Talla baja idiopática. Revisión y puesta al día / Idiopathic short stature. A literature review and update

Con la denominación de talla baja idiopática (TBI) se agrupan una serie de entidades clínicas de etiología desconocida que tienen en común un retraso crónico de crecimiento con talla inferior a −2 desviaciones estándar (DE), con preservación de la armonía entre los segmentos corporales y en las que, en su evolución espontánea, las expectativas de talla adulta son inferiores a −2 DE. Es un diagnóstico de exclusión que exige una evaluación clínica, bioquímica, hormonal y molecular minuciosa con el objetivo de descartar cualquier etiología conocida del retraso de crecimiento, especialmente el retraso constitucional del crecimiento y desarrollo (RCCD). La TBI es un diagnóstico frecuente entre los pacientes que consultan por retraso de crecimiento, existiendo lagunas y controversias sobre su abordaje diagnóstico y terapéutico. Este documento de consenso recoge información actualizada sobre la definición, diagnóstico y tratamiento de la TBI, y aporta datos y recomendaciones que no han sido contemplados en documentos anteriores (AU)

Idiopathic short stature (ISS) refers to all clinical conditions involving an alteration of growth (height <−2 SD) of unknown cause, with preservation of proportionality among body segments, with the expectation of adult height < −2 SDS, and in which a diagnosis of constitutional delay of growth and development has been previously ruled out. ISS is an exclusion diagnostic which requires clinical, biochemical, hormonal and molecular studies in order to rule out all known causes of growth retardation and short stature.ISS is a frequent diagnosis among children with short stature. Despite its frequency, there is still controversy on the best diagnostic and therapeutic approach when treating patients with ISS. This consensus document contains updated information on the definition, diagnosis and treatment of ISS, and provides new data and recommendations that have not been addressed in previous documents (AU)

[Idiopathic short stature. A literature review and update]. / Talla baja idiopática. Revisión y puesta al día.

Idiopathic short stature (ISS) refers to all clinical conditions involving an alteration of growth (height<-2 SD) of unknown cause, with preservation of proportionality among body segments, with the expectation of adult height < -2 SDS, and in which a diagnosis of constitutional delay of growth and development has been previously ruled out. ISS is an exclusion diagnostic which requires clinical, biochemical, hormonal and molecular studies in order to rule out all known causes of growth retardation and short stature. ISS is a frequent diagnosis among children with short stature. Despite its frequency, there is still controversy on the best diagnostic and therapeutic approach when treating patients with ISS. This consensus document contains updated information on the definition, diagnosis and treatment of ISS, and provides new data and recommendations that have not been addressed in previous documents.

Adolescente con síndrome de deleción 22q11.2 y endocrinopatía múltiple / An adolescent with 22q11.2 deletion syndrome and multiple endocrinopathies

Las anomalías endocrinológicas son frecuentes en los pacientes con deleción22q11.2 e incluyen, por orden de frecuencia, hipocalcemia por hipoparatiroidismo primario, talla baja y disfunción tiroidea. Presentamos un caso de deleción 22q11.2 de diagnóstico tardío con afectación endocrina múltiple y diabetes mellitus tipo 1, y se revisan los conocimientos actuales de las manifestaciones endocrinológicas descritas en los pacientes con esta anomalía genética (AU)

The endocrine abnormalities are common in patients with 22q11.2 deletion, and include hypocalcaemia due to primary hypoparathyroidism, short stature and thyroid dysfunction. We present a patient with delayed diagnosis of del22q11.2 who had multiple endocrine involvement and type 1 diabetes mellitus. A review is also made on the current knowledge of the endocrine manifestations described in patients with 22q11.2 deletion (AU)

[An adolescent with 22q11.2 deletion syndrome and multiple endocrinopathies]. / Adolescente con síndrome de deleción 22q11.2 y endocrinopatía múltiple.

The endocrine abnormalities are common in patients with 22q11.2 deletion, and include hypocalcaemia due to primary hypoparathyroidism, short stature and thyroid dysfunction. We present a patient with delayed diagnosis of del22q11.2 who had multiple endocrine involvement and type 1 diabetes mellitus. A review is also made on the current knowledge of the endocrine manifestations described in patients with 22q11.2 deletion.

