Insulin-like growth factor 1 and sex hormones for assessment of anthropometric and pubertal growth of Egyptian children and adolescents with type 1 diabetes mellitus (single center study).

BACKGROUND: This study aimed to assess the anthropometric measures and pubertal growth of children and adolescents with Type 1 diabetes mellitus (T1DM) and to detect risk determinants affecting these measures and their link to glycemic control. PATIENTS AND METHODS: Two hundred children and adolescents were assessed using anthropometric measurements. Those with short stature were further evaluated using insulin-like growth factor 1 (IGF-1), bone age, and thyroid profile, while those with delayed puberty were evaluated using sex hormones and pituitary gonadotropins assay. RESULTS: We found that 12.5% of our patients were short (height SDS < -2) and IGF-1 was less than -2 SD in 72% of them. Patients with short stature had earlier age of onset of diabetes, longer duration of diabetes, higher HbA1C and urinary albumin/creatinine ratio compared to those with normal stature (p < 0.05). Additionally, patients with delayed puberty had higher HbA1c and dyslipidemia compared to those with normal puberty (p < 0.05). The regression analysis revealed that factors associated with short stature were; age at diagnosis, HbA1C > 8.2, and albumin/creatinine ratio > 8 (p < 0.05). CONCLUSION: Children with uncontrolled T1DM are at risk of short stature and delayed puberty. Diabetes duration and control seem to be independent risk factors for short stature.

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.

Evaluation of copeptin in children after stimulation with clonidine or L-Dopa.

OBJECTIVES: Arginine-stimulated serum copeptin has been proposed as a new method to diagnose arginine vasopressin (AVP) deficiency in children and adolescents. Herein we investigated the secretagogic potential of clonidine or L-Dopa on the copeptin serum levels in children. METHODS: Eight stimulation tests (4 with clonidine and 4 with L-Dopa) were performed in eight children (5 boys and 3 girls) with a median age of 6.5 years-old, evaluated for short stature due to possible growth hormone deficiency. Serum copeptin levels were measured at 30, 60, 90, and 120 min after administration of clonidine or L-Dopa. RESULTS: Copeptin levels in serum did not show any significant change in either test (clonidine or L-Dopa). The values of copeptin levels compared to the baseline value did not deviate more than 5 % in the clonidine arm (p=0.60) or 8 % in the L-Dopa arm (p=0.75) respectively. CONCLUSIONS: Data do not support the use of L-Dopa or clonidine as stimulants for evaluating AVP relating disorders in clinical pediatric practice.

Global relevance of MGRS growth standards: the case of India.

The most common measures of childhood undernutrition are based on anthropometric measures such as height-for-age (stunting/chronic undernutrition) and weight-for-height (wasting/acute undernutrition). It is well recognised that the determinants of undernutrition are multiple, including food intake, dietary diversity, health, sanitation and women's status. Currently, most countries across the world including India use the globally accepted WHO-Multicentre Growth Reference Study (MGRS) growth standards (2006) for the purposes of measurement as well as for evaluating progress on these metrics. However, there is some discussion on the universal relevance of these standards, and in the Indian context, whether these standards overestimate the prevalence of stunting, considering differences in genetic potential for growth. This is especially relevant in the context of increasing burden of obesity and non-communicable diseases in India. Based on a detailed review of literature, policy documents and expert inputs, this review paper discusses the relevance of the WHO growth standards for height/stunting, in the context of India. Issues discussed related to the MGRS methodology include pooling of data and intersite and intrasite variability, opting for standards as opposed to references, and external validity. Other issues related to plasticity of stunting and the influence of maternal heights are also discussed, in the context of analysing the appropriateness of using universal growth standards. Based on the review, it is recommended that the current standards may continue to be used until a newer global standard is established through a similar study.

A significant increase in anthropometric indices during long-term follow-up of pediatric patients with celiac disease, with no endocrine disorders.

