El reto diagnóstico de la enfermedad de Cushing en pediatría: reporte de casos

Introducción: la enfermedad de Cushing (EC) se debe sospechar en el paciente pediátrico con retraso del crecimiento, aumento de peso y fenotipo característico. Se sugiere iniciar el protocolo diagnóstico, que consiste en: comprobación de hipercortisolemia, sitio de producción del cortisol e imágenes, para finalmente realizar el tratamiento quirúrgico curativo. Reporte de casos: se presentan los casos de tres pacientes con alteración de la velocidad de crecimiento, aumento de peso y fenotipo característico. Se realiza la secuencia diagnóstica para demostrar el hipercortisolismo, posteriormente se confirma EC y se realiza imagen por resonancia magnética nuclear (RMN) de hipófisis. Finalmente se lleva a cabo el tratamiento quirúrgico curativo. Conclusiones: la EC en pediatría sigue siendo un desafío diagnóstico. Un abordaje para su detección inicia con la sospecha clínica asociada a una adecuada interpretación de los estudios bioquímicos e imágenes, lo que permite realizar un diagnóstico oportuno y un tratamiento curativo definitivo.

Summary Introduction: Cushing's disease (CD) should always be suspected in a pediatric patient with growth delay, excessive weight gain and characteristic phenotype. It is suggested to start a diagnostic protocol sequence: verification of hypercortisolism, production site and images, to finally perform the definitive curative surgical treatment. Case reports: We report three CD patients with altered growth velocity, weight gain and characteristic phenotype. The diagnostic sequence was performed to demonstrate hypercortisolism. CD was subsequently confirmed, and a pituitary nuclear magnetic resonance (NMR) was performed. All patients underwent curative surgery. Conclusion: CD in pediatrics continues to be a diagnostic challenge for the clinician. An approach with high initial clinical suspicion, associated with paraclinical studies and obtaining the adequate images, are necessary to make an accurate diagnosis and a definitive curative treatment.

Raquitismo hipofosfatémico ligado al cromosoma X: un reto diagnóstico y terapéutico

La hipofosfatemia ligada al X es un desorden genético ocasionado por mutaciones del gen PHEX (phosphate regulating endopeptidase analog, X-linked). Esta afecta la codificación de una metaloproteasa que tiene como función inhibir el factor de crecimiento fibroblástico - 23 (FGF-23), promoviendo la pérdida renal de fosfato. A continuación, describimos el caso de un paciente de edad pediátrica a quien se le hace diagnóstico en la adolescencia con una mutación del gen PHEX. Posteriormente, la misma alteración genética fue encontrada en la madre, considerada como una mutación espontánea que fue trasmitida a su hijo. Esto aumenta la rareza del caso, donde el reto para diagnosticar esta patología necesita vencer dificultades administrativas, económicas y sociales. El diagnóstico y tratamiento oportuno ayudan a optimizar la talla final y minimizar todas las deformidades esqueléticas presentadas, tanto en la madre como en el hijo. En la actualidad se cuenta con el tratamiento tradicional y uno novedoso que fue ordenado para el paciente pediátrico de este reporte.

SUMMARY X-linked hypophosphatemia is a genetic disorder caused by PHEX gene mutations, which affects the encoding of a metalloprotease whose function is to inhibit fibroblastic growth factor-23 (FGF-23), promoting phosphate renal loss. Following we describe the case of a teenager diagnosed with a PHEX gene mutation. The same genetic alteration was found in the mother of the patient, considering a spontaneous mutation that was transmitted to her son, which makes the case, even rarer, where the diagnostic challenge needs to overcome administrative, economic and social difficulties. A timely diagnosis and treatment could help optimize the final height and minimize the skeletal deformities presented in both the mother and the child. Currently, there is a traditional treatment and a novel one that was ordered for the pediatric patient in this report.

