ABSTRACT
BACKGROUND: Congenital hypopituitarism (CH) and its associated syndromes, septo-optic dysplasia (SOD) and holoprosencephaly (HPE), are midline defects that cause significant morbidity for affected people. Variants in 67 genes are associated with CH, but a vast majority of CH cases lack a genetic diagnosis. Whole exome and whole genome sequencing of CH patients identifies sequence variants in genes known to cause CH, and in new candidate genes, but many of these are variants of uncertain significance (VUS). METHODS: The International Mouse Phenotyping Consortium (IMPC) is an effort to establish gene function by knocking-out all genes in the mouse genome and generating corresponding phenotype data. We used mouse embryonic imaging data generated by the Deciphering Mechanisms of Developmental Disorders (DMDD) project to screen 209 embryonic lethal and sub-viable knockout mouse lines for pituitary malformations. RESULTS: Of the 209 knockout mouse lines, we identified 51 that have embryonic pituitary malformations. These genes not only represent new candidates for CH, but also reveal new molecular pathways not previously associated with pituitary organogenesis. We used this list of candidate genes to mine whole exome sequencing data of a cohort of patients with CH, and we identified variants in two unrelated cases for two genes, MORC2 and SETD5, with CH and other syndromic features. CONCLUSIONS: The screening and analysis of IMPC phenotyping data provide proof-of-principle that recessive lethal mouse mutants generated by the knockout mouse project are an excellent source of candidate genes for congenital hypopituitarism in children.
Subject(s)
Hypopituitarism , Mice, Knockout , Pituitary Gland , Hypopituitarism/genetics , Animals , Humans , Pituitary Gland/metabolism , Pituitary Gland/abnormalities , Pituitary Gland/pathology , Mice , Phenotype , Female , Male , Disease Models, Animal , Exome Sequencing , Septo-Optic Dysplasia/geneticsABSTRACT
Introducción. Dada la dificultad en la interpretación de los valores de cortisol sérico en recién nacidos (RN), el objetivo de este estudio fue correlacionar los niveles basales de cortisol en el suero y la saliva, y describir las concentraciones de cortisol salival durante el primer mes de vida. Población y métodos. Estudio descriptivo, prospectivo, longitudinal y de correlación. Se seleccionaron RN de término del Servicio de Neonatología del Hospital Nacional Profesor Alejandro Posadas en 2014. En la saliva, se determinó cortisol; en la sangre, cortisol, globulina tansportadora de cortisol y albúmina. Se utilizó la correlación lineal para relacionar cortisol sérico y salival; el test de Friedman para comparar el cortisol durante el primer mes de vida y la diferencia para analizar el comportamiento de valores iguales o inferiores al primer cuartil. Resultados. Se evaluaron 55 RN. Cortisol sérico: 7,65 (1,0-18,1 gg/dl); cortisol salival: 35,88 (5,52107,64 nmol/L); globulina transportadora de cortisol: 22,07 (16,5-33,0 gg/µL), expresados como mediana y rango. El coeficiente de correlación entre el cortisol sérico y salival fue de 0,54; P= 0,001. El comportamiento del cortisol durante el primer mes de vida no mostró diferencias estadísticamente significativas y la diferencia entre la segunda y la primera muestra de valores iguales o inferiores al primer cuartil aumentó en 10 de 12 pacientes. Conclusión. La determinación de cortisol en la saliva refleja la concentración de cortisol sérico en RN normales. Algunos pacientes presentaron niveles bajos de cortisol a las 36 h de vida y mostraron una tendencia a incrementarse espontáneamente durante el primer mes de vida.
