Delayed Puberty Including Constitutional Delay: Differential and Outcome.

Constitutional delay of growth and puberty (CDGP) is the most common cause of delayed puberty in both male and female individuals. This article reviews the causes of delayed puberty focusing on CDGP, including new advances in the understanding of the genetics underpinning CDGP, a clinical approach to discriminating CDGP from other causes of delayed puberty, outcomes, as well as current and potential emerging management options.

Microbe-mediated intestinal NOD2 stimulation improves linear growth of undernourished infant mice.

The intestinal microbiota is known to influence postnatal growth. We previously found that a strain of Lactiplantibacillus plantarum (strain LpWJL) buffers the adverse effects of chronic undernutrition on the growth of juvenile germ-free mice. Here, we report that LpWJL sustains the postnatal growth of malnourished conventional animals and supports both insulin-like growth factor-1 (IGF-1) and insulin production and activity. We have identified cell walls isolated from LpWJL, as well as muramyl dipeptide and mifamurtide, as sufficient cues to stimulate animal growth despite undernutrition. Further, we found that NOD2 is necessary in intestinal epithelial cells for LpWJL-mediated IGF-1 production and for postnatal growth promotion in malnourished conventional animals. These findings indicate that, coupled with renutrition, bacteria cell walls or purified NOD2 ligands have the potential to alleviate stunting.

A gut bacterial strain rescues stunted growth.

Lactiplantibacillus plantarum promotes growth in undernourished mice.

Current clinical management of constitutional delay of growth and puberty.

BACKGROUND: Constitutional delay of growth and puberty (CDGP) is classified as the most frequent cause of delayed puberty (DP). Finding out the etiology of DP during first evaluation may be a challenge. In details, pediatricians often cannot differentiate CDGP from permanent hypogonadotropic hypogonadism (PHH), with definitive diagnosis of PHH awaiting lack of puberty by age 18 yr. Neverthless, the ability in providing a precise and tempestive diagnosis has important clinical consequences. MAIN TEXT: A growth failure in adolescents with CDGP may occur until the onset of puberty; after that the growth rate increases with rapidity. Bone age is typically delayed. CDGP is generally a diagnosis of exclusion. Nevertheless, other causes of DP must be evaluated. A family history including timing of puberty in the mother and in the father as well as physical examination may givee information on the cause of DP. Patients with transient delay in hypothalamic-pituitary-gonadal axis maturation due to associated conditions, such as celiac disease, inflammatory bowel diseases, kidney insufficiency and anorexia nervosa, may experience a functional hypogonadotropic hypogonadism. PHH revealing testosterone or estradiol low serum values and reduced FSH and LH levels may be connected to abnormalities in the central nervous system. So, magnetic resonance imaging is required in order to exclude either morphological alterations or neoplasia. If the adolescent with CDGP meets psychological difficulties, treatment is recommended. CONCLUSION: Even if CDGP is considered a variant of normal growth rather than a disease, short stature and retarded sexual development may led to psychological problems, sometimes associated to a poor academic performance. A prompt and precise diagnosis has an important clinical outcome. Aim of this mini-review is throwing light on management of patients with CDGP, emphasizing the adolescent diagnosis and trying to answer all questions from paediatricians.

A standard of care for individuals with PIK3CA-related disorders: An international expert consensus statement.

Growth promoting variants in PIK3CA cause a spectrum of developmental disorders, depending on the developmental timing of the mutation and tissues involved. These phenotypically heterogeneous entities have been grouped as PIK3CA-Related Overgrowth Spectrum disorders (PROS). Deep sequencing technologies have facilitated detection of low-level mosaic, often necessitating testing of tissues other than blood. Since clinical management practices vary considerably among healthcare professionals and services across different countries, a consensus on management guidelines is needed. Clinical heterogeneity within this spectrum leads to challenges in establishing management recommendations, which must be based on patient-specific considerations. Moreover, as most of these conditions are rare, affected families may lack access to the medical expertise that is needed to help address the multi-system and often complex medical issues seen with PROS. In March 2019, macrocephaly-capillary malformation (M-CM) patient organizations hosted an expert meeting in Manchester, United Kingdom, to help address these challenges with regards to M-CM syndrome. We have expanded the scope of this project to cover PROS and developed this consensus statement on the preferred approach for managing affected individuals based on our current knowledge.

