Contribution of Dynamic and Genetic Tests for Short Stature Diagnosing: A Case Report

Genetics; Macimorelin; Short statureGenètica; Macimorelina; Baixa estaturaGenética; Macimorelina; Baja estaturaGenetic tests have led to the discovery of many novel genetic variants related to growth failure, but the clinical significance of some results is not always easy to establish. The aim of this report is to describe both clinical phenotype and genetic characteristics in an adult patient with short stature associated with a homozygous variant in disintegrin and metalloproteinase with thrombospondin motifs type 17 gene (ADAMTS17) combined with a homozygous variant in the GH secretagogue receptor (GHS-R). The index case had severe short stature (SS) (−3.0 SD), small hands and feet, associated with eye disturbances. Genetic tests revealed homozygous compounds for ADAMTS17 responsible for Weill–Marchesani-like syndrome but a homozygous variant in GHS-R was also detected. Dynamic stimulation with an insulin tolerance test showed a normal elevation of GH, while the GH response to macimorelin stimulus was totally flattened. We show the implication of the GHS-R variant and review the molecular mechanisms of both entities. These results allowed us to better interpret the phenotypic spectrum, associated co-morbidities, its implications in dynamic tests, genetic counselling and treatment options not only to the index case but also for her relatives

Guía clínica de atención a menores transexuales, transgéneros y de género diverso

Transgénero; Terapia hormonal cruzada; Identidad de géneroTransgender; Hormone cross therapy; Gender identityTransgènere; Teràpia hormonal creuada; Identitat de gènereSome people, including minors, have a gender identity that does not correspond to the sex assigned at birth. They are known as trans* people, which is an umbrella term that encompasses transgender, transsexual, and other identities not conforming to the assigned gender. Healthcare units for trans* minors require multidisciplinary working, undertaken by personnel expert in gender identity, enabling, when requested, interventions for the minor and their social–familial environment, in an individualized and flexible way during the gender affirmation path. This service model also includes hormonal treatments tailored as much as possible to the individual's needs, beyond the dichotomic goals of a traditional binary model. This guide addresses the general aspects of professional care of trans* minors and presents the current evidence-based protocol of hormonal treatments for trans* and non-binary adolescents. In addition, it details key aspects related to expected body changes and their possible side effects, as well as prior counselling about fertility preservation.Algunas personas, también las menores de edad, tienen una identidad de género que no se corresponde con el sexo asignado al nacer. Se les conoce como personas trans*, que es el término paraguas que engloba transgénero, transexual y otras identidades no conformes con el género asignado. Las unidades de asistencia sanitaria a menores trans* requieren un trabajo multidisciplinario, realizado por personal experto en identidad de género, que permita, cuando así lo soliciten, intervenciones para el menor y su entorno sociofamiliar, de forma individualizada y flexible durante el camino de afirmación de género. Este modelo de servicio también incluye tratamientos hormonales adaptados en la medida de lo posible a las necesidades del individuo, más allá de los objetivos dicotómicos de un modelo binario tradicional. Esta guía aborda los aspectos generales de la atención profesional de menores trans* y presenta el protocolo actual basado en evidencia de tratamientos hormonales para adolescentes trans* y no binarios. Además, detalla aspectos clave relacionados con los cambios corporales esperados y sus posibles efectos secundarios, así como el asesoramiento previo sobre preservación de la fertilidad

Thyroid Function in 509 Premature Newborns Below 31 Weeks of Gestational Age : Evaluation and Follow-up

Preterm and low birth weight (LBW) neonates may present with thyroid dysfunction during a critical period for neurodevelopment. These alterations can be missed on routine congenital hypothyroidism (CH) screening which only measures thyroid stimulating hormone (TSH). The objective of this study was to evaluate a protocol for thyroid function screening (TFS) six years after national implementation. Serum TSH and free thyroxine (fT4) were measured during the second week of life in neonates below 31 weeks. Patients with abnormal TFS (fT4 5 mU/L) were followed up with repeated tests until normal levels were reported. Patients who were still on levothyroxine (LT4) at three years of age were re-evaluated. Five-hundred and nine neonates were included. Thyroid dysfunction was detected in 170 neonates (33%); CH n=20 (3.9%) including typical CH n=1; delayed TSH elevation CH n=19; hypothyroxinemia of prematurity (HOP) n=15 (2.9%); and transient hyperthyrotropinemia n=135 (26.5%). Twenty-one neonates (4.1%) were treated (20 for CH and 1 for HOP). At 3-year follow-up only three patients were diagnosed with permanent CH and still need treatment. LBW infants tended to have TSH levels higher than those with adequate weight. This protocol was able to detect thyroid dysfunction in preterm neonates who were not identified by the current program based on TSH determination in whole-blood. This thyroid dysfunction seems to resolve spontaneously in a few months in the great majority of neonates, but in some cases LT4 could be needed. There is a critical need for specific guidelines regarding the follow-up and re-evaluation of transient CH in preterm neonates

