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BACKGROUND/OBJECTIVES: Obesity has been ascribed to corticostriatal regions taking control over homeostatic areas. To test this assumption, we applied an effective connectivity approach to reveal the direction of information flow between brain regions and the valence of connections (excitatory versus inhibitory) as a function of increased BMI and homeostatic state. SUBJECTS/METHODS: Forty-one participants (21 overweight/obese) underwent two resting-state fMRI scans: after overnight fasting (hunger) and following a standardised meal (satiety). We used spectral dynamic causal modelling to unravel hunger and increased BMI-related changes in directed connectivity between cortical, insular, striatal and hypothalamic regions. RESULTS: During hunger, as compared to satiety, we found increased excitation of the ventromedial prefrontal cortex over the ventral striatum and hypothalamus, suggesting enhanced top-down modulation compensating energy depletion. Increased BMI was associated with increased excitation of the anterior insula over the hypothalamus across the hunger and satiety conditions. The interaction of hunger and increased BMI yielded decreased intra-cortical excitation from the dorso-lateral to the ventromedial prefrontal cortex. CONCLUSIONS: Our findings suggest that excess weight and obesity is associated with persistent top-down excitation of the hypothalamus, regardless of homeostatic state, and hunger-related reductions of dorso-lateral to ventromedial prefrontal inputs. These findings are compatible with eating without hunger and reduced self-regulation views of obesity.
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Índice de Masa Corporal , Hipotálamo/fisiopatología , Red Nerviosa/anomalías , Corteza Prefrontal/fisiopatología , Adulto , Femenino , Humanos , Hipotálamo/anomalías , Imagen por Resonancia Magnética/métodos , Imagen por Resonancia Magnética/estadística & datos numéricos , Masculino , Red Nerviosa/fisiopatología , Corteza Prefrontal/anomalíasRESUMEN
PURPOSE: Organic conditions underlying secondary hypogonadism (SH) may be ascertained by magnetic resonance imaging (MRI) of the hypothalamic-pituitary region that could not be systematically proposed to each patient. Based upon limited evidence, the Endocrine Society (ES) guidelines suggest total testosterone (T) < 5.2 nmol/L to identify patients eligible for MRI. The study aims to identify markers and their best threshold value predicting pathological MRI findings in men with SH. METHODS: A consecutive series of 609 men seeking medical care for sexual dysfunction and with SH (total T < 10.5 nmol/L and LH ≤ 9.4 U/L) was retrospectively evaluated. An independent cohort of 50 men with SH was used as validation sample. 126 men in the exploratory sample and the whole validation sample underwent MRI. RESULTS: In the exploratory sample, patients with pathological MRI findings (n = 46) had significantly lower total T, luteinizing hormone (LH), follicle stimulating hormone (FSH) and prostate specific antigen (PSA) than men with normal MRI (n = 80). Receiver Operating Characteristics analysis showed that total T, LH, FSH and PSA are accurate in identifying men with pathologic MRI (accuracy: 0.62-0.68, all p < 0.05). The Youden index was used to detect the value with the best performance, corresponding to total T 6.1 nmol/L, LH 1.9 U/L, FSH 4.2 U/L and PSA 0.58 ng/mL. In the validation cohort, only total T ≤ 6.1 nmol/L and LH ≤ 1.9 U/L were confirmed as significant predictors of pathologic MRI. CONCLUSION: In men with SH, total T ≤ 6.1 nmol/L or LH ≤ 1.9 U/L should arise the suspect of hypothalamus/pituitary structural abnormalities, deserving MRI evaluation.
