[X-linked intellectual disability syndrome with macrocephaly due to BRWD3 gene deletion]. / Síndrome de discapacidad intelectual ligada a X con macrocefalia por deleción del gen BRWD3.

INTRODUCTION: Pathogenic variants in BRWD3 gene have been described as a rare cause of syndromic X-linked intellectual disability. Its phenotype shows neurodevelopmental delay with intellectual disability in all reported patients, facial dysmorphic features, macrocephaly, overgrowth and obesity. The great majority of cases yield point variants in the gene, only three large deletions including only the BRWD3 gene have been reported. The BRWD3 protein is an epigenetic reader that regulates chromatin remodeling. We report a boy with a compatible phenotype and a deletion including only this gene. CASE REPORT: Boy, without family and perinatal pathological background, with neurodevelopmental delay: psychomotor delay, speech delay and intellectual disability, macrocephaly (p > 99) and obesity. Phenotype with facial dysmorphic features: wide forehead, deep set eyes, bulbous nose, prominent ears and pointed chin. The array-CGH analysis showed a 586 kb deletion at Xq21.1 including only one gene with associated disorder, BRWD3. Afterwards, the deletion was also identified in his asymptomatic mother and sister. CONCLUSIONS: Our patient confirms that the haploinsufficiency due to BRWD3 deletion is a causal genetic mechanism of the BRWD3-related syndromic X-linked intellectual disability. It is important to recognize the phenotype for the diagnosis and follow up of the patients, and also to carry out the family genetic analysis in order to identify and give genetic counselling to the women who also have the genetic defect, because the majority of them are asymptomatic, as the mother and sister of our patient.

TITLE: Síndrome de discapacidad intelectual ligada a X con macrocefalia por deleción del gen BRWD3.Introducción. Variantes patógenas en el gen BRWD3 son la causa de un tipo poco frecuente de discapacidad intelectual sindrómica ligada a X. Su fenotipo se asocia a la alteración neuroconductual con discapacidad intelectual, dismorfia facial, macrocefalia, sobrecrecimiento y obesidad. La gran mayoría de los pacientes presenta variantes puntuales en el gen y sólo se han descrito tres casos con deleciones parciales que incluyen únicamente al gen BRWD3. Funcionalmente es un lector epigenético que regula la remodelación de la cromatina. Presentamos un varón con fenotipo compatible con una deleción que incluye sólo este gen asociado a patología. Caso clínico. Varón sin antecedentes familiares ni perinatales de interés con alteración en el neurodesarrollo: retraso psicomotor, retraso del lenguaje y discapacidad cognitiva, macrocefalia (p > 99) y obesidad. Fenotipo con dismorfia facial: frente amplia, ojos hundidos, nariz bulbosa, pabellones auriculares despegados y mentón afilado. Array de hibridación genómica comparada con deleción de 586 kb en Xq21.1, que incluye un único gen asociado a la patología, BRWD3. Posteriormente se realizó un estudio a la madre y a la hermana, asintomáticas, y ambas portan la deleción. Conclusiones. Nuestro caso confirma que la haploinsuficiencia debida a la deleción del gen BRWD3 es un mecanismo genético causal de la discapacidad intelectual sindrómica ligada a X asociada al gen BRWD3. Es importante reconocer el fenotipo para el diagnóstico y el seguimiento, así como la realización del estudio familiar para asesoramiento genético a las mujeres que porten la alteración, puesto que en la mayoría de los casos son asintomáticas, como la madre y la hermana de este paciente.

Jejunal arteriovenous malformation and multiple acquired extrahepatic portosystemic shunts in a juvenile dog, presenting with melena.

