[Holt-Oram syndrome: characterization of a novel mutation]. / Síndrome de Holt-Oram: caracterización de una nueva mutación.

INTRODUCTION: Cardiomyelic syndromes encompass congenital heart disease and skeletal malformations of the upper limbs and are related to mutations in transcription factors with T-Box domains. Holt-Oram syndrome is caused by a dominant mutation in the TBX5 gene that alters the three-dimensional structure of the protein and its DNA binding function. Several point mutations and deletions in TBX5 have been reported in patients with the Holt-Oram syndrome phenotype. PATIENTS AND METHODS: The proband was a boy with a large atrial septal defect ostium secundum type and a ventricular septal defect, diagnosed by clinical findings (heart murmur) and echocardiography. He also presented slightly hypoplastic thumbs with distal bilateral placement and an implantation index of 0.19 (compared with an average of 0.50 for his gestational age at birth). The boy was referred to the department of medical genetics to rule out 22q11.2 microdeletion syndrome. RESULTS: Karyotype and fluorescence in situ hybridization at locus D22S75 were both normal. Because of his clinical findings, molecular study for Holt-Oram syndrome was indicated, leading to the finding of a mutation at intron 7 of TBX5, probably producing a splicing alteration of the gene and resulting in a protein truncated at its C-terminal end. The proband's parents presented the wild type sequence of the gene, thus indicating that the mutation was produced de novo, although a possible germinal mosaicism in the parents could not be ruled out. CONCLUSIONS: Holt-Oram syndrome is the most frequent cause of cardiomyelic syndrome. All children with heart malformations and abnormalities of the upper limbs such as absent, hypoplastic, distally placed or triphalangic thumbs should undergo molecular studies for this syndrome.

Síndrome de Holt-Oram: caracterización de una nueva mutación / Holt-Oram syndrome: characterization of a novel mutation

Introducción Los síndromes cardiomiélicos comprenden cardiopatías congénitas y malformaciones esqueléticas de los miembros superiores, y están relacionados con mutaciones deletéreas de factores de transcripción con dominios del tipo T-Box. El síndrome de Holt-Oram se debe a una mutación dominante en el gen TBX5 que altera la estructura tridimensional de la proteína impidiendo su correcta unión al ADN. Se han descrito varias mutaciones puntuales y deleciones de TBX5 en pacientes con fenotipo de síndrome de Holt-Oram. Pacientes y métodos El paciente es un niño con una comunicación interauricular (CIA) del tipo ostium secundum grande y una comunicación interventricular (CIV) diagnosticados por clínica (soplo) y ecocardiografía. Presenta además unos dedos pulgares algo hipoplásicos y con un emplazamiento distal bilateral, con un índice de implantación de 0,19 frente a una media normal de 0,50 para su edad gestacional al nacer. Es remitido a la consulta de Genética para descartar microdeleción 22q11.2. Resultados El cariotipo y la hibridación in situ de fluorescencia (FISH) con sonda D22S75 resultaron normales y debido a los hallazgos clínicos se realizó un estudio molecular para el síndrome de Holt-Oram. Se encontró una mutación en el intrón 7 de TBX5 que produce una probable alteración del splicing del gen que da lugar a una proteína truncada en su extremo C-terminal. Los padres del propósito presentan una secuencia normal para el gen, lo que indica que la mutación se produjo de novo, sin que pueda descartarse un mosaicismo germinal en los padres. Conclusiones El síndrome de Holt-Oram es la causa más frecuente de síndrome cardiomiélico. Debería ser objeto de estudio molecular todo niño con malformaciones cardíacas y alteraciones de las extremidades superiores como pulgares ausentes, hipoplásicos, distalmente emplazados o trifalángicos

Introduction Cardiomyelic syndromes encompass congenital heart disease and skeletal malformations of the upper limbs and are related to mutations in transcription factors with T-Box domains. Holt-Oram syndrome is caused by a dominant mutation in the TBX5 gene that alters the three-dimensional structure of the protein and its DNA binding function. Several point mutations and deletions in TBX5 have been reported in patients with the Holt-Oram syndrome phenotype. Patients and methods The proband was a boy with a large atrial septal defect ostium secundum type and a ventricular septal defect, diagnosed by clinical findings (heart murmur) and echocardiography. He also presented slightly hypoplastic thumbs with distal bilateral placement and an implantation index of 0.19 (compared with an average of 0.50 for his gestational age at birth). The boy was referred to the department of medical genetics to rule out 22q11.2 microdeletion syndrome. Results Karyotype and fluorescence in situ hybridization at locus D22S75 were both normal. Because of his clinical findings, molecular study for Holt-Oram syndrome was indicated, leading to the finding of a mutation at intron 7 of TBX5, probably producing a splicing alteration of the gene and resulting in a protein truncated at its C-terminal end. The proband's parents presented the wild type sequence of the gene, thus indicating that the mutation was produced de novo, although a possible germinal mosaicism in the parents could not be ruled out. Conclusions Holt-Oram syndrome is the most frequent cause of cardiomyelic syndrome. All children with heart malformations and abnormalities of the upper limbs such as absent, hypoplastic, distally placed or triphalangic thumbs should undergo molecular studies for this syndrome

[Clinical guide to the management of patients with Beckwith-Wiedemann syndrome]. / Guía clínica para el seguimiento de pacientes con síndrome de Beckwith-Wiedemann.