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Eunuquismo , Hormona Folículo Estimulante , Hipotálamo , Hormona Luteinizante , Imagen por Resonancia Magnética/métodos , Hipófisis , Disfunciones Sexuales Fisiológicas , Testosterona , Determinación de la Elegibilidad , Eunuquismo/sangre , Eunuquismo/complicaciones , Eunuquismo/diagnóstico , Hormona Folículo Estimulante/análisis , Hormona Folículo Estimulante/sangre , Humanos , Hipotálamo/anomalías , Hipotálamo/diagnóstico por imagen , Italia/epidemiología , Hormona Luteinizante/análisis , Hormona Luteinizante/sangre , Masculino , Persona de Mediana Edad , Hipófisis/anomalías , Hipófisis/diagnóstico por imagen , Disfunciones Sexuales Fisiológicas/diagnóstico , Disfunciones Sexuales Fisiológicas/epidemiología , Disfunciones Sexuales Fisiológicas/etiología , Testosterona/análisis , Testosterona/sangreRESUMEN
PURPOSE: Incomplete partition III (IP-III), characterized by congenital mixed or sensorineural hearing loss, is a rare genetic disease transmitted through X-linked mode of inheritance. Inner ear findings of IP-III have been well described and allow an immediate diagnosis to be made. Recently, an association between IP-III and distinct hypothalamic malformations has been reported in some of the patients with IP-III. The purpose of this study was to investigate the morphologic abnormalities of the hypothalamus in IP-III. MATERIALS AND METHODS: Magnetic resonance imaging studies of 8 subjects, including 1 set of brothers, who were diagnosed with IP-III based on their clinical and inner ear imaging findings, were analyzed. RESULTS: Of the 8 subjects, 7 demonstrated some degree of morphologic abnormality of the hypothalamus. Of these, 2 showed asymmetrical thickening, 1 showed symmetrical thickening, and 4 showed mass-like enlargement of the hypothalamus. Six of 7 subjects with hypothalamic abnormalities showed asymmetry in caudal extension of the abnormalities, which was more discernible on coronal oblique T2-weighted images. Clinically, none of the subjects had endocrinologic or neurologic symptoms. CONCLUSIONS: This retrospective analysis presents further magnetic resonance imaging evidence on the association between the rare IP-III malformations and the presence of hypothalamic morphologic abnormalities.
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Oído Interno , Enfermedades Genéticas Ligadas al Cromosoma X , Pérdida Auditiva Sensorineural , Hipotálamo , Adolescente , Adulto , Anciano , Preescolar , Oído Interno/anomalías , Oído Interno/diagnóstico por imagen , Oído Interno/patología , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico por imagen , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Pérdida Auditiva Sensorineural/diagnóstico por imagen , Pérdida Auditiva Sensorineural/patología , Humanos , Hipotálamo/anomalías , Hipotálamo/diagnóstico por imagen , Hipotálamo/patología , Imagen por Resonancia Magnética , Masculino , Estudios Retrospectivos , Adulto JovenRESUMEN
X-linked deafness-2 (DFNX2) is an X-linked recessive disorder characterized by profound sensorineural hearing loss and a pathognomonic temporal bone deformity. Because hypothalamic malformations associated with DFNX2 have been rarely described, we aimed to further describe these lesions and compare them with features of a nonaffected population. All patients diagnosed with DFNX2 between 2006 and 2019 were included and compared with age-matched patients with normal MR imaging findings and without hypothalamic dysfunction. MR imaging features differing between groups were selected to help identify DFNX2. Sensitivity and specificity were calculated for these features. Agreement among 3 radiologists was quantified using the index κ. Information on the presence or absence of gelastic seizures, precocious puberty, or delayed puberty was also gathered. We selected distinctive MR imaging features of hypothalamic malformations in DFNX2. The feature selected on axial T2 images was the folded appearance of the ventromedial hypothalamus (sensitivity, 100%; specificity, 95.8%) characterized by an abnormal internal/external cleft (sensitivity, 100%; specificity, 95.7%). On coronal T2, the first distinctive feature was a concave morphology of the medial eminence (sensitivity, 100%; specificity, 97.1%), the second feature was at least 1 hypothalamic-septum angle ≥90° (sensitivity, 90%; specificity, 72.5%), and the third feature was a forebrain-hypothalamic craniocaudal length of ≥6 mm (sensitivity, 70%; specificity, 79.7%). Clinical features were also distinctive because 9 patients with DFNX2 did not present with gelastic seizures or precocious puberty. One patient had delayed puberty. The κ index and intraclass correlation coefficient ranged between 0.78 and 0.95. Imaging and clinical features of the hypothalamus suggest that there is a hypothalamic malformation associated with DFNX2. Early assessment for pubertal delay is proposed.