A juvenile dog referred with a 1-month history of persistent melena and severe anaemia, was diagnosed with a jejunal arteriovenous malformation, and multiple acquired extrahepatic portosystemic shunts. A midline coeliotomy was performed, the jejunal arteriovenous malformation was localised intraoperatively and was successfully removed via an enterectomy. Histopathology confirmed a true arteriovenous malformation. Despite the initial improvement, the patient developed seizure episodes secondary to hepatic encephalopathy 8 months after surgery. Fifteen months after surgery, the owner opted for euthanasia due to the ongoing seizure episodes. Post-mortem histologic examination of the liver showed features consistent with portal vein hypoplasia. A congenital arteriovenous malformation should be considered as a differential diagnosis in juvenile patients with a chronic history of haemorrhage from the gastrointestinal tract. In addition, acquired portosystemic shunts may occur in patients with portal vein hypoplasia and jejunal arteriovenous malformations.

[Warsaw breakage syndrome: an etiology for congenital microcephaly and sensorineural deafness]. / Síndrome de rotura de Varsovia: una causa de microcefalia congénita y sordera neurosensorial.

INTRODUCTION: Warsaw breakage syndrome is a very rare genetic disorder due to biallelic pathogenic variants in DDX11 gene, with a role in the sister chromatid cohesion process, and classified in the cohesinophaties group. It is characterized by the clinical triad of growth restriction, microcephaly and sensorineural deafness. Additional, but less frequent features, are facial dysmorphism, and skeletal, heart, skin and genitourinary anomalies. CASE REPORT: We report a boy with the cardinal features of the syndrome: prenatal growth restriction, severe congenital microcephaly, and sensorineural deafness with cochlear nerves agenesis. He also has a cardiac anomaly, hypospadias, cryptorchidism, skin abnormality, and pes planus. The exome yielded two heterozygous likely pathogenic variants in the DDX11 gene, c.1403dup; p.(Ser469Valfs*32) and c.2371C>T; p.(Arg791Trp), inherited in trans from the parents. CONCLUSION: We review the clinical and genetic data of the 23 reported cases with the syndrome in the literature and analyze the etiopathogenic interpretation of our case variants based on the molecular and cellular functions of DDX11 described. Due to the clinical overlap with the chromosomal breakage syndromes and cohesinopathies we must make the differential diagnosis with these entities, overall, with Fanconi anemia, Nijmegen breakage syndrome, Cornelia de Lange syndrome and Roberts syndrome. In clinical practice we must think in Warsaw breakage syndrome in the neonatal period in a patient with intrauterine growth restriction, severe microcephaly, and sensorineural deafness.

TITLE: Síndrome de rotura de Varsovia: una causa de microcefalia congénita y sordera neurosensorial.Introducción. El síndrome de rotura de Varsovia es una alteración genética muy poco frecuente originada por variantes patógenas bialélicas en el gen DDX11, implicado en la cohesión de las cromátidas hermanas, que pertenece al grupo de las cohesinopatías. Clínicamente se caracteriza por retraso del crecimiento, microcefalia y sordera neurosensorial, con otras manifestaciones menos frecuentes: dismorfia facial, anomalías esqueléticas, cardíacas, cutáneas y genitourinarias. Caso clínico. Presentamos a un varón con las manifestaciones cardinales del síndrome: bajo peso en el nacimiento, microcefalia congénita grave y sordera neurosensorial con agenesia de los nervios cocleares. También presenta cardiopatía, hipospadias, criptorquidia, anomalía cutánea y pies planos. En el exoma se han identificado dos variantes en heterocigosis probablemente patógenas en el gen DDX11, c.1403dup; p.(Ser469Valfs*32) y c.2371C>T; p.(Arg791Trp), heredadas cada una de un progenitor. Conclusión. Revisamos a los 23 pacientes descritos con el síndrome en la bibliografía, tanto desde el punto de vista clínico como desde el genético. Analizamos el significado etiopatógeno de las variantes de nuestro caso basándonos en los datos moleculares y las funciones celulares de DDX11 de los estudios publicados. Debido al solapamiento clínico con los síndromes con rotura cromosómica y las cohesinopatías, debemos realizar el diagnóstico diferencial con estas entidades, fundamentalmente la anemia de Fanconi, el síndrome de rotura de Nijmegen, el síndrome de Cornelia de Lange y el síndrome de Roberts. En la práctica clínica, debemos sospechar este síndrome en el período neonatal en un paciente con retraso del crecimiento intrauterino, microcefalia grave y sordera neurosensorial.

