Tatton-Brown-Rahman syndrome: Novel pathogenic variants and new neuroimaging findings.

Tatton-Brown-Rahman syndrome (TBRS) or DNMT3A-overgrowth syndrome is characterized by overgrowth and intellectual disability associated with minor dysmorphic features, obesity, and behavioral problems. It is caused by variants of the DNMT3A gene. We report four patients with this syndrome due to de novo DNMT3A pathogenic variants, contributing to a deeper understanding of the genetic basis and pathophysiology of this autosomal dominant syndrome. Clinical and magnetic resonance imaging assessments were also performed. All patients showed corpus callosum anomalies, small posterior fossa, and a deep left Sylvian fissure; as well as asymmetry of the uncinate and arcuate fascicles and marked increased cortical thickness. These results suggest that structural neuroimaging anomalies have been previously overlooked, where corpus callosum and brain tract alterations might be unrecognized neuroimaging traits of TBRS syndrome caused by DNMT3A variants.

White-Matter Lesions and Cortical Cerebral Blood Flow Evaluation by 3D Arterial Spin-Labeled Perfusion MRI in Asymptomatic Divers: Correlation with Patent Foramen Ovale Ocurrence.

Cerebral white-matter lesions (cWML) can be caused by dilation of Virchow-Robin spaces or may correspond to true lacunar ischemic lesions. The aim of our study was to evaluate in asymptomatic divers the relationship between the presence of patent foramen ovale (PFO) and cWML, as well as their possible effects on cortical cerebral blood flow (CBF) by magnetic resonance (MRI) through the arterial spin labeling (ASL) sequence. Transthoracic echocardiography was performed for the identification of PFO, and cerebral magnetic resonance including the 3D-ASL sequence for CBF quantification. Thirty-eight divers, with a mean age 45.8 ± 8.6 years, were included. Nineteen healthy volunteers, mean age 41 ± 15.2 years, served as the control group. A total of 28.9% of divers had completed more than 1000 dives. It was found that 26.3% of divers presented with PFO in the echocardiographic study. cWML was evidenced in 10.5% of diver MRI studies. There was no statistically significant relationship between the presence of PFO and cWML (p = 0.95). We observed a lower blood flow in all brain areas assessed by the 3D-ASL sequence in the group of divers, compared with the control group. We did not find statistical differences in CBF as a function of the presence or absence of PFO, number of dives, or cWML evidence.

Síndrome cerebeloso cognitivo afectivo tras cerebelitis aguda / Cerebellar cognitive affective syndrome after acute cerebellitis

En el síndrome cerebeloso, cuya causa principal es la cerebelitis aguda, destacan principalmente las alteraciones motoras, si bien no son las únicas consecuencias de esta patología. Los pacientes que se presentan a continuación manifiestan, además de los signos motores, alteraciones cognitivo-afectivas, como déficit de atención, cambios de personalidad, etc. Esto se denomina síndrome cerebeloso cognitivo afectivo, cuyo diagnóstico es poco habitual a pesar de ser una complicación común. Estos casos llaman a reflexionar sobre la importancia de diagnosticar dicho síndrome para poder administrar un tratamiento adecuado y así mejorar la calidad de vida de los pacientes que lo padezcan (AU)

The most common cause of the cerebellar syndrome is acute cerebellitis. The motor disorders stand out in this syndrome. However, there are other symptoms apart from these. The patients presented below show, besides motor disorders, cognitive affective signs such as attention deficit, personality changes, etc. All these latter manifestations form the cerebellar cognitive affective syndrome. Despite having an uncommon diagnosis, it is a frequent complication. These cases prove the importance of diagnosing this syndrome to enhance the patient’s life quality by providing adequate treatment. (AU)

Mutations in the COL18A1 gen associated with knobloch syndrome and structural brain anomalies: a novel case report and literature review of neuroimaging findings.