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Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico por imagen , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Pérdida Auditiva Conductiva/diagnóstico por imagen , Pérdida Auditiva Conductiva/patología , Pérdida Auditiva Sensorineural/diagnóstico por imagen , Pérdida Auditiva Sensorineural/patología , Hipotálamo/anomalías , Hipotálamo/diagnóstico por imagen , Adolescente , Niño , Preescolar , Humanos , Interpretación de Imagen Asistida por Computador/métodos , Lactante , Imagen por Resonancia Magnética/métodos , Masculino , Estudios Retrospectivos , Sensibilidad y Especificidad , Adulto JovenRESUMEN
Sonic hedgehog (SHH) signaling plays a pivotal role in 2 different phases during brain development. Early SHH signaling derived from the prechordal plate (PrCP) triggers secondary Shh induction in the forebrain, which overlies the PrCP, and the induced SHH signaling, in turn, directs late neuronal differentiation of the forebrain. Consequently, Shh regulation in the PrCP is crucial for initiation of forebrain development. However, no enhancer that regulates prechordal Shh expression has yet been found. Here, we identified a prechordal enhancer, named SBE7, in the vicinity of a cluster of known forebrain enhancers for Shh This enhancer also directs Shh expression in the ventral midline of the forebrain, which receives the prechordal SHH signal. Thus, the identified enhancer acts not only for the initiation of Shh regulation in the PrCP but also for subsequent Shh induction in the forebrain. Indeed, removal of the enhancer from the mouse genome markedly down-regulated the expression of Shh in the rostral domains of the axial mesoderm and in the ventral midline of the forebrain and hypothalamus in the mouse embryo, and caused a craniofacial abnormality similar to human holoprosencephaly (HPE). These findings demonstrate that SHH signaling mediated by the newly identified enhancer is essential for development and growth of the ventral midline of the forebrain and hypothalamus. Understanding of the Shh regulation governed by this prechordal and brain enhancer provides an insight into the mechanism underlying craniofacial morphogenesis and the etiology of HPE.
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Elementos de Facilitación Genéticos , Regulación del Desarrollo de la Expresión Génica , Proteínas Hedgehog/fisiología , Proteínas del Tejido Nervioso/fisiología , Prosencéfalo/embriología , Animales , Sistemas CRISPR-Cas , Proteínas del Ojo/fisiología , Técnicas de Inactivación de Genes , Genes Reporteros , Proteínas Hedgehog/biosíntesis , Proteínas Hedgehog/genética , Holoprosencefalia/genética , Proteínas de Homeodominio/fisiología , Hipotálamo/anomalías , Hipotálamo/embriología , Hipotálamo/metabolismo , Operón Lac , Mesencéfalo/embriología , Mesencéfalo/metabolismo , Mesodermo/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/genética , Prosencéfalo/anomalías , Prosencéfalo/metabolismo , Transducción de Señal , Transgenes , Proteína Homeobox SIX3RESUMEN
Patients with X-linked deafness carry mutations in the POU3F4 gene and have pathognomonic inner ear malformations characterised by symmetrical incomplete partition type 3 (absent modiolus and lamina spiralis but preserved interscalar septum in a normal-sized cochlea) and large internal auditory meatus (IAM) with an increased risk of gusher during stapes surgery. We describe a range of fairly characteristic malformations in the hypothalamus of some patients with this rare condition, ranging from subtle asymmetric appearance and thickening of the tuber cinereum to more marked hypothalamic enlargement. We discuss the role of POU3F4 in the normal development of both the inner ear and hypothalamus and the proposed pathophysiology of incomplete partition type 3.
