Caracterización clínica de pacientes chilenos con displasia fibrosa/síndrome de McCune-Albright / Clinical features of Chilean patients with Fibrous Dysplasia/McCune-Albright Syndrome

BACKGROUND: Fibrous Dysplasia/McCune-Albright Syndrome (FD/MAS) is characterized by a spectrum of manifestations that may include fibrous dysplasia of bone and multiple endocrinopathies. AIM: To describe the clinical spectrum, the study and follow-up of patients with FD/MAS cared at our institution. MATERIAL AND METHODS: Review of medical records of 12 pediatric and adult patients (11 women) who met the clinical and genetic diagnostic criteria for FD/ MAS. RESULTS: The patients' mean age at diagnosis was 4.9 ± 5.5 years. The most common initial clinical manifestation was peripheral precocious puberty (PPP) in 67% of patients and 75% had café-au-lait spots. Fibrous dysplasia was present in 75% of patients and the mean age at diagnosis was 7.9 ± 4.7 years. Ten patients had a bone scintigraphy, with an age at the first examination that varied between 2 and 38 years of age. The most frequent location of dysplasia was craniofacial and appendicular. No patient had a recorded history of cholestasis, hepatitis, or pancreatitis. In four patients, a genetic study was performed that was positive for the pathogenic variant of guanine nucleotide binding protein, alpha stimulating (GNAS). CONCLUSIONS: These patients demonstrate the variable nature of the clinical presentation and study of FD/MAS. It is essential to increase the index of diagnostic suspicion and adherence to international recommendations.

Síndrome de McCune-Albright, una forma poco frecuente de pubertad precoz: diagnóstico, tratamiento y evolución / McCune-Albright syndrome, a rare form of precocious puberty: Diagnosis, treatment, and follow-up

Introducción. El síndrome de McCune-Albright (SMA) es un trastorno genético caracterizado por displasia ósea fibrosa, manchas cutáneas color "café con leche" e hiperfunción autónoma de uno o varios órganos endocrinos. El SMA es producido por mutaciones activadoras del gen GNAS1. La endocrinopatía más frecuente es la gonadal, que se manifiesta como pubertad precoz periférica. Objetivo. Describir las características clínicas y los estudios de laboratorio e imágenes en el momento del diagnóstico y a lo largo de la evolución de la enfermedad, con énfasis en la tríada clásica del síndrome. Población y métodos. Estudio clínico observacional, descriptivo, retrospectivo de las historias clínicas de pacientes con SMA de la División de Endocrinología del Hospital de Niños Ricardo Gutiérrez desde 1974 hasta 2019. Resultados. Se presentan 12 niñas. Todas tuvieron pubertad precoz periférica (PPP) secundaria a quistes ováricos funcionantes. La edad de presentación fue temprana (2,6 ± 1,3 años). Los niveles de gonadotrofinas estuvieron suprimidos o en rango prepuberal con niveles de estradiol generalmente elevados. Diez niñas tuvieron manchas "café con leche" desde el nacimiento. Durante la evolución se detectó displasia fibrosa poliostótica en todas las pacientes. Los tratamientos utilizados para disminuir la recurrencia de los quistes ováricos y los efectos del hiperestrogenismo mostraron diferente eficacia. Conclusiones. En esta serie, la aparición de PPP contribuyó al diagnóstico temprano del SMA y fue de difícil tratamiento. En la evolución persistió la hiperfunción gonadal y empeoraron las lesiones óseas.

Introduction. McCune-Albright syndrome (MAS) is a genetic disorder defined by fibrous dysplasia of bone, café-au-lait skin spots, and autonomous hyperfunction of one or more endocrine organs. MAS is caused by activating mutations of the GNAS1 gene. The most frequent type of endocrinopathy is gonadal endocrinopathy in the form of peripheral precocious puberty. Objective. To describe the clinical characteristics, laboratory and imaging tests at the time of diagnosis and over the course of the disease, focusing on the classical triad of MAS. Population and methods. Observational, descriptive, retrospective clinical study of patients with MAS seen at the Department of Endocrinology of Hospital de Niños Ricardo Gutiérrez between 1974 and 2019. Results. Twelve girls are described, all of whom developed peripheral precocious puberty (PPP) secondary to functional ovarian cysts. Their age at presentation was early (2.6 ± 1.3 years). Gonadotropin levels were suppressed or in the prepubertal range with generally high estradiol levels. Ten girls had café-au-lait skin spots since birth. During the course of disease, polyostotic fibrous dysplasia was detected in all patients. The treatments used to reduce ovarian cyst recurrence and hyperestrogenism effects showed varied effectiveness. Conclusions. In this series, the onset of PPP helped to make an early diagnosis of MAS and was difficult to treat. The course of disease showed persistent gonadal hyperfunction and worsening of bone injuries

Diagnóstico de causas secundarias de pubertad precoz / Diagnosis of secondary causes of precocious puberty: Clinical guideline for the diagnosis and treatment of precocious puberty

Resumen La Sociedad Mexicana de Endocrinología Pediátrica elaboró una guía de práctica clínica para el diagnóstico y el tratamiento de la pubertad precoz. Este documento presenta recomendaciones relacionadas con el diagnóstico de causas secundarias de pubertad precoz central. La descripción detallada de la metodología para el desarrollo de esta guía y del sistema de gradación, así como la síntesis de la evidencia en la que se basa, pueden consultarse en este mismo suplemento.

