerve/chiasm hypoplasia, agenesis of septum pellucidum and corpus callosum, and hypoplasia of the hypothalamic-pituitary axis.Herein, we report the clinical case of 2-year-old boy presenting with psychomotor delay, nystagmus, congenital hypothyroidism, and a clinically relevant growth delay. The neuroradiological examination showed partial segmental agenesis of the corpus callosum, agenesis of the septum pellucidum, optic nerve hypoplasia, and a small pituitary gland with a small median pituitary stalk. A whole-exome sequencing analysis detected a novel heterozygous de novo variant c.1069_1070delAG in SON, predicted as likely pathogenic.To date, SON pathogenic variants have been described as responsible for Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome, a multisystemic neurodevelopmental disorder mainly characterized by intellectual disability, facial dysmorphisms, visual abnormalities, brain malformations, feeding difficulties, and growth delay. The herein described case is the first recognized clinic-radiological occurrence of SOD syndrome with hypothalamic-pituitary dysfunction in a patient carrying a SON gene variant, considered responsible of ZTTK syndrome, suggesting a possible relationship between SOD and SON gene alterations, never described so far, making the search for SON gene mutations advisable in patients with SOD.
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Unbalanced X;autosome translocations are a rare occurrence with a wide variability in clinical presentation in which the X chromosome unbalance is usually mitigated by a favorable X inactivation pattern. In most cases, this compensation mechanism is incomplete, and the patients show a syndromic clinical presentation. We report the case of a family with 4 women, of 3 different generations, carrying an unbalanced X;7 translocation with a derivative X;7 chromosome and showing a skewed X inactivation pattern with a preferential activation of the normal X. None of the carriers show intellectual disability, and all of them have a very mild clinical presentation mainly characterized by gynecological/hormonal issues and autoimmune disorders. We underline the necessity of family testing for a correct genetic consultation, especially in the field of prenatal diagnosis. We indeed discuss the fact that X;autosome translocations may lead to self-immunization, as skewed X chromosome inactivation has already been proved to be related to autoimmune disorders.
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Doenças Autoimunes/genética , Transtornos Cromossômicos/genética , Cromossomos Humanos X/genética , Translocação Genética , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Linhagem , Fenótipo , Gravidez , Inativação do Cromossomo XAssuntos
Doenças Genéticas Ligadas ao Cromossomo X , Oftalmoplegia , Adulto , Feminino , Humanos , Apraxias , Contratura , Atrofia MuscularRESUMO
Marfan syndrome (MFS) is a rare hereditable disorder of connective tissue caused by mutations in the fibrillin-1 gene FBN1. Timely diagnosis of MFS is essential to prevent life-threatening cardiovascular complications; nevertheless it can be difficult owing to the phenotypic variability of the syndrome. No clear quantitative definition of facial abnormalities associated with MFS is available. The aim of this study was to improve the definition of the facial phenotype associated with MFS and to verify the usefulness of a 3D noninvasive quantitative approach for its early recognition. 3D facial images of 61 Italian subjects with MFS, aged 16-64 years (21 males, 38 ± 15 years; 40 females, 41 ± 13 years) were obtained by stereophotogrammetry. From the coordinates of 17 soft-tissue facial landmarks, linear distances and angles were computed; z score values were calculated to compare patients with healthy reference subjects (400 males, 379 females) matched for sex and age. Student's t test was used for statistical comparisons. All subjects with MFS showed greater facial divergence (P < 0.001; mean z score +1.9) and a lower facial height index (P < 0.001; mean z score -1.9) than reference subjects, both values being influenced by a shorter mandibular ramus (P < 0.001; mean z score -1.9) and a mild but significant increase in facial height (P < 0.001; mean z score +1.2). Palpebral down-slanting was found in 85% of MFS subjects. There were no sex differences. Quantitative abnormalities identified in this study enrich information about the facial dysmorphism in MFS and confirm its usefulness for early recognition of the disease. Clin. Anat. 31:380-386, 2018. © 2017 Wiley Periodicals, Inc.