Guía colombiana para el diagnóstico de la deficiencia de lipasa ácida / Colombian Guidelines for Diagnosis of Lipase Acid Deficiency

Resumen Introducción: la deficiencia de lipasa ácida lisosomal (LAL-D) es una entidad de herencia autosómica recesiva que lleva a la acumulación de esteres de colesterol y triglicéridos en el hígado, bazo y otros órganos. La edad de inicio y la tasa de progresión son muy variables, lo que posiblemente sea explicado por las mutaciones presentes en el gen LIPA. Las manifestaciones clínicas son las mismas que para otras patologías hepáticas, cardiovasculares y metabólicas, lo que hace difícil reconocerla en la práctica clínica. Objetivo: proveer una guía que permita a los clínicos reconocer los principales grupos de riesgo en los cuales se debe sospechar de LAL-D y mejorar su diagnóstico. Metodología: este documento se diseñó como un consenso de expertos en el cual participaron médicos especialistas en gastroenterología, hepatología, endocrinología, genética, patología y pediatría. Se realizó una revisión de la literatura acerca de las manifestaciones clínicas y de las herramientas para el diagnóstico de LAL-D y se siguió la metodología de técnica de grupo nominal. Resultados: se generaron algoritmos diagnósticos por consenso para cada uno de los grupos de riesgo, que facilitaran la sospecha y el diagnóstico de LAL-D. Conclusiones: esta guía propone algoritmos para el diagnóstico de LAL-D con base en el consenso clínico, que buscan optimizar la ruta diagnóstica en los pacientes con dicha patología.

Abstract Introduction: Lysosomal acid lipase deficiency (LAL-D) is an inherited autosomal recessive entity that leads to the accumulation of cholesterol and triglyceride esters in the liver, spleen and other organs. The age of onset and rate of progression vary greatly, possibly explained by mutations of the LIPA gene. Clinical manifestations are the same as those of other hepatic, cardiovascular and metabolic pathologies which makes it difficult to recognize in clinical practice. Objective: The objectives of these guidelines is to help clinicians recognize the major groups at risk for LAL-D and to improve its diagnosis. Methodology: This document was designed as a consensus of experts in gastroenterology, hepatology, endocrinology, genetics, pathology and pediatrics. A review of the literature regarding clinical manifestations and tools for diagnosis of LAL-D was conducted and the nominal group technique was followed. Results: Diagnostic algorithms which facilitate suspicion and diagnosis of LAL-D were generated by consensus for each of the risk groups. Conclusions: This guide proposes algorithms for the diagnosis of LAL-D based on clinical consensus. The algorithms seek to optimize diagnosis for patients with this pathology.

Diversification in species complexes: tests of species origin and delimitation in the Bursera simaruba clade of tropical trees (Burseraceae).

Molecular phylogenies are invaluable for testing morphology-based species delimitation in species complexes, as well as for examining hypotheses regarding the origination of species in these groups. Using five nucleotide markers, we reconstructed the phylogeny of the Bursera simaruba species complex of neotropical trees to test the notion that four "satellite" species originated from populations of the most widely distributed member of the genus, B. simaruba, which the satellites strongly resemble. In addition to molecular phylogenetic reconstruction, we tested species delimitation of B. simaruba and the satellites using multivariate analyses of morphological and ecological characters. The analyses evaluated the taxonomic value of these traditional characters and pinpointed those in need of further study, such as the expression of pubescence. Phylogenetic data rejected the origin of three satellite species from their purported ancestor, B. simaruba, and we ascribe their morphological similarity to convergence or parallelism. The fourth satellite species likely represents one end of a spectrum of inflorescence length variation within B. simaruba and is conspecific. Despite its marked morphological variability, we recovered B. simaruba as a single valid species, which implies that it maintains genetic cohesion among distant populations throughout its vast range.

Functional assessments of the rodent facial nerve: a synkinesis model.

OBJECTIVES/HYPOTHESIS: Rodent whisker movement has been used as a tool, after facial nerve manipulation, to quantify functional recovery. We have recently established a method to study functional correlates of aberrant regeneration of the facial nerve. Our objective was to establish normative parameters for both spontaneous and induced whisking and blinking behavior in a large group of normal rats. STUDY DESIGN: Prospective animal study. METHODS: Eighty animals underwent quantitative facial movement testing to measure simultaneous vibrissal movement and ocular closure for each side independently. Right and left C-1 whisker positions were continuously recorded for 5-minute sessions, and changes in infrared detection corresponding to eye closure were continuously recorded. Whisking and blinking were elicited by delivery of olfactory stimuli (10 s scented airflows) and corneal air puffs. Whisks were counted and analyzed, and eye closures were counted. RESULTS: Whisking amplitude, velocity, and acceleration were consistent with literature values. Air puff delivery elicited an ipsilateral blink 99% of the time, a contralateral blink 18% of the time, and changes in or initiation of bilateral whisking 70% of the time. Olfactory stimulus delivery prompted a change in whisking behavior 83% of the time, and eye closure 20% of the time. CONCLUSIONS: This study establishes normative data for assessing cranial nerve VII-controlled facial movement in four separate facial regions. We demonstrate the capability and tendency of animals to move their orbicularis oculi muscles independently of and simultaneously with their midfacial muscles. This model provides an excellent tool for the study of aberrant regeneration after facial nerve injury in the rodent.