Abstract The Mexican Society of Pediatric Endocrinology developed a clinical practice guide for the diagnosis and treatment of precocious puberty. This document presents recommendations related to the diagnosis of secondary causes of central PP. The detailed description of the methodology for the development of this guide and the grading system, as well as the synthesis of the evidence on which it is based can be consulted in this same supplement.

Efectos endocrinológicos tardíos del tratamiento oncológico en supervivientes de meduloblastoma / Endocrinological late effects of oncologic treatment on survivors of medulloblastoma

INTRODUCCIÓN: La radioterapia, quimioterapia y la cirugía empleada en el tratamiento de los tumores cerebrales tienen efectos en el eje hipotálamo-hipofisario y pueden resultar en disfunción endocrina hasta en el 96% de los casos. PACIENTES Y MÉTODO: Estudio retrospectivo y descriptivo en pacientes diagnos ticados de meduloblastoma sometidos a tratamiento con quimio y radioterapia en los últimos 20 años en un hospital terciario. Se analizan variables edad, sexo, peso, talla, índice de masa corporal (IMC) al final del seguimiento, estadio de maduración sexual, niveles séricos de TSH y T4 libre, ACTH/cortisol e IGF-1, FSH, LH, estradiol, testosterona, perfil lipídico (colesterol total) y prueba de función dinámica de hormona de crecimiento. RESULTADOS: Muestra total de 23 pacientes. El déficit de hormona de crecimiento es la secuela más frecuente (82 %) seguido de disfunción ti roidea (44,8%) y disfunción puberal (24,1%). Solo se diagnosticó un caso de diabetes insípida y 2 casos de déficit de corticotrofina. CONCLUSIONES: El seguimiento a largo plazo de los supervivientes de meduloblastoma tratados con quimio y radioterapia revela una prevalencia muy alta de disfun ción endocrina, particularmente de deficiencia de hormona del crecimiento y de hipotiroidismo. Creemos oportuna la monitorización y el seguimiento a largo plazo de estos pacientes con el fin de garantizar un manejo terapéutico adecuado de aquellas disfunciones tratables.

INTRODUCTION: Radiation therapy, chemotherapy, and surgery used to treat brain tumors have effects on the hy pothalamic-pituitary-adrenal axis and can result in endocrine dysfunction in up to 96% of cases. PATIENTS Y METHOD: Retrospective and descriptive study in patients diagnosed with medulloblasto ma who underwent treatment with chemo and radiotherapy in the last 20 years in a tertiary hospital. The variables analyzed were age, sex, weight, height, body mass index (BMI) at the end of follow-up, sexual maturity stage, serum levels of TSH and free T4, ACTH/cortisol and IGF-1, FSH, LH, estradiol, testosterone, lipid profile (total cholesterol), and growth hormone dynamic function test. RESULTS: Total sample of 23 patients. Growth hormone deficiency is the most frequent sequelae (82%) fo llowed by thyroid dysfunction (44.8%), and disorders of puberty (24.1%). Only one case of diabetes insipidus and two cases of corticotropin deficiency were diagnosed. CONCLUSIONS: Long-term follow- up of medulloblastoma survivors treated with chemo and radiotherapy reveals a very high prevalence of endocrine dysfunction, especially growth hormone deficiency and hypothyroidism. We believe that monitoring and long-term follow-up of these patients is necessary in order to ensure adequate therapeutic management of those treatable dysfunctions.

Pioneering studies on monogenic central precocious puberty

ABSTRACT Pubertal timing in humans is determined by complex interactions including hormonal, metabolic, environmental, ethnic, and genetic factors. Central precocious puberty (CPP) is defined as the premature reactivation of the hypothalamic-pituitary-gonadal axis, starting before the ages of 8 and 9 years in girls and boys, respectively; familial CPP is defined by the occurrence of CPP in two or more family members. Pioneering studies have evidenced the participation of genetic factors in pubertal timing, mainly identifying genetic causes of CPP in sporadic and familial cases. In this context, rare activating mutations were identified in genes of the kisspeptin excitatory pathway (KISS1R and KISS1 mutations). More recently, loss-of-function mutations in two imprinted genes (MKRN3 and DLK1) have been identified as important causes of familial CPP, describing novel players in the modulation of the hypothalamic-pituitary-gonadal axis in physiological and pathological conditions. MKRN3 mutations are the most common cause of familial CPP, and patients with MKRN3 mutations present clinical features indistinguishable from idiopathic CPP. Meanwhile, adult patients with DLK1 mutations present high frequency of metabolic alterations (overweight/obesity, early onset type 2 diabetes and hyperlipidemia), indicating that DLK1 may be a novel link between reproduction and metabolism. Arch Endocrinol Metab. 2019;63(4):438-44

Tumor ovárico de células de Leydig en una niña de 7 años que se presentó como pubarquia precoz con elevación de 17 hidroxiprogesterona / Ovarian tumor of Leydig cells in a 7-year-old girl who presented as precocious pubarche with elevation of 17 hydroxyprogesterone