Opsoclonus-myoclonus syndrome: Clinical characteristics, therapeutic considerations, and prognostic factors in a Spanish paediatric cohort.

INTRODUCTION: Opsoclonus-myoclonus-ataxia syndrome is a rare neuroinflammatory disorder with onset during childhood; aetiology may be paraneoplastic, para-infectious, or idiopathic. No biomarkers have yet been identified, and diagnosis is clinical. Better cognitive prognosis appears to be related to early onset of immunomodulatory therapy. METHODS: We describe the epidemiological, clinical, therapeutic, and long-term prognostic characteristics of a cohort of 20 Spanish patients. RESULTS: The mean age of onset was 21 months (range, 2-59). Ataxia and opsoclonus were the most frequent symptoms both at disease onset and throughout disease progression. The mean time from onset to diagnosis was 1.1 months. Neuroblast lineage tumours were detected in 45% of patients; these were treated with surgical resection in 7 cases and chemotherapy in 2. Cerebrospinal fluid analysis revealed pleocytosis in 4 cases (25%) and neither antineuronal antibodies nor oligoclonal bands were detected in any patient. Immunomodulatory drugs were used in all cases. Nine patients started combined immunomodulatory treatment at the time of diagnosis, and 5 patients after a mean of 2.2 months. In the long term, 6 of the 10 patients followed up for more than 5 years presented mild or moderate cognitive sequelae. Four patients presented relapses, generally coinciding with the decrease of corticosteroid doses. CONCLUSIONS: Early initiation of immunotherapy, as well as triple combination therapy, where needed, was associated with a lower frequency of cognitive impairment 2 years after onset.

Tillaux fracture in adults - Case report and review of literature.

Avulsion fractures of the distal tibia resulting from anterior inferior tibiofibular ligament are known as Tillaux fractures. This injury is usually seen among adolescents as a Salter Harris type 3 epiphysiolisis in relation to bone weakness in distal tibia due to ephiphyseal closure. Regarding adult patients, this pattern of fracture become such an atypical one due to supposed failure of ligament previous to bone, avoiding avulsion. However, some cases have been described in recent decades.The purpose of the present study is to present an adult Tillaux case and add an exhaustive review of literature regarding mechanism of injury, associated lesions, treatment, postoperative care and follow up. LEVEL OF EVIDENCE: Level V.

Opsoclonus-myoclonus syndrome: clinical characteristics, therapeutic considerations, and prognostic factors in a Spanish paediatric cohort. / Síndrome opsoclono-mioclono: características clínicas, aspectos terapéuticos y factores pronósticos en una cohorte pediátrica española.

INTRODUCTION: Opsoclonus-myoclonus-ataxia syndrome is a rare neuroinflammatory disorder with onset during childhood; aetiology may be paraneoplastic, para-infectious, or idiopathic. No biomarkers have yet been identified, and diagnosis is clinical. Better cognitive prognosis appears to be related to early onset of immunomodulatory therapy. METHODS: We describe the epidemiological, clinical, therapeutic, and long-term prognostic characteristics of a cohort of 20 Spanish patients. RESULTS: The mean age of onset was 21 months (range, 2-59). Ataxia and opsoclonus were the most frequent symptoms both at disease onset and throughout disease progression. The mean time from onset to diagnosis was 1.1 months. Neuroblast lineage tumours were detected in 45% of patients; these were treated with surgical resection in 7 cases and chemotherapy in 2. Cerebrospinal fluid analysis revealed pleocytosis in 4 cases (25%) and neither antineuronal antibodies nor oligoclonal bands were detected in any patient. Immunomodulatory drugs were used in all cases. Nine patients started combined immunomodulatory treatment at the time of diagnosis, and 5 patients after a mean of 2.2 months. In the long term, 6 of the 10 patients followed up for more than 5 years presented mild or moderate cognitive sequelae. Four patients presented relapses, generally coinciding with the decrease of corticosteroid doses. CONCLUSIONS: Early initiation of immunotherapy, as well as triple combination therapy, where needed, was associated with a lower frequency of cognitive impairment 2 years after onset.