. COL18A1 gene mutations have been associated with Knobloch syndrome, which is characterized by ocular and brain abnormalities. Here we report a 4.5 years-old male child with autism and two novel COL18A1 mutations (NM_030582.4: c.1883_1891dup and c.1787C>T). Hypermetropic astigmatism, but not brain migration disorders, was observed. However, an asymmetric pattern of cerebellar perfusion and a smaller arcuate fascicle were found.  Low levels of collagen XVIII were also observed in the patient´s serum. Thus, biallelic loss-of-function mutations in COL18A1 may be a new cause of autism  without the brain malformations typically reported in patients with Knobloch syndrome.

Abnormal frontal gyrification pattern and uncinate development in patients with KBG syndrome caused by ANKRD11 aberrations.

KBG syndrome is characterized by dental, craniofacial and skeletal anomalies, short stature and global developmental delay or intellectual disability. It is caused by microdeletions or truncating mutations of ANKRD11. We report four unrelated probands with this syndrome due to de novo ANKRD11 aberrations that may contribute to a better understanding of the genetics and pathophysiology of this autosomal dominant syndrome. Clinical, cognitive and MRI assessments were performed. Three of the patients showed normal intellectual functioning, whereas the fourth had a borderline level of intellectual functioning. However, all of them showed deficits in various cognitive and socioemotional processes such as attention, executive functions, empathy or pragmatic language. Moreover, all probands displayed marked asymmetry of the uncinate fascicles and an abnormal gyrification pattern in the left frontal lobe. Thus, structural neuroimaging anomalies seem to have been overlooked in this syndrome. Disturbed frontal gyrification and/or lower structural integrity of the uncinate fascisulus might be unrecognized neuroimaging features of KBG syndrome caused by ANKRD11 aberrations. Present results also point out that this syndrome is not necessarily associated with global developmental delay and intellectual disability, but it can be related to other neurodevelopmental disorders or subclinical levels of attention-deficit hyperactivity disorder, autism, communication disorders or specific learning disabilities.

Neuroimaging Findings in Patients with EBF3 Mutations: Report of Two Cases.

Early B cell factor 3 (EBF3) is a transcription factor involved in brain development. Heterozygous, loss-of-function mutations in EBF3 have been reported in an autosomal dominant neurodevelopmental syndrome characterized by hypotonia, ataxia, and developmental delay (sometimes described as "HADD"s). We report 2 unrelated cases with novel de novo EBF3 mutations: c.455G>T (p.Arg152Leu) and c.962dup (p.Tyr321*) to expand the genotype/phenotype correlations of this disorder; clinical, neuropsychological, and MRI studies were used to define the phenotype. IQ was in the normal range and diffusion tensor imaging revealed asymmetric alterations of the longitudinal fasciculus in both cases. Our results demonstrate that EBF3 mutations can underlie neurodevelopmental disorders without intellectual disability. Long tract abnormalities have not been previously recognized and suggest that they may be an unrecognized and characteristic feature in this syndrome.

Endometriosis torácica como causa de neumotórax espontáneo recurrente en mujer de 53 años / Thoracic endometriosis presenting as recurrent spontaneous pneumothorax in a 53-year-old female

Una mujer de 53 años asintomática es diagnosticada de tercer episodio de neumotórax en hemitórax derecho. En episodios previos no se había objetivado causa del neumotórax salvo bullas subpleurales. Una videotoracoscopia muestra lesiones típicas de endometriosis torácica junto con múltiples perforaciones diafragmáticas. Tras la reparación quirúrgica la paciente recibió tratamiento anti-estrogénico con buena evolución. Se trata de un caso excepcional por su forma de presentación, por la edad de la paciente y por la afectación diafragmática. (AU)

A 53-year-old asymptomatic female presented with a third episode of spontaneous pneumothorax in right hemithorax. Previous studies did not demonstrate the etiology of this disease but only sub-pleural bullae. We found typical thoracic endometriosis lesions through video thoracoscopy. After surgical correction and anti-estrogenic treatment, the patient remains asymptomatic. This case is relevant due its presentation, diaphragmatic involvement and the age of the patient. (AU)

ANO3 and early-onset dyskinetic encephalopathy.

