Diagnosing and treating anterior pituitary hormone deficiency in pediatric patients.

Hypopituitarism, or the failure to secrete hormones produced by the anterior pituitary (adenohypophysis) and/or to release hormones from the posterior pituitary (neurohypophysis), can be congenital or acquired. When more than one pituitary hormone axis is impaired, the condition is known as combined pituitary hormone deficiency (CPHD). The deficiency may be primarily due to a hypothalamic or to a pituitary disorder, or concomitantly both, and has a negative impact on target organ function. This review focuses on the pathophysiology, diagnosis and management of anterior pituitary hormone deficiency in the pediatric age. Congenital hypopituitarism is generally due to genetic disorders and requires early medical attention. Exposure to toxicants or intrauterine infections should also be considered as potential etiologies. The molecular mechanisms underlying the fetal development of the hypothalamus and the pituitary are well characterized, and variants in the genes involved therein may explain the pathophysiology of congenital hypopituitarism: mutations in the genes expressed in the earliest stages are usually associated with syndromic forms whereas variants in genes involved in later stages of pituitary development result in non-syndromic forms with more specific hormone deficiencies. Tumors or lesions of the (peri)sellar region, cranial radiation therapy, traumatic brain injury and, more rarely, other inflammatory or infectious lesions represent the etiologies of acquired hypopituitarism. Hormone replacement is the general strategy, with critical periods of postnatal life requiring specific attention.

Mutación DGAT1 en dos hermanas con falla de medro: reporte de caso / DGAT1 mutation in two sisters with failure to thrive: a case report

Las diarreas y enteropatías congénitas (CODE por su sigla en inglés) son un grupo de trastornos monogénicos que se han descrito en los últimos años. Dentro de las CODE, la mutación del gen de la diacilglicerol o-aciltransferasa 1 (DGAT1) es un trastorno enzimático poco común asociado con diarrea crónica grave de aparición temprana. El objetivo es presentar a dos hermanas que consultaron por diarrea crónica, retraso en el crecimiento, vómitos e hipoalbuminemia en la primera infancia. En ambas pacientes se encontró un compuesto heterocigota de la mutación del DGAT1. Esta mutación se describió previamente en la población asiática; sin embargo, estas son las dos primeras pacientes en tener esta mutación en la población latinoamericana. Estos dos casos pueden ampliar nuestro conocimiento sobre las diarreas congénitas en general y las características clínicas de los pacientes con mutaciones en DGAT1 en particular.

Congenital diarrhea and enteropathies (CODEs) are a group of monogenic disorders that have been described in recent years. Within the CODEs, the mutation in the diacylglycerol O-acyltransferase 1 (DGAT1) gene is a rare enzyme disorder associated with severe, early-onset chronic diarrhea. Our objective is to describe the case of 2 sisters who consulted for chronic diarrhea, growth retardation, vomiting, and hypoalbuminemia in early childhood. A compound heterozygous DGAT1 mutation was found in both patients. This mutation was previously described in the Asian population; however, these are the first 2 patients to show this mutation in the Latin American population. These 2 cases may expand our knowledge about congenital diarrhea in general and the clinical characteristics of patients with DGAT1 mutations in particular.

Canalización del crecimiento entre los 2 y los 5 años en niños aparentemente sanos con talla baja a los 2 años / Canalization of growth between 2 and 5 years of age in apparently healthy children with short stature at age 2 years

Introducción. El tamaño del recién nacido se asocia a condiciones intrauterinas. El potencial genético se expresa más tarde; la canalización del crecimiento se describe clásicamente hasta los 24 meses. Objetivo. Describir la canalización del crecimiento entre los 2 y los 5 años en niños aparentemente sanos con talla baja a los 2 años. Población y métodos. Estudio de cohorte retrospectiva. Se incluyeron niños seguidos en un hospital universitario de comunidad entre 2003 y 2019, con puntaje Z de talla menor a -2 DE para edad y sexo a los 2 años. Se excluyeron los nacidos prematuros, con bajo peso y con enfermedades crónicas. Se evaluó la trayectoria de crecimiento. Se definió canalización como la adquisición de talla normal para la población general. Resultados. Se incluyeron 64 niños, de los cuales 37 (58 %) presentaron canalización del crecimiento a los 5 años (20 a los 3 años, 8 a los 4 años, y 9 a los 5 años). La velocidad de crecimiento a los 3 y a los 5 años fue significativamente mayor en los que canalizaron en comparación con los que no lo hicieron; hubo una tendencia similar a los 4 años. De los 27 niños con talla baja a los 5 años, 25 tuvieron al menos un registro de velocidad de crecimiento anual menor al percentil 25. Conclusiones. La mayoría de los niños aparentemente sanos con baja talla a los 2 años alcanzan una talla normal a los 5 años. La velocidad de crecimiento anual permite detectar a los niños con riesgo de no canalizar.