Patient with adrenal insufficiency due to a de novo mutation in the NR0B1 gene

Adrenal insufficiency; Congenital adrenal hypoplasiaInsuficiència suprarenal; Hipoplàsia suprarenal congènitaInsuficiencia suprarrenal; Hipoplasia suprarrenal congénitaObjectives Congenital X-linked adrenal hypoplasia is a rare disease with a known genetic basis characterized by adrenal insufficiency, hypogonadotropic hypogonadism, and a wide variety of clinical manifestations. Case presentation We present the case of a 26-day old male newborn with symptoms consistent with adrenal insufficiency, hyponatremia, and hyperkalemia. Following NaCl and fludrocortisone supplementation, the patient remained clinically stable. 17-OH-progesterone testing excluded congenital adrenal hyperplasia. The rest of hormones were within normal limits, except for adrenocorticotropic hormone (ACTH), which was significantly elevated, and aldosterone, which was below the reference value. Further testing included very long chain fatty acids to exclude adrenoleukodystrophy, the CYP11B2 gene (aldosterone synthase), and an MRI to screen for other morphological abnormalities. All tests yielded normal results. Finally, after cortisol deficiency was detected, expanded genetic testing revealed a mutation in the NR0B1 gene, which led to a diagnosis of congenital adrenal hypoplasia. Conclusions Diagnosis of congenital adrenal hypoplasia is challenging due to the heterogeneity of both clinical manifestations and laboratory abnormalities. As a result, diagnosis requires close monitoring and genetic testing

Successful use of cinacalcet to treat parathyroid-related hypercalcemia in two pediatric patients

Summary Two pediatric patients with different causes of hyperparathyroidism are reported. First patient is a 13-year-old male with severe hypercalcemia due to left upper parathyroid gland adenoma. After successful surgery, calcium and phosphate levels normalized, but parathormone levels remained elevated. Further studies revealed a second adenoma in the right gland. The second patient is a 13-year-old female with uncommon hypercalcemia symptoms. Presence of pathogenic calcium-sensing receptor gene (CASR) mutation was found, resulting in diagnosis of symptomatic familial hypocalciuric hypercalcemia. Cinacalcet, a calcium-sensing agent that increases the sensitivity of the CASR, was used in both patients with successful results. Learning points: Hyperparathyroidism is a rare condition in pediatric patients. If not treated, it can cause serious morbidity. Genetic tests searching for CASR or MEN1 gene mutations in pediatric patients with primary hyperparathyroidism should be performed. Cinacalcet has been effective for treating different causes of hyperparathyroidism in our two pediatric patients. Treatment has been well tolerated and no side effects have been detected. </jats:sec

Genetic and Functional Studies of Patients with Thyroid Dyshormonogenesis and Defects in the TSH Receptor (TSHR)

Congenital hypothyroidism; Genetic variants; Thyroid dyshormonogenesisHipotiroïdisme congènit; Variants genètiques; Dishormonogènesi tiroideaHipotiroidismo congénito; Variantes genéticas; Dishormonogénesis tiroideaGenetic defects in the TSH receptor (TSHR) can cause poor thyroid differentiation (thyroid dysgenesis) and/or thyroid malfunction (thyroid dyshormonogenesis). The phenotype spectrum is wide: from severe congenital hypothyroidism to mild hyperthyrotropinemia. Over 250 TSHR variants have been published, many uncharacterized in vitro. We aimed to genetically characterize patients with thyroid dyshormonogenesis with TSHR defects and to study in vitro the effect of the genetic variants to establish the genotype-phenotype relationship. Pediatric patients with thyroid dyshormonogenesis (160 patients, Catalan CH neonatal screening program, confirmation TSH range: 18.4-100 mIU/L), were analyzed by a high-throughput gene panel. In vitro studies measuring the TSH-dependent cAMP-response-element activation were performed. Five patients with mild or severe thyroid dyshormonogenesis presented six TSHR variants, two unpublished. Each variant showed a different in vitro functional profile that was totally or partially deleterious. Depending on the genotype, some of the variants showed partial deficiency in both genotypes, whereas others presented a different effect. In conclusion, the percentage of patients with thyroid dyshormonogenesis and candidate variants in TSHR is 3.13%. Our in vitro studies contributed to the confirmation of the pathogenicity of the variants and highlighted the importance of studying the effect of the patient's genotype for a correct diagnostic confirmation.This research was supported by the Instituto de Salud Carlos III (www.isciii.es/, accessed on 2 August 2023; Madrid, Spain) Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, http://www.ciberer.es/, accessed on 2 August 2023) U-712 to N.B.-R., M.F.-C. and N.C.-T