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Face/patologia , Síndrome de Marfan/patologia , Adolescente , Adulto , Antropometria , Feminino , Humanos , Imageamento Tridimensional , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
In this study, we used deletions at 22q13, which represent a substantial source of human pathology (Phelan/McDermid syndrome), as a model for investigating the molecular mechanisms of terminal deletions that are currently poorly understood. We characterized at the molecular level the genomic rearrangement in 44 unrelated patients with 22q13 monosomy resulting from simple terminal deletions (72%), ring chromosomes (14%), and unbalanced translocations (7%). We also discovered interstitial deletions between 17-74 kb in 9% of the patients. Haploinsufficiency of the SHANK3 gene, confirmed in all rearrangements, is very likely the cause of the major neurological features associated with PMS. SHANK3 mutations can also result in language and/or social interaction disabilities. We determined the breakpoint junctions in 29 cases, providing a realistic snapshot of the variety of mechanisms driving non-recurrent deletion and repair at chromosome ends. De novo telomere synthesis and telomere capture are used to repair terminal deletions; non-homologous end-joining or microhomology-mediated break-induced replication is probably involved in ring 22 formation and translocations; non-homologous end-joining and fork stalling and template switching prevail in cases with interstitial 22q13.3. For the first time, we also demonstrated that distinct stabilizing events of the same terminal deletion can occur in different early embryonic cells, proving that terminal deletions can be repaired by multistep healing events and supporting the recent hypothesis that rare pathogenic germline rearrangements may have mitotic origin. Finally, the progressive clinical deterioration observed throughout the longitudinal medical history of three subjects over forty years supports the hypothesis of a role for SHANK3 haploinsufficiency in neurological deterioration, in addition to its involvement in the neurobehavioral phenotype of PMS.
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Deleção Cromossômica , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 22/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Pais , Cromossomos em Anel , Deleção de Sequência/genética , Translocação Genética , Adulto JovemRESUMO
BACKGROUND: Membrane Protein Palmitoylated 5 (MPP5) is a highly conserved apical complex protein, essential for cell polarity. Defects in neuronal cell polarity are associated with neurologic disorders. Only three patients with heterozygous MPP5 de novo variants have been reported so far, with global developmental delay, behavioral changes and in only one case epileptic seizures. OBJECTIVE: To describe a new patient with a novel truncating de novo mutation in MPP5 and to characterize in detail the epileptic phenotype and electroencephalographic features of the encephalopathy. METHODS: We identified a novel truncating de novo mutation in MPP5 in a 44 year old patient by exome sequencing (p.Ser498Phefs*15). We retrospectively analyzed his clinical and instrumental data along a thirty-year follow up. RESULT: Our patient presents with generalized tonic-clonic seizures, myoclonic and clonic seizures, non-epileptic myoclonus, tremor, severe intellectual disability, mild face dysmorphic traits, and psychosis. DISCUSSION AND CONCLUSION: We present a case of a childhood onset developmental encephalopathy with a likely-pathogenic variant in the MPP5 gene.. This represents the first complete description of the epileptic syndrome associated with the MPP5 gene.
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Encefalopatias , Epilepsia , Deficiência Intelectual , Humanos , Criança , Adulto , Estudos Retrospectivos , Epilepsia/genética , Convulsões/genética , Deficiência Intelectual/genética , Fenótipo , Encefalopatias/genética , Proteínas de Membrana/genética , Núcleosídeo-Fosfato Quinase/genéticaRESUMO
Marfan syndrome (MFS) is a rare inherited autosomic disorder, which encompasses a variety of systemic manifestations caused by mutations in the Fibrillin-1 encoding gene (FBN1). Cardinal clinical phenotypes of MFS are highly variable in terms of severity, and commonly involve cardiovascular, ocular, and musculoskeletal systems with a wide range of manifestations, such as ascending aorta aneurysms and dissection, mitral valve prolapse, ectopia lentis and long bone overgrowth, respectively. Of note, an accurate and prompt diagnosis is pivotal in order to provide the best treatment to the patients as early as possible. To date, the diagnosis of the syndrome has relied upon a systemic score calculation as well as DNA mutation identification. The aim of this review is to summarize the latest MFS evidence regarding the definition, differences and similarities with other connective tissue pathologies with severe systemic phenotypes (e.g., Autosomal dominant Weill-Marchesani syndrome, Loeys-Dietz syndrome, Ehlers-Danlos syndrome) and clinical assessment. In this regard, the management of MFS requires a multidisciplinary team in order to accurately control the evolution of the most severe and potentially life-threatening complications. Based on recent findings in the literature and our clinical experience, we propose a multidisciplinary approach involving specialists in different clinical fields (i.e., cardiologists, surgeons, ophthalmologists, orthopedics, pneumologists, neurologists, endocrinologists, geneticists, and psychologists) to comprehensively characterize, treat, and manage MFS patients with a personalized medicine approach.