Introduction. Newborn size is associated with intrauterine conditions. Genetic potential is expressed later; the canalization of growth is typically described up to 24 months of age. Objective. To describe the canalization of growth between 2 and 5 years of age in apparently healthy children with short stature at age 2 years. Population and methods. Retrospective, cohort study. Children seen at a community teaching hospital between 2003 and 2019, who had a Z-score for height below -2 SDs for age and sex at age 2 years were included. Infants born preterm, with a low birth weight, and chronic conditions were excluded. Growth patterns were assessed. Canalization was defined as reaching a normal stature for the general population. Results. Sixty-four children were included; 37 (58%) showed canalization of growth at 5 years old (20 at 3 years, 8 at 4 years, and 9 at 5 years). The growth rate at 3 and 5 years of age was significantly higher among those who showed canalization compared to those who did not; a similar trend was observed at 4 years of age. Among 27 children with short stature at 5 years of age, 25 had at least 1 annual growth velocity below the 25th centile. Conclusions. Most apparently healthy children with short stature at 2 years old reached a normal stature at 5 years old. The annual growth velocity allows to detect children at risk of not showing canalization.

Canalization of growth between 2 and 5 years of age in apparently healthy children with short stature at age 2 years. / Canalización del crecimiento entre los 2 y los 5 años en niños aparentemente sanos con talla baja a los 2 años.

Introduction. Newborn size is associated with intrauterine conditions. Genetic potential is expressed later; the canalization of growth is typically described up to 24 months of age. Objective. To describe the canalization of growth between 2 and 5 years of age in apparently healthy children with short stature at age 2 years. Population and methods. Retrospective, cohort study. Children seen at a community teaching hospital between 2003 and 2019, who had a Z-score for height below -2 SDs for age and sex at age 2 years were included. Infants born preterm, with a low birth weight, and chronic conditions were excluded. Growth patterns were assessed. Canalization was defined as reaching a normal stature for the general population. Results. Sixty-four children were included; 37 (58%) showed canalization of growth at 5 years old (20 at 3 years, 8 at 4 years, and 9 at 5 years). The growth rate at 3 and 5 years of age was significantly higher among those who showed canalization compared to those who did not; a similar trend was observed at 4 years of age. Among 27 children with short stature at 5 years of age, 25 had at least 1 annual growth velocity below the 25th centile. Conclusions. Most apparently healthy children with short stature at 2 years old reached a normal stature at 5 years old. The annual growth velocity allows to detect children at risk of not showing canalization.

Introducción. El tamaño del recién nacido se asocia a condiciones intrauterinas. El potencial genético se expresa más tarde; la canalización del crecimiento se describe clásicamente hasta los 24 meses. Objetivo. Describir la canalización del crecimiento entre los 2 y los 5 años en niños aparentemente sanos con talla baja a los 2 años. Población y métodos. Estudio de cohorte retrospectiva. Se incluyeron niños seguidos en un hospital universitario de comunidad entre 2003 y 2019, con puntaje Z de talla menor a -2 DE para edad y sexo a los 2 años. Se excluyeron los nacidos prematuros, con bajo peso y con enfermedades crónicas. Se evaluó la trayectoria de crecimiento. Se definió canalización como la adquisición de talla normal para la población general. Resultados. Se incluyeron 64 niños, de los cuales 37 (58 %) presentaron canalización del crecimiento a los 5 años (20 a los 3 años, 8 a los 4 años, y 9 a los 5 años). La velocidad de crecimiento a los 3 y a los 5 años fue significativamente mayor en los que canalizaron en comparación con los que no lo hicieron; hubo una tendencia similar a los 4 años. De los 27 niños con talla baja a los 5 años, 25 tuvieron al menos un registro de velocidad de crecimiento anual menor al percentil 25. Conclusiones. La mayoría de los niños aparentemente sanos con baja talla a los 2 años alcanzan una talla normal a los 5 años. La velocidad de crecimiento anual permite detectar a los niños con riesgo de no canalizar.