Crecimiento en pacientes nacidos Pequeños para Edad Gestacional sin crecimiento recuperador tratados con hormona de crecimiento desde edad prepuberal hasta talla adulta

Los nacidos Pequeños para Edad Gestacional (PEG) sin crecimiento recuperador son tributarios de recibir tratamiento con hormona de crecimiento (GH), que les permite alcanzar una talla adulta superior a menos de 2 desviaciones estándar (DE). Los objetivos del estudio son evaluar la evolución y la ganancia de talla, comparar el desarrollo puberal con la población de referencia [Estudios Españoles de Crecimiento 2010 (EEC 2010)], evaluar la variabilidad de la respuesta al tratamiento y las alteraciones en el perfil metabólico. Pacientes y métodos: Estudio descriptivo, longitudinal, observacional, retrospectivo y multicéntrico. Inicio de GH al menos 2 años antes del inicio de la pubertad. Dosis media 30 mcg/kg/día. Inicio de la pubertad definido por el incremento de la velocidad de crecimiento. Cohorte de 95 pacientes (64 varones y 31 mujeres), 21% prematuros. Peso y longitud medios al nacimiento de -1.9±0.8DE y -2.5±0.8DE, respectivamente. 78 pacientes alcanzaron talla adulta. Resultados: La edad de inicio del tratamiento fue de 6.98±2.15 años en niños y 5.94±1.74 años en niñas. Los niños recibieron tratamiento durante una media de 8.34 años y las niñas 7.81 años. La pubertad se inició a una edad media de 12.03 años en los niños y 10.17 años en las niñas. Edad media de la menarquía fue a los 13.04 años. La talla media al inicio del tratamiento fue -3.35DE, al inicio pubertad -1.78DE y a talla adulta -1.73DE. La ganancia de talla más importante fue durante el periodo prepuberal (+1.60DE). No hubo diferencias en la ganancia de talla adulta entre los pacientes clasificados según antecedente de prematuridad, según afectación de peso, longitud o ambos al nacimiento, según la respuesta a los test de estimulación de GH ni según el haber realizado discontinuación del tratamiento. Los pacientes PEG iniciaron la pubertad a la misma edad y tuvieron una distribución en los grupos maduradores igual que EEC 2010. Los PEG iniciaron la pubertad con una talla media inferior, y alcanzaron una talla adulta inferior respecto a EEC 2010. La ganancia puberal total de talla fue inferior en los PEG. Según la ganancia individual de talla desde el inicio del tratamiento hasta talla adulta, los pacientes se distribuyeron en cinco grupos: 1:0,5e≤1DE (13%), 3:>1e≤2DE (39%), 4:>2e≤3DE (26%),5:>3DE (9%). En los grupos 1, 2 y 3 se identifican tres patrones: A)mala respuesta desde el primer año de tratamiento, B)pérdida de talla durante pubertad, C)pérdida de talla desde finalización del tratamiento hasta talla adulta. La ganancia de talla adulta se correlacionó negativamente con el peso al inicio del tratamiento (R2=0.225) y positivamente con la velocidad de crecimiento durante el primer año de tratamiento (R2=0.225). Se observó un aumento progresivo de los valores de IGF-1 durante el tratamiento, para posteriormente mantenerse dentro de los límites normales y aumento de glucosa plasmática en ayunas en el periodo puberal y al finalizar tratamiento. No hubo alteraciones en el perfil lipídico. Conclusiones: Los PEG sin crecimiento recuperador tratados con GH alcanzaron una talla adulta superior a menos de 2DE. La mayor ganancia de talla fue durante la fase prepuberal. La edad de inicio de la pubertad y la distribución en los grupos maduradores fueron similares a la población de referencia. La respuesta al tratamiento con GH fue variable e individualizable. La ganancia de talla