Performance of the ACMG-AMP criteria in a large familial renal glucosuria cohort with identified SLC5A2 sequence variants.

Familial Renal Glucosuria (FRG) is a co-dominantly inherited trait characterized by orthoglycaemic glucosuria. From 2003 to 2015 we have reported several cohorts validating SLC5A2 (16p11.2), encoding SGLT2 (Na+/glucose cotransporter family member 2), as the gene responsible for FRG. The aim of this work was to validate the variants identified in our extended FRG cohort of published, as well more recent unreported cases, according to the ACMG-AMP 2015 criteria. Forty-six variants were evaluated, including 16 novel alleles first described in this study. All are rare, ultra-rare or absent from population databases and most are missense changes. According to the ACMG-AMP standards, only 74% of the variants were classified as P/LP. The lack of descriptions of unrelated patients with similar variants or failing to test additional affected family members, averted a conclusion for pathogenicity in the alleles that scored VUS, highlighting the importance of both family testing and variant reporting. Finally, the cryo-EM structure of the hSGLT2-MAP17 complex in the empagliflozin-bound state improved the ACMG-AMP pathogenicity score by identifying critical/functional protein domains.

Bringing the Pediatric Endocrine Spanish Speaking Community Together: First Virtual Pediatric Endocrine Meeting in Low- and Middle-Income Countries in Central and South America.

BACKGROUND: Pediatric endocrinology is a specialty that is struggling worldwide to maintain adequately trained professionals. Pediatric endocrine care in Central America and Caribbean countries is often performed by pediatricians or adult endocrinologists due to the limited number of pediatric endocrinologists. These health care providers are seldom members of endocrine societies and frequently lack formal training in the field. OBJECTIVE: In this study, we describe the scope of a virtual conference in pediatric endocrinology and diabetes targeted to low- and middle-income countries to provide equal opportunities for access to medical education for health care professionals. METHODS: The virtual conference was sponsored by the Pediatric Endocrine Society (North America), Asociación Costarricense de Endocrinología (previously, Asociación Nacional Pro Estudio de la Diabetes, Endocrinología y Metabolismo), and Asociacion Centroamericana y del Caribe de Endocrinologia Pediátrica. The conference was free to participants and comprised 23 sessions that were either synchronous with ability for real-time interactive sessions or asynchronous sessions, where content was available online to access at their convenience. Topics included idiopathic short stature, polycystic ovarian syndrome, diabetes mellitus, telemedicine, Turner syndrome, congenital adrenal hyperplasia, obesity, central precocious puberty, and subclinical hypothyroidism. The participants were asked to evaluate the conference after its completion with a questionnaire. RESULTS: A total of 8 speakers from Spain, Canada, Costa Rica, and the United States delivered the virtual event to 668 health care professionals from Guatemala, Venezuela, Dominican Republic, Costa Rica, Ecuador, Peru, Uruguay, Mexico, Honduras, Argentina, the United States, Bolivia, Chile, Panama, El Salvador, Nicaragua, Paraguay, Belize, Spain, and Colombia. Name, profession, and country were fully disclosed by 410 (61.4%) of the 668 health care professionals. The profession or level of training of participants were as follows: pediatric endocrinologists (n=129, 19.3%), pediatricians (n=116, 17.4%), general practitioners (n=77, 11.5%), adult endocrinologists (n=34, 5.1%), medical students (n=23, 3.4%), residents in various specialties (n=14, 2.1%), and others (n=17, 2.6%). A total of 23 sessions were offered, most of which were bilingual (Spanish and English). Feedback from the evaluation questionnaire indicated that the content of the conference was very relevant to the participants' professional practice. Additionally, the participants reported that they were very satisfied with the organization, the web-based platform, and the sessions of the conference. CONCLUSIONS: Lack of accessibility to the latest and cutting-edge medical education in pediatric endocrinology and diabetes for medical professionals from low- and middle-income countries can be overcome with a virtual conference. Online availability, low cost, and easy-to-use technology were well received from the participants, who were overall very satisfied by the quality and the relevance of the sessions to their professional practice.