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Sordera/genética , Oído Interno/anomalías , Oído Interno/diagnóstico por imagen , Hipotálamo/anomalías , Hipotálamo/diagnóstico por imagen , Factores del Dominio POU/genética , Adolescente , Niño , Preescolar , Estudios de Cohortes , Sordera/diagnóstico por imagen , Sordera/patología , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Adulto JovenRESUMEN
INTRODUCTION: An interhypothalamic adhesion (IHA) is a gray mater-like band of tissue traversing across the third ventricle anterior to the mammillary bodies and is similar but distinct from an interthalamic adhesion. These rare anatomic anomalies can be detected with magnetic resonance imaging or, incidentally, during endoscopic ventricular surgery. METHODS: All cases of interhypothalamic adhesions visualized during endoscopic third ventriculotomy (ETV), outside of the myelomeningocele setting, were identified from two institutions. Retrospective chart and imaging reviews were conducted and compared to intraoperative videos and photos for all cases. IHA variables collected included the following size, location, multiplicity, and associated anatomic anomalies. RESULTS: Four cases of interhypothalamic adhesions were identified during ETV-all of which, either partially or completely, obscured access to the third ventricular floor. The IHAs in our cohort were duplicated in two patients, large (> 3 mm and severely obstructing access to the third ventricular floor) in three patients, and adherent to the floor of the third ventricle in three patients. All four patients had primary absence of the septum pellucidum. Previous reports found associations of IHAs with other congenital, particularly midline, abnormalities. The IHAs in our cohort affected the surgery in three of four cases including misdirecting the ventriculostomy and requiring retraction or division of the IHA. In no case was postoperative pituitary or hypothalamic dysfunction observed. CONCLUSIONS: Although interhypothalamic adhesions are rare, these anomalies must be recognized as they may hinder access to the third ventricular floor. IHAs may be large, multiple, or adherent to adjacent ventricular structures, they can misdirect or occlude the ventriculostomy or impart risk of bleeding and hypothalamic injury. Techniques for management of IHA include aborting the attempt, re-siting the ventriculostomy, or retracting or dividing the IHA, which enabled technically successful ETV in three of four patients in this series.
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Hipotálamo/anomalías , Hipotálamo/diagnóstico por imagen , Hallazgos Incidentales , Neuroendoscopía/métodos , Tercer Ventrículo/cirugía , Ventriculostomía , Adulto , Femenino , Humanos , Lactante , Masculino , Estudios Retrospectivos , Tercer Ventrículo/diagnóstico por imagenRESUMEN
Several acquired or congenital hypothalamic abnormalities may cause growth failure (GF). We described two of these congenital abnormalities. First, a case of CHARGE syndrome, an epigenetic disorder mostly caused by heterozygous mutations in the gene encoding CHD7, a chromatin remodeling protein, causing several malformations, some life-threatening, with additional secondary hypothalamus-hypophyseal dysfunction, including GF. Second, a cohort of individuals with genetic isolated severe GH deficiency (IGHD), due to a homozygous mutation in the GH-releasing hormone (GHRH) receptor gene described in Itabaianinha County, in northeast Brazil. In this IGHD, with marked reduction of serum concentrations of IGF-I, and an up regulation of IGF-II, GF is the principal finding in otherwise normal subjects, with normal quality of life and longevity. This IGHD may unveil the effects of GHRH, pituitary GH and IGF-I, IGF-II and local GH and growth factor on the size and function of body and several systems. For instance, anterior pituitary hypoplasia, and impairment of the non-REM sleep may be due to GHRH resistance. Proportionate short stature, doll facies, high-pitched pre-pubertal voice, and reduced muscle mass reflect the lack of the synergistic effect of pituitary GH and IGF-I in bones and muscles. Central adiposity may be due to a direct effect of the lack of GH. Brain, eyes and immune system may also involve IGF-II and local GH or growth factors. A concept of physiological hierarchy controlling body size and function by each component of the GH system may be drawn from this model.