adulta se correlacionó negativamente con el peso al inicio del tratamiento y positivamente con la velocidad de crecimiento durante el primer año de tratamiento. Los tests de secreción de GH no predijeron mejor respuesta al tratamiento. El tratamiento con GH no comportó alteraciones en el perfil metabólico.Children born Small for Gestational Age (SGA) without catch-up growth can be treated with growth hormone (GH), which allows them to reach an adult height less than 2 standard deviations (SD). The aims of this study were to assess the long-term growth and the pubertal development compared to the reference population [Spanish Growth Studies 2010 (SGS 2010)], to evaluate the variability of the response to GH therapy, and to report changes in the metabolic profile. Patients and Methods: descriptive, longitudinal, observational, retrospective, multicenter study. GH was started at least 2 years before the onset of puberty. Mean daily GH dose was 30 mcg /kg/day. Onset of puberty was defined by an increase in growth velocity. There was a cohort of 95 patients (64 boys and 31 girls), 21% of them were preterm babies. Mean weight and length at birth were -1.9±0.8SD and -2.5±0.8SD, respectively. 78 patients reached adult-height. Results: Chronological age at the start of GH therapy was 6.98±2.1 years for boys and 5.94±1.74 for girls. Boys were treated for a mean of 8.34 years and girls for 7.81 years. Puberty onset was at mean age of 12.03 years for boys and 10.17 years for girls. Mean age of menarche was 13.04 years. Height-SD at start of GH therapy was -3.35SD, at pubertal growth spurt onset was -1.78SD and at adult-height was -1.73SD. The most important gain height was during the prepubertal period (+ 1.60SD). No differences at adult height gain were found among patients classified by being preterm, by being light, short or both at birth, by their response to GH stimulation test or by having had treatment discontinuation. Puberty onset of SGA patients and classification in their own growth standards were similar to the SGS 2010. SGA were shorter at puberty onset and also at adult-height compared to SGS 2010. Total pubertal height gain was lower in SGA. Depending on the individual height gain from the start of treatment until adult-height, patients were divided into five groups: 1: 0.5 andn≤1SD (13%), 3:>1 and ≤2SD (39%), 4:>2 and ≤3SD (26%), 5:>3SD (9%). Three growth patterns were identified in groups 1, 2 and 3: A) poor response from the beginning of the treatment, B) height loss during puberty, C) height loss from the end of treatment to adult-height. Adult height gain was negatively correlated with weight at baseline (R2= 0.225) and positively with growth velocity during the first year of treatment (R2= 0.225). There was a progressive increase of IGF-1 values during treatment that remained at the normal range afterwards. Increased fast plasmatic glucose levels were observed at puberty and at the end of treatment and no changes in lipid profile were reported. Conclusions: SGA without catch-up growth with GH therapy reached an adult height less than 2 SD. The greatest height gain was during the prepubertal period. Puberty onset of the SGA patients and classification in their own growth standards were similar to the reference population. Response to GH therapy is variable and should be individualized. Adult-height gain was negatively correlated with growth velocity during the first year of treatment. GH release after stimuli does not predict better response to GH therapy. No changes in the metabolic profile were reported