Mutations in the ANO3 gene have been associated with autosomal dominant craniocervical dystonia. However, little else is known about the genotype-phenotype characteristics of this disorder. Here we describe a 3 years-old girl with distal myoclonic dystonia. Whole exome sequencing in trio revealed a de novo missense ANO3 variant not previously described in international databases. A global psychomotor regression was observed once dystonia was present. Brain MRI changes paralleled these findings: whereas MRI at the age of 18 months was normal, mild brain and cerebellar atrophy was observed 18 months later. These results suggest that missense mutations in ANO3 may underlie complex disorders particularly characterized by early psychomotor regression and dystonia.

Prognosis and treatment-selection criteria for patients with high-grade stage IIIc-IV serous ovarian, fallopian tube or peritoneal cancer / Pronóstico y selección de tratamiento en pacientes con cáncer seroso de ovario, de trompas de Falopio o peritoneal de alto grado, estadio IIIc-IV

Objective: To determine the impact of implementing strict treatment-selection criteria on the overall outcome of women with high-grade serous advanced stage ovarian, fallopian tube, or primary peritoneal carcinoma. Material and methods: We included patients treated for high-grade serous advanced stage ovarian, fallopian tube, or primary peritoneal carcinoma at our Institution from January 2007 to March 2015. All other non-serous, low-grade histology tumors and secondary cytoreductions were excluded. strict treatment-selection criteria was used to decide on primary cytoreductive surgery versus neoad-juvant chemotherapy and type of adjuvant therapy. Collected data included patient and tumor characteristics, preoperative diagnostic procedures, surgical treatment, perioperative complications, and neoadjuvant and adjuvant chemotherapies. Appropriate statistical tests were used and survival analysis performed. Results: We identified 71 eligible patients. Mean age was 58.5 ± 11.8 years, 28.2% received neoadjuvant chemotherapy, and 77.5% had optimal cytoreductive surgery to < 1 cm residual disease. Major complications were observed in 16.9% of women, with no significant difference between neoadjuvant chemotherapy and primary cytoreductive surgery groups. With a median follow-up of 35.7 months, median overall survival was not achieved and 57.2% of patients were alive 54 months after surgery. A total of 24 out of 71 (33.8%) died of disease, 11 (45.8%) within two years after surgery. Median progression-free survival was 19.5 months (95% CI 14.8-24.3). Conclusions: Applying strict treatment-selection criteria for patients with high-grade serous advanced stage ovarian, fallopian tube, or primary peritoneal carcinoma ensures few surgical complications and excellent survival rates for the majority of these women

Objetivo: determinar el impacto de la implementación de criterios estrictos de selección de tratamiento sobre el pronóstico de las mujeres con carcinoma seroso de ovario, trompa de Falopio o peritoneal primario en estadio avanzado y de alto grado. Material y métodos: entre enero de 2007 y marzo de 2015 se incluyeron pacientes tratadas por carcinoma ovárico seroso avanzado de alto grado, trompa de Falopio o carcinoma peritoneal primario en nuestro hospital. Se utilizaron criterios estrictos de selección de tratamiento para decidir sobre la cirugía citorreductora primaria versus quimioterapia neoadyuvante y el tipo de tratamiento adyuvante. Los datos recogidos incluyeron características del paciente y del tumor, procedimientos diagnósticos preoperatorios, tratamiento quirúrgico, complicaciones perioperatorias y quimioterapias neoadyuvantes y adyuvantes. Se utilizaron pruebas estadísticas adecuadas y se realizó un análisis de supervivencia. Resultados: se incluyeron 71 pacientes. La edad media fue de 58,5 ± 11,8 años, el 28,2% recibió quimioterapia neoadyuvante y el 77,5% tuvo una cirugía citorreductora óptima (< 1 cm de enfermedad residual). Se observaron complicaciones mayores en el 16,9% de las mujeres, sin diferencias significativas entre los grupos de quimioterapia neoadyuvante y de cirugía citorreductora primaria. Con una mediana de seguimiento de 35,7 meses, no se alcanzó la mediana de supervivencia global y el 57,2% de los pacientes estaban vivas 54 meses después de la cirugía. Un total de 24 de 71 (33.8%) murieron de enfermedad, 11 (45.8%) en los dos años después de la cirugía. La mediana de supervivencia libre de progresión fue de 19,5 meses (IC del 95%: 14,8-24,3). Conclusiones: la aplicación de criterios estrictos de selección de tratamiento para pacientes con carcinoma seroso ovárico, de trompa de Falopio o carcinoma peritoneal primario en estadio avanzado de alto grado asegura pocas complicaciones quirúrgicas y buenas tasas de supervivencia para la mayoría de estas pacientes

Cingulate Cortical Thickness and Dopamine Transporter ( DAT1) Genotype in Children and Adolescents With ADHD.