Clinical case: a girl of 7 ½ years who consulted for early pubarche without thelark, with a percentile size of 75 for a genetic target size in the 10th percentile, overweight with a 90th percentile BMI, and normal blood pressure. The biochemical study showed high levels of androgens: testosterone: 7.2 ng/dL, androstenedione of 5.1 ng / ml, 17OHP: 15 ng / dL with low normal DHEAS (0.26 ug/ml), Plasma Renin Activity normal low: 0.22 ng/mL/h. Initial imaging study showed a bone age of 10 years 6 months and normal abdominal and pelvic ultrasound. Molecular study showed no pathogenic variants in the CYP21A2 gene (21 Hydroxylase). With a probable diagnosis of non-classical congenital adrenal hyperplasia (HSRNC) and no known mutation, he started treatment with hydrocortisone (12 mg/m2). At 8.7 years, pubertal development begins and braking begins with LHRH analogues, which are administered for 18 months. Despite the treatment, signs of virilization and elevation of androgens (testosterone up to 130 ng/ml) are progressively accentuated, which do not diminish when trying different corticosteroid schemes. MRI of the abdomen and pelvis shows the normal adrenal glands and a solid nodular image of 2.1 x 1.6 cm in the right ovary (Figure 2), later demonstrated with pelvic ultrasound (Figure 2). Right laparoscopic oophorectomy was performed, whose biopsy demonstrated a Leydig cell tumor. One month after surgery, all androgenic levels were normalized, so the gradual suspension of corticosteroids began. Conclusion: Although HSRNC is the most frequent pathological cause of early pubarche, when it is associated with progressive clinical and biochemical hyperandrogenism despite adequate treatment and without pathogenic variants in the CYP21A2 gene, even with high levels of 17OHP, other causes should be considered, specifically, androgen producing tumors.

Caso clínico: niña de 7½ años que consulta por pubarquia precoz sin telarquia, con talla en percentil 75 para una talla objetivo genético en percentil 10, sobrepeso con IMC percentil 90 y presión arterial normal. El estudio bioquímico mostró niveles elevados de andrógenos: testosterona: 7,2 ng/dL, androstenediona de 5,1 ng/ml, 17OHP: 15 ng/dL con DHEAS normal baja (0,26 ug/ml), Actividad de Renina Plasmática normal baja: 0.22 ng/ mL/h. Estudio de imágenes inicial mostró una edad ósea de 10 años 6 meses y ecografía abdominal y pelviana normales. Estudio molecular no mostró variantes patogénicas en el gen CYP21A2 (21 Hidroxilasa). Con diagnosticó probable de hiperplasia suprarrenal congénita no clásica (HSRNC) y sin mutación conocida,inició el tratamiento con hidrocortisona (12 mg/m2). A los 8.7 años comienza desarrollo puberal y se inicia frenación con análogos de LHRH, los cuales se administran por 18 meses. A pesar del tratamiento se acentúan progresivamente los signos de virilización y hayelevación de los andrógenos (testosterona hasta 130 ng/ml), que no disminuyen intentando diferentes esquemas de corticoides. Se realiza RM de abdomen y pelvis que muestra las glándulas suprarrenales normales y una imagen nodular sólida de 2.1 x 1.6 cm en el ovario derecho (Figura 2), demostrada posteriormente con Ecografía pelviana (Figura 2). Se realiza ooforectomía derecha por vía laparoscópica, cuya biopsia demostró un tumor de células de Leydig. Un mes después de la cirugía, se normalizan todos los niveles androgénicos por lo que se inició la suspensión gradual de los corticoides. Conclusión: Aunque la HSRNC es la causa patológica más frecuente de la pubarquia precoz, cuando se asocia con un hiperandrogenismo clínico y bioquímico progresivo a pesar de un tratamiento adecuado y sin variantes patógenicas en el gen CYP21A2, incluso con niveles elevados de 17OHP, otras causas deben ser consideradas, específicamente tumores productores de andrógenos.

El adelanto en la telarquia y edad de la menarquia se relacióna con la malnutrición por exceso en niñas chilenas pero no en varones: estudio de base poblacional / The advance in thelarche and age of menarche is related to malnutrition by excess in Chilean girls but not in boys: population-based study

Introduction: Puberty normally begins after 8 years in girls and 9 years in boys. Objective: To determine the prevalence of signs of precocious puberty (PP), breast development in girls, premature gonadal development (PGD), premature adrenarche (PA), menarche age (MA) and its association with nutritional status (NS). Material and Methods: From a sample of 3.010 children from 5 to 14 years randomly selected in Santiago of Chile were chosen a subsample of 873 kids according to the cutoff to define PP. Survey was applied to obtain MA. Logistic regression were used to evaluate the relationship between PP and NS. Results: In boys the prevalence of PGD and PP was 8.55% and 3.16% respectively, no relationship was found with nutritional status In girls the prevalence of breast development and PA was 8.13% and 0.9% respectively. Only there be association between PP and NS in women: with a prevalence of 1,2%, 13,9% and 21,1% in well-nourished, Overweight and obesity are at greater risk of showing PP compared with eutrophic girls with an OR of 25,5 (IC 95% 3,2-203,0) and 46.93 (IC 95% 6,1-361,5). MA was 12,01 ± 0,94 years in eutrophic girls and 11,40 ± 0,96years in obese girls (p< 0,05). Conclusion: There was a positive correlation in females between overweight and obesity an PP and MA. There is a secular trend in MA, to compare these findings with other national studies. Obesity could have an important role in explaining the advancement observed in pubertal development.

