Mouse Model of Alagille Syndrome and Mechanisms of Jagged1 Missense Mutations.

BACKGROUND & AIMS: Alagille syndrome is a genetic disorder characterized by cholestasis, ocular abnormalities, characteristic facial features, heart defects, and vertebral malformations. Most cases are associated with mutations in JAGGED1 (JAG1), which encodes a Notch ligand, although it is not clear how these contribute to disease development. We aimed to develop a mouse model of Alagille syndrome to elucidate these mechanisms. METHODS: Mice with a missense mutation (H268Q) in Jag1 (Jag1+/Ndr mice) were outbred to a C3H/C57bl6 background to generate a mouse model for Alagille syndrome (Jag1Ndr/Ndr mice). Liver tissues were collected at different timepoints during development, analyzed by histology, and liver organoids were cultured and analyzed. We performed transcriptome analysis of Jag1Ndr/Ndr livers and livers from patients with Alagille syndrome, cross-referenced to the Human Protein Atlas, to identify commonly dysregulated pathways and biliary markers. We used species-specific transcriptome separation and ligand-receptor interaction assays to measure Notch signaling and the ability of JAG1Ndr to bind or activate Notch receptors. We studied signaling of JAG1 and JAG1Ndr via NOTCH 1, NOTCH2, and NOTCH3 and resulting gene expression patterns in parental and NOTCH1-expressing C2C12 cell lines. RESULTS: Jag1Ndr/Ndr mice had many features of Alagille syndrome, including eye, heart, and liver defects. Bile duct differentiation, morphogenesis, and function were dysregulated in newborn Jag1Ndr/Ndr mice, with aberrations in cholangiocyte polarity, but these defects improved in adult mice. Jag1Ndr/Ndr liver organoids collapsed in culture, indicating structural instability. Whole-transcriptome sequence analyses of liver tissues from mice and patients with Alagille syndrome identified dysregulated genes encoding proteins enriched at the apical side of cholangiocytes, including CFTR and SLC5A1, as well as reduced expression of IGF1. Exposure of Notch-expressing cells to JAG1Ndr, compared with JAG1, led to hypomorphic Notch signaling, based on transcriptome analysis. JAG1-expressing cells, but not JAG1Ndr-expressing cells, bound soluble Notch1 extracellular domain, quantified by flow cytometry. However, JAG1 and JAG1Ndr cells each bound NOTCH2, and signaling from NOTCH2 signaling was reduced but not completely inhibited, in response to JAG1Ndr compared with JAG1. CONCLUSIONS: In mice, expression of a missense mutant of Jag1 (Jag1Ndr) disrupts bile duct development and recapitulates Alagille syndrome phenotypes in heart, eye, and craniofacial dysmorphology. JAG1Ndr does not bind NOTCH1, but binds NOTCH2, and elicits hypomorphic signaling. This mouse model can be used to study other features of Alagille syndrome and organ development.

Novel mutations in KMT2B offer pathophysiological insights into childhood-onset progressive dystonia.

Rapid progress has recently been made in the elucidation of the genetic basis of childhood-onset inherited generalized dystonia (IGD) due to the implementation of genomic sequencing methodologies. We identified four patients with childhood-onset IGD harboring novel disease-causing mutations in lysine-specific histone methyltransferase 2B gene (KMT2B) by whole-exome sequencing. The main focus of this paper is to gain novel pathophysiological insights through understanding the molecular consequences of these mutations. The disease course is mostly progressive, evolving from lower limbs into generalized dystonia, which could be associated with dysarthria, dysphonia, intellectual disability, orofacial dyskinesia, and sometimes distinct dysmorphic facial features. In two patients, motor performances improved after bilateral implantation of deep brain stimulation in the globus pallidus internus (GPi-DBS). Pharmacotherapy with trihexyphenidyl reduced dystonia in two patients. We discovered three novel KMT2B mutations. Our analyses revealed that the mutation in patient 1 (c.7463A > G, p.Y2488C) is localized in the highly conserved FYRC domain of KMT2B. This mutation holds the potential to alter the inter-domain FYR interactions, which could lead to KMT2B instability. The mutations in patients 2 and 3 (c.3596_3697insC, p.M1202Dfs*22; c.4229delA, p.Q1410Rfs*12) lead to predicted unstable transcripts, likely to be subject to degradation by non-sense-mediated decay. Childhood-onset progressive dystonia with orofacial involvement is one of the main clinical manifestations of KMT2B mutations. In all, 26% (18/69) of the reported cases have T2 signal alterations of the globus pallidus internus, mostly at a younger age. Anticholinergic medication and GPi-DBS are promising treatment options and shall be considered early.