[Benefits of robotics in gait rehabilitation in cerebral palsy: A systematic review]. / Beneficios de la robótica en la rehabilitación de la marcha en la parálisis cerebral: una revisión sistemática.

BACKGROUND AND AIM: Cerebral palsy is the most common motor disability in childhood, with an estimated incidence of two out of every 1,000 live births. The impairment mostly affects gait. The aim of rehabilitation programmes is to enhance independence in affected individuals, especially mobility. To do this, robot-assisted gait rehabilitation programmes have been developed. Therefore, this study aimed to identify the benefits of robotics in gait rehabilitation in cerebral palsy. MATERIAL AND METHODS: We performed a literature search using the MeSH terms «cerebral palsy¼, «robotics¼ and «gait¼. RESULTS: After applying the selection criteria, we obtained 10 research studies and three protocols analysing the benefits of robotics in cerebral palsy and demonstrating that their use provides major advantages.

Assessment of male urinary incontinence postprostatectomy through the Consultation on Incontinence Questionnaire-Short Form.

OBJECTIVE: The objective of this study is to assess the correlation between the urinary incontinence results of the ICIQ-SF, and those obtained in the 1-hour and 24-hour pad tests, in a sample of men that underwent prostatectomy. MATERIAL AND METHODS: A prospective observational study was carried out in patients from the Integrated Management Area of Vigo (EOXI de Vigo) who underwent prostatectomy and suffered from urinary incontinence in the post-surgery period. Loss of urine was assessed by means of the 1-hour and 24-hour pad tests and the ICIQ-SF. A comparative analysis of the questionnaire findings was performed for both urinary incontinence tests. RESULTS: A correlation is observed between the ICIQ-SF and the amount of urine loss in the 1-hour and the 24-hour pad tests. However, the severity of urine loss established by instruments is less consistent. The 24-hour pad test is the one that obtained better correlation with the ICIQ-SF. CONCLUSIONS: The ICIQ-SF should be validated in a male population after prostatectomy in order to reinterpret the severity values observed in the different instruments studied. LEVEL OF EVIDENCE: 4.

Cell fishing: A similarity based approach and machine learning strategy for multiple cell lines-compound sensitivity prediction.

The prediction of cell-lines sensitivity to a given set of compounds is a very important factor in the optimization of in-vitro assays. To date, the most common prediction strategies are based upon machine learning or other quantitative structure-activity relationships (QSAR) based approaches. In the present research, we propose and discuss a straightforward strategy not based on any learning modelling but exclusively relying upon the chemical similarity of a query compound to reference compounds with annotated activity against cell lines. We also compare the performance of the proposed method to machine learning predictions on the same problem. A curated database of compounds-cell lines associations derived from ChemBL version 22 was created for algorithm construction and cross-validation. Validation was done using 10-fold cross-validation and testing the models on new data obtained from ChemBL version 25. In terms of accuracy, both methods perform similarly with values around 0.65 across 750 cell lines in 10-fold cross-validation experiments. By combining both methods it is possible to achieve 66% of correct classification rate in more than 26000 newly reported interactions comprising 11000 new compounds. A Web Service implementing the described approaches (both similarity and machine learning based models) is freely available at: http://bioquimio.udla.edu.ec/cellfishing.

[What is the best exercise for rehabilitation of abdominal diastasis rehabilitation?] / ¿Cuál es el mejor ejercicio para la rehabilitación de la diástasis abdominal?

The aim of this study was to analyse the scientific literature to identify the different types of exercises that influence inter-rectus distance with a view to subsequently including them in the treatment of diastasis rectus abdominis. A search made in the CINHAL, PEDRo, Pubmed, and Scopus databases. Fourteen valid articles were included in the analysis. The articles were divided into 2 groups: those analysing exercise with an immediate effect and those presenting an exercise programme with a delayed effect (long term); the most commonly used exercise was the curl-up. There is a lack of consensus on the effects of the different types of exercises evaluated on inter-rectus distance. However, curl ups decrease inter-rectus distance when it is checked immediately. Abdominal muscle training through an exercise programme helps to reduce inter-rectus distance but the optimal exercises to include in an exercise programme remain to be elucidated.