Celiac disease (CeD) is likely to be associated with growth impairment and poor weight gain. However, long-term growth patterns following diagnosis are poorly characterized. We evaluated long-term anthropometric changes in a large cohort of pediatric patients with CeD. A retrospective chart review of patients diagnosed with CeD between 1999 and 2018 was conducted. Demographic and clinical data were collected, and anthropometrics were analyzed from diagnosis and throughout follow-up. The study included 500 patients (59.8% females, median (IQR) age at diagnosis 5.7 (3.7-8.9) years), with a mean follow-up of 5.5 (range 1.5-16.2) years. Weight, height, and BMI Z-score-for-age (WAZ, HAZ, and BMIZ) increased significantly from a mean (± SD) of - 0.82 (± 1.21), - 0.73 (± 1.16), and - 0.32 (± 1.11) at diagnosis to - 0.41 (± 1.23), - 0.45(± 1.16), and - 0.17 (± 1.14) at last follow-up, respectively (p < 0.001 for WAZ and HAZ and p = 0.002 for BMIZ). The largest improvements were observed in patients diagnosed before 3 years of age (p < 0.01). Patients for whom the final adult height was available (n = 86) improved from HAZ mean (± SD) - 0.89 ± 1.37 at diagnosis to - 0.51 ± 1.28 at adulthood measurement, p < 0.05. Wasting was present in 19.7% and stunting in 16.4% of the cohort at diagnosis and normalized in 77.3% and 64.8%, respectively, within a median (IQR) time of 0.79 (0.42-4.24) and 2.3 (0.72-6.02) years, respectively. Gluten-free diet adherence and frequency of visits were not associated with normalization of wasting or stunting in all age groups.  Conclusion: Over a long-term follow-up, pediatric patients with CeD demonstrate significant increases in weight, height, and BMI-for-age. Younger age at diagnosis is associated with greater improvement in weight and linear growth, emphasizing the importance of early diagnosis of CeD. What is Known: • Celiac disease (СeD) is likely to be associated with growth impairment and poor weight gain. • Long-term changes in anthropometric indices after diagnosis of CeD are not well characterized. What is New: • Over a long-term follow-up, pediatric patients with CeD demonstrate significant increases in weight, height, and BMI-for-age. • Young age at diagnosis is associated with larger improvement in weight and linear growth.

Predicting and identifying factors associated with undernutrition among children under five years in Ghana using machine learning algorithms.

BACKGROUND: Undernutrition among children under the age of five is a major public health concern, especially in developing countries. This study aimed to use machine learning (ML) algorithms to predict undernutrition and identify its associated factors. METHODS: Secondary data analysis of the 2017 Multiple Indicator Cluster Survey (MICS) was performed using R and Python. The main outcomes of interest were undernutrition (stunting: height-for-age (HAZ) < -2 SD; wasting: weight-for-height (WHZ) < -2 SD; and underweight: weight-for-age (WAZ) < -2 SD). Seven ML algorithms were trained and tested: linear discriminant analysis (LDA), logistic model, support vector machine (SVM), random forest (RF), least absolute shrinkage and selection operator (LASSO), ridge regression, and extreme gradient boosting (XGBoost). The ML models were evaluated using the accuracy, confusion matrix, and area under the curve (AUC) receiver operating characteristics (ROC). RESULTS: In total, 8564 children were included in the final analysis. The average age of the children was 926 days, and the majority were females. The weighted prevalence rates of stunting, wasting, and underweight were 17%, 7%, and 12%, respectively. The accuracies of all the ML models for wasting were (LDA: 84%; Logistic: 95%; SVM: 92%; RF: 94%; LASSO: 96%; Ridge: 84%, XGBoost: 98%), stunting (LDA: 86%; Logistic: 86%; SVM: 98%; RF: 88%; LASSO: 86%; Ridge: 86%, XGBoost: 98%), and for underweight were (LDA: 90%; Logistic: 92%; SVM: 98%; RF: 89%; LASSO: 92%; Ridge: 88%, XGBoost: 98%). The AUC values of the wasting models were (LDA: 99%; Logistic: 100%; SVM: 72%; RF: 94%; LASSO: 99%; Ridge: 59%, XGBoost: 100%), for stunting were (LDA: 89%; Logistic: 90%; SVM: 100%; RF: 92%; LASSO: 90%; Ridge: 89%, XGBoost: 100%), and for underweight were (LDA: 95%; Logistic: 96%; SVM: 100%; RF: 94%; LASSO: 96%; Ridge: 82%, XGBoost: 82%). Age, weight, length/height, sex, region of residence and ethnicity were important predictors of wasting, stunting and underweight. CONCLUSION: The XGBoost model was the best model for predicting wasting, stunting, and underweight. The findings showed that different ML algorithms could be useful for predicting undernutrition and identifying important predictors for targeted interventions among children under five years in Ghana.