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Submicroscopic copy-number variations make a considerable contribution to the genetic etiology of human disease. We have analyzed subjects with idiopathic mental retardation (MR) by using whole-genome oligonucleotide-based array comparative genomic hybridization (aCGH) and identified familial and de novo recurrent Xp11.22-p11.23 duplications in males and females with MR, speech delay, and a peculiar electroencephalographic (EEG) pattern in childhood. The size of the duplications ranges from 0.8-9.2 Mb. Most affected females show preferential activation of the duplicated X chromosome. Carriers of the smallest duplication show X-linked recessive inheritance. All other affected individuals present dominant expression and comparable clinical phenotypes irrespective of sex, duplication size, and X-inactivation pattern. The majority of the rearrangements are mediated by recombination between flanking complex segmental duplications. The identification of common clinical features, including the typical EEG pattern, predisposing genomic structure, and peculiar X-inactivation pattern, suggests that duplication of Xp11.22-p11.23 constitutes a previously undescribed syndrome.
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Cromossomos Humanos X/genética , Eletroencefalografia , Duplicação Gênica , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/complicações , Transtornos do Desenvolvimento da Linguagem/genética , Feminino , Humanos , Masculino , LinhagemRESUMO
We describe a 5-year-old girl who was diagnosed at birth with 18q de novo homogeneous deletion at G-banding karyotype. Her clinical condition, characterized by hypotonia, psychomotor retardation, short stature, deafness secondary to bilateral atresia of the external auditory canals, was in agreement with the 18q deletion syndrome though presence of coloboma of a single eye only suggested a mosaic condition as an unusual sign. By combining multiple technologies including array-CGH, FISH, and WGS, we found that the terminal deletion 18q21.32q23 (21 Mb) was in segmental mosaicism of the proximal region 18q21.31q21.32 (2.7 Mb), which showed a variable number of copies: one, two, or three, in 7, 41 and 55% of the cells respectively. Breakpoint junction analysis demonstrated the presence of an inv-dup del (18q) with a disomic segment of 4.7 kb between the inverted and non-inverted copies of the duplicated region 18q21.31q21.32. From these results, we propose that all three types of abnormal chr18 (the inv-dup del and the two 18q terminal deletions of different sizes) arisen from breaks in a dicentric mirror chromosome 18q, either in more than one embryo cell or from subsequent breaking-fusion-bridge cycles. The duplication region was with identical polymorphisms as in all non-recurrent inv-dup del rearrangements though, in contrast with most of them, the 18q abnormality was of maternal origin. Taking into account that distal 18q deletions are not rarely associated with inv-dup del(18q) cell lines, and that the non-disjunction of chromosome 18 takes place especially at maternal meiosis II rather than meiosis I, multiple rescue events starting from trisomic zygotes could be considered alternative to the postmitotic ones. From the clinical point of view, our case, as well as those of del(18q) in mosaic with the dic(18q), shows that the final phenotype is the sum of the different cell lines that acted on embryonic development with signs typical of both the 18q deletion syndrome and trisomy 18. Asymmetrical malformations, such as coloboma of the iris only in the right eye, confirm the underlying mosaicism regardless of whether it is still detectable in the blood.
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Cromossomos Humanos Par 18 , Coloboma , Linhagem Celular , Deleção Cromossômica , Transtornos Cromossômicos , Inversão Cromossômica , Cromossomos Humanos Par 18/genética , Feminino , Humanos , Mosaicismo , GravidezRESUMO
Pathogenic variants of the SCN2A gene (MIM 182390) are associated with several epileptic syndromes ranging from benign familial neonatal-infantile seizures (BFNIS) to early infantile epileptic encephalopathy. The aim of this work was to describe clinical features among five patients with concomitant SCN2A gene variants and cryptogenic epileptic syndromes, thus expanding the SCN2A spectrum of phenotypic heterogeneity. De novo variants were identified in four patients, while one inherited variant was identified in a patient with an unaffected carrier biological father with somatic mosaicism. Two of five patients were diagnosed with a neonatal epileptic encephalopathy. The remaining three patients manifested a focal epileptic syndrome associated with autistic spectrum disorders (ASD) or with a variable degree of intellectual disability (ID), one of them displaying a hitherto unreported atypical late onset epilepsy. Overall, the pattern of clinical manifestations among these patients suggest that any observed neurological impairment may not be directly related to the severity of the electroclinical pattern, but instead likely associated with the mutation itself. Moreover, our results highlight the importance of SCN2A mutational screening in cases of ID/ASD with or without epilepsy.