[Circumstances that may decrease the reliability of instruments to assess male urinary incontinence]. / Circunstancias que pueden disminuir la fiabilidad de los instrumentos para valorar la incontinencia urinaria masculina.

OBJECTIVE: To identify situations that may alter the results of the 1-hour and 24-hour Pad test and the short-form International Consultation in Incontinence Questionnaire (SF-ICIQ). PARTICIPANTS: Five physiotherapists, who conducted the interviews and treatment of 81 patients undergoing radical prostatectomy. METHOD: A qualitative descriptive phenomenological study was carried out, using a focus group technique with five people (4 women and 1 man) responsible for the treatment and assessment of patients with urinary incontinence after prostatectomy. Recordings were transcribed and the Atlas.ti7 programme was used to carry out the coding of the variables. RESULTS: Important factors were identified in the use of measuring instruments for the diagnosis and assessment of urinary incontinence in all the tools used. CONCLUSIONS: Some situations can modify the objectivity of the various tests for the assessment of urinary incontinence. Some of the factors identified were lower fluid intake, less activity, use of manual clamp or urinals to avoid leakage, as well as the interference of certain drugs.

Correlation between the 1-hour and 24-hour pad test in the assessment of male patients with post-prostatectomy urinary incontinence.

INTRODUCTION: This study is aimed at studying the correlation between the 1-hour and 24-hour pad tests for urinary incontinence following prostatectomy; the second objective is to check whether the severity level established by both tests is adequate for male urinary incontinence. MATERIAL AND METHODS: The study population includes patients who had undergone prostatectomy at a single center between February 2015 and December 2016, using 159 measurements consisting of 24-hour and 1-hour pad tests, belonging 45 patients. Both tests have been performed according to the protocol standardized by the International Continence Society. Once all the data have been obtained, the levels marked by each of the pads have been established, and the statistical analysis has started. RESULTS: The relationship between the amounts recorded in grams by the two test is highly significant (P=0.000), however, when comparing the incontinence levels established by each test (mild, moderate and severe), discrepancies have been found. The median of the severe cases in the 24-hour pad test was 389.5 grams, and in the 1-hour pad test was 92 grams. So, patient's loss values are well above the cut-off point defined for severe urinary incontinence in both 24-hour (50 grams) and 1-hour pad test (75 grams). CONCLUSIONS: There is a diagnostic discrepancy between the 24-hour pad test and the 1-hour pad test in terms of defined urinary incontinence severity levels. In our opinion, these levels should be redefined for male urinary incontinence since the amount of urine loss is well above the threshold established for severe incontinence. LEVEL OF EVIDENCE: 4.

[RIT1: a novel gene associated with Noonan syndrome]. / RIT1: un nuevo gen causal del sindrome de Noonan.

INTRODUCTION: Noonan syndrome is the most frequent of the congenital group of malformation syndromes caused by germline mutations that encode components of the RAS/MAPK pathway, termed RASopathies, one of the most frequent congenital genetic disorders in the clinical practice. Recently RIT1 mutations have been reported in patients with Noonan syndrome. CASE REPORT: A 7 years-old girl with a clinical diagnosis of Noonan syndrome, and with a hypertrophic cardiomyopathy included in her clinical manifestations, where a de novo heterozygous, probably pathogenic, novel mutation in RIT1, c.295T>C (p.Phe99Leu), has been identified. CONCLUSIONS: RIT1 shares homology with other RAS proteins and the expression of mutant alleles demonstrates a gain-of-function effect supporting a causative role in Noonan syndrome pathogenesis. Data suggest that the frequency of RIT1 mutations can be estimated as 3-5% in Noonan syndrome patients. These cases compared with Noonan patients harboring mutations in other genes are characterized by high frequency of prenatal abnormalities and hypertrophic cardiomyopathy, and lower frequencies of short stature and pectus abnormalities. We emphasize the importance of the novel identified genes in order to be included in the diagnostic panels.