Comparison of international height and BMI-for-age growth references and their correlation with adiposity in Brazilian schoolchildren.

This study verified the diagnostic accuracy of the nutritional status classified by the international height and BMI references of the World Health Organization (WHO) (WHO/2007), International Obesity Task Force (IOTF/2012) and MULT (2023). The data pool was composed by 22 737 subjects aged five to 16 years from the Santos and Porto Alegre surveys. A correlation matrix between the z-scores of the BMI references and the skinfold measurements was calculated through the Pearson correlation coefficient (r), and the subject's nutritional status was classified according to the international growth references. The accuracy for diagnosing obesity was performed separately by sex and using the 95th percentile of the triceps and subscapular skinfold sum, while Lin's concordance coefficient, Bland-Altman method and the Cohen's Kappa coefficient (Kappa) were used to verify the concordance and reliability among the BMI references. The correlation matrix showed a high positive correlation among the BMI z-scores (r ≥ 0·99) and among the skinfold measurements (r ≥ 0·86). The prevalence of stunting was higher when applying the MULT reference (3·4 %) compared with the WHO reference (2·3 %). The Bland-Altman plots showed the lowest critical difference (CD) between the height references of WHO and MULT (CD = 0·22). Among the BMI references, the WHO obesity percentile presented lower performance than MULT for boys, presenting a lower +LR value (WHO = 6·99/MULT 18 years = 10·99; 19 years = 8·99; 20 years = 8·09) for the same -LR values (0·04). Therefore, MULT reference holds promise as a valuable tool for diagnosing childhood obesity, particularly when considering sex differences. This enhances its suitability for assessing the nutritional status of Brazilian schoolchildren.

Molecular diagnosis is an important indicator for response to growth hormone therapy in children with short stature.

BACKGROUND: Significant differences have been observed in the efficacy of recombinant human growth hormone (rhGH) treatment for short children. The present study aimed to identify the genetic etiology of short stature and to assess the role of molecular diagnosis in predicting responses to rhGH treatment. METHODS: A total of 407 short children were included in the present study, 226 of whom received rhGH treatment. Whole-exome sequencing (WES) was conducted on short children to identify the underlying genetic etiology. Correlations between molecular diagnosis and the efficacy of rhGH treatment were examined. RESULTS: Pathogenic or likely pathogenic mutations were identified in 86 of the 407 patients (21.1%), including 36 (41.9%) novel variants. Among the multiple pathways affecting short stature, genes involved in fundamental cellular processes (38.7%) play a larger role, especially the RAS-MAPK pathway. In general, patients without pathogenic mutations responded better to rhGH than those with mutations. Furthermore, patients with hormone signaling pathway mutations had a better response to rhGH, while those with paracrine factor mutations had a worse response to rhGH. CONCLUSIONS: This study highlights the utility of WES in identifying genetic etiology in children with short stature. Identifying likely causal mutations is an important factor in predicting rhGH response.

The Genetic Landscape of Children Born Small for Gestational Age with Persistent Short Stature.