Correction to: Novel mutations in KMT2B offer pathophysiological insights on childhood-onset progressive dystonia.

Rapid progress has recently been made in the elucidation of the genetic basis of childhood-onset inherited generalized dystonia (IGD) due to the implementation of genomic sequencing methodologies. We identified four patients with childhood-onset IGD harboring novel disease-causing mutations in lysine-specific histone methyltransferase 2B gene (KMT2B) by whole-exome sequencing. The main focus of this paper is to gain novel pathophysiological insights through understanding the molecular consequences of these mutations.The disease course is mostly progressive, evolving from lower limbs into generalized dystonia, which could be associated with dysarthria, dysphonia, intellectual disability, orofacial dyskinesia, and sometimes distinct dysmorphic facial features. In two patients, motor performances improved after bilateral implantation of deep brain stimulation in the globus pallidus internus (GPi-DBS). Pharmacotherapy with trihexyphenidyl reduced dystonia in two patients.We discovered three novel KMT2B mutations. Our analyses revealed that the mutation in patient 1 (c.7463 A > G, p.Y2488C) is localized in the highly conserved FYRC domain of KMT2B. This mutation holds the potential to alter the inter-domain FYR interactions, which could lead to KMT2B instability. The mutations in patients 2 and 3 (c.3602dupC, p.M1202Dfs*22; c.4229delA, p.Q1410Rfs*12) lead to predicted unstable transcripts, likely to be subject to degradation by non-sense mediated decay.Childhood-onset progressive dystonia with orofacial involvement is one of the main clinical manifestations of KMT2B mutations. In all, 26% (18/69) of the reported cases have T2 signal alterations of the globus pallidus internus, mostly at a younger age. Anticholinergic medication and GPi-DBS are promising treatment options and shall be considered early.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

miR-142-3p balances proliferation and differentiation of mesenchymal cells during lung development.

The regulation of the balance between proliferation and differentiation in the mesenchymal compartment of the lung is largely uncharacterized, unlike its epithelial counterpart. In this study, we determined that miR-142-3p contributes to the proper proliferation of mesenchymal progenitors by controlling the level of WNT signaling. miR-142-3p can physically bind to adenomatous polyposis coli mRNA, functioning to regulate its expression level. In miR-142-3p loss-of-function experiments, proliferation of parabronchial smooth muscle cell progenitors is significantly impaired, leading to premature differentiation. Activation of WNT signaling in the mesenchyme, or Apc loss of function, can both rescue miR-142-3p knockdown. These findings show that in the embryonic lung mesenchyme, the microRNA machinery modulates the level of WNT signaling, adding an extra layer of control in the feedback loop between FGFR2C and ß-catenin-mediated WNT signaling.

Hmga2 is required for canonical WNT signaling during lung development.

BACKGROUND: The high-mobility-group (HMG) proteins are the most abundant non-histone chromatin-associated proteins. HMG proteins are present at high levels in various undifferentiated tissues during embryonic development and their levels are strongly reduced in the corresponding adult tissues, where they have been implicated in maintaining and activating stem/progenitor cells. Here we deciphered the role of the high-mobility-group AT-hook protein 2 (HMGA2) during lung development by analyzing the lung of Hmga2-deficient mice (Hmga2(-/-)). RESULTS: We found that Hmga2 is expressed in the mouse embryonic lung at the distal airways. Analysis of Hmga2(-/-) mice showed that Hmga2 is required for proper cell proliferation and distal epithelium differentiation during embryonic lung development. Hmga2 knockout led to enhanced canonical WNT signaling due to an increased expression of secreted WNT glycoproteins Wnt2b, Wnt7b and Wnt11 as well as a reduction of the WNT signaling antagonizing proteins GATA-binding protein 6 and frizzled homolog 2. Analysis of siRNA-mediated loss-of-function experiments in embryonic lung explant culture confirmed the role of Hmga2 as a key regulator of distal lung epithelium differentiation and supported the causal involvement of enhanced canonical WNT signaling in mediating the effect of Hmga2-loss-of-fuction. Finally, we found that HMGA2 directly regulates Gata6 and thereby modulates Fzd2 expression. CONCLUSIONS: Our results support that Hmga2 regulates canonical WNT signaling at different points of the pathway. Increased expression of the secreted WNT glycoproteins might explain a paracrine effect by which Hmga2-knockout enhanced cell proliferation in the mesenchyme of the developing lung. In addition, HMGA2-mediated direct regulation of Gata6 is crucial for fine-tuning the activity of WNT signaling in the airway epithelium. Our results are the starting point for future studies investigating the relevance of Hmga2-mediated regulation of WNT signaling in the adult lung within the context of proper balance between differentiation and self-renewal of lung stem/progenitor cells during lung regeneration in both homeostatic turnover and repair after injury.