Beckwith-Wiedemann syndrome (BWS) is characterized by congenital overgrowth, macroglossia and omphalocele or umbilical hernia. Children with BWS may also have all or some of the following features: asymmetry (hemihypertrophy) of the limbs, torso or face, hypoglycemia, organomegaly, ear pits or creases, and embryonal tumors. The frequency of BWS is approximately 1:14,000 births. We present a guide for the management of children with BWS aimed at helping pediatricians and general practitioners or specialists in the clinical follow-up of these patients. This guide has been structured according to different age groups and is based on published evidence.

Guía clínica para el seguimiento de pacientes con síndrome de Beckwith-Wiedemann / Clinical guide to the management of patients with Beckwith Wiedemann syndrome

Los pacientes con síndrome de Beckwith-Wiedemann (SBW) suelen identificarse al nacer por la presencia de macrosomía, macroglosia y onfalocele o hernia umbilical. Muchos de estos niños pueden tener además todos o algunos de los siguientes hallazgos: asimetría (hemihipertrofia) de miembros, torso o cara, hipoglucemia, organomegalia, alteraciones de las orejas (apéndices auriculares, fosetas en el hélix o surcos en la región del lóbulo de la oreja) y tumores embrionarios. La frecuencia del SBW es aproximadamente de 1:14.000 nacimientos. Presentamos una guía cronológica de seguimiento clínico para pacientes con SBW con el objeto de facilitar al pediatra y al médico general o especialista el seguimiento clínico de los pacientes con esta patología. La guía ha sido estructurada para diferentes períodos de edad y está basada principalmente en las evidencias publicadas

Beckwith-Wiedemann syndrome (BWS) is characterized by congenital overgrowth, macroglossia and omphalocele or umbilical hernia. Children with BWS may also have all or some of the following features: asymmetry (hemihypertrophy) of the limbs, torso or face, hypoglycemia, organomegaly, ear pits or creases, and embryonal tumors. The frequency of BWS is approximately 1:14,000 births. We present a guide for the management of children with BWS aimed at helping pediatricians and general practitioners or specialists in the clinical follow-up of these patients. This guide has been structured according to different age groups and is based on published evidence

[Williams-Beuren syndrome: presentation of 82 cases]. / Síndrome de Williams-Beuren: presentación de 82 casos.

OBJECTIVE: We performed a retrospective review of a series of 82 cases of Williams-Beuren syndrome (WBS) and associated diseases. MATERIAL AND METHODS: A series of 82 patients (47 males and 35 females) who consulted at the hospital because of mental retardation and/or congenital cardiopathy were included. The patients were studied mainly from a neurological and cardiological point of view, and secondarily because of endocrinological and nephrological problems. Since description of the chromosomal abnormalities provoking the syndrome, we perform karyotyping in all patients with suspected WBS. RESULTS: Alterations mainly consisted of distinctive facial appearance (100 %), mental retardation with friendly behavior (90 %), congenital cardiopathy (85.4 %), mostly consisting of supravalvular aortic stenosis (72 %), with (12 %) or without (60 %) pulmonary stenosis, and behavior typical of attention deficit-hyperactivity disorder, which usually manifested at the age of 4 to 5 years in both boys and girls. Approximately 90 % started to walk and speak later than average. Birthweight was below 3000 g in 65 % of the patients in whom this datum was included in the medical record. Eleven of the 13 patients (84.5 %) studied showed the typical deletion of WBS. CONCLUSION: Study of patients with WBS should be multidisciplinary. Most patients require help during schooling and subsequent vocational guidance.

Síndrome de Williams-Beuren: presentación de 82 casos / Williams-Beuren syndrome. PResentation of 82 cases

Objetivo: Revisión retrospectiva de una serie de 82 casos de síndrome de Williams-Beuren y los trastornos asociados. Material y métodos: Cohorte de 82 pacientes, 47 varones y 35 mujeres, que consultaron en hospital por retraso psicomotor y/o por cardiopatía congénita. Se estudiaron principalmente desde el punto de vista neurológico y cardiológico y, en segundo lugar, endocrinológico y nefrológico. Desde que se describió la alteración cromosómica que provoca el cuadro, se practica el cariotipo a todos los casos sospechosos de síndrome de Williams-Beuren. Resultados: Las alteraciones principales consistieron en: facies peculiar (100 por ciento); retraso psíquico con actitud amistosa (90 por ciento); cardiopatía congénita (85,4 por ciento), siendo las estenosis aórtica supravalvular, aislada (60 por ciento) o asociada a estenosis pulmonar (12 por ciento), la malformación más frecuente (72 por ciento); trastorno por déficit de atención con hiperactividad (SDAHA), que se apreciaba en la mayoría de los casos, varones y mujeres, a partir de los 5-6 años; iniciación de la marcha y del lenguaje tardíos en aproximadamente el 90 por ciento. El peso al nacer estaba por debajo de los 3.000 g en el 65 por ciento de los casos en que este dato era consignado en las historias clínicas. Once de nuestros 13 casos estudiados (84,5 por ciento) mostraron la deleción del síndrome de WilliamsBeuren. Conclusión: Los pacientes con este síndrome deben ser estudiados multidisciplinarmente. La mayoría de ellos precisan ayuda en su escolaridad y encauzamiento profesional posterior (AU)

Familial deletion of 22q11.2.

We present a mother and her son, both carrying a deletion of chromosome 22q.11.2. They manifest clinical heterogeneity. The mother has schizophrenia, an IQ of 70. Tetralogy of Fallot, a hypernasal voice, but does not have the characteristic facies. Her son has mild psychomotor developmental delay. Tetralogy of Fallot and mild facial features characteristic of VCFS.