A new approach to the diagnosis of short stature.

Growth is the task of children. We review the normal process of linear growth from the fetus through adolescence and note that growth is the result of age- and gender-dependent interactions among key genetic, environmental, dietary, socioeconomic, developmental, behavioral, nutritional, metabolic, biochemical, and hormonal factors. We then define the wide range of normative data at each stage of growth and note that a pattern within this range is generally indicative of good general health and that growth significantly slower than this range may lead to growth faltering and subsequent short stature. Although not often emphasized, we detail how to properly measure infants and children because height velocity is usually determined from two height measurements (both relatively large values) to calculate the actual height velocity (a relatively much smaller number in comparison). Traditionally the physiology of growth has been taught from an endocrine-centric point-of-view. Here we review the hypothalamic-pituitary-end organ axes for the GH/IGF-1 and gonadal steroid hormones (hypothalamic-pituitary-gonadal axis), both during "mini"-puberty as well as at puberty. However, over the past few decades much more emphasis has been placed on the growth plate and its many interactions with the endocrine system but also with its own intrinsic physiology and gene mutations. These latter, whether individually (large effect size) or in combination with many others including endocrine system-based, may account in toto for meaningful differences in adult height. The clinical assessment of children with short stature includes medical, social and family history, physical exam and importantly proper interpretation of the growth curve. This analysis should lead to judicious use of screening laboratory and imaging tests depending on the pre-test probability (Bayesian inference) of a particular diagnosis in that child. In particular for those with no pathological features in the history and physical exam and a low, but normal height velocity, may lead only to a bone age exam and reevaluation (re-measurement), perhaps 6 months later. he next step depends on the comfort level of the primary care physician, the patient, and the parent; that is, whether to continue with the evaluation with more directed, more sophisticated testing, again based on Bayesian inference or to seek consultation with a subspecialist pediatrician based on the data obtained. This is not necessarily an endocrinologist. The newest area and the one most in flux is the role for genetic testing, given that growth is a complex process with large effect size for single genes but smaller effect sizes for multiple other genes which in the aggregate may be relevant to attained adult height. Genetics is a discipline that is rapidly changing, especially as the cost of exome or whole gene sequencing diminishes sharply. Within a decade it is quite likely that a genetic approach to the evaluation of children with short stature will become the standard, truncating the diagnostic odyssey and be cost effective as fewer biochemical and imaging studies are required to make a proper diagnosis.

Acylated ghrelin concentrations are markedly decreased during pregnancy in mothers with and without gestational diabetes: relationship with cholinesterase.

Acylated (octanoylated) ghrelin stimulates food intake and growth hormone secretion and is deacylated into desacyl ghrelin by butyrylcholinesterase. Acylated and desacyl ghrelin both promote adipogenesis. Ghrelin concentrations decrease with hyperglycemia and hyperinsulinism. We hypothesized that 1) acylated ghrelin increases during pregnancy, contributing positively to energy balance, but is lower in women with gestational diabetes and 2) butyrylcholinesterase activity is inversely correlated with acylated ghrelin concentrations. In a first group of subjects, using two-site sandwich ghrelin assays that specifically detect full-length forms, we investigated women with and without gestational diabetes (n = 14/group) during pregnancy and after delivery. We examined whether changes in ghrelin during a test meal were correlated with changes in pituitary growth hormone [assessed through calculation of the area under the curve (AUC) during the test meal]. In postpartum subjects, the percent of total ghrelin that is acylated was four to five times higher than previously observed using single antibody assays. During pregnancy, acylated ghrelin concentrations (mean +/- SE) were lower compared with the postpartum period throughout the meal (AUC 1.2 +/- 0.2 vs. 10.2 +/- 1.9 ng.ml(-1).90 min(-1), P < 0.001). In the postpartum, acylated ghrelin and growth hormone were positively correlated (r = 0.50, P = 0.007). Desacyl (but not acylated) ghrelin was increased in subjects with gestational diabetes during and after pregnancy (AUC 15.4 +/- 1.9 vs. 8.6 +/- 1.2 ng.ml(-1).90 min(-1), P = 0.005). In a second group of subjects (n = 13), acylated ghrelin was similarly suppressed during pregnancy. Circulating octanoate concentrations (3.1 +/- 0.5 vs. 4.5 +/- 0.6 microg/ml, P = 0.029) and cholinesterase activity (705 +/- 33 vs. 1,013 +/- 56 U/ml, P < 0.001) were lower during pregnancy compared with the postpartum period. In conclusion, acylated ghrelin markedly decreases during pregnancy, likely because of a decrease in the acylation process. Desacyl ghrelin increases in gestational diabetes, possibly reflecting resistance to the inhibitory effect of insulin on ghrelin secretion.