Introducción: El desarrollo puberal se inicia normalmente después de los 8 años en niñas y de los 9 años en varones. Objetivo: Estimar la prevalencia de signos de pubertad precoz (sPP): crecimiento genital (CG) en varones, telarquia en niñas y vello púbico (VP) en ambos sexos; y determinar edad de la menarquia (EM) en una muestra de escolares de Santiago de Chile), y evaluar la asociación de estas variables con el estado nutricional (EN). Material y Métodos: Se examinaron 3.010 escolares de clase media baja de 6 a 14 años, pertenecientes a 10 colegios de Santiago de Chile y seleccionados aleatoriamente. En todos ellos se consignó peso, talla, IMC y desarrollo puberal según Tanner. Se aplicó una encuesta a los padres para obtener la EM a la población total de mujeres (n= 1.433). Para determinar sPP se analizaron por separado los 867 niños (62% mujeres) menores a la edad establecida como puntos de corte para definir PP. Se utilizó regresión logística para determinar la asociación existente entre sPP y el EN. Resultados: En varones la prevalencia de CG y VP fue de 8,55% y 3,16% y no se asocio al EN. La prevalencia de telarquia y VP en niñas fue de 8,13% y 0,9% respectivamente. Se observó una fuerte asociación entre telarquia y EN con prevalencias de 1.2%, 13.9% y 21.1% en eutróficas, sobrepeso y obesas, respectivamente (p< 0,0001) (Gráfico 1). La presencia de sobrepeso y/o obesidad otorgan un mayor riesgo de presentar telarquia, vs comparación con las niñas eutróficas con un OR de 25,5 (IC 95% 3,2-203,0) y 46.93 (IC 95% 6,1-361,5), respectivamente. La EM fue 12,01 ± 0,94 años en niñas eutróficas siendo de 11,40 ± 0,96 años en niñas obesas (p< 0,05). Conclusión: Se observó una correlación positiva solo en el sexo femenino entre malnutrición por exceso, telarquia precoz y EM. Se observa una tendencia secular en la EM al comparar los hallazgos con otros estudios nacionales.

Teratoma tímico productor de beta-HCG: una causa infrecuente de pubertad precoz periférica / Beta-hCG-producing thymic teratoma: an uncommon cause of peripheral precocious puberty

INTRODUCCIÓN: Entre las causas de pubertad precoz periférica en el varón están los tumores secretores de betagonadotrofina coriónica humana (Β-HCG), como hepatoblastomas, disgerminomas, corio-carcinomas y teratomas inmaduros. En pediatría los teratomas mediastínicos son raros, representan el 7-10% de los teratomas extragonadales. OBJETIVO: Describir caso de un paciente que cursa con pubertad precoz periférica debida a teratoma tímico secretor de Β-HCG. CASO CLÍNICO: Escolar masculino de 7 años 10 meses consultó por cuadro de 3 meses de cambios de la voz, ginecomastia, aparición de vello pubiano y aumento de volumen genital. En exámenes destacaba edad ósea de 9 años, testosterona total 9,33ng/ml (< 0,4ng/ml), dehidroepiandrosterona sulfato (DHEAS), 17-hidroxi-progesterona (17-OH-P) y prueba de hormona adrenocorticotrofina (ACTH) normales, hormona luteinizante (LH) y hormona folículo estimulante (FSH) basales bajas, Β-HCG 39,5mU/ml (< 2,5 mUI/ml), alfa fetoproteína (α-FP) 11,2ng/ml (0,6-2,0 ng/ml). Estudio de imágenes para determinar origen de secreción de Β-HCG incluye: ecografía testicular y tomografla axial computarizada (TAC) torácica, abdominal y pelviana normales; resonancia cerebral y selar sin hallazgos significativos. Tomografía por emisión de positrones/tomografía computada (PET SCAN) evidenció imagen de tumor en mediastino antero-superior. Se resecó el tumor, cuya biopsia evidenció teratoma quístico inmaduro en timo. Evolución postoperatoria fue satisfactoria, con normalización de niveles hormonales. CONCLUSIÓN: La presentación de un teratoma en paciente pediátrico es infrecuente, aún más, si es inmaduro, su localización es tímica y es secretor de Β-HCG. Es relevante considerarlo dentro de diagnósticos diferenciales frente a pubertad precoz, de modo que pueda efectuarse un manejo oportuno.