Academy of Nutrition and Dietetics Nutrition Research Network: A Home Garden Intervention Improves Child Length-for-Age Z-Score and Household-Level Crop Count and Nutritional Functional Diversity in Rural Guatemala.

Home gardens may help address childhood malnutrition in low- and middle-income countries. In this quasi-experimental pilot study, the Academy of Nutrition and Dietetics, in collaboration with Maya Health Alliance, evaluated the feasibility of augmenting a standard-of-care nutrition-specific package for Maya children with length-for-age z score ≤-2 (stunting) in rural Guatemala with a nutrition-sensitive home garden intervention. Two agrarian municipalities in Guatemala were included. Families of 70 children with stunting from 1 municipality received the standard-of-care package (food supplementation, multiple micronutrient powders, monthly nutrition home visits, group nutrition classes). Families of 70 children with stunting from another municipality received the standard-of-care package plus a home garden intervention (garden materials, monthly agricultural home visits, agriculture classes). Maternal and child dietary diversity, household food insecurity, child growth, and agricultural indicators were collected at baseline and 6 months later and were analyzed using mixed linear and logistic regression models. Compared with the standard-of-care group, the garden intervention group had improved child (odds ratio [OR] 3.66, 95% CI 0.89-15.10, P = 0.07) and maternal dietary diversity (OR 2.31, 95% CI 0.80-6.65, P = 0.12) and decreased food insecurity (OR 0.38, 95% CI 0.11-1.35, P = 0.14); however, these effects were not statistically significant. Participation in gardens predicted a higher length-for-age z-score (change difference [CD] 0.22 SD, 95% CI 0.05-0.38, P = 0.009), greater crop species count (CD 2.97 crops, 95% CI 1.79-4.16, P < 0.001), and greater nutritional functional diversity (CD 0.04 points, 95% CI 0.01-0.07, P = 0.006) than standard-of-care alone. Home garden interventions are feasible in rural Guatemala and may have potential benefits for child growth when added to other nutrition-specific interventions.

Potential Benefits of Bovine Colostrum in Pediatric Nutrition and Health.

Bovine colostrum (BC), the first milk produced from cows after parturition, is increasingly used as a nutritional supplement to promote gut function and health in other species, including humans. The high levels of whey and casein proteins, immunoglobulins (Igs), and other milk bioactives in BC are adapted to meet the needs of newborn calves. However, BC supplementation may improve health outcomes across other species, especially when immune and gut functions are immature in early life. We provide a review of BC composition and its effects in infants and children in health and selected diseases (diarrhea, infection, growth-failure, preterm birth, necrotizing enterocolitis (NEC), short-bowel syndrome, and mucositis). Human trials and animal studies (mainly in piglets) are reviewed to assess the scientific evidence of whether BC is a safe and effective antimicrobial and immunomodulatory nutritional supplement that reduces clinical complications related to preterm birth, infections, and gut disorders. Studies in infants and animals suggest that BC should be supplemented at an optimal age, time, and level to be both safe and effective. Exclusive BC feeding is not recommended for infants because of nutritional imbalances relative to human milk. On the other hand, adverse effects, including allergies and intolerance, appear unlikely when BC is provided as a supplement within normal nutrition guidelines for infants and children. Larger clinical trials in infant populations are needed to provide more evidence of health benefits when patients are supplemented with BC in addition to human milk or formula. Igs and other bioactive factors in BC may work in synergy, making it critical to preserve bioactivity with gentle processing and pasteurization methods. BC has the potential to become a safe and effective nutritional supplement for several pediatric subpopulations.