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INTRODUCTION: The structural validity and reliability of the Short-Form Health Survey 12 (SF-12) has not yet been tested in adults with the Marfan syndrome (MFS). This gap could undermine an evidence-grounded practice and research, especially considering that the need to assess health-related quality of life in patients with MFS has increased due to the improved life expectancy of these patients and the need to identify their determinants of quality of life. For this reason, this study aimed to confirm the dimensionality (structural validity) of the SF-12, its concurrent validity, and its reliability (internal consistency). METHODS: We performed a cross-sectional study in a convenience sample of 111 Italian adults with MFS, collecting anamnestic and socio-demographic information, the SF-12, and short-form Health Survey 36 (SF-36). A confirmatory factor analysis was performed to verify whether the items of SF-12 related to physical restrictions, physical functioning, and bodily pain were retained by the physical summary component of the SF-12. The items referred to the role limitations due to emotional issues, social functioning, and mental health were retained by the mental summary component (MCS12). SF-36 was used to assess the concurrent validity of SF-12, hypothesizing positive correlations among the equivalent summary scores. RESULTS: The two-factor structural solution resulted in fitting the sample statistics adequately. The internal consistency was adequate for the two factors. Furthermore, the physical and mental summary scores of the SF-36 were positively correlated with their equivalent summary scores derived from the SF-12. CONCLUSIONS: This study confirmed the factor structure of the SF-12. Therefore, the use of SF-12 in clinical practice and research for assessing the health-related quality of life among adults with MFS is evidence-grounded. Future research is recommended to determine whether the SF-12 shows measurement invariance in different national contexts and determine eventual demographic variation in the SF-12 scores among patients with MFS.
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Inquéritos Epidemiológicos/normas , Síndrome de Marfan/fisiopatologia , Síndrome de Marfan/psicologia , Psicometria/instrumentação , Qualidade de Vida , Adulto , Estudos Transversais , Análise Fatorial , Feminino , Nível de Saúde , Humanos , Masculino , Reprodutibilidade dos TestesRESUMO
Marfan syndrome (MFS) is an autosomal genetic disorder of connective tissue, due to alterated fibrillin-1. The aim of our study was to verify the rate of fractures in children with MFS in correlation to bone mineral density and compare the prevalence to the general population in the same latitude. We enrolled 80 patients (37 girls and 43 boys) with the diagnosis of Marfan syndrome, median age 10 y (3 to 17â¯years). Fracture occurrence was inferred from medical records of patients with MFS. Bone mineral density (BMD) was measured at lumbar spine, femoral neck and total femur by dual-energy x-ray absorptiometry. BMD values were expressed as z-scores, and adjusted for height using height-for-age z-scores. Bone turnover markers and vitamin D were measured. We assessed incidence of fracture in general pediatric population of our geographic area (45°N latitude). A total of 24 fractures were recorded in 21 patients (15 boys and 6 girls), involving both short and long bones, due to mild or moderate trauma. An incidence estimate has been calculated for each year, and an average incidence of 29.2/1000 MFS patients was obtained, markedly higher (P=0.034) than the incidence of fracture calculated in the same geographical area in pediatric patients (15.8/1000). We did not detect differences in anthropometric measurements, BMD values and biochemical indices between patients who fractured and patients who did not. Similarly, no differences were found between patients on losartan therapy and patients not in treatment for the same variables. In conclusion, the incidence of fractures was higher in patients with MFS compared to general population of the same age and latitude. The management of MFS must account bone status health and start strategies of fracture prevention.
