Mosaicism in Fragile X syndrome: A family case series.

Fragile X syndrome (FXS) has a classic phenotype, however its expression can be variable among full mutation males. This is secondary to variable methylation mosaicisms and the number of CGG triplet repeats in the non-coding region of the Fragile X Mental Retardation 1 (FMR1) gene, producing a variable expression of the Fragile X Mental Retardation Protein (FMRP). Here we report a family with several individuals affected by FXS: a boy with a hypermethylated FMR1 mutation and a classic phenotype; a man with an FMR1 gene mosaicism in the range of premutation (PM) and full mutation (FM), who has a mild phenotype due to which FXS was initially disregarded; and the cases of four women with a FM and mosaicism. This report highlights the importance of DNA molecular testing for the diagnosis of FXS in patients with developmental delay, intellectual disability and/or autism due to the variable phenotype that occurs in individuals with FMR1 mosaicisms.

Fragile X syndrome: clinical presentation, pathology and treatment.

Fragile X syndrome is the monogenetic condition that produces more cases of autism and intellectual disability. The repetition of CGG triplets (> 200) and their methylation entail the silencing of the FMR1 gene. The FMRP protein (product of the FMR1 gene) interacts with ribosomes by controlling the translation of specific messengers, and its loss causes alterations in synaptic connectivity. Screening for fragile X syndrome is performed by polymerase chain reaction. Current recommendation of the American Academy of Pediatrics is to test individuals with intellectual disability, global developmental retardation or with a family history of presence of the mutation or premutation. Hispanic countries such as Colombia, Chile and Spain report high prevalence of fragile X syndrome and have created fragile X national associations or corporations that seek to bring patients closer to available diagnostic and treatment networks.

El síndrome X frágil es la condición monogenética que produce más casos de autismo y de discapacidad intelectual. La repetición de tripletes CGG (> 200) y su metilación conllevan el silenciamiento del gen FMR1. La proteína FMRP (producto del gen FMR1) interacciona con los ribosomas, controlando la traducción de mensajeros específicos y su pérdida produce alteraciones de la conectividad sináptica. El tamizaje de síndrome X frágil se realiza por reacción en cadena de la polimerasa. La recomendación actual de la Academia Americana de Pediatría es realizar pruebas a quienes presenten discapacidad intelectual, retraso global del desarrollo o antecedentes familiares de afección por la mutación o premutación. Países hispanos como Colombia, Chile y España reportan altas prevalencias de síndrome X frágil y han creado asociaciones o corporaciones nacionales de X frágil que buscan acercar a los pacientes a redes disponibles de diagnóstico y tratamiento.

Síndrome X frágil: presentación clínica, patología y tratamiento / Fragile X syndrome: clinical presentation, pathology and treatment

Resumen El síndrome X frágil es la condición monogenética que produce más casos de autismo y de discapacidad intelectual. La repetición de tripletes CGG (> 200) y su metilación conllevan el silenciamiento del gen FMR1. La proteína FMRP (producto del gen FMR1) interacciona con los ribosomas, controlando la traducción de mensajeros específicos y su pérdida produce alteraciones de la conectividad sináptica. El tamizaje de síndrome X frágil se realiza por reacción en cadena de la polimerasa. La recomendación actual de la Academia Americana de Pediatría es realizar pruebas a quienes presenten discapacidad intelectual, retraso global del desarrollo o antecedentes familiares de afección por la mutación o premutación. Países hispanos como Colombia, Chile y España reportan altas prevalencias de síndrome X frágil y han creado asociaciones o corporaciones nacionales de X frágil que buscan acercar a los pacientes a redes disponibles de diagnóstico y tratamiento.