Quantitative proteome analysis of alveolar type-II cells reveals a connection of integrin receptor subunits beta 2/6 and WNT signaling.

Alveolar type-II cells (ATII cells) are lung progenitor cells responsible for regeneration of alveolar epithelium during homeostatic turnover and in response to injury. Characterization of ATII cells will have a profound impact on our understanding and treatment of lung disease. The identification of novel ATII cell-surface proteins can be used for sorting and enrichment of these cells for further characterization. Here we combined a high-resolution mass spectrometry-based membrane proteomic approach using lungs of the SILAC mice with an Affymetrix microarray-based transcriptome analysis of ATII cells. We identified 16 proteins that are enriched in the membrane fraction of ATII cells and whose genes are highly expressed in these cells. Interestingly, we confirmed our data for two of these genes, integrin beta 2 and 6 (Itgb2 and Itgb6), by qRT-PCR expression analysis and Western blot analysis of protein extracts. Moreover, flow cytometry and immunohistochemistry in adult lung revealed that ITGB2 and ITGB6 are present in subpopulations of surfactant-associated-protein-C-positive cells, suggesting the existence of different types of ATII cells. Furthermore, analysis of the Itgb2(-/-) mice showed that Itgb2 is required for proper WNT signaling regulation in the lung.

[Reference values for the blood coagulation tests in Mexico: usefulness of the pooled plasma from blood donors]. / Valores de referencia para las pruebas de coagulación en México: utilidad de la mezcla de plasmas de donadores de sangre.

INTRODUCTION: The blood coagulation system maintains the blood in a liquid state and bleeding and thrombosis are the manifestations of its malfunction. Blood coagulation laboratory evaluates the physiology of this system. OBJECTIVE: To establish both, the reference values for several tests performed at the blood coagulation laboratory as well as the utility of the pooled plasma to perform these assays. MATERIAL AND: METHODS: In this descriptive, cross-sectional, randomized study, we collected plasma from Mexican Mestizos. Each pooled plasma was prepared with the plasma from at least 20 blood donors. We performed screening and special tests and the Levey-Jennings graphs were built and interpreted after each pass. Results of the tests were analyzed and their distribution was established using the Kolmogorov-Smirnov test. To establish the reference values we used 95% confidence intervals. RESULTS: We collected 72 pooled plasmas. The distribution for PT, APTT, and TT tests was abnormal. Although the PT test showed a bimodal distribution it was normal for factor VII. The reference values for the hemostatic, anticoagulant, and fibrinolytic factors were different from those suggested by the manufacturers. CONCLUSION: We established the reference values for the blood coagulation tests in the adult Mexican population. We have shown that the pooled plasma must be used for the screening tests. We suggest that each clinical laboratory should establish its own reference values (at least for the screening tests). To reach this objective, we encourage the use of the pooled plasma.

Extended CT Void Analysis in FDM Additive Manufacturing Components.

Additive manufacturing (AM) is the term for a number of processes for joining materials to build physical components from a digital 3D model. AM has multiple advantages over other construction techniques, such as freeform, customization, and waste reduction. However, AM components have been evaluated by destructive and non-destructive testing and have shown mechanical issues, such as reduced resistance, anisotropy and voids. The build direction affects the mechanical properties of the built part, including voids of different characteristics. The aim of this work is an extended analysis of void shape by means of X-ray computed tomography (CT) applied to fused deposition modeling (FDM) samples. Furthermore, a relation between the tensile mechanical properties and digital void measurements is established. The results of this work demonstrate that void characteristics such as quantity, size, sphericity and compactness show no obvious variations between the samples. However, the angle between the main void axis and the mechanical load axis α shows a relation for FDM components: when its mean value µ(α) is around 80 (degrees) the yield strength and Young's modulus are reduced. These results lead to the formulation of a novel criterion that predicts the mechanical behavior of AM components.