DGAT1 mutation in two sisters with failure to thrive: a case report. / Mutación DGAT1 en dos hermanas con falla de medro: reporte de caso.

Congenital diarrhea and enteropathies (CODEs) are a group of monogenic disorders that have been described in recent years. Within the CODEs, the mutation in the diacylglycerol O-acyltransferase 1 (DGAT1) gene is a rare enzyme disorder associated with severe, early-onset chronic diarrhea. Our objective is to describe the case of 2 sisters who consulted for chronic diarrhea, growth retardation, vomiting, and hypoalbuminemia in early childhood. A compound heterozygous DGAT1 mutation was found in both patients. This mutation was previously described in the Asian population; however, these are the first 2 patients to show this mutation in the Latin American population. These 2 cases may expand our knowledge about congenital diarrhea in general and the clinical characteristics of patients with DGAT1 mutations in particular.

Las diarreas y enteropatías congénitas (CODE por su sigla en inglés) son un grupo de trastornos monogénicos que se han descrito en los últimos años. Dentro de las CODE, la mutación del gen de la diacilglicerol o-aciltransferasa 1 (DGAT1) es un trastorno enzimático poco común asociado con diarrea crónica grave de aparición temprana. El objetivo es presentar a dos hermanas que consultaron por diarrea crónica, retraso en el crecimiento, vómitos e hipoalbuminemia en la primera infancia. En ambas pacientes se encontró un compuesto heterocigota de la mutación del DGAT1. Esta mutación se describió previamente en la población asiática; sin embargo, estas son las dos primeras pacientes en tener esta mutación en la población latinoamericana. Estos dos casos pueden ampliar nuestro conocimiento sobre las diarreas congénitas en general y las características clínicas de los pacientes con mutaciones en DGAT1 en particular.

The Role of Growth Hormone in Chronic Kidney Disease.

Growth hormone (GH) has become a critical therapy for treating growth delay and failure in pediatric chronic kidney disease. Recombinant human GH treatment is safe and significantly improves height and height velocity in these growing patients and improved growth outcomes are associated with decreased morbidity and mortality as well as improved quality of life. However, the utility of recombinant human GH in adults with chronic kidney disease and end-stage renal disease for optimization of body habitus and reducing frailty remains uncertain. Semin Nephrol 41:x-xx © 2021 Elsevier Inc. All rights reserved.

Hallazgos en la endoscopia digestiva alta en niños con talla baja / Findings of upper gastrointestinal endoscopy in children with short stature

Resumen Introducción: en el estudio de la baja talla de origen digestivo en niños no hay un patrón de paraclínicos preestablecido; sin embargo, la endoscopia de vías digestivas puede ser una herramienta útil para tal fin. Objetivo: reportar una serie de casos de niños con diagnóstico de baja talla a quienes se les indicó una endoscopia de vías digestivas altas como parte de su estudio. Reporte de casos: se incluyeron 15 niños entre los 2 y 16 años de edad, 53,3% niñas, 26,7% desnutridos según el índice de masa corporal y la talla para la edad, 66,7% con baja talla grave y 33,3% con baja talla moderada. El 53,3% presentó dolor abdominal, el 46,7% no tuvo ganancia de peso, el 26,7% tuvo inapetencia y el 13,3% tuvo vómito, entre otros. Entre el 40,0% y el 93,4% presentaron macro- o microscópicamente esofagitis, gastritis y duodenitis. Los hallazgos microscópicos más importantes fueron duodenitis crónica con giardiasis, úlceras duodenales, hiperplasia nodular linfoide duodenal, Helicobacter pylori y duodenitis crónica eosinofílica. Conclusiones: a pesar de que la endoscopia de vías digestivas es un método poco utilizado y no bien descrito en el estudio de niños con baja talla, este reporte de casos describe organicidad en un 80,0% de los niños analizados.

