Increasing maternal prepregnancy body mass index is associated with reduced insulin sensitivity and increased blood pressure in their children.

OBJECTIVE: We aimed to assess the effects of maternal prepregnancy body mass index (BMI) on insulin sensitivity, metabolism and blood pressure in the offspring. METHODS: We studied 70 prepubertal children aged 8·9 ± 1·9 years (range 4-11 years), born 38-40 weeks of gestation and appropriate-for-gestational-age birthweight. Maternal prepregnancy body mass index (MPP BMI) was calculated from self-reported weight. Children's insulin sensitivity was measured using intravenous glucose tolerance tests and Bergman's minimal model. Other clinical assessments included auxology, fasting lipid and hormonal profiles, DXA-derived body composition and 24-h ambulatory blood pressure monitoring. Data were analysed using random effect mixed models, adjusting for important confounders and a random factor to account for sibling clusters. RESULTS: Increasing MPP BMI was correlated with increasing BMI standard deviation scores (SDS) (r = 0·30; P = 0·012) and lower insulin sensitivity in their children (r = -0·34; P = 0·004). In multivariate regression models, increasing MPP BMI was associated with lower insulin sensitivity (ß = -0·040; P = 0·005), with every 1 kg/m(2) increase in MPP BMI associated with a 4·0% decrease in offspring insulin sensitivity. Greater MPP BMI was associated with higher systolic blood pressure in the daytime (ß = 0·794; P = 0·010) and night-time (ß = 0·800; P = 0·017), as well as higher 24-h mean arterial pressure (ß = 0·508; P = 0·025) in the offspring. CONCLUSION: Greater maternal prepregnancy BMI is associated with lower insulin sensitivity and higher blood pressure in their children, effects that were independent of offspring adiposity. Thus, higher maternal BMI prior to pregnancy (even among women of normal BMI) may contribute to increased risk of type 2 diabetes and other metabolic diseases in the subsequent generation.

Metabolic, cardiovascular and anthropometric differences between prepubertal girls and boys.

OBJECTIVE: We aimed to assess possible differences in insulin sensitivity and other metabolic, anthropometric and cardiovascular parameters between boys and girls prior to puberty. METHODS: We studied 85 healthy prepubertal children (33 girls and 52 boys) aged 8.7 ± 1.9 years (range 4.0-11.9 years), born 38-40 weeks gestation, and of birth weight appropriate-for-gestational-age. Insulin sensitivity was measured using frequently sampled intravenous glucose tests and Bergman's minimal model. Other clinical assessments included anthropometric measures, fasting lipid and hormonal profiles, body composition from whole-body dual-energy X-ray absorptiometry and 24-h ambulatory blood pressure monitoring. RESULTS: Prepubertal girls and boys were of similar parent-adjusted height SDS (P = 0.26), but girls had considerably more body fat (P < 0.0001), less fat-free mass (P = 0.0002) and greater abdominal adiposity (P < 0.0001). These differences in body composition were independent of adrenal androgens. Insulin sensitivity was 18% lower in girls (11.0 vs 13.4 × 10(-4) /min (mU/l); P = 0.028), but this difference disappeared with adjustment for adiposity and DHEAS concentrations. There were, however, some apparent sex differences in cardiovascular parameters, with girls displaying increased heart rate and reduced blood pressure dipping. Girls also had higher triglyceride concentrations (+23%; P = 0.036). CONCLUSION: There are a number of anthropometric, metabolic and cardiovascular differences between sexes prior to the appearance of external signs of puberty. Although differences in insulin sensitivity were eliminated when adiposity and DHEAS concentrations were accounted for, there were independent differences in body composition and cardiovascular parameters. Thus, gender, adrenarche and adiposity should be accounted for in studies examining metabolic and cardiovascular outcomes prior to puberty.

Hyperemesis gravidarum and long-term health of the offspring.

Nausea and vomiting of pregnancy is a very common occurrence, but the reported incidence of hyperemesis gravidarum (a more severe form of vomiting in pregnancy) is much lower, estimated to vary from 0.3-3.6%. Studies have shown that nausea and vomiting of pregnancy is associated with improved fetal outcomes, such as lower rates of miscarriage. However, there are limited data on outcomes associated with hyperemesis gravidarum, which have focused on pregnancy and neonatal outcomes. Recently, studies showed adverse health outcomes, such as a reduction in insulin sensitivity in childhood and increased incidence of psychological disorders in adulthood. The effects of hyperemesis gravidarum in the offspring need to be further examined throughout childhood, adolescence, and into adulthood, so that long-term disease risks can be evaluated.

Gynecomastia.