OBJECTIVE: This study aimed to examine the influence of dopamine transporter gene ( DAT1) 3'UTR genotype on cingulate cortical thickness in a large sample of children and adolescents with ADHD. METHOD: Brain MRIs were acquired from 46 ADHD patients with homozygosity for the 10-repeat allele and 52 ADHD patients with a single copy or no copy of the allele. The cingulate cortex of each MRI scan was automatically parceled into sulci and gyri as well as into Brodmann areas (BA). RESULTS: There were no group differences in age, gender, full-scale intelligence quotient, symptom severity, treatment status, comorbidity, or mean overall cortical thickness. Sulcus/gyrus- and BA-based analyses revealed that patients homozygous for the 10-repeat allele showed significantly greater thickness in right cingulate gyrus and right BA 24 compared with 9-repeat carriers. CONCLUSION: These findings suggest that thickness of cingulate cortex is influenced by the presence of the 10-repeat allele in ADHD.

Migraña hemipléjica y secuencia pseudocontinuous arterial spin-labeling / Hemiplegic migraine and arterial spin labelling sequence

No disponible

Neuroanatomía del trastorno por déficit de atención/hiperactividad: correlatos neuropsicológicos y clínicos / The neuroanatomy of attention deficit hyperactivity disorder: neuropsychological and clinical correlates

Introducción. El desarrollo de la resonancia magnética estructural y de nuevos métodos de análisis ha permitido examinar, como nunca antes, las bases neuroanatómicas del trastorno por déficit de atención/hiperactividad (TDAH). No obstante, poco se sabe todavía sobre la relación de los síntomas clínicos y las disfunciones neuropsicológicas características del TDAH con las alteraciones neuroanatómicas observadas. Objetivo. Explorar la relación entre neuroanatomía, clínica y neuropsicología en el TDAH. Desarrollo. A nivel de grupo, existen diferencias marcadas entre el cerebro de niños adolescentes y adultos con TDAH y el cerebro de personas con desarrollo típico. Estas diferencias se observan transversal y longitudinalmente en todas las medidas, tanto de la sustancia gris como de la sustancia blanca. Aunque todavía escasa, cada vez existe mayor evidencia que señala que estas diferencias se relacionan con los síntomas nucleares del trastorno y con el grado de disfunción clínica. También parecen asociarse con el funcionamiento cognitivo (principalmente, atención y control inhibitorio). Conclusiones. La relación entre los distintos niveles de análisis de estudio del TDAH acerca la investigación a la clínica y permite comprender y tratar mejor el trastorno. Aunque el avance en este campo es innegable, todavía son muchas las cuestiones que hay que explorar y profundizar en mayor detalle. Se requiere comprender mejor la asociación entre las medidas neuroanatómicas y cada dimensión sintomatológica, y la relación con otros procesos neuropsicológicos también implicados en el trastorno (AU)

Introduction. The development of structural magnetic resonance scanning and new methods of analysis has made it possible to explore, in a hitherto unknown way, the neuroanatomical bases of attention deficit hyperactivity disorder (ADHD). Yet, little is known about the relation between the clinical symptoms and the neuropsychological dysfunctions characterising ADHD and the neuroanatomical alterations that are observed. Aim. To explore the relation between neuroanatomy, clinical features and neuropsychology in ADHD. Development. At group level, there are a number of marked differences between the brain of children, adolescents and adults with ADHD and the brain of subjects with a typical development. These differences are observed cross-sectionally and longitudinally in all the measurements, both in the grey matter and in the white matter. Although still scarce, there is an increasing body of evidence showing that these differences are related with the core symptoms of the disorder and with the degree of clinical dysfunction. They also appear to be associated with cognitive functioning (mainly attention and inhibitory control). Conclusions. The relation among the different levels of analysis in the study of ADHD bring research closer to the clinical features and allows a better understanding and management of the disorder. Although progress is undoubtedly being made in this field, there are still many questions that need exploring in greater depth. There is a need for a better understanding of the association between the neuroanatomical measurements and each dimension of the symptoms, and their relationship with other neuropsychological processes that are also involved in the disorder (AU)