INTRODUCTION: Among the causes of peripheral precocious puberty in men are the beta- human cho rionic gonadotropin (Β-HCG)-secreting tumors, such as hepatoblastomas, dysgerminomas, chorio carcinomas, and immature teratomas. In pediatrics, the mediastinal teratomas are rare, representing the 7-10% of extragonadal teratomas. OBJECTIVE: To describe the case of a patient with peripheral precocious puberty due to a Β-HCG -secreting thymic teratoma. CLINICAL CASE: A seven-years-old schoolboy presents a three-months history of voice changes, gynecomastia, pubic hair appearance, and increased genital volume. In the exams, bone age of nine years, total testosterone 9.33ng/ml (< 0.4ng/ml), dehydroepiandrosterone sulfate (DHEAS), 17-hydroxyprogesterone (17-OHP), and normal adrenocorticotropic hormone (ACTH) test stand out; luteinizing hormone (LH) and follicle stimulating hormone (FSH) with low basal levels, P-HCG 39.5mU/ml (< 2.5 mUI/ml), alpha feto protein (Α-FP) 11,2ng/ml (0.6-2.0 ng/ml). Imaging study to determine the origin of P-HCG secretion shows normal testicular ultrasound and thoracic, abdominal, and pelvic computerized axial tomo graphy (CAT); brain and sellar resonance without significant findings. The positron emission tomography/computed scan (PET SCAN) shows a tumor image in the anterosuperior mediastinum. The tumor is resected, and the biopsy shows an immature cystic teratoma in the thymus. Post-operatory evolution was satisfactory, with normalization of hormonal levels. CONCLUSION: The appearance of a teratoma in a pediatric patient is rare, even more if it is immature, with thymic location and Β-HCG- secretor. It is important to consider it within the differential diagnosis facing precocious puberty, as a better way to handle appropriately.

Tumor de las células de granulosa: pubertad precoz en lactante menor de 1 año. Caso clínico / Granulosa cell ovarian tumor: precocious puberty in infant less than 1 year of age. Case report

Resumen Introducción: Los tumores de las células de la granulosa de tipo juvenil (TCGJ) son muy poco fre cuentes, especialmente en menores de 1 año. Los signos de pubertad precoz constituyen la presenta ción clínica más importante. Objetivo: Presentar una lactante con pubertad precoz periférica, con diagnóstico de TCGJ, discutiendo las claves de su tratamiento y seguimiento. Caso Clínico: Lactante de 10 meses que presentó telarquia, vello púbico y tumor abdominal palpable acompañado de niveles plasmáticos de Estradiol aumentados, gonadotrofinas muy bajas e imágenes que mostraban masa ovárica gigante. Se realizó salpingooforectomía, obteniéndose regresión absoluta de signos y síntomas. La biopsia demostró TCGJ por lo que se tomó inhibina B (InB) como marcador después de la cirugía. Esta hormona estaba alta inicialmente, pero descendió rápidamente. El seguimiento se basó en InB, Hormona antimulleriana (AMH) y estradiol como se describe en este tipo de tumores. Conclusiones: Los TCGJ son muy infrecuentes en pediatría; deben sospecharse en niñas con puber tad precoz periférica. El tratamiento quirúrgico en la gran mayoría es curativo, pero debe mantenerse un estricto control con marcadores tumorales, siendo los más específicos la InB y la AMH y en menor escala los niveles de Estradiol.

Abstract Introduction: Juvenile granulosa cell tumors (JGCT) are very rare, especially in infants under the age of one. The most frequent presentation is with signs of precocious puberty. Objective: Present an in fant with peripheral precocious puberty, diagnosis of JGCT and follow up. Clinical case: 10-month-old female infant with thelarche, pubic hair and palpable abdominal mass accompanied with eleva ted levels of estradiol, very low gonadotrophins and images that show a very large ovarian mass. A sapingooforectomy was carried out with full regression of symptoms and signs and improvement of laboratory exams. The biopsy showed TCGJ so inhibin B (InB) was taken as tumoral marker after surgery. This hormone was high initially, but rapidly declined. Follow-up was based on InB, antimu-llerian Hormone (AMH) and estradiol as described in this type of tumors. Conclusions: Juvenil gra nulosa cell tumors are very infrequent in pediatric age, but should be suspected in girl with peripheral precocious puberty. The majority of cases improve with surgery, but strict surveillance of tumoral markers is needed. The most specific markers are inhibin B and anti mullerian hormone (AMH), followed by estradiol levels.

Causa muy rara de pubertad precoz periférica en una niña: tumor de cordones sexuales con túbulos anulares / A very rare cause of peripheral precocious puberty in a girl: ovarian sex cord tumor with annular tubules

El tumor de los cordones sexuales con túbulos anulares es una neoplasia del estroma gonadal muy infrecuente. Representa el 0,05-0,6% de todos los tumores ováricos, según series. Se presenta un caso especialmente inusual, en una niña de 6 años, detectado a raíz de una pubertad precoz periférica isosexual. Su interés radica en que no se halló ninguna masa anexa al ovario, sino únicamente una asimetría gonadal, sin signos radiológicos de malignidad. Se realizó una salpingo-ooforectomía unilateral con linfadenectomía pélvica y paraaórtica ipsilateral, por vía laparoscópica, tras confirmarse la presencia de células tumorales en la biopsia intraoperatoria. La evolución posterior de la paciente fue favorable.

Sex cord tumor with annular tubules is an extremely uncommon gonadal stromal neoplasm. It represents 0.05-0.6% of all ovarian tumors, according to series. An unusual case is presented in a 6-year-old girl, detected as a result of an isosexual peripheral precocious puberty. The highlight of this case is that no mass attached to the ovary was found, but only a gonadal asymmetry without radiological signs of malignancy. After confirming the presence of tumoral cells by intraoperative biopsy, unilateral salpingo-oophorectomy with ipsilateral para-aortic and pelvic lymphadenectomy was performed. Afterwards, the evolution of the patient was favorable.