Abstract Introduction: The study of short stature of digestive origin in children shows no pre-established laboratory patterns. However, endoscopy of the digestive tract may be a useful tool for this purpose. Objective: To report a series of cases of children with a diagnosis of short stature who underwent upper digestive tract endoscopy as part of their study. Case report: 15 children between the ages of 2 and 16 years were included; 53.3% were girls. 26.7% presented with malnutrition according to their body mass index and height-for-age, 66.7% had short stature, and 33.3% moderate short stature. Abdominal pain was reported in 53.3% of the cases, and no weight gain in 46.7%. Other symptoms were lack of appetite in 26.7%, vomiting in 13.3%, among others. Between 40% and 93.4% of the children presented macro and/or microscopic esophagitis, gastritis, and duodenitis. The most important microscopic findings were chronic duodenitis with giardiasis, duodenal ulcers, duodenal nodular lymphoid hyperplasia, Helicobacter pylori, and chronic eosinophilic duodenitis. Conclusions: Although endoscopy of the digestive tract is a method barely used and not well described in the study of children with short stature, this case report describes organicity in 80% of the children analyzed.

Improved Outcomes for Liver Transplantation in Patients with Biliary Atresia Since Pediatric End-Stage Liver Disease Implementation: Analysis of the Society of Pediatric Liver Transplantation Registry.

OBJECTIVE: To identify changes in demographics, outcomes, and risk factors for patient and graft loss in patients with biliary atresia undergoing liver transplantation since Pediatric End-Stage Liver Disease implementation (2002). STUDY DESIGN: Demographics and outcomes were compared between patients enrolled in the Society of Pediatric Liver Transplantation registry before (n = 547) and after (n = 1477) 2002. Kruskal-and χ2 Wallis tests identified significant differences between eras. Risk factors for patient and graft loss after 2002 were determined by Cox regression model analysis of time to event data. RESULTS: Significant patient differences after 2002 support increasing disease severity including more status 1 patients and those with a derived Model for End-Stage Liver Disease/Pediatric End-Stage Liver Disease score of greater than 30 awaiting transplant. Both patient and graft survival improved after 2002 from 90% to 97% and 81% to 90%, respectively (primary transplant; P < .0001). Significant differences in complications within 30 days included reduced relisting for transplant, rejection, culture-positive infection, repeat operation, hepatic artery thrombosis, portal vein thrombosis, and death/transplant before discharge. Multivariable analysis identified deceased technical variant vs whole graft and retransplantation predictive for patient death, hazard ratios of 4.041 and 8.308, respectively. Deceased technical variant vs whole graft (hazard ratio, 1.963) and donor age 0-5 months vs 1-17 years (hazard ratio, 5.525) were risk factors for graft loss. CONCLUSIONS: The overall outcomes of patients receiving liver transplantation for patients with biliary atresia have improved since 2002 despite evidence of increased disease severity at the time of transplant. Risk factors impacting post-transplant morbidity and mortality in patients with biliary atresia are now mainly surgical including donor variables.

Development and Validation of a Prediction Rule for Growth Hormone Deficiency Without Need for Pharmacological Stimulation Tests in Children With Risk Factors.