Human Growth and Growth Hormone: From Antiquity to the Recominant Age to the Future.

Since antiquity Man has been fascinated by the variations in human (and animal) growth. Stories and art abound about giants and little people. Modern genetics have solved some of etiologies at both extremes of growth. Serious study began with the pathophysiology of acromegaly followed by early attempts at treatment culminating in modern endoscopic surgery and multiple pharmacologic agents. Virtually at the same time experiments with the removal of the pituitary from laboratory animals noted the slowing or stopping of linear growth and then over a few decades the extraction and purification of a protein within the anterior pituitary that restored, partially or in full, the animal's growth. Human growth hormone was purified decades after those from large animals and it was noted that it was species specific, that is, only primate growth hormone was metabolically active in primates. That was quite unlike the beef and pork insulins which revolutionized the care of children with diabetes mellitus. A number of studies included mild enzymatic digestion of beef growth hormone to determine if those "cores" had biologic activity in primates and man. Tantalizing data showed minimal but variable metabolic efficacy leading to the "active core" hypothesis, for these smaller peptides would be amenable to peptide synthesis in the time before recombinant DNA. Recombinant DNA changed the landscape remarkably promising nearly unlimited quantities of metabolically active hormone. Eight indications for therapeutic use have been approved by the Food and Drug Administration and a large number of clinical trials have been undertaken in multiple other conditions for which short stature in childhood is a sign. The future predicts other clinical indications for growth hormone therapy (and perhaps other components of the GH?IGF-1 axis), longer-acting analogues and perhaps a more physiologic method of administration as virtually all methods at present are far from physiologic.

Improvement in appetite among stunted children receiving nutritional intervention in Bangladesh: results from a community-based study.

BACKGROUND/OBJECTIVES: Stunted children often have poor appetite, which may limit their response to nutritional interventions. We investigated the effect of a nutritional intervention on the appetite status of stunted children. METHODS: A longitudinal prospective intervention study was conducted with 50 stunted (length for age; LAZ < -2) (age and sex matched) aged 12-18 months and their mothers in Bauniabadh slum of Dhaka city. The stunted children received the following intervention package: one boiled egg and 150 ml milk daily 6 days a week for 3 months; psychosocial stimulation including structured play activities and parental counseling for 6 months; routine clinical care. Appetite status was measured using an interview-based tool "Early Childhood Appetite and Satiety Tool." RESULTS: Over the period of nutritional intervention, the mean appetite score increased from 49 to 60 in the stunted children and was associated with increased food consumption. Over the intervention period, both egg and milk consumption increased (40.3-49.6 g and 83.8-138.5 ml, respectively). CONCLUSIONS: Assessment of appetite status using EACST appears to be a useful tool for monitoring a nutritional intervention in stunted children. This tool may be useful for programs in managing child stunting in low-income countries and an important way to assess the efficacy of a nutritional intervention in these children.

Racial and Ethnic Disparities in the Investigation and Treatment of Growth Hormone Deficiency.

OBJECTIVE: To determine if the racial/ethnic inequity in growth hormone (GH) use is due to differences in GH stimulation testing and/or prescribing patterns in children referred for endocrine evaluation of short stature. STUDY DESIGN: Retrospective chart review was performed including children aged 2-16 years, height z-score of ≤-1.5, and of non-Hispanic White (NHW), non-Hispanic Black (NHB), or Hispanic race/ethnicity, referred for endocrine growth evaluation between January 2012 and December 2019. RESULTS: This study included 7425 children (5905 NHW, 800 NHB, and 720 Hispanic). GH stimulation testing was performed in 992, and 576 were prescribed GH. NHW children were 1.4 (95% CI, 1.04-1.8) times more likely than NHB children and 1.7 (95% CI, 1.2-2.2) times more likely than Hispanic children to undergo GH stimulation testing. GH-treated NHB children had (1) a lower median peak GH concentration when compared with NHW (P = .02) and Hispanic (P = .08) children (NHB 4.7 ng/mL [95% CI, 1.2-8.3 ng/mL] ng/mL, NHW 7.2 ng/mL [95% CI, 4.9-9.7 ng/mL], Hispanic 7.1 ng/mL [95% CI, 4.3-11.9 ng/mL]); (2) lower median height z-scores than NHW (P = .01) but not Hispanic children (P = .5); and (3) a greater height deficit from midparental height when compared with NHW (P = .01) and Hispanic (P = .002) children. CONCLUSIONS: Racial and ethnic disparities exist in the evaluation and treatment of children with disordered growth. This likely results from both overinvestigation of NHW children as well as underinvestigation and undertreatment of children from minority communities. The evaluation and treatment of children with short stature should be determined by clinical concern alone, but this is not current practice.