Abstract Fragile X syndrome is the monogenetic condition that produces more cases of autism and intellectual disability. The repetition of CGG triplets (> 200) and their methylation entail the silencing of the FMR1 gene. The FMRP protein (product of the FMR1 gene) interacts with ribosomes by controlling the translation of specific messengers, and its loss causes alterations in synaptic connectivity. Screening for fragile X syndrome is performed by polymerase chain reaction. Current recommendation of the American Academy of Pediatrics is to test individuals with intellectual disability, global developmental retardation or with a family history of presence of the mutation or premutation. Hispanic countries such as Colombia, Chile and Spain report high prevalence of fragile X syndrome and have created fragile X national associations or corporations that seek to bring patients closer to available diagnostic and treatment networks.

Increased severity of fragile X spectrum disorders in the agricultural community of Ricaurte, Colombia.

Premutation carriers of the FMR1 gene (CGG repeats between 55 and 200) usually have normal intellectual abilities but approximately 20% are diagnosed with developmental problems or autism spectrum disorder. Additionally, close to 50% have psychiatric problems such as anxiety, ADHD and/or depression. The spectrum of fragile X disorders also includes Fragile-X-associated primary ovarian insufficiency (FXPOI) in female carriers and Fragile-X-associated tremor/ataxia syndrome (FXTAS) in older male and female carriers. We evaluated 25 premutation carriers in the rural community of Ricaurte Colombia and documented all behavioral problems, social deficits and clinical signs of FXPOI and FXTAS as well as reviewed the medical and obstetric history. We found an increased frequency and severity of symptoms of fragile X spectrum disorders, which might be related to the vulnerability of FMR1 premutation carriers to higher exposure to neurotoxic pesticides in this rural community.

Caries experience and salivary aspects in individuals with fragile X syndrome.

Fragile X syndrome (FXS) is the most common cause of hereditary mental retardation, but studies on the oral health condition of these patients are rare. The aim of this study was to determine the experience of dental caries in individuals with FXS, by examining the saliva profile, oral hygiene, socioeconomic characteristics and use of controlled drugs in these patients. Dental health was estimated using the decayed, missing and filled teeth index (DMF-T) and sialometry, and the pH value and buffering capacity of the saliva, colony forming units of S. mutans (CFU/mL), visible biofilm index, and socioeconomic status were all examined. The sample, comprising 23 individuals, had an average age of 17.3 ± 5.6 years, a DMF-T index of 5.5, a diminished salivary flow (78.3%), and a low (73.9%) saliva buffering capacity. Most (52.2%) individuals presented with a high abundance (CFU/mL) of S. mutans. The experience of caries was correlated with salivary parameters, poor oral hygiene, lower socioeconomic status and an increased count of S. mutans in saliva.

MANAGEMENT OF ENDOCRINE DISEASE: Diagnostic and therapeutic approach of tall stature.

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

Caries experience and salivary aspects in individuals with fragile X syndrome

Abstract Fragile X syndrome (FXS) is the most common cause of hereditary mental retardation, but studies on the oral health condition of these patients are rare. The aim of this study was to determine the experience of dental caries in individuals with FXS, by examining the saliva profile, oral hygiene, socioeconomic characteristics and use of controlled drugs in these patients. Dental health was estimated using the decayed, missing and filled teeth index (DMF-T) and sialometry, and the pH value and buffering capacity of the saliva, colony forming units of S. mutans (CFU/mL), visible biofilm index, and socioeconomic status were all examined. The sample, comprising 23 individuals, had an average age of 17.3 ± 5.6 years, a DMF-T index of 5.5, a diminished salivary flow (78.3%), and a low (73.9%) saliva buffering capacity. Most (52.2%) individuals presented with a high abundance (CFU/mL) of S. mutans. The experience of caries was correlated with salivary parameters, poor oral hygiene, lower socioeconomic status and an increased count of S. mutans in saliva.

FXTAS in an unmethylated mosaic male with fragile X syndrome from Chile.