Failure to Down-Regulate miR-154 Expression in Early Postnatal Mouse Lung Epithelium Suppresses Alveologenesis, with Changes in Tgf-ß Signaling Similar to those Induced by Exposure to Hyperoxia.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a lung disease of preterm born infants, characterized by alveolar simplification. MicroRNA (miR) are known to be involved in many biological and pathological processes in the lung. Although a changed expression has been described for several miR in BPD, a causal role remains to be established. RESULTS: Our results showed that the expression level of miR-154 increases during lung development and decreases postnatally. Further, hyperoxia treatment maintains high levels of miR-154 in alveolar type 2 cells (AT2). We hypothesized that the decrease in miR-154 expression in AT2 cells is required for normal alveologenesis. To test this hypothesis, we generated a novel transgenic mouse allowing doxycycline-based miR-154 overexpression. Maintenance of miR-154 expression in the postnatal distal lung epithelium under normoxia conditions is sufficient to reproduce the hypoalveologenesis phenotype triggered by hyperoxia. Using a pull-down assay, we identified Caveolin1 as a key downstream target of miR-154. Caveolin1 protein is downregulated in response to overexpression of miR-154. This is associated with increased phosphorylation of Smad3 and Tgf-ß signaling. We found that AT2 cells overexpressing miR-154 display decreased expression of AT2 markers and increased expression of AT1 markers. CONCLUSION: Our results suggest that down-regulation of miR-154 in postnatal lung may function as an important physiological switch that permits the induction of the correct alveolar developmental program, while conversely, failure to down-regulate miR-154 suppresses alveolarization, leading to the common clinically observed phenotype of alveolar simplification.

Shorter Phosphorodiamidate Morpholino Splice-Switching Oligonucleotides May Increase Exon-Skipping Efficacy in DMD.

Duchenne muscular dystrophy is a fatal muscle disease, caused by mutations in DMD, leading to loss of dystrophin expression. Phosphorodiamidate morpholino splice-switching oligonucleotides (PMO-SSOs) have been used to elicit the restoration of a partially functional truncated dystrophin by excluding disruptive exons from the DMD messenger. The 30-mer PMO eteplirsen (EXONDYS51) developed for exon 51 skipping is the first dystrophin-restoring, conditionally FDA-approved drug in history. Clinical trials had shown a dose-dependent variable and patchy dystrophin restoration. The main obstacle for efficient dystrophin restoration is the inadequate uptake of PMOs into skeletal muscle fibers at low doses. The excessive cost of longer PMOs has limited the utilization of higher dosing. We designed shorter 25-mer PMOs directed to the same eteplirsen-targeted region of exon 51 and compared their efficacies in vitro and in vivo in the mdx52 murine model. Our results showed that skipped-dystrophin induction was comparable between the 30-mer PMO sequence of eteplirsen and one of the shorter PMOs, while the other 25-mer PMOs showed lower exon-skipping efficacies. Shorter PMOs would make higher doses economically feasible, and high dosing would result in better drug uptake into muscle, induce higher levels of dystrophin restoration in DMD muscle, and, ultimately, increase the clinical efficacy.

MiCEE is a ncRNA-protein complex that mediates epigenetic silencing and nucleolar organization.

The majority of the eukaryotic genome is transcribed into noncoding RNAs (ncRNAs), which are important regulators of different nuclear processes by controlling chromatin structure. However, the full extent of ncRNA function has remained elusive. Here we deciphered the function of the microRNA Mirlet7d as a key regulator of bidirectionally transcribed genes. We found that nuclear Mirlet7d binds ncRNAs expressed from these genes. Mirlet7d-ncRNA duplexes are further bound by C1D, which in turn targets the RNA exosome complex and the polycomb repressive complex 2 (PRC2) to the bidirectionally active loci. The exosome degrades the ncRNAs, whereas PRC2 induces heterochromatin and transcriptional silencing through EZH2. Moreover, this multicomponent RNA-protein complex, which we named MiCEE, tethers the regulated genes to the perinucleolar region and thus is required for proper nucleolar organization. Our study demonstrates that the MiCEE complex mediates epigenetic silencing of bidirectionally expressed genes and global genome organization.

[Klippel-Feil syndrome with tracheoesophageal fistula, bifid thumb and cerebral angiolipoma.] / Síndrome de Klippel-Feil con fístula traqueoesofágica, pulgar bífido y angiolipoma cerebral.

The Klippel-Feil syndrome is a congenital malformation of the skull flap involving complex cervical vertebrae and organs, characterized by a classic triad: short neck, limitation of movement of the head due to cervical spine fusion and low hairline in occipital region. It results from an error in the axial skeleton segmentation of the embryo; its incidence is estimated at 1/40,000-42,000 births and predominates in females. The aim of this paper is to describe the clinical picture of a patient with Klippel-Feil syndrome and multiple malformations, including tracheoesophageal fistula, bifid thumb and intracranial lipomas/angiolipomas,that have not been previously described in the syndrome, so it is considered an exceptional finding.