TITLE: RIT1: un nuevo gen causal del sindrome de Noonan.Introduccion. El sindrome de Noonan es el mas frecuente del grupo de los sindromes malformativos congenitos originados por mutaciones germinales en genes de la via RAS/MAPK, denominados genericamente RAS-opatias, uno de los grupos mas comunes de alteraciones geneticas congenitas en la practica clinica. Recientemente se han descrito mutaciones en el gen RIT1 en pacientes con sindrome de Noonan. Caso clinico. Nina de 7 anos con diagnostico clinico de sindrome de Noonan, que entre sus manifestaciones clinicas incluye miocardiopatia hipertrofica, en la que se ha identificado una mutacion de novo en heterocigosis, en RIT1, c.295T>C (p.Phe99Leu), no descrita previamente, probablemente causal. Conclusiones. RIT1 comparte homologia con otras proteinas RAS y la expresion de alelos mutantes origina un efecto de ganancia de funcion que apoya su papel causal en el sindrome de Noonan. Podemos estimar actualmente que es responsable de un 3-5% de los casos del sindrome. Estos casos con sindrome de Noonan, respecto a los que presentan mutaciones en otros genes, se caracterizan por una mayor frecuencia de alteraciones prenatales, alta frecuencia de miocardiopatia hipertrofica y menor frecuencia de talla baja y deformidad toracica. Destaca la importancia de incorporar los nuevos genes identificados en los paneles diagnosticos.

Antiresorptive treatment, when initiated after a first hip fracture, may not protect of a second contralateral episode in elderly population: A study with 685 patients.

INTRODUCTION: Osteoporosis predisposes for a higher risk of hip fracture and its treatment is frequently underprescribed. Our purpose was to assess the relation between having a second hip fracture and receiving osteoporosis treatment. Also to assess the relation between this second fracture and using central nervous system drugs or being institutionalised. PATIENTS AND METHODS: We reviewed all the patients that were admitted to our hospital with an osteoporotic proximal femoral fracture between September 2009 and February 2011. We identified 685 patients, 74 of which presented a contralateral fracture. We evaluated if they were receiving osteoporosis treatment or taking any medication that could affect the central nervous system and if they were institutionalised. RESULTS: A 10.8% of patients had a second fracture and the mean time between the two of them was 20 months (1-122). There was a clear female predominance (76.35%). The mean age at occurrence of the primary fracture was 83.02 years and 85 for the second. A 90.8% did not follow any type of osteoporosis medication before the first fracture. A 50.9% did not receive central nervous system drugs and 79.1% lived at home at the time of the first fracture. 12.8% of the patients that did not follow the osteoporosis treatment, had a contralateral fracture, 3% more than those that did follow some kind of treatment, but this difference was not significant (p=0.2). DISCUSSION: We identified a similar number of patients undergoing osteoporotic treatment as registered in literature. There was no significant difference between suffering a second hip fracture and following osteoporosis treatment, using psychotropic drugs or being institutionalised.

[Occipital condyle fracture: clinical case and a review of the literature]. / Fractura del cóndilo occipital. Reporte clínico y revisión de la literatura.

OBJECTIVE: We present a case report of an occipital condyle fracture, a rarely seen injury in patients of any age, and particularly so in paediatric patients. The objective of this article is to inform about this lesion, such often going unnoticed, but should be especially looked for in cranial trauma cases with neck pain. An X-ray may be normal and diagnosis is best made by using computed tomography imaging. Treatment should depend on whether the fracture is stable or not. MATERIAL AND METHODS: We report on two patients, 17 and 40 -year-old males who presented with an impacted right occipital condyle fracture following a motorbike accident. Cervical immobilization was carried out with a hard collar. RESULTS: Good results were obtained and there were no secondary effects of a neurological or functional nature. CONCLUSION AND CLINICAL RELEVANCE: In conclusion, the knowledge of this condition, its correct diagnosis and the correct treatment choice is crucial to the avoidance of brachial plexus injuries and other important sequelae.