INTRODUCTION: Among children born small for gestational age, 10-15% fail to catch up and remain short (SGA-SS). The underlying mechanisms are mostly unknown. We aimed to decipher genetic aetiologies of SGA-SS within a large single-centre cohort. METHODS: Out of 820 patients treated with growth hormone (GH), 256 were classified as SGA-SS (birth length and/or birth weight <-2 SD for gestational age and life-minimum height <-2.5 SD). Those with the DNA triplet available (child and both parents) were included in the study (176/256). Targeted testing (karyotype/FISH/MLPA/specific Sanger sequencing) was performed if a specific genetic disorder was clinically suggestive. All remaining patients underwent MS-MLPA to identify Silver-Russell syndrome, and those with unknown genetic aetiology were subsequently examined using whole-exome sequencing or targeted panel of 398 growth-related genes. Genetic variants were classified using ACMG guidelines. RESULTS: The genetic aetiology was elucidated in 74/176 (42%) children. Of these, 12/74 (16%) had pathogenic or likely pathogenic (P/LP) gene variants affecting pituitary development (LHX4, OTX2, PROKR2, PTCH1, POU1F1), the GH-IGF-1 or IGF-2 axis (GHSR, IGFALS, IGF1R, STAT3, HMGA2), 2/74 (3%) the thyroid axis (TRHR, THRA), 17/74 (23%) the cartilaginous matrix (ACAN, various collagens, FLNB, MATN3), and 7/74 (9%) the paracrine chondrocyte regulation (FGFR3, FGFR2, NPR2). In 12/74 (16%), we revealed P/LP affecting fundamental intracellular/intranuclear processes (CDC42, KMT2D, LMNA, NSD1, PTPN11, SRCAP, SON, SOS1, SOX9, TLK2). SHOX deficiency was found in 7/74 (9%), Silver-Russell syndrome in 12/74 (16%) (11p15, UPD7), and miscellaneous chromosomal aberrations in 5/74 (7%) children. CONCLUSIONS: The high diagnostic yield sheds a new light on the genetic landscape of SGA-SS, with a central role for the growth plate with substantial contributions from the GH-IGF-1 and thyroid axes and intracellular regulation and signalling.

Floating-Harbor syndrome with chorioretinal colobomas.

BACKGROUND: We present a case of a child with Floating-Harbor Syndrome (FHS) with bilateral chorioretinal coloboma (CC). To the best of our knowledge, this is the first case report of this association. Floating- Harbor syndrome is an extremely rare autosomal dominant genetic disorder with approximately 100 cases reported. It is characterized by a series of atypical features that include short stature with delayed bone age, low birth weight, skeletal anomalies, delayed speech development, and dysmorphic facial characteristics that typically portray a triangular face, deep-set eyes, long eyelashes, and prominent nose. MATERIALS AND METHODS: Our patient was examined by a pediatric ophthalmologist for the time at age of 7. Visual acuity, optical coherence tomography (OCT) and Optos imaging were collected on every visit. The patient had whole genome sequencing ordered by a pediatric geneticist to confirm Floating-Harbor syndrome. RESULTS: We present the patient's OCT and Optos images that illustrate the location of the patient's inferior chorioretinal coloboma in both eyes. The whole genome sequencing report collected revealed a heterozygous de novo pathogenic variant in the SRCAP gene, consistent with a Floating-Harbor syndrome diagnosis in the literature. DISCUSSION: Both genetic and systemic findings are consistent with the diagnosis of Floating-Harbor syndrome in our patient. Rubenstein-Taybi and Floating-Harbor syndrome share a similarity in molecular and physical manifestations, but because of the prevalence in Rubenstein-Taybi diagnoses, it is a syndromic condition that includes coloboma and frequently associated with each other. Therefore, a retinal exam should become part of the standard protocol for those with FHS, as proper diagnosis, examination and treatment can prevent irreversible retinal damage.

The utility of IGF1 in the evaluation of pediatric patients with endogenous hypercortisolemia.

BACKGROUND: Cushing Disease (CD) is a rare endocrine disorder associated with impaired growth hormone (GH) and short stature. Insulin-like growth factor-1 (IGF-1) is a marker of GH secretion. METHODS: Patients with young onset CD (<21 years old) and available IGF-1 levels at diagnosis and/or follow-up were studied (total = 194, diagnosis = 174, follow-up = 104). IGF-1 was reported as z-score (IGF1z). RESULTS: IGF1z was lower than expected in the general population (median IGF1z: -0.92 [-1.54, 0.07], p < 0.0001) at diagnosis and remained low at follow-up (median: -1.13 [-1.78, -0.66], p < 0.0001). There was no correlation of IGF1z at diagnosis with BMI; there was a weak correlation with height (rs = 0.19, p = 0.035). IGF1z was inversely correlated with markers of hypercortisolemia, including morning (rs = -0.31, p < 0.0001) and midnight cortisol (rs = -0.30, p < 0.0001), and with insulin resistance (Homeostatic Model Assessment for Insulin Resistance, HOMA-IR, rs = -0.27, p < 0.01). CONCLUSIONS: IGF-1 levels in CS are on the lower side of the normal range during active disease and remain low at one year after treatment. IGF-1 levels correlated mainly with markers of hypercortisolemia rather than the short stature of patients and should not be used in the assessment of growth in this population. IMPACT: We report that IGF-1 levels in childhood during active hypercortisolemia and up to 1 year after resolution are on the lower side of the normal range. Our results demonstrate that IGF-1 levels during active hypercortisolemia correlate mainly with markers of Cushing syndrome. This report adds data to the current literature where reports of IGF-1 in Cushing syndrome have shown variable results. Understanding the lack of utility of IGF-1 in assessing growth parameters in the pediatric Cushing syndrome population is important for physicians caring for these patients who should not use IGF-1 for diagnostic or treatment decisions.