Introduction: Practice guidelines cannot recommend establishing a diagnosis of growth hormone deficiency (GHD) without performing growth hormone stimulation tests (GHST) in children with risk factors, due to the lack of sufficient evidence. Objective: Our goal was to generate an evidence-based prediction rule to diagnose GHD in children with growth failure and clinically identifiable risk factors. Methods: We studied a cohort of children with growth failure to build the prediction model, and a second, independent cohort to validate the prediction rule. To this end, we assessed the existence of: pituitary dysgenesis, midline abnormalities, (supra)sellar tumor/surgery, CNS infection, traumatic brain injury, cranial radiotherapy, chemotherapy, genetic GHD, pituitary hormone deficiencies, and neonatal hypoglycemia, cholestasis, or hypogenitalism. Selection of variables for model building was performed using artificial intelligence protocols. Specificity of the prediction rule was the main outcome measure in the validation set. Results: In the first cohort (n=770), the resulting prediction rule stated that a patient would have GHD if (s)he had: pituitary dysgenesis, or two or more anterior pituitary deficiencies, or one anterior pituitary deficiency plus: neonatal hypoglycemia or hypogenitalism, or diabetes insipidus, or midline abnormalities, or (supra)sellar tumor/surgery, or cranial radiotherapy ≥18 Gy. In the validation cohort (n=161), the specificity of the prediction rule was 99.2% (95% CI: 95.6-100%). Conclusions: This clinical rule predicts the existence of GHD with high specificity in children with growth disorders and clinically identifiable risk factors, thus providing compelling evidence to recommend that GHD can be safely diagnosed without recurring to GHST in neonates and children with growth failure and specific comorbidities.

Linear growth and bone metabolism in pediatric patients with inflammatory bowel disease.

OBJECTIVE: To review the pathophysiology and evaluation methods of linear growth and bone mineral density in children and adolescents diagnosed with inflammatory bowel disease. SOURCE OF DATA: Narrative review carried out in the PubMed and Scopus databases through an active search of the terms: inflammatory bowel disease, growth, failure to thrive, bone health, bone mineral density, and children and adolescents, related to the last ten years, searching in the title, abstract, or keyword fields. SYNTHESIS OF FINDINGS: Inflammatory bowel diseases of childhood onset may present as part of the clinical picture of delayed linear growth in addition to low bone mineral density. The presence of a chronic inflammatory process with elevated serum levels of inflammatory cytokines negatively interferes with the growth rate and bone metabolism regulation, in addition to increasing energy expenditure, compromising nutrient absorption, and favoring intestinal protein losses. Another important factor is the chronic use of glucocorticoids, which decreases the secretion of growth hormone and the gonadotrophin pulses, causing pubertal and growth spurt delay. In addition to these effects, they inhibit the replication of osteoblastic lineage cells and stimulate osteoclastogenesis. CONCLUSION: Insufficient growth and low bone mineral density in pediatric patients with inflammatory bowel disease are complex problems that result from multiple factors including chronic inflammation, malnutrition, decreased physical activity, late puberty, genetic susceptibility, and immunosuppressive therapies, such as glucocorticoids.

Linear growth and bone metabolism in pediatric patients with inflammatory bowel disease / Crescimento linear e metabolismo ósseo em pacientes pediátricos com doença inflamatória intestinal

Abstract Objective: To review the pathophysiology and evaluation methods of linear growth and bone mineral density in children and adolescents diagnosed with inflammatory bowel disease. Source of data: Narrative review carried out in the PubMed and Scopus databases through an active search of the terms: inflammatory bowel disease, growth, failure to thrive, bone health, bone mineral density, and children and adolescents, related to the last ten years, searching in the title, abstract, or keyword fields. Synthesis of findings: Inflammatory bowel diseases of childhood onset may present as part of the clinical picture of delayed linear growth in addition to low bone mineral density. The presence of a chronic inflammatory process with elevated serum levels of inflammatory cytokines negatively interferes with the growth rate and bone metabolism regulation, in addition to increasing energy expenditure, compromising nutrient absorption, and favoring intestinal protein losses. Another important factor is the chronic use of glucocorticoids, which decreases the secretion of growth hormone and the gonadotrophin pulses, causing pubertal and growth spurt delay. In addition to these effects, they inhibit the replication of osteoblastic lineage cells and stimulate osteoclastogenesis. Conclusion: Insufficient growth and low bone mineral density in pediatric patients with inflammatory bowel disease are complex problems that result from multiple factors including chronic inflammation, malnutrition, decreased physical activity, late puberty, genetic susceptibility, and immunosuppressive therapies, such as glucocorticoids.