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Fraturas Ósseas , Síndrome de Marfan , Absorciometria de Fóton , Adolescente , Densidade Óssea , Criança , Feminino , Colo do Fêmur , Fraturas Ósseas/epidemiologia , Humanos , Masculino , Síndrome de Marfan/complicações , Síndrome de Marfan/epidemiologiaRESUMO
The diagnosis of Marfan spectrum includes a large number of clinical criteria. Although the identification of pathogenic variants contributes to the diagnostic process, its value to the prediction of clinical outcomes is still limited. An important novelty of the present study is represented by the statistical approach adopted to investigate genotype-phenotype correlation. The analysis has been improved considering the extended genetic information obtained by Next Generation Sequencing (NGS) and combining the effects of both rare and common genetic variants in an inclusive model. To this aim a cohort of 181 patients were analyzed with a NGS panel including 11 genes associated with Marfan spectrum. The genotype-phenotype correlation was also investigated considering the possibility to predict presence of a pathological mutation in Marfan syndrome (MFS) main genes based only on the analysis of phenotypic traits. Results obtained indicate that information about clinical traits can be summarized in a new variable that resulted significantly associated with the probability to find a pathological mutation in MFS main genes. This is important since the choice of the genetic test is often influenced by the phenotypic characterization of patients. Moreover, both rare and common variants were found to significantly contribute to clinical spectrum and their combination allowed to increase the percentage of phenotype variability that could be explained based on genetic factors. Results highlight the opportunity to take advantage of the overall genetic information obtained by NGS data to have a better clinical classification of patients.
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Estudos de Associação Genética/métodos , Variação Genética/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Síndrome de Marfan/genética , Adulto , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Síndrome de Marfan/patologia , Melhoria de QualidadeRESUMO
Background Several devices have been proposed to assess arterial stiffness in clinical daily use over the past few years, by estimating aortic pulse wave velocity (PWV) from a single measurement of brachial oscillometric blood pressure, using patented algorithms. It is uncertain if these systems are able to provide additional elements, beyond the contribution carried by age and blood pressure levels, in the definition of early vascular damage expressed by the stiffening of the arterial wall. Methods and Results The aim of our study was to compare the estimated algorithm-based PWV values, provided by the Mobil-O-Graph system, with the standard noninvasive assessment of aortic PWV in patients with Marfan syndrome (ie, in subjects characterized by premature aortic stiffening and low blood pressure values). Aortic stiffness was simultaneously evaluated by carotid-femoral PWV with a validated arterial tonometer and estimated with an arm cuff-based ambulatory blood pressure monitoring Mobil-O-Graph device on 103 patients with Marfan syndrome (50 men; mean± SD age, 38±15 years). Aortic PWV, estimated by the Mobil-O-Graph, was significantly ( P<0.0001) lower (mean± SD, 6.1±1.3 m/s) than carotid-femoral PWV provided by arterial tonometry (mean± SD , 8.8±3.1 m/s). The average of differences between PWV values provided by the 2 methods (±1.96×SD) was -2.7±5.7 m/s. Conclusions The Mobil-O-Graph provides PWV values related to an ideal subject for a given age and blood pressure, but it is not able to evaluate early vascular aging expressed by high PWV in the individual patient. This is well shown in patients with Marfan syndrome.
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Algoritmos , Pressão Sanguínea/fisiologia , Síndrome de Marfan/fisiopatologia , Análise de Onda de Pulso/métodos , Rigidez Vascular/fisiologia , Adulto , Determinação da Pressão Arterial , Velocidade da Onda de Pulso Carótido-Femoral/métodos , Feminino , Humanos , Masculino , Manometria , Pessoa de Meia-Idade , Reprodutibilidade dos TestesRESUMO
Most patients with an interstitial deletion of 6q16 have Prader-Willi-like phenotype, featuring obesity, hypotonia, short hands and feet, and developmental delay. In all reported studies, the chromosome rearrangement was detected by karyotype analysis, which provides an overview of the entire genome but has limited resolution. Here we describe a detailed clinical presentation of five patients, two of whom were previously reported, with overlapping interstitial 6q16 deletions and Prader-Willi-like phenotype. Our patients share the following main features with previously reported cases: global developmental delay, hypotonia, obesity, hyperphagia, and eye/vision anomalies. All rearrangement breakpoints have been accurately defined through array-CGH at about 100 Kb resolution. We were able to narrow the shortest region of deletion overlap for the presumed gene(s) involved in the Prader-Willi-like syndrome to 4.1 Mb located at 6q16.1q16.2. Our results support the evidence that haploinsufficiency of the SIM1 gene is responsible for obesity in these patients. A possible involvement of the GRIK2 gene in autistic-like behaviour, of POPDC3 in heart development, and of MCHR2 in the control of feeding behaviour and energy metabolism is also hypothesized.