Valoración del peso, talla e IMC en niños, adolescentes y adultos jóvenes de la Comunidad Autónoma de Madrid / Evaluation of weight, height and BMI in children, adolescents and young adults from the Community of Madrid

Introducción: Recientemente se han fusionado los datos de 4 estudios de crecimiento realizados en poblaciones de Andalucía, Barcelona, Bilbao y Zaragoza, configurándose el estudio transversal español de crecimiento 2008.Con el objetivo de comprobar si existían o no diferencias entre la población de Madrid y las incluidas en el estudio español y de esta forma evaluar la aplicabilidad de este estándar de referencia también en nuestra comunidad autónoma, hemos realizado un estudio transversal en la Comunidad de Madrid valorando peso, talla e IMC en una muestra de sujetos. Pacientes y métodos: Hemos analizado una muestra de 6.463 sujetos (3.055 mujeres y 3.408 varones) con edades comprendidas entre 3 y 24 años. Todos estaban sanos, eran de raza caucásica y tenían origen español. Las diferencias entre los datos de Madrid y las poblaciones incluidas en el estudio transversal español 2008 se evaluaron mediante regresión lineal múltiple del logaritmo de la talla, el peso y el IMC ajustado por grupo de edad y por área geográfica de procedencia. Se ha utilizado el procedimiento de comparaciones múltiples de Tukey para los contrastes de los diferentes rangos de edad. El análisis estadístico se realizó mediante el paquete estadístico SAS versión 8.2. Resultados: Se exponen los valores de la media aritmética y desviación estándar de peso, talla e IMC por grupos de edades para varones y mujeres, así como su distribución percentilada. No encontramos diferencias de relevancia clínica para los valores de peso, talla e IMC de nuestra población y los correspondientes del estudio transversal español 2008. Respecto a otros estudios realizados hace más de 20 años observamos un incremento en los valores de todos los percentiles de peso y talla. Conclusiones: En resumen, los datos de referencia que ofrece el estudio español de crecimiento 2008 son aplicables en la Comunidad Autónoma de Madrid. Además teniendo en cuenta que la comparación de los estudios transversales recientes realizados en 5 comunidades autónomas (Andalucía, Aragón, Cataluña, Madrid y País Vasco) no mostraron diferencias significativas en las medias de los parámetros antropométricos de peso, talla, IMC, ni en la talla final, podría considerarse a la población española actual como una población homogénea desde el punto de vista antropométrico y extender por tanto la aplicabilidad del estudio español de crecimiento 2008 al resto del país (AU)

Introduction: The data of four growth studies involving populations from Andalusia, Barcelona, Bilbao and Zaragoza have recently been reported as part of the Spanish Cross-sectional Growth Study 2008 (SCGS).With the aim of detecting possible differences between the population of the Madrid region and those of the SCGS, and by so-doing assess the applicability of the conclusions of this reference work to the Madrid region, a cross-sectional study of the latter was undertaken, recording the weight, height and body mass index (BMI). Subjects and methods: We have analyzed 6463 subjects (3055 females and 3408 males) aged 3–24 years. All subjects were healthy, Caucasian, and of Spanish origin. Differences between the results of the Madrid and SCGS studies were sought by multiple linear regression analysis of the log of the height, weight and BMI data adjusted for age and geographical area. The Tukey multiple comparisons test was used to analyse differences in age ranges. All calculations were performed using SAS v. 8.2 software. Results: Means and standard deviations are provided for the weight, height and BMI of women and men; distributions by percentiles are also provided.No differences of clinical importance were seen in the weight, height or BMI between the subjects of the Madrid region and those of the SCGS. However, comparisons with the results of other studies performed more than 20 years ago revealed an increase in the weight and height values in all percentiles. Conclusions: In summary, the official Spanish SCGS reference data for 2008 are similar to those recorded for the Madrid region. Bearing in mind that recent cross-sectional studies undertaken in Andalusia, Aragon, Catalonia, the Basque Country and the present work show no significant differences in mean weights, heights or BMIs in any age group, nor in the final height attained by adults, the Spanish population would appear to be anthropometrically homogeneous. The conclusions of the SCGS may therefore be applicable to the entire country (AU)

Valores normales de hormona antimülleriana en niños españoles / Normal rate of anti-Müllerian hormone concentration in Spanish boys