Carriers of an FMR1 premutation allele (55-200 CGG repeats) often develop the neurodegenerative disorders, fragile X-associated tremor/ataxia syndrome (FXTAS). Neurological signs of FXTAS, parkinsonism and rapid onset of cognitive decline have not been reported in individuals with an unmethylated full mutation (FM). Here, we report a Chilean family affected with FXS, inherited from a parent carrier of an FMR1 unmethylated full mosaic allele, who presented with a fast progressing FXTAS. This case suggests that the definition of FXTAS may need to be broadened to not only include those with a premutation but also those with an expanded allele in FM range with a lack of methylation leading to elevated FMR1-mRNA expression levels and subsequent RNA toxicity.

[Fragile X syndrome with Dandy-Walker variant: a clinical study of oral and written communicative manifestations]. / Síndrome do X Frágil com variante de Dandy-Walker: estudo clínico das manifestações comunicativas orais e escritas.

The Fragile X syndrome is the most frequent cause of inherited intellectual disability. The Dandy-Walker variant is a specific constellation of neuroradiological findings. The present study reports oral and written communication findings in a 15-year-old boy with clinical and molecular diagnosis of Fragile X syndrome and neuroimaging findings consistent with Dandy-Walker variant. The speech-language pathology and audiology evaluation was carried out using the Communicative Behavior Observation, the Phonology assessment of the ABFW - Child Language Test, the Phonological Abilities Profile, the Test of School Performance, and the Illinois Test of Psycholinguistic Abilities. Stomatognathic system and hearing assessments were also performed. It was observed: phonological, semantic, pragmatic and morphosyntactic deficits in oral language; deficits in psycholinguistic abilities (auditory reception, verbal expression, combination of sounds, auditory and visual sequential memory, auditory closure, auditory and visual association); and morphological and functional alterations in the stomatognathic system. Difficulties in decoding the graphical symbols were observed in reading. In writing, the subject presented omissions, agglutinations and multiple representations with the predominant use of vowels, besides difficulties in visuo-spatial organization. In mathematics, in spite of the numeric recognition, the participant didn't accomplish arithmetic operations. No alterations were observed in the peripheral hearing evaluation. The constellation of behavioral, cognitive, linguistic and perceptual symptoms described for Fragile X syndrome, in addition to the structural central nervous alterations observed in the Dandy-Walker variant, caused outstanding interferences in the development of communicative abilities, in reading and writing learning, and in the individual's social integration.

Síndrome do X Frágil com variante de Dandy-Walker: estudo clínico das manifestações comunicativas orais e escritas / Fragile X syndrome with Dandy-Walker variant: a clinical study of oral and written communicative manifestations

A síndrome do X Frágil é a causa mais frequente de deficiência intelectual hereditária. A variante de Dandy-Walker trata-se de uma constelação específica de achados neurorradiológicos. Este estudo relata achados da comunicação oral e escrita de um menino de 15 anos com diagnóstico clínico e molecular da síndrome do X-Frágil e achados de neuroimagem do encéfalo compatíveis com variante de Dandy-Walker. A avaliação fonoaudiológica foi realizada por meio da Observação do Comportamento Comunicativo, aplicação do ABFW - Teste de Linguagem Infantil - Fonologia, Perfil de Habilidades Fonológicas, Teste de Desempenho Escolar, Teste Illinois de Habilidades Psicolinguísticas, avaliação do sistema estomatognático e avaliação audiológica. Observou-se: alteração de linguagem oral quanto às habilidades fonológicas, semânticas, pragmáticas e morfossintáticas; déficits nas habilidades psicolinguísticas (recepção auditiva, expressão verbal, combinação de sons, memória sequencial auditiva e visual, closura auditiva, associação auditiva e visual); e alterações morfológicas e funcionais do sistema estomatognático. Na leitura verificou-se dificuldades na decodificação dos símbolos gráficos e na escrita havia omissões, aglutinações e representações múltiplas com o uso predominante de vogais e dificuldades na organização viso-espacial. Em matemática, apesar do reconhecimento numérico, não realizou operações aritméticas. Não foram observadas alterações na avaliação audiológica periférica. A constelação de sintomas comportamentais, cognitivos, linguísticos e perceptivos, previstos na síndrome do X-Frágil, somada às alterações estruturais do sistema nervoso central, pertencentes à variante de Dandy-Walker, trouxeram interferências marcantes no desenvolvimento das habilidades comunicativas, no aprendizado da leitura e escrita e na integração social do indivíduo.