Crecimiento en pacientes nacidos Pequeños para Edad Gestacional sin crecimiento recuperador tratados con hormona de crecimiento desde edad prepuberal hasta talla adulta /

Los nacidos Pequeños para Edad Gestacional (PEG) sin crecimiento recuperador son tributarios de recibir tratamiento con hormona de crecimiento (GH), que les permite alcanzar una talla adulta superior a menos de 2 desviaciones estándar (DE). Los objetivos del estudio son evaluar la evolución y la ganancia de talla, comparar el desarrollo puberal con la población de referencia [Estudios Españoles de Crecimiento 2010 (EEC 2010)], evaluar la variabilidad de la respuesta al tratamiento y las alteraciones en el perfil metabólico. Pacientes y métodos: Estudio descriptivo, longitudinal, observacional, retrospectivo y multicéntrico. Inicio de GH al menos 2 años antes del inicio de la pubertad. Dosis media 30 mcg/kg/día. Inicio de la pubertad definido por el incremento de la velocidad de crecimiento. Cohorte de 95 pacientes (64 varones y 31 mujeres), 21% prematuros. Peso y longitud medios al nacimiento de -1.9±0.8DE y -2.5±0.8DE, respectivamente. 78 pacientes alcanzaron talla adulta. Resultados: La edad de inicio del tratamiento fue de 6.98±2.15 años en niños y 5.94±1.74 años en niñas. Los niños recibieron tratamiento durante una media de 8.34 años y las niñas 7.81 años. La pubertad se inició a una edad media de 12.03 años en los niños y 10.17 años en las niñas. Edad media de la menarquía fue a los 13.04 años. La talla media al inicio del tratamiento fue -3.35DE, al inicio pubertad -1.78DE y a talla adulta -1.73DE. La ganancia de talla más importante fue durante el periodo prepuberal (+1.60DE). No hubo diferencias en la ganancia de talla adulta entre los pacientes clasificados según antecedente de prematuridad, según afectación de peso, longitud o ambos al nacimiento, según la respuesta a los test de estimulación de GH ni según el haber realizado discontinuación del tratamiento. Los pacientes PEG iniciaron la pubertad a la misma edad y tuvieron una distribución en los grupos maduradores igual que EEC 2010. Los PEG iniciaron la pubertad con una talla media inferior, y alcanzaron una talla adulta inferior respecto a EEC 2010. La ganancia puberal total de talla fue inferior en los PEG. Según la ganancia individual de talla desde el inicio del tratamiento hasta talla adulta, los pacientes se distribuyeron en cinco grupos: 1: 0.5DE (13%), 2:>0,5e≤1DE (13%), 3:>1e≤2DE (39%), 4:>2e≤3DE (26%),5:>3DE (9%). En los grupos 1, 2 y 3 se identifican tres patrones: A)mala respuesta desde el primer año de tratamiento, B)pérdida de talla durante pubertad, C)pérdida de talla desde finalización del tratamiento hasta talla adulta. La ganancia de talla adulta se correlacionó negativamente con el peso al inicio del tratamiento (R2=0.225) y positivamente con la velocidad de crecimiento durante el primer año de tratamiento (R2=0.225). Se observó un aumento progresivo de los valores de IGF-1 durante el tratamiento, para posteriormente mantenerse dentro de los límites normales y aumento de glucosa plasmática en ayunas en el periodo puberal y al finalizar tratamiento. No hubo alteraciones en el perfil lipídico. Conclusiones: Los PEG sin crecimiento recuperador tratados con GH alcanzaron una talla adulta superior a menos de 2DE. La mayor ganancia de talla fue durante la fase prepuberal. La edad de inicio de la pubertad y la distribución en los grupos maduradores fueron similares a la población de referencia. La respuesta al tratamiento con GH fue variable e individualizable. La ganancia de talla adulta se correlacionó negativamente con el peso al inicio del tratamiento y positivamente con la velocidad de crecimiento durante el primer año de tratamiento. Los tests de secreción de GH no predijeron mejor respuesta al tratamiento. El tratamiento con GH no comportó alteraciones en el perfil metabólico

Growth Hormone Treatment and Papilledema : A Prospective Pilot Study

To investigate the incidence of pseudotumor cerebri syndrome (PTCS) in children treated with growth hormone (GH) in a paediatric hospital and to identify risk factors for this complication. Prospective pilot study of paediatric patients treated with recombinant human GH, prescribed by the Paediatric Endocrinology Department, between February 2013 and September 2017. In all these patients, a fundus examination was performed before starting treatment and 3-4 months later. Two hundred and eighty-nine patients were included, of whom 244 (84.4%) had GH deficiency, 36 (12.5%) had short stature associated with small for gestational age, six (2.1%) had a mutation in the SHOX gene and three (1.0%) had Prader-Willi syndrome. Five (1.7%) developed papilledema, all were asymptomatic and had GH deficiency due to craniopharyngioma (n=1), polymalformative syndrome associated with hypothalamic-pituitary axis anomalies (n=2), a non-specified genetic disease with hippocampal inversion (n=1) and one with normal magnetic resonance imaging who had developed a primary PTCS years before. GH treatment is a cause of PTCS. In our series, at risk patients had GH deficiency and hypothalamic-pituitary anatomic anomalies or genetic or chromosomal diseases. Fundus examination should be systematically screened in all patients in this at-risk group, irrespective of the presence or not of symptoms