El síndrome de Klippel-Feil es una malformación congénita de la charnela cráneo-cervical compleja que involucra vértebras y vísceras, caracterizada por la tríada clásica de cuello corto, limitación de movimientos de la cabeza por la fusión de vértebras cervicales e implantación baja del cabello en la región occipital. Se presenta por falla de segmentación en el esqueleto axial del embrión. Su incidencia se estima en 1/40 000-42 000 nacimientos y predomina en el sexo femenino. El objetivo del presente trabajo es describir el cuadro clínico de un paciente con síndrome de Klippel-Feil y múltiples malformaciones asociadas, entre ellas, fístula traqueoesofágica, pulgar bífido y lipomas/angiolipomas intracraneales, las cuales, hasta ahora, no han sido descritas en el síndrome, por lo que se considera un hallazgo excepcional.

[Intrathoracic kidney in a newborn with breathing difficulty syndrome secondary to congenital diaphragmatic hernia]. / Riñón intratorácico en recién nacido con síndrome de dificultad respiratoria por hernia diafragmática congénita.

UNLABELLED: Congenital diaphragmatic hernia (CDH) is found frequently in from 0.17 to 0.57 among 1000 newborns and is associated with intrathoracic kidney (IK) in 0.25%. The objective of the present work was to describe both present pathologies in a newborn and to review the literature in this respect. CLINICAL CASE: male newborns, who presented tachypnea sudden and persistent for the first 24 h of life. For the that was physical exam, we included breathing difficult, (eight points of Silverman's) and cyanosis; initial arterial gases: hypoxemia and hypocapnia (acute respiratory failure type I); thorax X-ray; increase of bronchial plot and of parahiliary density; normal lungs, pleuro-peritoneal membrane and solid mass superimposed on heart silhouette were observed and confirmed by echocardiogram. Computed axial tomography (CAT) revealed left kidney and part of spleen inside thorax, beside inferior lobe of left lung. Immediately, the patient was mechanically ventilated and after 2 days, was operated surgically for correction of CDH and descent of left kidney. After surgical intervention, initial symtomatology disappeared and evolution was satisfactory. The present case illustrates how the kidney on occasion can emigrate due to congenital default to the thorax of the wall of the diaphragm and be a casual discovery at the moment of radiologic exploration.

Alimentos ancestrales que sanan / Ancestral food to heal

En esta época de transformaciones de la humanidad, sembrar, cosechar y cocer alimentos propios y sanos que garanticen una buena alimentación y nutrición es un acto político y revolucionario por antonomasia, que abona en el afán de romper el monopolio de la agroindustria y la industria farmacéutica ligada a la producción de alimentos, preservar las semillas originarias y mantener la identidad cultural y memoria histórica a través de la práctica de la seguridad, soberanía y decolonialidad alimentaria. Alimentos ancestrales que sanan, es un conjunto de reflexiones que se inscriben dentro del proyecto "Alimentos Sagrados que Sanan" ejecutado en comunidades de Cañar y Saraguro con el apoyo de ReAct Latinoamérica. El ensayo aborda determinantes de los cambios de la alimentación, sustenta la temática de la alimentación de los pueblos originarios como alternativa y desarrolla un ejemplo del manejo de los procesos bacterianos ligados a la alimentación, todos ellos en el marco de la agricultura ancestral.

In this time of transformations of humanity, planting, harvesting and cooking healthy food that guarantee a good diet and nutrition, is a political and revolutionary act by antonomasia, which tries to break the monopoly of the agroindustry and the pharmaceutical industry linked to the production of food, preserve the original seeds and maintain the cultural identity and historical memory through the alimentary practice of Security, Sovereignty and Decoloniality Ancestral foods that heal, it is a set of reflections that are part of the project "Sacred Foods that Heal" executed in communities of Cañar and Saraguro with the support of ReAct Latin America. The essay addresses some determinants of changes in diet, supports the theme of feeding in indigenous people as an alternative and develops an example of the management of bacterial processes linked to food, all of them within the framework of ancestral agriculture.