Hamartomas hipotalámicos: distintas formas de debut. Casos clínicos / Hypothalamyc hamartomas: different ways of clinical debut. Cases report

Los hamartomas hipotalámicos son malformaciones no neoplásicas de sustancia gris compuestas por neuronas hiperplásicas. Suelen ser lesiones pequenas localizadas en la base del cerebro, en el piso del tercer ventrículo y, generalmente, asintomáticas. Sin embargo, pueden ocurrir con alteraciones conductuales-cognitivas, crisis epilépticas y/o signos de pubertad precoz central en función de la localización en la que se encuentren. Se presentan dos pacientes de 2 años 8 meses y 7 años, con presencia de hamartomas hipotalámicos diagnosticados tras el estudio de pubertad precoz central. La paciente de menor edad presenta, además, crisis gelásticas, típicamente asociadas a hamartomas hipotalámicos. Tras los hallazgos clínicos y radiológicos, se trataron con análogos de gonadotropinas, y se observó una regresión de los signos puberales y una no progresión del tamano de los hamartomas.

Hypothalamic hamartomas are benign tumors of gray substance composed by hyperplasic neurons. They are usually asymptomatic small masses with extensions into the third ventricular cavity. In some instances they can cause cognitive behavioral alterations, seizures and/or central precocious puberty depending on the location. Here we present two cases of central precocious puberty due to hypothalamic hamartomas at 2(8/12) and 7 years of age. The younger patient also presents gelastic seizures, typically associated with hypothalamic hamartomas. After the clinical and radiological findings, they started treatment with GnRH analogues and a regression of the puberty signs without progression in the hamartomas size was observed.

Impacto da ativação da intenção na prática da atividade física em diabéticos tipo II: ensaio clínico randomizado / Impact of the activation of intention to perform physical activity in type II diabetics: a randomized clinical trial

O diabetes mellitus, tipo II, é uma doença com alta prevalência na população adulta brasileira e que pode ser controlada, dentre outras intervenções, por meio da atividade física. Este estudo teve como objetivo avaliar o impacto de uma estratégia motivacional tradicional, bem como sua associação à estratégia de ativação da intenção, na adesão à atividade física, nos portadores do diabetes mellitus, tipo II, usuários do Sistema Único de Saúde (SUS), por meio de um ensaio clínico randomizado. Os participantes foram alocados em Grupo Controle (GC) e Grupo Intervenção (GI). Ambos os grupos receberam uma estratégia motivacional tradicional, porém, somente o GI recebeu a estratégia de ativação da intenção. Após dois meses de seguimento, observaram-se diferenças estatisticamente significativas entre os grupos, relativas à prática de caminhada (p = 0,0050), número de dias por semana (p = 0,0076), minutos por dia (p = 0,0050) e minutos por semana (p = 0,0015) de caminhada. Ao final das intervenções, observaram-se, também, diferenças na circunferência abdominal (p = 0,0048) entre os grupos. Conclui-se que a estratégia de ativação da intenção teve maior impacto na adesão à prática de atividade física e diminuição da circunferência abdominal de diabéticos, tipo II, do que a estratégia motivacional tradicional.

Type II diabetes mellitus is a highly prevalent disease among the adult Brazilian population, and one that can be controlled by interventions such as physical activity, among others. The aim of this randomized controlled study was to evaluate the impact of a traditional motivational strategy, associated with the activation of intention theory, on adherence to physical activity in patients with type II, diabetes mellitus who are part of the Unified Health System (SUS). Participants were divided into a control group (CG) and an intervention group (IG). In both groups, the traditional motivational strategy was applied, but the activation of intention strategy was only applied to the IG Group. After a two-month follow-up, statistically significant differences were verified between the groups, related to the practice of walking (p = 0.0050), number of days per week (p = 0.0076), minutes per day (p = 0.0050) and minutes walking per week (p = 0.0015). At the end of the intervention, statistically significant differences in abdominal circumference (p = 0.0048) between the groups were observed. The conclusion drawn is that the activation of intention strategy had greater impact on adherence to physical activity and reduction in abdominal circumference in type II diabetics, than traditional motivational strategy.

Telarquia precoz en la niñez: causas y estudio / Premature thelarche in childhood: causes and study

Se define Telarquía Precoz como la aparición del botón mamario antes de los ocho años en ausencia de otros signos de pubertad. En los primeros años de vida puede ser secundaria al fenómeno de la minipubertad, mientras que en la etapa escolar podría ocurrir debido a la interacción entre disruptores endocrinológicos y la obesidad. Una parte importante se mantiene estacionaria o revierte, mientras que un pequeño porcentaje puede evolucionar hacia la pubertad precoz. Se debe realizar una anamnesis y examen físico adecuado buscando otros signos puberales, una buena curva de crecimiento y puede complementarse con imágenes y con un seguimiento para intentar determinar aquellas pacientes que evolucionarán hacia la pubertad precoz.

Premature thelarche is defined as the breast bud appearance before eight years, without other signs of puberty development. During the first years of life it can be secondary to the minipuberty phenomenon, while during school period it's usually secondary to the interaction between endocrine disruptors and obesity. Although most of cases remain stable or regresses, a small percentage can evolve to precocious puberty. An appropriate clinical history and physical exam looking for other signs of precocious puberty must be held, complemented with the correspondent follow up and images studies, in order to diagnose patients that will evolve to precocious puberty.