A system for studying facial nerve function in rats through simultaneous bilateral monitoring of eyelid and whisker movements.

The occurrence of inappropriate co-contraction (synkinesis) of facially innervated muscles in humans is a common sequela of facial nerve injury and recovery. We have developed a system for studying facial nerve function and synkinesis in restrained rats using non-contact opto-electronic techniques that enable simultaneous bilateral monitoring of eyelid and whisker movements. Whisking is monitored in high spatio-temporal resolution using laser micrometers, and eyelid movements are detected using infrared diode and phototransistor pairs that respond to the increased reflection when the eyelids cover the cornea. To validate the system, 8 rats were tested with multiple 5-min sessions that included corneal air puffs to elicit blink and scented air flows to elicit robust whisking. Four rats then received unilateral facial nerve section and were tested at weeks 3-6. Whisking and eye blink behavior occurred both spontaneously and under stimulus control, with no detectable difference from published whisking data. Proximal facial nerve section caused an immediate ipsilateral loss of whisking and eye blink response, but some ocular closures emerged due to retractor bulbi muscle function. The independence observed between whisker and eyelid control indicates that this system may provide a powerful tool for identifying abnormal co-activation of facial zones resulting from aberrant axonal regeneration.

Biomechanics of the vibrissa motor plant in rat: rhythmic whisking consists of triphasic neuromuscular activity.

The biomechanics of a motor plant constrain the behavioral strategies that an animal has available to extract information from its environment. We used the rat vibrissa system as a model for active sensing and determined the pattern of muscle activity that drives rhythmic exploratory whisking. Our approach made use of electromyography to measure the activation of all relevant muscles in both head-fixed and unrestrained rats and two-dimensional imaging to monitor the position of the vibrissae in head-fixed rats. Our essential finding is that the periodic motion of the vibrissae and mystacial pad during whisking results from three phases of muscle activity. First, the vibrissae are thrust forward as the rostral extrinsic muscle, musculus (m.) nasalis, contracts to pull the pad and initiate protraction. Second, late in protraction, the intrinsic muscles pivot the vibrissae farther forward. Third, retraction involves the cessation of m. nasalis and intrinsic muscle activity and the contraction of the caudal extrinsic muscles m. nasolabialis and m. maxillolabialis to pull the pad and the vibrissae backward. We developed a biomechanical model of the whisking motor plant that incorporates the measured muscular mechanics along with movement vectors observed from direct muscle stimulation in anesthetized rats. The results of simulations of the model quantify how the combination of extrinsic and intrinsic muscle activity leads to an enhanced range of vibrissa motion than would be available from the intrinsic muscles alone.

Topography of rodent whisking--I. Two-dimensional monitoring of whisker movements.

During 'active touch' the rodent whiskers scan the environment in a series of repetitive movements ('whisks') generating afferent signals which transform the spatial properties of objects into spatio-temporal patterns of neural activity. Based upon analyses carried out in a single movement plane, it has been generally assumed that these trajectories are essentially uni-dimensional, although more complex movements have been described in some rodents. The present study was designed to examine this assumption and to more precisely characterize whisking topography by monitoring whisking trajectories along both the antero-posterior and dorso-ventral axes. Using optoelectronic monitoring techniques with high-spatio-temporal resolution, movement data were obtained from a population of vibrissae sampled at different locations on the mystacial pad in head-fixed rats isolated from the perturbing effects of contact. For a substantial proportion of the population of whisking movements sampled, the trajectories generated by a single whisker is most accurately described as occupying an expended two-dimensional space in which the A-P component predominates. However, the whisker system exhibits a considerable range of trajectory types, suggesting a high degree of movement flexibility. For each vibrissa position, it was possible to delineate a 'trajectory' domain-that portion of the animal's whisking space which is scanned by the movements of that vibrissa during whisking. Since the 'domains' of adjacent whiskers in the same row tend to overlap, synchronized movements of a subset of whiskers could generate a set of overlapping somatosensory fields analogous to overlapping retinal receptive fields. The organization of such trajectory domains within the rats' whisking space could provide the spatial component of the spatio-temporal integration process required to extract information about environmental features from the inputs generated by its recursive whisking movements.