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Deleção Cromossômica , Cromossomos Humanos Par 6 , Fenótipo , Síndrome de Prader-Willi/genética , Adolescente , Adulto , Pré-Escolar , Mapeamento Cromossômico , Análise Citogenética , Feminino , Genótipo , Humanos , Lactente , MasculinoRESUMO
Pendred syndrome (PS) is an autosomal recessive disorder due to mutations in the SLC26A4 gene (chr7q22. 3) and characterized by sensorineural hearing loss and variable thyroid phenotype. Silver-Russell syndrome (SRS) is a heterogeneous imprinting disorder including severe intrauterine and postnatal growth retardation, and dysmorphic features. Maternal uniparental disomy of either the whole chromosome 7 (upd(7)mat) or 7q (upd(7q)mat) is one of the multiple mechanisms impacting the expression of imprinted genes in SRS, and is associated with milder clinical features. Here, we report genetic and clinical characterization of a female child with PS, postnatal growth retardation, and minor dysmorphic features. A gross homozygous deletion of SLC26A4 exons 17-20 was suspected by Sanger sequencing and then confirmed by array-CGH. Moreover, an insertion of about 1 kb of the CCDC126 gene (7p15.3), which does not appear to be clinically relevant, was detected. The possible occurrence of a balanced rearrangement between 7p and 7q was excluded. The absence of the deletion in the father led to the investigation of upd, and microsatellite segregation analysis revealed a segmental 7q (upd(7q)mat), leading to SLC26A4 homozygosity and responsible for both PS and SRS-like traits. The proband matched 3 out of 6 major SRS criteria. In conclusion, this is the first report of uniparental isodisomy encompassing almost the whole long arm of chromosome 7 resulting in PS and SRS-like features. Whereas, the inner ear phenotype of PS is typical, the clinical features suggestive of SRS might have been overlooked.
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OBJECTIVE: Marfan syndrome (MFS) is an autosomal dominant genetic disorder characterized by aortic root dilation and dissection and an abnormal fibrillin-1 synthesis. In this observational study, we evaluated aortic stiffness in MFS and its association with ascending aorta diameters and fibrillin-1 genotype. METHODS: A total of 116 Marfan adult patients without history of cardiovascular surgery, and 144 age, sex, blood pressure and heart rate matched controls were enrolled. All patients underwent arterial stiffness evaluation through carotid-femoral pulse wave velocity (PWV) and central blood pressure waveform analysis (PulsePen tonometer). Fibrillin-1 mutations were classified based on the effect on the protein, into 'dominant negative' and 'haploinsufficient' mutations. RESULTS: PWV and central pulse pressure were significantly higher in MFS patients than in controls [respectively 7.31 (6.81-7.44) vs. 6.69 (6.52-6.86)âm/s, Pâ=â0.0008; 41.3 (39.1-43.5) vs. 34.0 (32.7-35.3)âmmHg, Pâ<â0.0001], with a higher age-related increase of PWV in MFS (ß 0.062 vs. 0.036). Pressure amplification was significantly reduced in MFS [18.2 (15.9-20.5) vs. 33.4 (31.6-35.2)%, Pâ<â0.0001]. Central pressure profile was altered even in MFS patients without aortic dilatation. Multiple linear regression models showed that PWV independently predicted aortic diameters at the sinuses of Valsalva (ßâ=â0.243, Pâ=â0.002) and at the sinotubular junction (ßâ=â0.186, Pâ=â0.048). PWV was higher in 'dominant negative' than 'haploinsufficient' fibrillin-1 mutations [7.37 (7.04-7.70) vs. 6.60 (5.97-7.23)âm/s, Pâ=â0.035], although this difference was not significant after adjustment. CONCLUSION: Aortic stiffness is increased in MFS, independently from fibrillin-1 genotype and is associated with diameters of ascending aorta. Alterations in central hemodynamics are present even when aortic diameter is within normal limits. Our findings suggest an accelerated arterial aging in MFS.