Growth hormone treatment and risk of recurrence or progression of brain tumors in children: a review.

INTRODUCTION: Brain tumors are one of the most common types of solid neoplasm in children. As life expectancy of these patients has increased with new and improved therapies, the morbidities associated with the treatments and the tumor itself have become more important. DISCUSSION: One of the most common morbidities is growth hormone deficiency, and since recombinant growth hormone (GH) became available, its use has increased exponentially. There is concern that in the population of children with brain tumors, GH treatment might increase the risk of tumor recurrence or progression or the appearance of a second neoplasm. In the light of this ongoing concern, the current literature has been reviewed to provide an update on the risk of tumor recurrence, tumor progression, or new intracranial tumor formation when GH is used to treat GH deficiency in children, who have had or have intracranial tumors. CONCLUSION: On the basis of this review, the authors conclude that the use of GH in patients with brain tumor is safe. GH therapy is not associated with an increased risk of central nervous system tumor progression or recurrence, leukemia (de novo or relapse), or extracranial non-leukemic neoplasms.

Long-acting octreotide treatment causes a sustained decrease in ghrelin concentrations but does not affect weight, behaviour and appetite in subjects with Prader-Willi syndrome.

OBJECTIVE: Ghrelin is secreted primarily by the stomach and circulates as both acylated and desacyl ghrelin. Acylated (but not desacyl) ghrelin stimulates appetite. Both concentrations are elevated in Prader-Willi syndrome (PWS), suggesting that ghrelin may contribute to hyperphagia and overweight in these subjects. We evaluated whether long-acting octreotide (Oct) decreases acylated and desacyl ghrelin concentrations, body mass, appetite and compulsive behaviour towards food in adolescents with PWS. DESIGN: A 56-week prospective, randomized, cross-over trial. METHODS: Nine subjects with PWS (age 14.6 (10.8-18.9) years, body mass index (BMI) Z-score +1.9 (0.6-3.0)) received either Oct (30 mg) or saline i.m. every 4 weeks for 16 weeks and were switched over to the other treatment after a 24-week washout period. RESULTS: Eight subjects completed the study. Oct caused a decrease in both acylated (-53%) and desacyl (-54%) fasting ghrelin concentrations (P<0.05) but did not significantly affect BMI. Oct had no significant effect on peptide YY concentrations, appetite or compulsive behaviour towards food. Oct caused a decrease in insulin-like growth factor-I concentrations, an increase in HbA1c and transient elevation of blood glucose in two subjects. Three subjects developed gallstones. CONCLUSIONS: Oct treatment caused a prolonged decrease in ghrelin concentrations in adolescents with PWS but did not improve body mass or appetite. Future intervention studies aiming at clarifying the role of ghrelin in PWS should focus on the administration of specific inhibitors of ghrelin secretion or ghrelin receptor activity that do not interfere with other appetite-regulating peptides.