Factores histológicos relacionados con resultados discordantes entre la biopsia y la prueba de ADN, en el diagnóstico del virus papiloma humano (VPH) / Histological factors associated with discordant results between biopsy and DNA testing in the diagnosis of human papillomavirus (HPV)

El diagnóstico de la infección cervical ocasionada por el virus del papiloma humano (VPH), se realiza básicamente a través de la biopsia y/o de métodos moleculares como la reacción en cadena de la polimerasa (PCR). Los resultados de estos estudios en ocasiones no coinciden. En este estudio se evalúa la posible influencia de diferentes factores asociados a resultados falsos positivos y a falsos negativos de ambas pruebas. Se analizaron 271 muestras de cuello uterino de pacientes que acudieron a la consulta ginecológica durante el período 1999-2009, a las cuales se les tomó biopsia por presentar hallazgos colposcópicos y/o citológicos sospechosos de infección por VPH. Tomando en consideración al resultado de PCR como prueba estándar de oro, la biopsia presentó 14% de falsos positivos y 16,6% de falsos negativos, el diagnóstico de VPH en biopsia y PCR presentó mayor concordancia cuando las muestras abarcan la zona de transformación endo-exocervical, así como la presencia de metaplasia escamosa en la muestra y el tamaño del fragmento mayor (>0,5 cm); mientras que el tiempo de fijación, el tipo e intensidad de la inflamación, la hemorragia y la erosión del epitelio no fueron significativos. En conclusión, a fin de disminuir la discrepancia de los resultados entre la biopsia y prueba de ADN, sería importante que la muestra de biopsia incluya la zona de transformación del cuello uterino y al menos un fragmento mayor de 0,5 cm.

The diagnosis of cervical infection caused by human papilloma virus (HPV) is made basically through the biopsy and/or molecular methods such as polymerase chain reaction (PCR). The results of these studies sometimes do not match. In this work is evaluated the possible influence of different factors associated with results false positive and false negative of both tests. Were analyzed 271 samples from uterin cervix of patients presenting to the gynecologist during the period 1999-2009, to which were taken biopsies due present findings colposcopics and/or cytological suspicious of HPV infection. Considering the result of PCR as gold standard test, biopsy showed 14% false positive and false negative 16.6%, the diagnostic of VPH in biopsy and PCR showed greater concordance when samples include endo-exocervical transformation zone, and the presence of squamous metaplasia in the sample and size of the largest fragment (>0.5 cm); while the fixation time, the type and intensity of inflammation, bleeding and erosion of the epithelium were not significant. In conclusion, in order to reduce the discrepancy between the results of the biopsy and test DNA, it is important that the biopsy sample includes the transformation zone of the uterin cervix and at least one fragment greater than 0.5 cm.

Síndrome de Klippel-Feil con fistula traqueoesofagica, pulgar bifido y angiolipoma cerebral / Klippel-Feil syndrome with tracheoesophageal fistula, bifid thumb and cerebral angiolipoma

El síndrome de Klippel-Feil es una malformación congénita de la charnela cráneo-cervical compleja que involucra vértebras y visceras, caracterizada por la tríada clásica de cuello corto, limitación de movimientos de la cabeza por la fusión de vértebras cervicales e implantación baja del cabello en la región occipital. Se presenta por falla de segmentación en el esqueleto axial del embrión. Su incidencia se estima en 1/40 000-42 000nacimientos y predomina en el sexo femenino. El objetivo del presente trabajo es describir el cuadro clínico de un paciente con síndrome de Klippel-Feil y múltiples malformaciones asociadas, entre ellas, fístula traqueoesofágica, pulgar bífido y lipomas/angiolipomas intracraneales, las cuales, hasta ahora, no han sido descritas en el síndrome, por lo que se considera un hallazgo excepcional.

The Klippel-Feil syndrome is a congenital malformation of the skull flap involving complex cervical vertebrae and organs, characterized by a classic triad: short neck, limitation of movement of the head due to cervical spine fusion and low hairline in occipital region. It results from an error in the axial skeleton segmentation of the embryo; its incidence is estimated at 1/40,000-42,000 births and predominates in females. The aim of this paper is to describe the clinical picture of a patient with Klippel-Feil syndrome and multiple malformations, including tracheoesophageal fistula, bifid thumb and intracranial lipomas/angiolipomas,that have not been previously described in the syndrome, so it is considered an exceptional finding.