Enlargement of breasts among boys is termed gynecomastia. This could be due to an alteration in the androgen-estrogen ratio along with the effects of other hormones including growth hormone, insulin like growth factor 1, prolactin, and other factors affecting aromatase enzyme. The common causes of gynecomastia are pubertal gynecomastia, obesity, drugs and hypogonadism. Several other diseases including liver or renal failure, thyrotoxicosis, Klinefelter syndrome, tumors and environmental pollutants can cause gynecomastia. History and clinical examination will help formulate targeted investigations and management. The factors to be evaluated in these include examination of breasts and testes, in addition to other parts of systemic examination. Treatment of underlying disorders can improve gynecomastia, such as use of testosterone in hypogonadism. Some boys may not need any intervention as gynecomastia may resolve on its own. Medical management is useful in simple gynecomastia. Tamoxifen has been tried successfully in adolescents with gynecomastia. Other drugs including clomiphene, danazol, letrozole and anastrozole have not been consistently useful in this age group. In severe chronic gynecomastia, surgery is the treatment of choice.

Van Wyk Grumbach Syndrome and Ovarian Hyperstimulation in Juvenile Primary Hypothyroidism: Lessons From a 30-Case Cohort.

Context: Prolonged hypothyroidism in children commonly causes short stature with delayed bone maturation, and delayed puberty. However, a paradoxical occurrence of peripheral precocious puberty and pituitary enlargement in chronically untreated juvenile hypothyroidism was first reported by Van Wyk and Grumbach in 1960. Objective: To create increased awareness and a better understanding of this clinical entity among emergency room physicians, pediatricians, surgeons, gynecologists and oncologists. Methods: Case records of children diagnosed with Van Wyk-Grumbach syndrome (VWGS) were analyzed retrospectively. Results: Twenty-six girls and 4 boys were identified (2005-2020). All had profound primary hypothyroidism (total thyroxine [T4]: 2.5-33.5 nmol/L, thyrotropin: > 75-3744 µIU/mL). Hypothyroidism was not the referral diagnosis in any of the girls. Among them, 17 were referred for precocious puberty, 5 with a diagnosis of pituitary tumor on magnetic resonance imaging, and others for acute surgical abdomen in 7 girls (painful abdominal mass-2, ovarian tumor-2, ovarian torsion-2, ruptured ovarian cyst-1), acute myelopathy in 1, and menorrhagia with headache in another. All girls were successfully managed with levothyroxine replacement alone, except for the 2 with ovarian torsion, who required surgery. Menstruation ceased promptly with T4 therapy in all girls, occurring at an age-appropriate later date. All boys had testicular enlargement at presentation that regressed partially after T4 treatment. Catch-up growth was remarkable during the first treatment year, but the final height was compromised in all. Conclusion: Increased awareness of varied presentations of VWGS is vital among pediatricians to facilitate early diagnosis and targeted investigations, and to help in the initiation of the simple yet highly rewarding T4 replacement therapy to avoid all possible complications.

Indian Academy of Pediatrics Revised Guidelines on Evaluation, Prevention and Management of Childhood Obesity.

JUSTIFICATION: The last guidelines for pediatric obesity were released in 2004 by Indian Academy of Pediatrics (IAP). Since then, there has been an alarming increase in prevalence and a significant shift in our understanding in the pathogenesis, risk factors, evaluation, and management of pediatric obesity and its complications. Thus, it was decided to revise and update the previous recommendations. OBJECTIVES: To review the existing literature on the burden of childhood obesity and its underlying etiology and risk factors. To recommend evaluation of childhood obesity and suggest optimum prevention and management strategies of childhood obesity. PROCESS: The following IAP chapters (Pediatric and Adolescent Endocrinology, Infant and Young Child feeding, Nutrition, Non-Communicable Disease and Adolescent Health Academy) were invited to nominate members to become part of the writing committee. The Committee held discussions on various aspects of childhood obesity through online meetings between February and August, 2023. Recommendations were then formulated, which were analyzed, revised and approved by all members of the Committee. RECOMMENDATIONS: Exogenous or primary obesity accounts for the majority of cases of childhood obesity. It is important to differentiate it from endogenous or secondary obesity as evaluation and management changes depending on the cause. In Indian, in children under 5 years of age, weight for length/height using WHO charts, and in children 5-18 years, BMI using IAP 2015 charts is used to diagnose overweight and obesity. Waist circumference should be routinely measured in all overweight and obese children and plotted on India specific charts, as it is a key measure of cardio-metabolic risk. Routine evaluation for endocrine causes is not recommended, except in short and obese children with additional diagnostic clues. All obese children more than ten years old should be evaluated for comorbidities like hypertension, dyslipidemia, hyperglycemia and non-alcoholic fatty liver disease/metabolic dysfunction associated steatotic liver disease (NAFLD/ MASLD). Prevention and management of childhood obesity mainly involves healthy diet practices, daily moderate to vigorous physical activity and reduced screen time. Pharmacotherapy may be offered as an addition to lifestyle interventions only in cases of class 3 obesity or if there are any life-threatening comorbidities. Finally, surgical management may be offered in children older than 12 years of age with class 2 obesity and associated comorbidities or class 3 obesity with/without comorbidities, only after failure of a proper trial of intense lifestyle modifications and pharmacotherapy for at least 6 months.