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Síndrome CHARGE/etiología , Enanismo Hipofisario/etiología , Trastornos del Crecimiento/etiología , Hipotálamo/anomalías , Mutación , Receptores de Neuropéptido/deficiencia , Receptores de Hormona Reguladora de Hormona Hipofisaria/deficiencia , Adulto , Preescolar , Femenino , Humanos , Masculino , Receptores de Neuropéptido/genética , Receptores de Hormona Reguladora de Hormona Hipofisaria/genéticaRESUMEN
Major depressive disorder (MDD) is a debilitating disease that is characterized by depressed mood, diminished interests, impaired cognitive function and vegetative symptoms, such as disturbed sleep or appetite. MDD occurs about twice as often in women than it does in men and affects one in six adults in their lifetime. The aetiology of MDD is multifactorial and its heritability is estimated to be approximately 35%. In addition, environmental factors, such as sexual, physical or emotional abuse during childhood, are strongly associated with the risk of developing MDD. No established mechanism can explain all aspects of the disease. However, MDD is associated with alterations in regional brain volumes, particularly the hippocampus, and with functional changes in brain circuits, such as the cognitive control network and the affective-salience network. Furthermore, disturbances in the main neurobiological stress-responsive systems, including the hypothalamic-pituitary-adrenal axis and the immune system, occur in MDD. Management primarily comprises psychotherapy and pharmacological treatment. For treatment-resistant patients who have not responded to several augmentation or combination treatment attempts, electroconvulsive therapy is the treatment with the best empirical evidence. In this Primer, we provide an overview of the current evidence of MDD, including its epidemiology, aetiology, pathophysiology, diagnosis and treatment.
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Trastorno Depresivo Mayor/complicaciones , Trastorno Depresivo Mayor/diagnóstico , Calidad de Vida/psicología , Corteza Suprarrenal/anomalías , Corteza Suprarrenal/fisiopatología , Médula Suprarrenal/anomalías , Médula Suprarrenal/fisiopatología , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Monoaminas Biogénicas , Cognición/efectos de los fármacos , Cognición/fisiología , Costo de Enfermedad , Trastorno Depresivo Mayor/epidemiología , Humanos , Hipotálamo/anomalías , Hipotálamo/fisiopatología , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Prevalencia , Psicoterapia/métodosRESUMEN
Growth hormone deficiency affects roughly between one in 3000 and one in 4000 children with most instances of growth hormone deficiency being idiopathic. Growth hormone deficiency can also be associated with genetic diseases or chromosome abnormalities. Association of growth hormone deficiency together with hypothalamic-pituitary axis malformation and Cat-Eye syndrome is a very rare condition. We report a family with two brothers presenting with growth delay due to a growth hormone deficiency associated with a polymalformation syndrome. They both displayed pre-auricular pits and tags, imperforate anus and Duane retraction syndrome. Both parents and a third unaffected son displayed normal growth pattern. Cerebral MRI showed a hypothalamic-pituitary axis malformation in the two affected brothers. Cytogenetic studies revealed a type I small supernumerary marker chromosome derived from chromosome 22 resulting in a tetrasomy 22pter-22q11.21 characteristic of the Cat-Eye syndrome. The small supernumerary marker chromosome was present in the two affected sons and the mother in a mosaic state. Patients with short stature due to growth hormone deficiency should be evaluated for chromosomal abnormality. Family study should not be underestimated.
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Trastornos de los Cromosomas/diagnóstico , Anomalías del Ojo/diagnóstico , Hormona de Crecimiento Humana/deficiencia , Hipófisis/anomalías , Anomalías Múltiples/genética , Aneuploidia , Aberraciones Cromosómicas , Trastornos de los Cromosomas/tratamiento farmacológico , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 22/genética , Anomalías del Ojo/tratamiento farmacológico , Anomalías del Ojo/genética , Terapia de Reemplazo de Hormonas , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Hipotálamo/anomalías , Hibridación Fluorescente in Situ , Recién Nacido , Cariotipificación , MasculinoRESUMEN
Interhypothalamic adhesion is a newly described disease entity, characterized by an abnormal parenchymal band connecting the medial margins of the hypothalami across the third ventricle. Additional anomalies, including cleft palate, gray matter heterotopia, cerebellar hypoplasia, optic atrophy, hippocampal under-rotation, and white matter lesions, may coexist. The purpose of this clinical report is to describe the imaging findings from a series of 13 patients with interhypothalamic adhesions discovered on brain MR imaging.