Growth hormone deficiency and other endocrinopathies after childhood brain tumors: results from a close follow-up in a cohort of 242 patients.

PURPOSE: Brain tumors are the most common solid tumor in children. The prevalence of survivors from these cancers has been increasing, presenting endocrine sequelae in more than 40% of the cases. Our aim was to characterize the endocrinopathies diagnosed in this population, exploring the outcomes of growth hormone treatment. METHODS: We have performed a retrospective analysis of the survivors that were followed-up through a close protocol at our endocrine late-effects clinic. RESULTS: 242 survivors, followed during 6.4 (0-23.4) years, were considered. The median age at tumor diagnosis was 6.7 (0-18) years and pilocytic astrocytoma was the most frequent neoplasm (33.5%). The prevalence of endocrinopathies was of 71.5%, with growth hormone deficiency being the most frequent (52.9%). An indirect correlation between the age at the beginning of somatropin and growth velocity in the first year of treatment was observed. Those treated with craniospinal radiotherapy presented a smaller final upper/lower segments ratio comparing with those that only received cranial radiotherapy. However, their final height was not compromised when compared to their family height target. We found pubertal delay in 12%; accelerated/precocious puberty in 13.2%; central and primary hypogonadism in 21.9% and 3.3%, respectively; primary and central hypothyroidism in 23.6% and 14.5%, respectively; thyroid nodules in 7.4%; ACTH deficiency in 10.3% and diabetes insipidus in 12%. CONCLUSION: This study reveals a higher prevalence of endocrinopathies in brain tumors survivors and explores the influence of craniospinal irradiation in the adult body proportions. It reinforces the importance of routine follow-up among survivors.

High Early Parenteral Lipid in Very Preterm Infants: A Randomized-Controlled Trial.

OBJECTIVE: To determine whether high early parenteral soybean oil lipid intake in very low birth weight (VLBW) infants in the first week after birth decreases the proportion of weight loss and subsequently the incidence of extrauterine growth restriction (EUGR). STUDY DESIGN: This was a randomized controlled trial of appropriate for gestational- ge VLBW infants. Lipid intake in the control group started at 0.5-1 g/kg per day and increased daily by 0.5-1 g/kg per day till reaching 3 g/kg per day. The intervention group was started on 2 g/kg per day that increased to 3 g/kg per day the following day. RESULTS: Of the 176 infants assessed for eligibility, 83 were included in the trial. Infants in the intervention group were started on lipid sooner (13.8 ± 7.8 vs 17.5 ± 7.8 hour; P = .03) and had higher cumulative lipid intake in the first 7 days of age (13.5 ± 4.2 vs 10.9 ± 3.5 g/kg per day; P = .03). Infants in the intervention group had a lower percentage of weight loss (10.4 vs 12.7%; P = .02). The mean triglyceride level was higher in the intervention group (1.91 ± 0.79 vs 1.49 ± 0.54 mmol/L; P = .01), however, hypertriglyceridemia was similar between the 2 groups. The incidence of EUGR was lower in the intervention group (38.6% vs 67.6%; P = .01). Head circumference z score was higher in the intervention group (-1.09 ± 0.96 vs -1.59 ± 0.98; P = .04). CONCLUSIONS: In VLBW infants, provision of a high early dose of parenteral lipid in the first week of age results in less weight loss and lower incidence of EUGR. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03594474.