The Auxological and Metabolic Consequences for Children Born Small for Gestational Age.

'Small for gestational age' (SGA) is an auxological and not an etiological definition that characterizes children born small based upon low-birth-weight and/or birth-length criteria [≥ 2 standard deviations (SD) below the mean for gestational age]. Most SGA children exhibit catch-up growth into the normal range within 6 mo of age. Overall SGA children are 4 cm shorter than expected based upon midparental height and being born SGA is a common cause of adult short stature. Recombinant human growth hormone (rhGH) has been shown to improve adult height by 0.9 SDs and is a safe treatment. Surprisingly, a higher rhGH dose (67 µgm/kg/d) did not lead to a greater adult height than a conventional dose (33 µgm/kg/d). At least 85% of SGA children treated through childhood with rhGH achieve a height within the normal adult range. Other long-term consequences for children born SGA include insulin resistance, abdominal adiposity, dyslipidemia, type 2 diabetes mellitus, and metabolic syndrome. Cross-sectional studies have found reduced insulin sensitivity in the neonatal, childhood, and young adult periods. Increased abdominal fat has been shown in preschool SGA children and is more evident in young adults. Increased adiposity markedly accentuates reduction in insulin sensitivity. Many SGA children have suffered from in utero nutritional restriction that leads to long-term growth restriction and adverse metabolic sequelae.

Clinical application of a novel next generation sequencing assay for CYP21A2 gene in 310 cases of 21- hydroxylase congenital adrenal hyperplasia from India.

PURPOSE: Accurate diagnosis is required for management of Congenital adrenal hyperplasia (CAH). The conventional method for detection of mutations in the CYP21A2 gene is targeted capillary sequencing which is labor intensive and has limited multiplexing capability. Next generation sequencing (NGS) provides data with high sequence coverage and depth. Our objective was to develop an accurate NGS-based assay to characterize the mutation spectrum in CYP21A2 gene in Indian patients suspected to have 21-OH CAH. METHODS: Cases with 21-OH CAH from 12 endocrine units across India were studied. DNA was extracted from proband's and parent's(subset) blood. Locus-specific long-range PCR and gel electrophoresis of amplicons was followed by NGS where no visible 30 kb homozygous/whole gene deletion was observed. Orthogonal confirmation was performed by capillary sequencing (ABI 3500) and Multiplex Ligation-dependent Probe Amplification (MLPA, MRC-Holland). PCR products were purified and individual libraries were pooled and sequenced (Illumina). RESULTS: Of the 310 CAH cases, biallelic mutations (pathogenic/ likely pathogenic variants involving both CYP21A2 gene copies) were detected in 256 (82.6%), heterozygous mutations in 13 (4.2 %), and none in 41 (13.2%). Most common mutation was c.293-13A/C>G (29.03%), followed by 30 kb deletion (18.24%). Thirty samples tested orthogonally (by capillary sequencing or MLPA) showed 100% concordance with NGS assay. Nine novel variants were identified. CONCLUSIONS: We have developed and validated a comprehensive NGS-based assay for detection of variants in CYP21A2 gene in patients with 21-OH CAH. We describe CYP21A2 mutation spectrum and novel variants in a large cohort of Indian patients with CAH.

Severe Familial Hypertriglyceridemia: Successful Treatment With Insulin and a Modified Meal Plan.

CONTEXT: Mutations in genes encoding the lipoprotein lipase enzyme, its cofactor, or transport proteins can cause severe familial hypertriglyceridemia, resulting in serious complications, such as severe pancreatitis, hepatosplenomegaly, lipid encephalopathy, and failure to thrive. Current treatment includes a low-saturated-fat formula enriched with high medium-chain triglyceride (TGs), oral fibrates, omega-3 fatty acids, or plasmapheresis. CASE DESCRIPTION: A 71-day-old infant with very severe hypertriglyceridemia and recurrent pancreatitis associated with a likely pathogenic variant in the LPL gene was treated successfully with insulin infusion and a locally prepared low-fat formula feed after stopping breast milk. Subcutaneous insulin was administered daily from 9 to 30 months of age. His serum TG level was markedly lower, although higher than normal. No episodes of hypoglycemia were noted. Fenofibrate and omega-3 fatty acids were ineffective in this infant. At the last follow-up visit, he was 36 months old and growing normally. He was consuming a special meal plan and receiving insulin injections during high-fat meals. Two other young infants with severe hypertriglyceridemia were growing normally after a short course of insulin infusion and the same modified reduced long chain fat diet. CONCLUSIONS: Insulin is an unusual and affordable therapeutic option for some patients with severe hypertriglyceridemia and can be helpful in the prevention of acute and chronic complications. Locally available cereals and millets with high crude fiber and a low glycemic index, along with medium chain TGs, was used to prepare an economical special formula at home to maintain TG concentrations in the acceptable limits.