The Fragile X syndrome is the most frequent cause of inherited intellectual disability. The Dandy-Walker variant is a specific constellation of neuroradiological findings. The present study reports oral and written communication findings in a 15-year-old boy with clinical and molecular diagnosis of Fragile X syndrome and neuroimaging findings consistent with Dandy-Walker variant. The speech-language pathology and audiology evaluation was carried out using the Communicative Behavior Observation, the Phonology assessment of the ABFW - Child Language Test, the Phonological Abilities Profile, the Test of School Performance, and the Illinois Test of Psycholinguistic Abilities. Stomatognathic system and hearing assessments were also performed. It was observed: phonological, semantic, pragmatic and morphosyntactic deficits in oral language; deficits in psycholinguistic abilities (auditory reception, verbal expression, combination of sounds, auditory and visual sequential memory, auditory closure, auditory and visual association); and morphological and functional alterations in the stomatognathic system. Difficulties in decoding the graphical symbols were observed in reading. In writing, the subject presented omissions, agglutinations and multiple representations with the predominant use of vowels, besides difficulties in visuo-spatial organization. In mathematics, in spite of the numeric recognition, the participant didn't accomplish arithmetic operations. No alterations were observed in the peripheral hearing evaluation. The constellation of behavioral, cognitive, linguistic and perceptual symptoms described for Fragile X syndrome, in addition to the structural central nervous alterations observed in the Dandy-Walker variant, caused outstanding interferences in the development of communicative abilities, in reading and writing learning, and in the individual's social integration.

Sintomas de linguagem e Síndrome de X Frágil: estudo de caso / Language symptoms and Fragile X Syndrome: case study

Esta pesquisa aborda um estudo de caso de um menino com sintomas de linguagem e com diagnóstico médico de Síndrome de X Frágil e acompanha seu processo terapêutico fonoaudiológico dos quatro aos seis anos de idade, visando identificar, de forma mais específica, como as leis da estrutura da linguagem se manifestam na fala da criança. O foco escolhido privilegia o olhar sobre a entrada ou a recusa do falante no funcionamento relativamente autônomo da língua, afastando-se da noção de causalidade linear entre a síndrome genética e os sintomas na linguagem. Elegeu-se, para análise, episódios clínicos extraídos de gravações de sessões fonoaudiológicas que foram considerados enigmáticos. Fundamentando-se na Clínica Fonoaudiológica que se sustenta na dialogia, ou seja, na relação do falante e Outro, buscou-se uma prática clínica assentada sobre a subjetividade e a intersubjetividade. As análises permitiram hipotetizar o percurso da criança no enlaçamento singular de sua fala ao modo de funcionamento da língua, pontuando interpretações e escansões, isto é, cortes marcados pelos gradientes de entonação, ritmo e melodia da fala. Concluiu-se que tanto os atos interpretativos sobre as ecolalias e estereotipias como o silenciamento do terapeuta podem deslocar a criança para a posição de falante, identificando-se neste manejo terapêutico, caminhos promissores para a instância terapêutica da Clínica Fonoaudiológica que atua com sujeitos com falas ditas patológicas.

he present research approaches a case study of a boy with language symptoms and medical diagnosis of Fragile X Syndrome following on the Speech-Language therapeutic process from the age of four up to six years old, with the purpose of identifying, in a more specific way, how the language structure laws emerge in the child's speech. The elected focus aims to privilege a view on the speaker entrance or refusal on the relative autonomy of language, moving away from the notion of lineal causality of the genetic syndrome and the language symptoms. Were elected, for analysis, clinical episodes that were considered enigmatic extracted from the therapeutic Speech-Language sessions. Based on the Speech-Language Therapy Clinics that is supported on the dialogy, or, in the relationship between the speaker and the Other, clinical practice was approached based on subjectivity and inter-subjectivity. The analyses allowed to outline the child's trajectory in the singular interlacement of his speech to the language way of functioning, pointing out the language therapist's interpretations and scansions, which are cuts marked by speech variations of intonation, rhythm and melody. It was concluded that interpretative actions resting on the verbal stereotypeand echolalia as well as on the therapist's silence can generate changes in the child's position, identifying in this therapeutic approach, promising ways to the therapeutic instance of Speech-Language Clinics that deals with speaker with the so-called pathological speech.