Introducción: La hormona antimülleriana (AMH) es el factor testicular responsable de la regresión de las estructuras derivadas de los conductos de Müller. En este trabajo se presentan los valores normales de la concentración de AMH en los varones españoles en edad pediátrica. Asimismo, se ofrece un gráfico de distribución en percentiles de la concentración de AMH, que puede resultar útil para conseguir diagnósticos precisos en la evaluación diagnóstica de gónadas bilateralmente no palpables y en los procesos intersexuales. Pacientes y métodos: Se obtuvieron 240 muestras de sangre de niños de 0-18 años de edad, que fueron remitidos a nuestro servicio por diversas causas; 35 de las muestras se obtuvieron de sangre de cordón umbilical y se utilizaron para determinarla concentración de la hormona en el periodo neonatal. Se determinó la concentración por medio de radioinmunoanálisis por adsorción de enzimas usando anticuerpos contra la hormona recombinante humana. Resultados: La concentración de AMH (en ng/mL) muestra un valor mínimo (desviación estándar) en el periodo neonatal de 31,90 (21,46), durante el cual no se encontraron diferencias estadísticamente significativas entre individuos de este grupo según su edad gestacional o su peso al nacimiento; entre el mes de vida y los 4 años se observa un aumento de la concentración (51,55 [30,36]), seguido de un periodo en meseta hasta los 8 años (50,85 [36,77]). Posteriormente, se aprecia un descenso hasta un mínimo a los 12 años (38,60 [28,92]), con una disminución hasta niveles basales a los 14 años (14,50 [16,65]), que se mantiene tras esta edad (12,05 [28,43]). Conclusiones: Los resultados de este estudio coinciden con los de otros autores y confirman que la AMH puede utilizarse como marcador específico de tejido testicular en niños, especialmente en los neonatos, utilizando suero obtenido de sangre de cordón umbilical (AU)

Introduction: Anti-Müllerian hormone (AMH) is the testicular factor responsible of the müllerian duct derived structures regression. We present in this report a percentile graphic chart of AMH concentration, which would be useful to reach the adequate diagnosis in bilateral no palpable gonads and intersex disorders. Patients and methods: 240 blood samples were obtained from boys between 0-18 years of age who were referred to our department. 35 of these samples were obtained from umbilical cord blood and were used to determine hormone measurement at newborn age. AMH was measured by enzyme-linked immunosorbentas say using antibodies raised against human recombinant AMH. Results: AMH concentration (in ng/mL) shows a minimum amount in newborn (31.90, standard deviation [SD] 21.46).There was not statistical significant difference between AMH concentration in this group depending on gestational age or birth weight. AMH level increases between 1 month and 4 years of life (51.55, SD 30.36) and then remains without variation, to 8 yr (50.85, SD 36.77). AMH level then decreases to a minimum at 12 yr (38.60, SD 28.92) and decreases to a basal level at 14 yr (14.50, SD 16.65) that persists afterwards (12.05, SD 28.43). Conclusions: These data are according to other author’s reports and confirm that AMH can be used as a testis-specific marker during infancy and childhood, particularly in newborns using serum obtained from blood of the umbilical cord (AU)

[Evaluation of weight, height and BMI in children, adolescents and young adults from the Community of Madrid]. / Valoración del peso, talla e IMC en niños, adolescentes y adultos jóvenes de la Comunidad Autónoma de Madrid.

INTRODUCTION: The data of four growth studies involving populations from Andalusia, Barcelona, Bilbao and Zaragoza have recently been reported as part of the Spanish Cross-sectional Growth Study 2008 (SCGS). With the aim of detecting possible differences between the population of the Madrid region and those of the SCGS, and by so-doing assess the applicability of the conclusions of this reference work to the Madrid region, a cross-sectional study of the latter was undertaken, recording the weight, height and body mass index (BMI). SUBJECTS AND METHODS: We have analyzed 6463 subjects (3055 females and 3408 males) aged 3-24 years. All subjects were healthy, Caucasian, and of Spanish origin. Differences between the results of the Madrid and SCGS studies were sought by multiple linear regression analysis of the log of the height, weight and BMI data adjusted for age and geographical area. The Tukey multiple comparisons test was used to analyse differences in age ranges. All calculations were performed using SAS v. 8.2 software. RESULTS: Means and standard deviations are provided for the weight, height and BMI of women and men; distributions by percentiles are also provided. No differences of clinical importance were seen in the weight, height or BMI between the subjects of the Madrid region and those of the SCGS. However, comparisons with the results of other studies performed more than 20 years ago revealed an increase in the weight and height values in all percentiles. CONCLUSIONS: In summary, the official Spanish SCGS reference data for 2008 are similar to those recorded for the Madrid region. Bearing in mind that recent cross-sectional studies undertaken in Andalusia, Aragon, Catalonia, the Basque Country and the present work show no significant differences in mean weights, heights or BMIs in any age group, nor in the final height attained by adults, the Spanish population would appear to be anthropometrically homogeneous. The conclusions of the SCGS may therefore be applicable to the entire country.