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Encefalopatías/patología , Hipotálamo/anomalías , Encéfalo/anomalías , Femenino , Humanos , Imagen por Resonancia Magnética , MasculinoRESUMEN
BACKGROUND AND PURPOSE: Periventricular nodular heterotopia are common malformations of cortical development that are associated with many clinical syndromes and with many different neuroimaging phenotypes. The purpose of this study was to determine whether specific malformation phenotypes may be related to location, side, or number of PNH as assessed by MR imaging. MATERIALS AND METHODS: MR images of 200 patients previously diagnosed with PNH were retrospectively analyzed. PNH were classified according to their location along the ventricles (anterior, posterior, or diffuse), side (unilateral or bilateral), and number of nodules (<5, 6-10, or >10). The cerebrum, brain stem and cerebellum were analyzed to assess associated anomalies. Associations between PNH location and the presence of other anomalies were tested by using Fisher exact test and χ2 test. RESULTS: Posterior PNH were significantly associated with malformations of the cerebral cortex, diminished white matter volume, and mid-/hindbrain anomalies. Diffuse PNH were associated with diminished white matter volume, callosal "anomalies," and the presence of megacisterna magna. Unilateral PNH were strongly associated with cortical malformations. CONCLUSIONS: Certain malformation complexes are associated with PNH in specific locations: posterior PNH with cerebral cortical and mid-/hindbrain malformations and diffuse PNH with callosal anomalies and megacisterna magna. Knowledge of these associations should allow more directed analyses of brain MR imaging in patients with PNH. In addition, knowledge of these associations may help to direct studies to elucidate the causes of these malformation complexes.
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Ventrículos Laterales/anomalías , Imagen por Resonancia Magnética , Heterotopia Nodular Periventricular/patología , Adolescente , Adulto , Anciano , Ganglios Basales/anomalías , Niño , Preescolar , Cisterna Magna/anomalías , Cuerpo Calloso/patología , Femenino , Feto/anomalías , Hipocampo/anomalías , Humanos , Hipotálamo/anomalías , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Fenotipo , Estudios Retrospectivos , Tálamo/anomalías , Adulto JovenRESUMEN
Hypothalamic hamartoma (HH) is usually associated with refractory epilepsy, cognitive impairment, and behavioral disturbance. There is now increasing evidence that HH can be treated effectively with a variety of neurosurgical approaches. Treatment options for intractable gelastic seizure in HH patients include direct open surgery with craniotomy, endoscopic surgery, radiosurgery with gamma knife (GKS) and stereotactic radiofrequency thermocoagulation. Selection of treatment modalities depends on type and size of the HH and the surgeon's preference. Two surgical techniques, resection and disconnection, had been described with favorable outcomes. Pretreatment evaluation, patient selection, surgical techniques, complications, and possible selection of treatment are discussed in this chapter.
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Epilepsia , Hamartoma , Enfermedades Hipotalámicas , Hipotálamo/anomalías , Neuroendoscopía/métodos , Radiocirugia/métodos , Niño , Epilepsia/etiología , Epilepsia/patología , Epilepsia/cirugía , Hamartoma/complicaciones , Hamartoma/patología , Hamartoma/cirugía , Humanos , Enfermedades Hipotalámicas/complicaciones , Enfermedades Hipotalámicas/patología , Enfermedades Hipotalámicas/cirugía , Hipotálamo/cirugíaRESUMEN
Girdin is an Akt substrate and actin-binding protein. Mice with germ-line deletions of Girdin (a non-conditional knockout, (ncKO)) exhibit complete postnatal lethality accompanied by growth retardation and neuronal cell migration defects, which results in hypoplasia of the olfactory bulb and granule cell dispersion in the dentate gyrus. However, the physiological and molecular abnormalities in Girdin ncKO mice are not fully understood. In this study, we first defined the distribution of Girdin in neonates (P1) and adults (6months or older) using ß-galactosidase activity in tissues from ncKO mice. The results indicate that Girdin is expressed throughout the nervous system (brain, spinal cord, enteric and autonomic nervous systems). In addition, ß-galactosidase activity was detected in non-neural tissues, particularly in tissues with high tensile force, such as tendons, heart valves, and skeletal muscle. In order to identify the cellular population where the Girdin ncKO phenotype originates, newly generated Girdin flox mice were crossed with nestin promoter-driven Cre transgenic mice to obtain Girdin conditional knockout (cKO) mice. The phenotype of Girdin cKO mice was almost identical to ncKO mice, including postnatal lethality, growth retardation and decreased neuronal migration. Our findings indicate that loss of Girdin in the nestin cell lineage underlies the phenotype of Girdin ncKO mice.