Resumo Objetivo: Revisar a fisiopatologia e os métodos de avaliação do crescimento linear e densidade mineral óssea em crianças e adolescentes com diagnóstico de doença inflamatória intestinal. Fontes dos dados: Revisão narrativa a partir de pesquisa nas bases de dados PubMed e Scopus por meio de busca ativa dos termos inflammatory bowel disease, growth, failure to thrive, bone health, bone mineral density, children e adolescents nos últimos dez anos e com busca nos campos título, resumo ou palavra-chave. Resumo dos achados: As doenças inflamatórias intestinais com início na infância podem apresentar como parte do quadro clínico atraso do crescimento linear, além de baixa densidade mineral óssea. A presença de processo inflamatório crônico com elevados níveis séricos das citocinas inflamatórias interfere negativamente na velocidade do crescimento e na regulação do metabolismo ósseo, além de aumentar o gasto energético, comprometer a absorção de nutrientes e favorecer perdas proteicas intestinais. Outro fator importante é o uso crônico de glicocorticoides, que diminuem a secreção de hormônio do crescimento e dos pulsos das gonadotrofinas e ocasionam atraso puberal e no estirão do crescimento. Além desses efeitos, inibem a reprodução das células da linhagem osteoblástica e estimulam a osteoclastogênese. Conclusão: A insuficiência do crescimento e a baixa densidade mineral óssea em pacientes pediátricos com doença inflamatória intestinal são problemas complexos e que decorrem de múltiplos fatores, inclusive inflamação crônica, desnutrição, diminuição da atividade física, puberdade tardia, suscetibilidade genética a terapias imunossupressoras, como os glicocorticoides.

Growth and growth hormone: An overview.

Growth is a good indicator of a child's health. Growth disturbances, including short stature or growth failure, could be indications of illnesses such as chronic disease, nutritional deficits, celiac disease or hormonal abnormalities. Therefore, a careful assessment of the various requirements for normal growth needs to be done by history, physical examination, and screening laboratory tests. More details will be reviewed about the GH-IGF axis, its abnormalities with special emphasis on GH deficiency, its diagnosis and treatment. GH treatment indications in the US will be reviewed and a few only will be highlighted. They will include GH deficiency, as well as the treatment of children born SGA, including the results of a US study using FDA approved dose of 0.48mg/kg/week. GH deficiency in adults will also be briefly reviewed. Treatment of patients with SHOX deficiency will also be discussed. Possible side effects of GH treatment and the importance of monitoring safety will be highlighted.

Assessment of environmental enteropathy in the MAL-ED cohort study: theoretical and analytic framework.

Individuals in the developing world live in conditions of intense exposure to enteric pathogens due to suboptimal water and sanitation. These environmental conditions lead to alterations in intestinal structure, function, and local and systemic immune activation that are collectively referred to as environmental enteropathy (EE). This condition, although poorly defined, is likely to be exacerbated by undernutrition as well as being responsible for permanent growth deficits acquired in early childhood, vaccine failure, and loss of human potential. This article addresses the underlying theoretical and analytical frameworks informing the methodology proposed by the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study to define and quantify the burden of disease caused by EE within a multisite cohort. Additionally, we will discuss efforts to improve, standardize, and harmonize laboratory practices within the MAL-ED Network. These efforts will address current limitations in the understanding of EE and its burden on children in the developing world.

Individualized therapy for growth hormone deficiency.

The use of human growth hormone to treat children with short stature resulting from growth hormone deficiency or insufficiency has now accrued over 40 years of clinical experience with a satisfactory safety and efficacy record. Growth hormone deficiency is the primary indication for growth hormone treatment in childhood. It is basically a clinical diagnosis, based upon auxologic features, and confirmed by biochemical testing. For assurance of compliance, dosing and, perhaps, safety considerations, a dosing algorithm based upon insulin-like growth factor-I response seems to be appropriate. Current data suggest that such algorithms reflect the true growth hormone needs of a patient, and allow optimization of growth hormone treatment. For patients who display a suboptimal growth response or in whom the insulin growth factor levels remain low with assurance of adherence to the injection schedule, it is reasonable to increase the growth hormone dose. The availability of recombinant human insulin-like growth factor-I treatment may provide an alternative for massively increasing the dose of growth hormone. Dose reductions should be considered for patients with serum insulin-like growth factor-I levels substantially above the normal range.