Catch-up Growth in Prepubertal Children Treated for Juvenile Hypothyroidism and Growth Hormone Deficiency can be Modelled with a Monomolecular Function

Objective: We hypothesized that modelling catch-up growth (CUG) as developed for coeliac disease (CD), might also fit CUG in adequately treated children with juvenile hypothyroidism (JHT) or growth hormone deficiency (GHD). Methods: We used a monomolecular function for all available prepubertal data on height standard deviation score (HSDS) minus target height SDS (adjHSDS) in children with JHT (n=20) and GHD (n=18) on a conventional (CoD) or high GH dose (HD), based either on a national height reference with an age cut-off of 10 (girls) and 12 (boys) years (model 1) or prepubertal height reference values, if age (0) was ≥3, with no upper age limit (model 2). Results: The models could be fitted in 83-90% of cases; in other cases the HSDS decreased after several measurements, which violated the assumption of an irreversible growth process. In JHT, the rate constant (k) and adjHSDS (0) were lower than in CD (p=0.02), but adjHSDS (end) was similar. In GHD (model 1), k was lower than for CD (p=0.004) but similar to JHT, while adjHSDS (0) and adjHSDS (end) were similar to CD and JHT. Thus, the shape of CUG is similar for children with JHT and GHD, while children with CD had less growth deficit at start and a faster CUG. The differences in CUG parameters between GH dose subgroups did not reach statistical significance. Conclusion: Modelling CUG of prepubertal children with JHT and GHD can be used for assessing the adequacy of CUG and the influence of clinical treatment modalities on its speed and magnitude.

Best practices, challenges and innovations in pediatrics in 2019.

This paper runs through key progresses in epidemiology, pathomechanisms and therapy of various diseases in children that were issued in the Italian Journal of Pediatrics at the end of last year. Novel research and documents that explore areas such as allergy, critical care, endocrinology, gastroenterology, infectious diseases, neonatology, neurology, nutrition, and respiratory tract illnesses in children have been reported. These observations will help to control childhood illnesses.

Factors Associated with Stunting among Children under 5 Years in Five South Asian Countries (2014-2018): Analysis of Demographic Health Surveys.

South Asia continues to be the global hub for child undernutrition with 35% of children still stunted in 2017. This paper aimed to identify factors associated with stunting among children aged 0-23 months, 24-59 months, and 0-59 months in South Asia. A weighted sample of 564,518 children aged 0-59 months from the most recent Demographic and Health Surveys (2014-2018) was combined of five countries in South Asia. Multiple logistic regression analyses that adjusted for clustering and sampling weights were used to examine associated factors. The common factors associated with stunting in three age groups were mothers with no schooling ([adjusted odds ratio (AOR) for 0-23 months = 1.65; 95% CI: (1.29, 2.13)]; [AOR for 24-59 months = AOR = 1.46; 95% CI: (1.27, 1. 69)] and [AOR for 0-59 months = AOR = 1.59; 95% CI: (1.34, 1. 88)]) and maternal short stature (height < 150 cm) ([AOR for 0-23 months = 2.00; 95% CI: (1.51, 2.65)]; [AOR for 24-59 months = 3.63; 95% CI: (2.87, 4.60)] and [AOR for 0-59 months = 2.87; 95% CI: (2.37, 3.48)]). Study findings suggest the need for a balanced and integrated nutrition strategy that incorporates nutrition-specific and nutrition-sensitive interventions with an increased focus on interventions for children aged 24-59 months.

Comparative effectiveness of East Asian traditional medicine for treatment of idiopathic short stature in children: A protocol for systematic review and network meta-analysis.