Tumor de células de Leydig, presentación con pubertad precoz

Objetivos: Presentar un caso de pubertad precoz secundaria a tumor de células de Leydig. Caso Clínico: Paciente preescolar masculino de 5 años, quien fue referido por presentar aparición de vello púbico, aumento de tamaño del pene, piel oleosa y crecimiento acelerado para la edad, sin antecedentes de traumatismo craneal o procesos infecciosos cerebrales. Al examen físico: peso 22,7kg y talla 117,2 cm, ambos en el percentil 97, masas musculares evidentes en tórax y miembros superiores, vello púbico tanner II, pene de 6cm de longitud, con volumen testicular de 4 mL el derecho y de 3 mL el izquierdo, observándose mucho adelanto de caracteres sexuales secundarios para el volumen testicular. Los estudios de laboratorio revelaron valores elevados de andrógenos: testosterona libre: 237 ng/dL, 17OHP: 3.7 ng/mL, prueba de GnRH con respuesta prepuberal, no plana (pico de LH: 3,4 y de FSH: 1,8 ng/mL), prueba de estimulación con ACTH reporta 17OHP basal 5.3 y postestímulo 6 ng/mL, TSH: 2,1 mUI/mL, T4L: 1,10 ng/dL. Edad ósea de 10 años, relación EO/EC de 1.9, predicción de talla final de 157 cm, con potencial genético de talla de 169,7. Se planteó Pubertad Precoz Periférica (HAC hiperplasia adonal congénita vs. Gonadal) que desencadenó una pubertad verdadera. Se indicó tratamiento con Triptorelina e Hidrocortisona a dosis habituales por kg de peso. En su evolución clínica, a pesar del tratamiento y mostrando normalización de niveles de 17OHP (1.4 ng/mL) y adecuada supresión del eje Hipotálamo-Hipófisis-Gónada, continuó progresión de caracteres sexuales secundarios, aumentando la asimetría testicular VD: 8mL y VI: 6mL, pene de 9 cm y la velocidad de crecimiento de 12 cm/año. Nuevos niveles de testosterona muy elevados (770 ng/dL). TAC de abdomen normal y ultrasonido testicular reportó LOE sólido en testículo derecho. Marcadores tumorales normales, excepto ligera elevación de Gonadotropina Coriónica. Se realiza orquidectomía derecha y ligadura alta de cordón. El estudio anatomopatológico reportó tumor de células de Leydig sin signos de malignidad. Conclusiones: Los tumores testiculares son muy raros en niños (1 a 2%) y aproximadamente el 1 a 3% de éstos, corresponden a los de células de Leydig, que se presentan con desarrollo somático precoz y virilización progresiva, siendo una causa de precocidad puberal.

Objectives: To report a case of precocious puberty due to a Leydig cell tumor. Clinical Case: A 5 years old male patient, with pubic hair, penis enlargement, oiliness of skin and accelerated growth was referred. There was no previous cranial traumatism or cerebral disease. Physical examination: weight 22,7 kg, height 117,2 cm, both over 97th percentile for age, muscular development in thorax and upper extremities, pubic hair (Tanner II), penis of 6 cm of longitude, volume of right testicle 4 mL and left 3 mL. More signs of pubertal development than would be expected for the size of the testis were evident. The laboratory analysis showed elevated levels of androgens: free testosterone: 237 ng/dL, 17OHP: 3,7 and 5,3 ng/mL basally and 6 ng/mL post stimulation with ACTH, slight response to the GnRH stimulation test (LH peak: 3,4 and FSH peak: 1,8 ng/mL), normal levels of TSH and FT4. Bone age of 10 years, BA/CA of 1,9, predicted adult height of 157 and target height of 169,7 cm. The diagnostic of peripheral precocious puberty (congenital adrenal hyperplasia vs gonadal tumor) that triggered a central precocity was suggested. Treatment with Triptorelin and Hydrocortisone was initiated in usual doses. With this therapy, the 17OHP levels were normal and a suppression of LH and FSH were obtained. Nevertheless, the boy showed progression of the pubertal development, right testicle of 8 mL, left of 6 mL, penis of 9 cm and growth velocity of 12 cm/ year. Testosterone levels were higher (770 ng/dL). Abdominal computerized axial tomography was normal and the testicular ultrasonography disclosed a solid tumor in the right testicle. Tumor markers were normal. Surgical removal of the right testicle was done. The histopathology study revealed a Leydig cell tumor without malignancy signs. Conclusions: Testicular tumors are rare in children (1 a 2%) and 1-3% of them are Leydig cell tumors. They may cause incomplete precocious puberty with somatic development and progressive virilization.