Avanços na etiologia, no diagnóstico e no tratamento da puberdade precoce central / Advances in the etiology, diagnosis and treatment of central precocious puberty

O início da puberdade caracteriza-se pelo aumento de amplitude e frequência dos pulsos do hormônio secretor de gonadotrofinas (GnRH) após um período de relativa supressão hormonal durante a infância. A reemergência da secreção pulsátil do GnRH resulta em aumento na secreção de gonadotrofinas, hormônio luteinizante (LH) e folículo estimulante (FSH), pela hipófise anterior e consequente ativação gonadal. A ativação prematura do eixo hipotálamo-hipófise-gonadal resulta em puberdade precoce dependente de gonadotrofinas, também conhecida como puberdade precoce central (PPC), e se caracteriza pelo desenvolvimento dos caracteres sexuais secundários antes dos 8 anos nas meninas e 9 anos nos meninos. O início do desenvolvimento puberal provém da interação complexa de fatores genéticos, nutricionais, ambientais e socioeconômicos. O diagnóstico clínico da PPC baseia-se em reconhecimento de desenvolvimento puberal progressivo, concentrações púberes de LH em condição basal e/ou após estímulo com GnRH e avanço de idade óssea. A ressonância magnética de encéfalo é útil no estabelecimento de diagnóstico diferencial entre as formas orgânica ou idiopática. Os análogos de GnRH de ação prolongada representam o tratamento de escolha da PPC. O componente genético da PPC foi recentemente fortalecido pela evidência de mutações no gene MKRN3, localizado no braço longo do cromossomo 15, em crianças com PPC familial. Nessa revisão, dados clínicos e terapêuticos da PPC serão amplamente discutidos, visando à atualização e à conduta criteriosa dessa condição clínica de grande relevância na endocrinologia pediátrica.

The onset of puberty is first detected as an increase in the amplitude and frequency of pulses of gonadotropin-releasing hormone (GnRH) after a quiescent period during childhood. The reemergence of pulsatile GnRH secretion leads to increases in the secretion of the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) by the pituitary gland, and the consequent activation of gonadal function. Early activation of the hypothalamic–pituitary–gonadal axis results in gonadotropin-dependent precocious puberty, also known as central precocious puberty (CPP), which is clinically defined by the development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys. Pubertal timing is influenced by complex interactions among genetic, nutritional, environmental, and socioeconomic factors. CPP is diagnosed on the basis of clinical signs of progressive pubertal development before the age of 8 years in girls and 9 years in boys, pubertal basal and/or GnRH-stimulated LH levels, and advanced bone age. Magnetic resonance imaging of the central nervous system is essential for establishing the CPP form as organic or idiopathic. Depot GnRH-analogues represent the first-line of therapy in CPP. Very recently, the genetic component of CPP was demonstrated by the evidence that the deficiency of the MKRN3 gene, located on long arm of chromosome 15, causes familial CPP in humans. In this current review, clinical and therapeutic aspects of the CPP will be discussed, contributing to adequate diagnosis and criterious approach of this relevant condition of pediatric endocrinology.

Puberdade precoce central como única manifestação de cisto aracnoide supraselar / Central precocious puberty as a sole manifestation of suprasellar arachnoid cyst

OBJETIVO: Os cistos aracnoides são achados raros. Em 10 por cento dos casos, sua localização é supraselar e ocorrem quase exclusivamente em crianças. Em geral, apresentam manifestações neurológicas e visuais, sendo incomum a puberdade precoce central como sinal clínico de sua presença. DESCRIÇÃO DO CASO: Menina avaliada aos dois anos e sete meses por telarca iniciada com um ano e oito meses e pubarca e axilarca com dois anos, com aumento da velocidade de crescimento (13cm/ano) e da idade óssea (sete anos e um mês). Ao exame, apresentou peso de 22,6kg (Z+4,0), estatura de 106cm (Z+3,5) e Tanner de M3P2. Exames realizados: teste de estímulo com GnRH (LH basal 8,3 UI/L, pico aos 30 minutos 94,3 UI/L; FSH basal=10,1 UI/L, pico aos 30 minutos 29,5 UI/L), ressonância nuclear magnética de crânio com cisto aracnoide supraselar e demais testes de função hipofisária normais. Foi iniciado tratamento com análogo de GnRH. Atualmente, aos quatro anos e três meses com estadio puberal M3P2, velocidade de crescimento e desenvolvimento neuropsicomotor normais para a idade. COMENTÁRIOS: A puberdade precoce central pode ser manifestação única de um cisto aracnoide, sendo essenciais o diagnóstico e o tratamento precoces, além de seguimento prolongado, uma vez que outras disfunções hipofisárias podem ocorrer tardiamente.