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Linaje de la Célula , Proteínas de Microfilamentos/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Secuencia de Aminoácidos , Animales , Encéfalo/anomalías , Encéfalo/metabolismo , Células Germinativas/metabolismo , Hipotálamo/anomalías , Hipotálamo/metabolismo , Factor I del Crecimiento Similar a la Insulina/genética , Proteínas de Filamentos Intermediarios/genética , Ratones , Ratones Noqueados , Proteínas de Microfilamentos/genética , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso/genética , Nestina , Fenotipo , ARN Mensajero/análisis , ARN Mensajero/biosíntesis , Proteínas de Transporte Vesicular/genética , beta-Galactosidasa/biosíntesisRESUMEN
Haploinsufficiency for the HMG-box transcription factor SOX2 results in abnormalities of the human ventral forebrain and its derivative structures. These defects include anophthalmia (absence of eye), microphthalmia (small eye) and hypothalamic hamartoma (HH), an overgrowth of the ventral hypothalamus. To determine how Sox2 deficiency affects the morphogenesis of the ventral diencephalon and eye, we generated a Sox2 allelic series (Sox2(IR), Sox2(LP), and Sox2(EGFP)), allowing for the generation of mice that express germline hypomorphic levels (<40%) of SOX2 protein and that faithfully recapitulate SOX2 haploinsufficient human phenotypes. We find that Sox2 hypomorphism significantly disrupts the development of the posterior hypothalamus, resulting in an ectopic protuberance of the prechordal floor, an upregulation of Shh signaling, and abnormal hypothalamic patterning. In the anterior diencephalon, both the optic stalks and optic cups (OC) of Sox2 hypomorphic (Sox2(HYP)) embryos are malformed. Furthermore, Sox2(HYP) eyes exhibit a loss of neural potential and coloboma, a common phenotype in SOX2 haploinsufficient humans that has not been described in a mouse model of SOX2 deficiency. These results establish for the first time that germline Sox2 hypomorphism disrupts the morphogenesis and patterning of the hypothalamus, optic stalk, and the early OC, establishing a model of the development of the abnormalities that are observed in SOX2 haploinsufficient humans.
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Anomalías del Ojo/genética , Hipotálamo/anomalías , Factores de Transcripción SOXB1/genética , Animales , Diencéfalo/anomalías , Diencéfalo/patología , Modelos Animales de Enfermedad , Embrión de Mamíferos/anomalías , Embrión de Mamíferos/patología , Haploinsuficiencia , Humanos , Hipotálamo/patología , Ratones , Ratones Transgénicos , Microscopía Electrónica de Rastreo , Especificidad de Órganos , Factores de Transcripción SOXB1/deficienciaRESUMEN
Objetivo El objetivo de nuestro trabajo fue analizar las posibles causas del déficit de hormona de crecimiento (DGH) aislado o en combinación con otras deficiencias hipofisarias, catalogado como idiopático. Pacientes y métodos Estudiamos a los pacientes con DGH idiopático incluidos en el protocolo de tratamiento con GH sintética para adultos en seguimiento por el Servicio de Endocrinología y Nutrición del Hospital Universitario San Cecilio. Se evaluaron de forma retrospectiva los antecedentes de la historia perinatal, los hallazgos en la resonancia magnética (RM) hipotálamo-hipofisaria y el diagnóstico de DGH y otros déficits hormonales. Resultados Se revisaron las historias de 17 pacientes: 14 varones y 3 mujeres con una edad media al diagnóstico de 8,4±7,3 años. Se presentaron eventos adversos perinatales en 12 pacientes (69,2%). El análisis de las imágenes de RM mostró silla turca vacía (2 pacientes), hipoplasia hipofisaria o ausencia del tallo hipofisario (7 pacientes) e hipoplasia hipofisaria con neurohipófisis ectópica (6 pacientes); en los 2 restantes no se pudo acceder a estos datos. En todos ellos se había establecido el diagnóstico de DGH, en 15 (88,2%) déficit de gonadotropinas, en 9 (52,9%) déficit de corticotropina y en 8 (47,1%) déficit de tirotropina. Conclusiones En nuestros pacientes, los eventos adversos durante la gestación o en la historia perinatal y la presencia de alteraciones anatómicas identificadas por RM suponen un marcador de disfunción hipofisaria y pueden ser importantes en la patogenia de esta entidad. El espectro de la enfermedad es variable desde el DGH aislado hasta múltiples déficits hormonales (AU)