Riñón intratorácico en recién nacido con síndrome de dificultad respiratoria por hernia diafragmática congénita

La hernia diafragmática congénita (HDC) se presenta con frecuencia de 0.17 a 0.57 por 1000 recién nacidos vivos y se asocia con riñón intratorácico (RI) en 0.25%. El objetivo del presente trabajo es describir las dos patología presentes en un neonato y revisar la literatura al respecto. Caso clínico: recién nacido, masculino, quien a las cuatro horas de vida presentó taquipnea de aparición súbita y persistente. Al examen físico: dificultad respiratoria (Silverman de ocho puntos) y cianosis; gases arteriales a su ingreso: hipoxemia e hipocapnia (insuficiencia respiratoria tipo I). Radiografía de tórax: aumento discreto de la trama bronquial y de la densidad parahiliar; pulmones normales, evidencia de membrana pleuroperitoneal y masa sólida superpuesta sobre silueta cardiaca, confirmada por ecocardiograma. Tomografía axial computada (TAC): riñón izquierdo y parte de bazo dentro del tórax, al lado del lóbulo inferior del pulmón izquierdo. Inmediatamente se le instaló al paciente ventilación mecánica convencional y dos días después, se intervino quirúrgicamente para corrección de HDC y descenso de riñón izquierdo. Posterior al acto operatorio, desapareció la sintomatología inicial y su evolución posterior fue satisfactoria. El presente caso ilustra como el riñón en ocasiones puede emigrar al tórax por defecto congénito de la pared del diafragma y ser un hallazgo causal al momento de la exploración radiológica.

Congenital diaphragmatic hernia (CDH) is found frequently in from 0.17 to 0.57 among 1000 newborns and is associated with intrathoracic kidney (IK) in 0.25%. The objective of the present work was to describe both present pathologies in a newborn and to review the literature in this respect. Clinical case: male newborns, who presented tachypnea sudden and persistent for the first 24 h of life. For the that was physical exam, we included breathing difficulty (eight points of Silverman's) and cyanosis; initial arterial gases: hypoxemia and hypocapnia (acute respiratory failure type I); thorax X-ray; increase of bronchial plot and of parahiliary density; normal lungs, pleuroperitoneal membrane and solid mass superimposed on heart silhouette were observed and confirmed by echocardiogram. Computed axial tomography (CAT) revealed left kidney and part of spleen inside thorax, beside inferior lobe of left lung. Immediately, the patient was mechanically ventilated and after 2 days, was operated sourgically for correction of CDH and descent of left kidney. After surgical intervention, initial syntomatology disappeared and evolution was satisfactory. The present case illustrates how the kidney on occasion can emigrate due to congenital default to the thorax of the wall of the diaphragm and be a casual discovery at the moment of radiologic exploration.

Incidencia de la hendidura labio palatina / Cleft lip incidence of the

La hendidura labio palatina es considerada como la malformación congénita más frecuente de la región facial. la finalidad de este estudio fue determinar su frecuencia en el estado Mérida durante el período 1991 al 2001, relacionándola con factores etiológicos, con el manejo y el establecimiento de programas de prevención. La investigación de tipo descriptivo y longitudinal se realizó en el Instituto Autónomo Hospitital Universitario de Los Andes. (IAHULA) en Mérida, Venezuela; se revisaron 302 historias clínicas y se tomaron 187 correspondientes a los pacientes menores de 14 años. Relacionándose con los nacidos vivos (nv) se obtuvo una tasa de 1.02 casos por cada 1000 nv. El 50,3 por ciento correspondió al sexo femenino, el 60,7 por ciento provenían de la zona agrícola y sólo 17,7 por ciento tenían antecedentes familiares portadores de la patología. El 66,8 por ciento de las madres se encontraban entre los 20 y 34 años de edad, predominando oficios del hogar en un 85 por ciento y el 63,7 por ciento de los padres eran agricultortes y obreros. Sólo el 23,6 por ciento de las madres enfermearon durante el embarazo. El 76,6 por ciento de los niños presentaban al nacer entre 2.501 y 3.500 gramos y sólo el 37,4 por ciento recibió lactancia materna. La hendidura con hendidura palatina fue mas frecuente (55 por ciento), 33 casos (17,4 por ciento) presentaron anomalías congénitas asociadas. Se realizó tratamiento ortopédico de maxilar al 54 por ciento de la población estudiada y 80,7 por ciento de los casos fueron intervenidos quirúrgicamente, la fístula palatina (28 por ciento) fue complocación postoperatoria más frecuente. En nustro estado la elevada incidencia presenta un problema de salud pública, por lo tanti es imperativo la elaboración de estrategias destinada a la prevención y el manejo integral de los niños con hendidura u labio palatina

Divertículo uretral: a propósito de dos casos / Urethral diverticulum: concerning a two case

El divertículo uretral es una patología poco frecuente de etiología congénita o adquirida, se manifiesta de forma variable, el examen físico es primordial al momento de hacer diagnóstico y es de manejo quirúrgico. El objetivo del presente trabajo es exponer dos casos de diverticulo uretral que se han presentado en el Instituto Autónomo Hospital Universitario de Los Andes en los últimos años