Deleción 9p-. Disgenesia gonadal asociada a retraso mental e hipoplasia del cuerpo calloso. ¿Síndrome de genes contiguos? / Chromosome 9P deletion: Gonadal dysgenesis associated with mental retardation and hypoplasia of the corpus callosum: a contiguous gene syndrome

Antecedentes: Son muchos los genes que se han implicado en la diferenciación testicular, cuyas alteraciones dan cuadros de trastornos de la diferenciación sexual y cariotipo 46XY. Caso clínico: Recién nacido con hipospadias interescrotal, gónadas palpables y pene hipoplásico. Cariotipo 46XY. Ecografía abdominal: testes y sin restos müllerianos. Buena respuesta al test corto de gonadotropinas. Al año presenta retraso psicomotor, hipotonía. Resonancia magnética con atrofia de sustancia blanca frontotemporal y disminución del cuerpo calloso. Biopsia testicular compatible con disgenesia gonadal. Dada la situación intersexual al nacimiento, el retraso psicomotor y la presencia de dismorfias faciales se solicita cariotipo de alta resolución: deleción 46, XY, del(9p)(p23-pter).ish tel (9p-). Comentarios: Son muchos los genes implicados en la diferenciación testicular, algunos de ellos también influyen sobre el desarrollo de otros tejidos. En el brazo corto del cromosoma 9 se encuentran dos genes, DMRT1 y DMRT2, implicados en la diferenciación sexual, cuyas alteraciones también han sido descritas como causantes de retraso mental. En la evaluación de los trastornos de la diferenciación sexual son muy importantes los signos acompañantes para poder orientar el estudio genético (AU)

Background: Many genes are involved in testicular differentiation. The alterations of these genes are responsible for sexual differentiation disorders with 46 XY karyotype. Case: We report the case of a newborn who had an interscrotal hypospadias, palpable gonads and hypoplastic penis. Karyotype 46 XY. Abdominal ultrasound revealed testes and absence of Müllerian remnants. There was a good response to the short gonadotrophin test. At one year he had signs of psychomotor retardation and hypotonia. The magnetic resonance revealed frontal-temporal atrophy and a decrease in the corpus callosum. Testicular biopsy was compatible with gonadal dysgenesis. A preoperative cystography showed a vaginal remnant. Due to the presence of a sexual differentiation disorder, psychomotor retardation and facial dysmorphism, we requested a high-resolution karyotype: deletion 46, XY, del (9p) (p23-pter). Ish tel (9p-). Discussion: Many genes are involved in testicular differentiation, some of which also affect the development of other tissues. In the short arm of chromosome 9, two genes, DMRT1 and DMRT2, are involved in sexual differentiation. Their alterations have also been described as causing mental retardation. In the evaluation of 46,XY disorders of sex differentiation, the accompanying signs are very important for guiding the genetic study (AU)

[Chromosome 9P deletion: Gonadal dysgenesis associated with mental retardation and hypoplasia of the corpus callosum: A contiguous gene syndrome?]. / Deleción 9p-. Disgenesia gonadal asociada a retraso mental e hipoplasia del cuerpo calloso. ¿Síndrome de genes contiguos?

BACKGROUND: Many genes are involved in testicular differentiation. The alterations of these genes are responsible for sexual differentiation disorders with 46 XY karyotype. CASE: We report the case of a newborn who had an interscrotal hypospadias, palpable gonads and hypoplastic penis. Karyotype 46 XY. Abdominal ultrasound revealed testes and absence of Müllerian remnants. There was a good response to the short gonadotrophin test. At one year he had signs of psychomotor retardation and hypotonia. The magnetic resonance revealed frontal-temporal atrophy and a decrease in the corpus callosum. Testicular biopsy was compatible with gonadal dysgenesis. A preoperative cystography showed a vaginal remnant. Due to the presence of a sexual differentiation disorder, psychomotor retardation and facial dysmorphism, we requested a high-resolution karyotype: deletion 46, XY, del (9p) (p23-pter). Ish tel (9p-). DISCUSSION: Many genes are involved in testicular differentiation, some of which also affect the development of other tissues. In the short arm of chromosome 9, two genes, DMRT1 and DMRT2, are involved in sexual differentiation. Their alterations have also been described as causing mental retardation. In the evaluation of 46,XY disorders of sex differentiation, the accompanying signs are very important for guiding the genetic study.

Novel (60%) and recurrent (40%) androgen receptor gene mutations in a series of 59 patients with a 46,XY disorder of sex development.