Objective To analyze the possible causes of growth hormone (GH) deficiency, whether isolated (GHD) or in combination with other pituitary deficiencies classified as idiopathic. Patients and methods We studied patients with idiopathic GHD included in a protocol of recombinant GH treatment in adults attending the outpatient clinic of the Endocrinology and Nutrition Service of the San Cecilio University Hospital. Perinatal history, findings on magnetic resonance imaging (MRI) of the hypothalamic-pituitary axis and diagnosis of GHD and other deficiencies were retrospectively evaluated. Results A total of 17 patients were included: 14 men and 3 women with a mean age at diagnosis of 8.4±7.3 years. Perinatal adverse events occurred in 12 patients (69.2%). MRI showed empty sella (2 patients), pituitary hypoplasia or absence of the pituitary stalk (7 patients) and pituitary hypoplasia with ectopic posterior pituitary gland (6 patients); in the remaining 2 patients these data were not available. All had an established diagnosis of GHD: 15 with (88.2%) gonadotropin deficiency, 9 (52.9%) with adrenocorticotropic hormone (ACTH) deficiency and 8 (47.1%) with thyroid-stimulating hormone (TSH) deficiency. Conclusions In our patients, adverse events during pregnancy or the perinatal period and the presence of anatomical abnormalities identified by MRI are a marker of pituitary dysfunction and may be important in the pathogenesis of this entity. The clinical spectrum of disease varies from isolated GH deficiency to multiple pituitary hormone deficiencies (AU)
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Humanos , Masculino , Femenino , Recién Nacido , Niño , Hipotálamo/anomalías , Hipófisis/anomalías , Hormona de Crecimiento Humana/deficiencia , Hipopituitarismo/complicaciones , Estudios Retrospectivos , Factores de Riesgo , Feto , Estudios de SeguimientoRESUMEN
OBJECTIVE: To analyze the possible causes of growth hormone (GH) deficiency, whether isolated (GHD) or in combination with other pituitary deficiencies classified as idiopathic. PATIENTS AND METHODS: We studied patients with idiopathic GHD included in a protocol of recombinant GH treatment in adults attending the outpatient clinic of the Endocrinology and Nutrition Service of the San Cecilio University Hospital. Perinatal history, findings on magnetic resonance imaging (MRI) of the hypothalamic-pituitary axis and diagnosis of GHD and other deficiencies were retrospectively evaluated. RESULTS: A total of 17 patients were included: 14 men and 3 women with a mean age at diagnosis of 8.4+/-7.3 years. Perinatal adverse events occurred in 12 patients (69.2%). MRI showed empty sella (2 patients), pituitary hypoplasia or absence of the pituitary stalk (7 patients) and pituitary hypoplasia with ectopic posterior pituitary gland (6 patients); in the remaining 2 patients these data were not available. All had an established diagnosis of GHD: 15 with (88.2%) gonadotropin deficiency, 9 (52.9%) with adrenocorticotropic hormone (ACTH) deficiency and 8 (47.1%) with thyroid-stimulating hormone (TSH) deficiency. CONCLUSIONS: In our patients, adverse events during pregnancy or the perinatal period and the presence of anatomical abnormalities identified by MRI are a marker of pituitary dysfunction and may be important in the pathogenesis of this entity. The clinical spectrum of disease varies from isolated GH deficiency to multiple pituitary hormone deficiencies.