Introduction. Given that serum cortisol level interpretation in newborn infants (NBIs) is hard, the objective of this study was to correlate baseline salivary and serum cortisol levels and to describe salivary cortisol levels in the first month of life. Population and Methods. Descriptive, prospective, longitudinal, and correlational study. Term NBIs were selected from the Division of Neonatology of Hospital Nacional Profesor Alejandro Posadas in 2014. Cortisol was measured in saliva specimens while cortisol, cortisol-binding globulin, and albumin were measured in blood specimens. A linear correlation was performed to relate serum and salivary cortisol levels; Friedman test was conducted to compare cortisol levels during the first month of life, and the difference was used to analyze the performance of values equal to or lower than the first quartile. Results. Fifty-five NBIs were studied. Serum cortisol: 7.65 (1.0-18.1 gg/dL); salivary cortisol: 35.88 (5.52-107.64 mmol/L); cortisol-binding globulin: 22.07 (16.5-33.0 gg/µL), expressed as median and range. The correlation coefficient between serum and salivary cortisol was 0.54, P = 0.001. Cortisol performance during the first month of life showed no statistically significant differences, and the difference between the second and the first specimen of values equal to or lower than the first quartile increased in 10 out of 12 patients. Conclusion. The measurement of cortisol in saliva reflects serum cortisol levels in normal NBIs. Some patients had low levels of cortisol at 36 hours of life and showed a trend towards a spontaneous increase during the first month of life.
Subject(s)
Humans , Male , Female , Infant, Newborn , Saliva/chemistry , Hydrocortisone/analysis , Hydrocortisone/blood , Prospective Studies , Statistics as Topic , Longitudinal StudiesABSTRACT
INTRODUCTION: Given that serum cortisol level interpretation in newborn infants (NBIs) is hard, the objective of this study was to correlate baseline salivary and serum cortisol levels and to describe salivary cortisol levels in the first month of life. POPULATION AND METHODS: Descriptive, prospective, longitudinal, and correlational study. Term NBIs were selected from the Division of Neonatology of Hospital Nacional Profesor Alejandro Posadas in 2014. Cortisol was measured in saliva specimens while cortisol, cortisol-binding globulin, and albumin were measured in blood specimens. A linear correlation was performed to relate serum and salivary cortisol levels; Friedman test was conducted to compare cortisol levels during the first month of life, and the difference was used to analyze the performance of values equal to or lower than the first quartile. RESULTS: Fifty-five NBIs were studied. Serum cortisol: 7.65 (1.0-18.1 gg/dL); salivary cortisol: 35.88 (5.52-107.64 mmol/L); cortisol-binding globulin: 22.07 (16.5-33.0 gg/mL), expressed as median and range. The correlation coefficient between serum and salivary cortisol was 0.54, P = 0.001. Cortisol performance during the first month of life showed no statistically significant differences, and the difference between the second and the first specimen of values equal to or lower than the first quartile increased in 10 out of 12 patients. CONCLUSION: The measurement of cortisol in saliva reflects serum cortisol levels in normal NBIs. Some patients had low levels of cortisol at 36 hours of life and showed a trend towards a spontaneous increase during the first month of life.
INTRODUCCIÓN: Dada la dificultad en la interpretación de los valores de cortisol sérico en recién nacidos (RN), el objetivo de este estudio fue correlacionar los niveles basales de cortisol en el suero y la saliva, y describir las concentraciones de cortisol salival durante el primer mes de vida. POBLACIÓN Y MÉTODOS: Estudio descriptivo, prospectivo, longitudinal y de correlación. Se seleccionaron RN de término del Servicio de Neonatología del Hospital Nacional Profesor Alejandro Posadas en 2014. En la saliva, se determinó cortisol; en la sangre, cortisol, globulina tansportadora de cortisol y albúmina. Se utilizó la correlación lineal para relacionar cortisol sérico y salival; el test de Friedman para comparar el cortisol durante el primer mes de vida y la diferencia para analizar el comportamiento de valores iguales o inferiores al primer cuartil. RESULTADOS: Se evaluaron 55 RN. Cortisol sérico: 7,65 (1,0-18,1 gg/dl); cortisol salival: 35,88 (5,52107,64 nmol/L); globulina transportadora de cortisol: 22,07 (16,5-33,0 gg/ml), expresados como mediana y rango. El coeficiente de correlación entre el cortisol sérico y salival fue de 0,54; P= 0,001. El comportamiento del cortisol durante el primer mes de vida no mostró diferencias estadísticamente significativas y la diferencia entre la segunda y la primera muestra de valores iguales o inferiores al primer cuartil aumentó en 10 de 12 pacientes. CONCLUSIÓN: La determinación de cortisol en la saliva refleja la concentración de cortisol sérico en RN normales. Algunos pacientes presentaron niveles bajos de cortisol a las 36 h de vida y mostraron una tendencia a incrementarse espontáneamente durante el primer mes de vida.