OBJECTIVE: Arachnoid cysts (AC) are a rare finding; 10 percent of them are suprasellar and occur almost exclusively in children. They are frequently associated with neurological and visual manifestations. Central precocious puberty as a sole manifestation is uncommon. CASE DESCRIPTION: Girl evaluated at the age of two years and seven months. She started breast development at the age of one year and eight months, pubic and axillary hair at the age of two years, with growth velocity acceleration (13cm/year) and increased bone age (seven years and one month). On exam: weight: 22.6kg (Z+4.0), height: 106cm (Z+3.5) and puberal stage of B3P2. The GnRH stimulus test was performed (basal LH 8.3 IU/L, at 30 minutes 94.3 IU/L; FSH basal=10.1 IU/L, at 30 minutes 29.5 IU/L). Nuclear Magnetic Resonance of the skull showed a suprasellar arachnoid cyst. Others stimulation tests were performed and excluded pituitary deficiencies. Treatment with a GnRH analog was started. At the age of four years and three months, she was B3P2, with normal growth velocity and neurologic development. COMMENTS: Central precocious puberty can be the only manifestation of AC. It is essential to establish early diagnosis and treatment. A prolonged follow up is recommended, since late pituitary dysfunctions can occur.

Pubarquia precoz: Experiencia en 173 casos / Precocious pubarche: Experience in 173 cases

Background: Precocious pubarche (PP), defined as the development of sexual pubic hair before 8 years of age in females and before 9 years in males, is usually a benign condition but it can also be the first sign of an underlying disease. Aim: To analyze the etiology andperform a short term follow up in a cohort of patients with PP. Material and methods: A group of 173 patients (158 females) consulted for PP with a mean age of 7.4±0.1 years. These patients were followed between 15 to 60 months. Anthropometric measurements, bone age, serum levels of total testosterone, 17 OH progesterone (17 OHP) and dehydroepiandrosterone sulphate (DHEAS) were evaluated. Results: Mean birth weight and length was 3024.1±50.5 g and 48.5±0.3 cm,respectively. Ten percent of children were small for gestational age at birth. Bone age was accelerated by 1.1±0.01 years. One hundred and twelve patients were classified as having idiopathicPP (64.7%; 105 females), 29 as central precocious puberty (16.8%; only females), 16 as exaggerated adrenarche (EA 9.2%; 13 females) and 16 as non classical adrenal hyperplasia (9.2%; 11 females). Conclusions: PP represents a common and usually benign sign. However, 26% of cases had apathologic underlying condition. Therefore, all children with PP should be evaluated by a pediatric endocrinologist. Low birth weight was not frequent in this cohort and these patients did not show EA

Update on the etiology, diagnosis and therapeutic management of sexual precocity: [review]

Precocious puberty is defined as the development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys. Gonadotropin-dependent precocious puberty (GDPP) results from the premature activation of the hypothalamic-pituitary-gonadal axis and mimics the physiological pubertal development, although at an inadequate chronological age. Hormonal evaluation, mainly through basal and GnRH-stimulated LH levels shows activation of the gonadotropic axis. Gonadotropin-independent precocious puberty (GIPP) is the result of the secretion of sex steroids, independently from the activation of the gonadotropic axis. Several genetic causes, including constitutive activating mutations in the human LH-receptor gene and activating mutations in the Gs protein a-subunit gene are described as the etiology of testotoxicosis and McCune-Albright syndrome, respectively. The differential diagnosis between GDPP and GIPP has direct implications on the therapeutic option. Long-acting gonadotropin-releasing hormone (GnRH) analogs are the treatment of choice in GDPP. The treatment monitoring is carried out by clinical examination, hormonal evaluation measurements and image studies. For treatment of GIPP, drugs that act by blocking the action of sex steroids on their specific receptors (cyproterone, tamoxifen) or through their synthesis (ketoconazole, medroxyprogesterone, aromatase inhibitors) are used. In addition, variants of the normal pubertal development include isolated forms of precocious thelarche, precocious pubarche and precocious menarche. Here, we provide an update on the etiology, diagnosis and management of sexual precocity.

A puberdade precoce é definida como o desenvolvimento dos caracteres sexuais secundários antes dos 8 anos nas meninas e dos 9 anos nos meninos. A puberdade precoce dependente de gonadotrofinas (PPDG) resulta da ativação prematura do eixo hipotálamo-hipófise-gonadal e mimetiza o desenvolvimento puberal fisiológico, embora em idade cronológica inadequada. A avaliação hormonal, principalmente os valores de LH basal e após estímulo com GnRH exógeno confirmam a ativação do eixo gonadotrófico. A puberdade precoce independente de gonadotrofinas (PPIG) é o resultado da secreção de esteróides sexuais independentemente da ativação do eixo gonadotrófico. Diversas causas genéticas, incluindo mutações ativadoras constitutivas no gene do receptor do LH humano e mutações ativadoras no gene da subunidade a da proteína G representam as etiologias da testotoxicose e da síndrome de McCune Albright, respectivamente. O diagnóstico diferencial entre PPDG e PPIG tem implicação direta na opção terapêutica. Análogos de GnRH de ação prolongada é o tratamento de escolha da PPDG. A monitorização do tratamento da PPDG é realizada pelo exame clínico, avaliação hormonal e exames de imagem. Para o tratamento da PPIG, são usadas drogas que bloqueiam a ação dos esteróides sexuais nos seus receptores específicos (ciproterona, tamoxifeno) ou bloqueiam a sua síntese (cetoconazol, medroxiprogesterona e inibidores da aromatase). Variantes do desenvolvimento puberal normal incluem as formas isoladas de telarca, pubarca e menarca precoces. Nesta revisão, atualizamos a etiologia, o diagnóstico e tratamento da precocidade sexual.