Mutations in BRAT1 cause autosomal recessive progressive encephalopathy: Report of a Spanish patient.

We describe a 4-year-old male child born to non-consanguineous Spanish parents with progressive encephalopathy (PE), microcephaly, and hypertonia. Whole exome sequencing revealed compound heterozygous BRAT1 mutations [c.1564G > A (p.Glu522Lys) and c.638dup (p.Val214Glyfs*189)]. Homozygous and compound heterozygous BRAT1 mutations have been described in patients with lethal neonatal rigidity and multifocal seizure syndrome (MIM# 614498). The seven previously described patients suffered from uncontrolled seizures, and all of those patients died in their first months of life. BRAT1 acts as a regulator of cellular proliferation and migration and is required for mitochondrial function. The loss of these functions may explain the cerebral atrophy observed in this case of PE. This case highlights the extraordinary potential of next generation technologies for the diagnosis of rare genetic diseases, including PE. Making a prompt diagnosis of PE is important for genetic counseling and disease management.

Cortical thickness at the time of the initial attack in two patients with paediatric relapsing-remitting multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system with a low incidence in the paediatric population; cortical atrophy is often striking, even in the early stages of the disease. Evidence of cortical thinning in childhood MS is scant. AIMS: This study aimed to assess cortical thickness in paediatric patients during the initial attack of remitting-relapsing MS. METHODS: We report two cases of remitting-relapsing MS, with initial attacks at 12 and 16 years of age. We analysed brain cortical thickness (CTh) in these patients and compared these data to the CTh of a control group comprised of six 12-year-old females and six 16-year-old males. RESULTS: Both cases exhibited a total brain CTh significantly below that of the control group. This difference was also observed when analysing the CTh of all lobes except the left parietal lobe in one of the cases. CONCLUSIONS: Cortical atrophy is already present at the time of onset of MS. Studies with larger patient populations that have a more homogenous clinical presentation could identify the time of onset of cortical atrophy and use this parameter as a prognostic and/or treatment marker of MS.

In utero diagnosis of PHACE syndrome by fetal magnetic resonance imaging (MRI).

The acronym PHACE describes the association of facial hemangioma with anomalies of the posterior fossa, cerebral arteries, and cardiovascular and ocular alterations. This study presents a case of diagnostic suspicion based on fetal MRI. We report the case of a pregnant woman whose 26-week MRI revealed a female fetus with hypoplasia of the right cerebellar hemisphere and right microphthalmia, leading to the suspicion of PHACE syndrome. The diagnosis was confirmed at birth, together with other criteria: facial hemangioma, absent posterior inferior cerebellar artery, and dysplasia of the right internal carotid artery. To our knowledge, this is the first live case described prenatally with both ocular and cerebellar findings on fetal MRI that suggest PHACE syndrome. The prenatal presence of 2 PHACE criteria led to the suspicion of this syndrome, and prenatal diagnostic criteria might be developed to improve information regarding the prognosis of cerebellar malformations.

Prenatal diagnosis of frontonasal dysplasia associated with bilateral periventricular nodular heterotopia.

Frontonasal dysplasia is an etiologically heterogeneous development alteration including a set of anomalies affecting the eyes, forehead, and nose as a result of a malformation of the frontonasal elevation. It could occur either in isolation or as part of a syndrome such as frontonasal dysplasia associated with periventricular heterotopia. Our goal is to document the first clinical case of prenatal diagnosis for frontonasal dysplasia associated with periventricular heterotopia by fetal magnetic resonance imaging (MRI) at weeks 19.5 and 29 and postnatal MRI. In conclusion, the presence of frontonasal dysplasia in a prenatal ultrasonography should always be followed by a fetal MRI with routine screening for periventricular nodular heterotopias so as to establish a more adequate prognosis for the family.