Esta investigación analiza un estudio de caso de un niño con síntomas de lenguaje con diagnóstico de Síndrome X Frágil y sigue su proceso terapéutico fonoaudiológico de cuatro a seis años de edad, para identificar, más específicamente, cómo las leyes de la estructura del lenguaje se manifiestan en el habla del niño. El enfoque elegido privilegia la atención sobre la entrada o la denegación del hablante en el funcionamiento autónomo de la lengua, alejándose de la noción de causalidad lineal entre el síndrome genético y los síntomas en el lenguaje. Fueron elegidos para el análisis, episodios clínicos que consideramos enigmáticos extraídos de grabaciones de sesiones fonoaudiológicas. Basándose en la Clínica Fonoaudiológica que se sustenta en el proceso dialógico, es decir, en la relación del hablante y Otro, intentase una práctica clínica asentada en la subjetividad y ínter subjetividad. Los análisis permitieron plantear la hipótesis de la ruta del niño en el entrelazamiento singular de su habla al funcionamiento de la lengua, puntuando interpretaciones y escansiones, es decir, cortes marcados por los gradientes de entonación, ritmo y melodía del habla. Se concluyó que tanto los actos interpretativos sobre las ecolalias y estereotipias como el silenciamiento del terapeuta pueden mover al niño a la posición de hablante, identificándose en este manejo terapéutico, posibilidades prometedoras para la instancia terapéutica de la Clínica Fonoaudiológica que trabaja con sujetos con habla entendida como patológica.

Prevalencia del Sìndrome de fragilidad en adultos mayores del consultorio externo del hospital Buongermini en noviembre 2009 / Prevalence of frailty syndrome in older adults hospital`s outpatient clinic in november 2009 Buongermini

El estado de fragilidad es un sìndrome clìnico,biològico y psicosocial;y se puede dar definiciòn poniendo ènfasis en cualquiera de los antes mencionados puntos o en todos y se encuentran mas o menos estandarizados.

Síndrome de Turner, a propósito de un caso / Turner síndrome, a case report

El Síndrome de Turner es una alteración cromosómica producida por una pérdida parcial o total de un cromosoma X durante el desarrollo sexual. Se presenta con una frecuencia de 1 en 2.500 a 5.000 recién nacidos de sexo femenino, cerca del 1 % de las concepciones presentan una monosomía X, de las cuales la mayoría terminanen abortos espontáneos generalmente durante el primer trimestre del embarazo.

Laboratorial diagnosis of fragile-X syndrome: experience in a sample of individuals with pervasive developmental disorders.

Fragile X syndrome is a frequent genetic disease associated to developmental disorders, including learning disability, mental retardation, behavioral problems and pervasive developmental disorders (autism and related conditions). We studied a sample of 82 individuals (69 males and 13 females) presenting with pervasive developmental disorders using three techniques for the diagnosis of fragile X syndrome (FXS). Cytogenetic analysis detected the fragile site in four males, but only one showed a consistent positive rate. Molecular study based on the PCR technique was inconclusive for most females (92.3%), which where latter submitted to Southern blotting analysis, and for one male (1.4%), excluding the FRAXA mutation in the remaining male individuals (98.6%). Molecular tests using the Southern blotting technique confirmed only one positive case (1.2%) in a male subject. These results showed that Southern blotting analysis of the FRAXA mutation has the best sensitivity and specificity for the diagnosis of FXS but also validated the PCR technique as a confinable screening test.