Exome Sequencing Identifies Multiple Genetic Diagnoses in Children with Syndromic Growth Disorders.

OBJECTIVE: To evaluate the presence of multiple genetic diagnoses in syndromic growth disorders. STUDY DESIGN: We carried out a cross-sectional study to evaluate 115 patients with syndromic tall (n = 24) or short stature (n = 91) of unknown cause from a tertiary referral center for growth disorders. Exome sequencing was performed to assess germline single nucleotide, InDel, and copy number variants. All variants were classified according to ACMG/AMP guidelines. The main outcome measured was the frequency of multiple genetic diagnoses in a cohort of children with syndromic growth disorders. RESULTS: The total diagnostic yield of the cohort was 54.8% (63/115). Six patients had multiple genetic diagnoses (tall stature group = 2; short stature group = 4). The proportion of multiple diagnoses within total cases was 5.2% (6/115), and within solved cases was 9.5% (6/63). No characteristics were significantly more frequent when compared with patients with single or multiple genetic findings. Among patients with multiple diagnoses, 3 had syndromes with overlapping clinical features, and the others had syndromes with distinct phenotypes. CONCLUSION: Recognition of multiple genetic diagnoses as a possibility in complex cases of syndromic growth disorders opens a new perspective on treatment and genetic counseling for affected patients, defying the medical common sense of trying to fit all findings into one diagnosis.

[Attaching great importance to the scientific assessment of short stature in children]. / 高度重视儿童矮身材的科学评估.

Short stature is a common physical developmental abnormality in children. Without timely and accurate diagnosis, as well as early intervention, it can impose a heavy burden on the children and their families. There are numerous causes for short stature, and the diagnostic process essentially involves identifying its underlying causes. Based on a thorough understanding of the regular patterns of child physical development and the characteristics of individuals at high risk of short stature, a scientific definition of short stature needs to be established, along with standardized diagnostic and treatment protocols, to achieve early diagnosis or referral for short stature. Furthermore, it is necessary to enhance scientific awareness of short stature among parents and primary care pediatricians, in order to avoid over-treatment, missed diagnoses, and misdiagnoses arising from "misconceptions", and to improve the scientific assessment of short stature.

Measuring growth in critically ill neonates and children.

Critical illness increases the risk of malnutrition in both infants and children. Malnutrition risk is multifactorial and includes premorbid factors as well as changes in nutrient metabolism and energy demands during critical illness. Inadequate nutrition has been linked to poor health outcomes and prolonged length of stay in the intensive care unit, demonstrating the importance of both recognizing and addressing malnutrition in this population. Assessing growth and identifying malnutrition requires methodical measurement of growth and a collaborative, multimodal approach to nutrition assessment. Among the nutrition assessment and growth evaluation tools, neonatal, preterm, pediatric, and disease-specific growth charts remain an important component of growth assessment and should be used along with a nutrition-focused physical examination. Routine measurement promotes the identification of potential growth delays that may require interventions. Indirect calorimetry adds an additional layer of detail for a complete picture of each infant or child's unique nutrition status and progress. Quality improvement research on a national level is urgently needed to assess the adequacy and availability of resources in neonatal and pediatric critical care units and to further the development of standard clinical outcome measures for nutrition assessment and intervention in the critically ill neonate and child.

Correspondence on "Sex steroid priming for growth hormone stimulation testing in children and adolescents with short stature: A systematic review".

Duncan et al. reviewed the response to growth hormone stimulation testing after priming in peripubertal children. The concern is that there is little research documenting the response to growth hormone treatment in patients with sex hormone primed growth hormone stimulation testing and those unprimed. The controversy about priming or not can be summarized as follows: if one wants to know if the production of growth hormone during puberty will be adequate in terms of peak growth hormone responses then stimulation with priming should be done.