BACKGROUND: There are many East Asian traditional medicine (EATM) therapies that are widely used and effective for idiopathic short stature (ISS) in children. However, the comparative effectiveness of these therapies remains unclear. We describe the methods that will be used to comparatively evaluate the efficacy and safety of EATM therapies for the treatment of pediatric ISS. METHODS AND ANALYSIS: Fourteen electronic English, Korean, Chinese, and Japanese databases will be searched up to August 2020 for relevant randomized controlled trials of various EATMs for the treatment of pediatric ISS, without language or publication status restrictions. The primary outcome will be growth-related anthropometric indicators, and acceptability, measured through drop-outs that occur during treatment for any reason. We will conduct a pairwise meta-analysis for direct comparisons if multiple studies use the same types of intervention, comparison, and outcome measure. A frequentist network meta-analysis will be performed to summarize the available direct and indirect evidence regarding various EATM options for pediatric ISS. The risk of bias for the included studies will be evaluated using the Cochrane Collaboration's risk of bias tool. CONCLUSIONS: The findings of this review will provide evidence for the comparative effectiveness and ranks of current EATMs and help to inform clinical practitioners, patients, and policy makers in decision making. ETHICS AND DISSEMINATION: Ethical approval is not required because individual patient data are not included. The findings of this systematic review will be disseminated through a peer-reviewed publication or conference presentations. PROTOCOL REGISTRATION NUMBER: OSF (URL: https://osf.io/s4vp7), PROSPERO CRD42020187160.

Priorities for intervention of childhood stunting in northeastern Ethiopia: A matched case-control study.

BACKGROUND: Stunting is a worldwide public health problem caused by factors that vary across regions, including in Ethiopia. Limited evidence to prevent stunting makes it difficult to design and prioritize appropriate interventions. Therefore, this study investigated the intervention priorities for the prevention of stunting among children 6-59 months old in Kemissie City Administration, northeastern Ethiopia. METHODS: A community-based individual matched case-control study was conducted from January to April 2017 including 107 cases and 214 controls. Controls were selected and matched with cases using the matching variable of child's age. Data were collected by open data kit (ODK) software using a structured questionnaire. Data were analyzed using STATA version 13.0 and WHO (World Health Organization) Anthro 2005. A conditional logistic regression model was used for data analysis. From multivariable conditional logistic regression analysis, determinants of stunting were identified. A statistically significant level was declared by a conditional adjusted odds ratio (cAOR) with 95% confidence interval (CI) and p-value of less than 0.05. MAIN FINDINGS: The wealth index 52 (48.6%) of the cases and 108 (50.5%) controls were categorized as poor. The mean height-for-age z-score (HAZ) for the cases and controls was -2.79±.67 and -0.55±.92, respectively. One-sixth (16.8%) of the cases and 29 (13.6%) of the controls were given prelacteal feeding. A majority 82 (86.9%) of the cases and 137 (69.1%) of the controls had undernourished mothers/care-givers. Slightly less than one-third 35 (32.7%) of cases and one-fourth 53 (24.8%) of controls were affected by repeated episodes of diarrhea. Mother's body mass index (BMI) (conditional adjusted odds ratio [cAOR]) = 2.64; 95% CI: 1.28, 5.43), giving food priority to father (cAOR = 2.42; 95% CI: 1.23, 4.75), lack of exclusive breastfeeding for at least 6 months (cAOR = 2.44; 95% CI: 1.15, 5.17), no intake of meat by child (cAOR = 2.35; 95% CI: 1.21, 4.58) and child having repeated diarrheal episodes (cAOR = 2.0: 95% CI: 1.07, 3.86) were factors associated with childhood stunting. CONCLUSION: Maternal nutritional status, food priority, duration of exclusive breastfeeding, no intake of meat and repeated episodes of diarrhea were the main determinants of stunting among children aged 6-59 months. Therefore, intervention measures to avert childhood stunting should include strengthening action on provision of essential nutrition, providing counseling to parents on giving food priority to children, promotion of optimal duration of breastfeeding and preventing diarrheal disease among children 6-59 months old.