BACKGROUND: Androgen receptor (AR) gene mutations are the most frequent cause of 46,XY disorders of sex development (DSD) and are associated with a variety of phenotypes, ranging from phenotypic women [complete androgen insensitivity syndrome (CAIS)] to milder degrees of undervirilization (partial form or PAIS) or men with only infertility (mild form or MAIS). OBJECTIVE: The aim of the study was to characterize the contribution of the AR gene to the molecular cause of 46,XY DSD in a series of Spanish patients. SETTING: We studied a series of 133 index patients with 46,XY DSD in whom gonads were differentiated as testes, with phenotypes including varying degrees of undervirilization, and in whom the AR gene was the first candidate for a molecular analysis. METHODS: The AR gene was sequenced (exons 1 to 8 with intronic flanking regions) in all patients and in family members of 61% of AR-mutated gene patients. RESULTS: AR gene mutations were found in 59 individuals (44.4% of index patients), of whom 46 (78%) were CAIS and 13 (22%) PAIS. Fifty-seven different mutations were found: 21.0% located in exon 1, 15.8% in exons 2 and 3, 57.9% in exons 4-8, and 5.3% intronic. Twenty-three mutations (40.4%) had been previously described and 34 (59.6%) were novel. CONCLUSIONS: AR gene mutation is the most frequent cause of 46,XY DSD, with a clearly higher frequency in the complete phenotype. Mutations spread along the whole coding sequence, including exon 1. This series shows that 60% of mutations detected during the period 2002-2009 were novel.

Tumoración hipofisaria secundaria a hipotiroidismo primario: un caso de hiperplasia tirotropa que simula un adenoma hipofisario / Hypophyseal tumour growth secondary to primary hypothyroidism: a case of a hypophyseal adenoma induced by thyrotropic hyperplasia

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[Neonatal diabetes mellitus and KCNJ11 gene mutation: report of a family case]. / Diabetes mellitus neonatal y mutación del gen KCNJ11: presentación de un caso familiar.

Neonatal diabetes mellitus (NDM) is characterized by hyperglycemia within the first month of life and insulin dependence for at least two weeks. There are two types of NDM, transient (TNDM) and permanent (PNDM), which are genetically different. We report the case of two brothers who developed hyperglycemia without ketosis on the 18th day and 2 h of life, respectively. Thyroid function tests, abdominal ultrasound and karyotype where normal and there were no pancreatic antibodies. The first one required insulin therapy for the first 92 days of life and the second for 5 months. The mother developed gestational diabetes during both pregnancies and she was later diagnosed diabetes mellitus (without antibodies). They were studied for mutations in KCNJ11 gene (principally related to the permanent form). The three of them showed the E229K mutation (frequently associated with the transient form). A genetic study is essential in NDM to achieve the most accurate prognosis possible.

Diabetes mellitus neonatal y mutación del gen KCNJ11: presentación de un caso familiar / Neonatal diabetes mellitus and KCNJ11 gene mutation: report of a family case

La diabetes mellitus neonatal (DMN) se caracteriza por hiperglucemia que se manifiesta en el primer mes de vida, precisa insulinoterapia y dura como mínimo 2 semanas. Existen dos formas de DMN: transitoria (DMNT) y permanente (DMNP), genéticamente diferentes. Presentamos dos hermanos, con hiperglucemia sin cetosis, a los 18 días y a las 2 h de vida, respectivamente. En ambos casos las pruebas complementarias (función tiroidea, ecografías abdominales, cariotipo) resultaron normales y los anticuerpos antipancreáticos, negativos. Precisaron insulinoterapia hasta los 92 días y los 5 meses de vida, respectivamente. La madre presentó diabetes gestacional en ambos embarazos y, posteriormente, se le diagnosticó diabetes mellitus, con anticuerpos negativos. En el estudio del gen KCNJ11, cuyas alteraciones se asocian principalmente a DMNP, se halló en los tres pacientes la mutación E229K, la cual está relacionada con DMNT. En la DMN es imprescindible el estudio genético para establecer el pronóstico más preciso possible (AU)

Neonatal diabetes mellitus (NDM) is characterized by hyperglycemia within the first month of life and insulin dependence for at least two weeks. There are two types of NDM, transient (TNDM) and permanent (PNDM), which are genetically different. We report the case of two brothers who developed hyperglycemia without ketosis on the 18th day and 2 h of life, respectively. Thyroid function tests, abdominal ultrasound and karyotype where normal and there were no pancreatic antibodies. The first one required insulin therapy for the first 92 days of life and the second for 5 months. The mother developed gestational diabetes during both pregnancies and she was later diagnosed diabetes mellitus (without antibodies).They were studied for mutations in KCNJ11 gene (principally related to the permanent form). The three of them showed the E229K mutation (frequently associated with the transient form). A genetic study is essential in NDM to achieve the most accurate prognosis posible (AU)