Difusión en resonancia magnética en el estudio de lesiones hepáticas / Diffusion MRI in the study of hepatic lesions

Actualmente la imagen potenciada en difusión (diffusion weighted image [DWI]) en resonancia magnética (RM) constituye una importante herramienta para la detección y caracterización de lesiones hepáticas, así como para la monitorización y evaluación de la respuesta al tratamiento de la enfermedad tumoral. Por otro lado se está estudiando también la utilidad de esta técnica para el estudio de la enfermedad hepática difusa. Entre las ventajas adicionales de la DWI-RM, destaca la ausencia de emisión de radiaciones ionizantes y la ausencia de necesidad de utilizar contraste paramagnético, por lo que se puede realizar el estudio en pacientes con insuficiencia renal. Otra ventaja es la corta duración de la secuencia de difusión por lo que apenas incrementa el tiempo de exploración de la RM abdominal. Por lo tanto, es importante que el médico conozca esta técnica diagnóstica, ya que la DWI es una secuencia que debería ser incluida de forma rutinaria en el protocolo de estudio de la RM hepática (AU)

Diffusion weighted imaging (DWI) in magnetic resonance imaging (MRI) is currently an important tool for detecting and characterising hepatic lesions, as well as for monitoring and evaluating the response to the treatment of the tumour disease. The use of this technique is also being assessed for the study of diffuse liver disease. Among the additional advantages of DWI-MRI, is the absence of emission of ionising radiation and not having to use paramagnetic contrasts, which means it can be used in the study of patients with renal failure. Another advantage is the short duration of the diffusion sequence, which means that the examination time in abdominal MRI is scarcely increased. Therefore, it is important that the physician is aware of this diagnostic technique, since DWI is a sequence that should be routinely included in the liver MRI study protocol (AU)

[Diffusion MRI in the study of hepatic lesions]. / Difusión en resonancia magnética en el estudio de lesiones hepáticas.

Diffusion weighted imaging (DWI) in magnetic resonance imaging (MRI) is currently an important tool for detecting and characterising hepatic lesions, as well as for monitoring and evaluating the response to the treatment of the tumour disease. The use of this technique is also being assessed for the study of diffuse liver disease. Among the additional advantages of DWI-MRI, is the absence of emission of ionising radiation and not having to use paramagnetic contrasts, which means it can be used in the study of patients with renal failure. Another advantage is the short duration of the diffusion sequence, which means that the examination time in abdominal MRI is scarcely increased. Therefore, it is important that the physician is aware of this diagnostic technique, since DWI is a sequence that should be routinely included in the liver MRI study protocol.

Role of New Functional MRI Techniques in the Diagnosis, Staging, and Followup of Gynecological Cancer: Comparison with PET-CT.

Recent developments in diagnostic imaging techniques have magnified the role and potential of both MRI and PET-CT in female pelvic imaging. This article reviews the techniques and clinical applications of new functional MRI (fMRI) including diffusion-weighted MRI (DWI), dynamic contrast-enhanced (DCE)-MRI, comparing with PET-CT. These new emerging provide not only anatomic but also functional imaging, allowing detection of small volumes of active tumor at diagnosis and early disease relapse, which may not result in detectable morphological changes at conventional imaging. This information is useful in distinguishing between recurrent/residual tumor and post-treatment changes and assessing treatment response, with a clear impact on patient management. Both PET-CT and now fMRI have proved to be very valuable tools for evaluation of gynecologic tumors. Most papers try to compare these techniques, but in our experience both are complementary in management of these patients. Meanwhile PET-CT is superior in diagnosis of ganglionar disease; fMRI presents higher accuracy in local preoperative staging. Both techniques can be used as biomarkers of tumor response and present high accuracy in diagnosis of local recurrence and peritoneal dissemination, with complementary roles depending on histological type, anatomic location and tumoral volume.