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Doenças da Aorta/genética , Artérias/fisiopatologia , Fibrilina-1/genética , Síndrome de Marfan/fisiopatologia , Rigidez Vascular , Adulto , Aorta/diagnóstico por imagem , Doenças da Aorta/diagnóstico por imagem , Pressão Sanguínea , Estudos Transversais , Dilatação , Feminino , Humanos , Masculino , Síndrome de Marfan/complicações , Síndrome de Marfan/diagnóstico por imagem , Síndrome de Marfan/genética , Pessoa de Meia-Idade , Análise de Onda de PulsoRESUMO
The diagnosis of a subtelomeric rearrangement has immediate impact on counseling, particularly in the case of familial rearrangements. However, the existence of subtelomeric imbalances with absent phenotypic effects may hamper genetic counseling, particularly when the rearrangement has not been previously described. We report on a new subtelomeric polymorphism, consisting of a familial subtelomeric rearrangement of chromosome 19 resulting in distal trisomy for 21q, detected in a child with Angelman Syndrome (AS) due to an UBE3A mutation. This report shows that new, previously unknown, benign subtelomeric variants may complicate the correct clinical diagnosis.
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Síndrome de Down/genética , Variação Genética , Telômero/genética , Síndrome de Angelman/genética , Pré-Escolar , Cromossomos Humanos Par 19/genética , Feminino , Humanos , Translocação Genética , Ubiquitina-Proteína Ligases/genéticaRESUMO
To gain a better understanding of the clinical and genetic features associated with agenesis of corpus callosum, we enrolled and characterized 162 patients with complete or partial agenesis of corpus callosum. Clinical and genetic protocols allowed us to categorize patients as syndromic subjects, affected by complex extra-brain malformations, and nonsyndromic subjects without any additional anomalies. We observed slight differences in sex ratio (56% males) and agenesis type (52% complete). Syndromic agenesis of corpus callosum subjects were prevalent (69%). We detected associated cerebral malformations in 48% of patients. Neuromotor impairment, cognitive and language disorders, and epilepsy were frequently present, regardless of the agenesis of corpus callosum subtype. Long-term follow-up allowed us to define additional indicators: syndromic agenesis of corpus callosum plus patients showed the most severe clinical features while isolated complete agenesis of corpus callosum patients had the mildest symptoms, although we observed intellectual disability (64%) and epilepsy (15%) in both categories. We achieved a definitive (clinical and/or genetic) diagnosis in 42% of subjects.
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Agenesia do Corpo Caloso/genética , Agenesia do Corpo Caloso/terapia , Adolescente , Adulto , Agenesia do Corpo Caloso/fisiopatologia , Agenesia do Corpo Caloso/psicologia , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Eletroencefalografia , Epilepsia/genética , Epilepsia/fisiopatologia , Epilepsia/psicologia , Epilepsia/terapia , Feminino , Seguimentos , Humanos , Lactente , Masculino , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND: Marfan syndrome is characterized by aortic root dilation, beginning in childhood. Data about aortic pulsatile hemodynamics and stiffness in pediatric age are currently lacking. METHODS AND RESULTS: In 51 young patients with Marfan syndrome (12.0±3.3 years), carotid tonometry was performed for the measurement of central pulse pressure, pulse pressure amplification, and aortic stiffness (carotid-femoral pulse wave velocity). Patients underwent an echocardiogram at baseline and at 1 year follow-up and a genetic evaluation. Pathogenetic fibrillin-1 mutations were classified between "dominant negative" and "haploinsufficient." The hemodynamic parameters of patients were compared with those of 80 sex, age, blood pressure, and heart-rate matched controls. Central pulse pressure was significantly higher (38.3±12.3 versus 33.6±7.8 mm Hg; P=0.009), and pulse pressure amplification was significantly reduced in Marfan than controls (17.9±15.3% versus 32.3±17.4%; P<0.0001). Pulse wave velocity was not significantly different between Marfan and controls (4.98±1.00 versus 4.75±0.67 m/s). In the Marfan group, central pulse pressure and pulse pressure amplification were independently associated with aortic diameter at the sinuses of Valsalva (respectively, ß=0.371, P=0.010; ß=-0.271, P=0.026). No significant difference in hemodynamic parameters was found according to fibrillin-1 genotype. Patients who increased aortic Z-scores at 1-year follow-up presented a higher central pulse pressure than the remaining (42.7±14.2 versus 32.3±5.9 mm Hg; P=0.004). CONCLUSIONS: Central pulse pressure and pulse pressure amplification were impaired in pediatric Marfan syndrome, and associated with aortic root diameters, whereas aortic pulse wave velocity was similar to that of a general pediatric population. An increased central pulse pressure was present among patients whose aortic dilatation worsened at 1-year follow-up.