Surgically Induced Necrotizing Scleritis Following Strabismus Surgery Treated Successfully with Topical N-acetylcysteine in a Child with Congenital Fibrosis of Extraocular Muscles and Varadi Papp Syndrome.

INTRODUCTION: Surgically induced necrotizing scleritis (SINS) is a rare but serious disorder that can develop many years after strabismus surgery. It is generally treated with high-dose steroids or immunosuppression. CASE REPORT: We describe a patient with Varadi Papp syndrome and congenital fibrosis of the extraocular muscles, who developed surgically induced necrotizing scleritis a month after strabismus surgery and was successfully managed by oral vitamin C and topical N-acetylcysteine 10%. DISCUSSION: While SINS is conventionally treated with steroids/immunosuppression, a conservative approach may be tried in milder cases. The role of topical N-acetylcysteine in managing this complication needs to be explored.

Elimination of pain and improvement of exercise capacity in Camurati-Engelmann disease with losartan.

BACKGROUND: Camurati-Engelmann disease (CED) is a rare disorder, with approximately 250 described cases in the literature. Treatment options are limited and have been suboptimal so far. PATIENT AND METHODS: A prepubertal girl aged 9 years was diagnosed with CED. Treatment with losartan was initiated at a daily dose of 0.75 mg/kg. Over a period of 12 weeks, the dose was gradually increased to 1.0 mg/kg/d. The patient was reviewed in clinic regularly and underwent thorough clinical assessments 9, 17, and 38 months after treatment initiation. RESULTS: The patient experienced marked clinical improvements with losartan. In particular, losartan treatment led to the complete elimination of the previously severe and incapacitating pain, with an increased ability to walk and perform physical activities. There was also a considerable improvement in body composition with increased lean and adipose tissue. Notably, the improvement in fat deposition had not been previously observed with other treatments in CED. Hematology, liver, and renal function tests were within normal ranges at presentation and remained so over the course of treatment. CONCLUSIONS: In light of our findings, losartan may be a useful option in CED management.

First-born children have reduced insulin sensitivity and higher daytime blood pressure compared to later-born children.

BACKGROUND: Evidence suggests that first-born children and adults are phenotypically different to later-born children. Therefore, we aimed to assess whether birth order would be associated with changes in metabolism in childhood. METHODS: We studied 85 healthy prepubertal children aged 4 to 11 years, born 38 to 40 weeks' gestation, and birth weight appropriate for gestational age: 32 first-born and 53 later-born children. Clinical assessments included measurement of children's height, weight, fasting lipid and hormonal profiles, and dual-energy x-ray absorptiometry-derived body composition. Children also underwent 24-hour ambulatory blood pressure monitoring, and frequently sampled intravenous glucose tests with Bergman's minimal model. RESULTS: First-born children were approximately 3 cm taller (height SD scores 0.88 vs 0.39; P = .009) and were slimmer (body mass index SD scores -0.05 vs 0.39; P = .048) than later-born children. Consistent with their taller stature, first-born children also had a 27% increase in IGF-I concentrations (227 vs 173 ng/mL; P = .002). Insulin sensitivity was reduced by 21% among first-borns compared to later-borns (8.4 vs 10.6 × 10(-4)/min/[mU/L]; P = .019). Further, 24-hour ambulatory blood pressure monitoring showed that first-borns had higher daytime systolic (+5 mm Hg; P = .032) and diastolic (+4 mm Hg; P = .029) blood pressure. Blood lipids were unaffected by birth order. CONCLUSIONS: Although first-borns were taller and slimmer, these children had reduced insulin sensitivity and increased daytime blood pressure compared to later-borns. Thus, first-borns may be at a greater risk of metabolic and cardiovascular diseases in adult life. This finding may have important public health implications, in light of a worldwide trend toward smaller families.

Severe hyperemesis gravidarum is associated with reduced insulin sensitivity in the offspring in childhood.

BACKGROUND: Hyperemesis gravidarum alters maternal (and possibly fetal) nutrition throughout pregnancy, but there are no data on long-term effects on offspring metabolism. Thus, we aimed to assess whether severe hyperemesis gravidarum (SHG) affects glucose homeostasis and body composition in the offspring in childhood. METHODS: Healthy prepubertal children (aged 4-11 years) born at term were studied: offspring of mothers who were admitted to hospital with SHG (n = 36) and offspring of mothers from control pregnancies (n = 42). Primary outcome was insulin sensitivity measured using iv glucose tolerance tests and Bergman's minimal model. Other assessments included lipid and hormonal profiles and body composition using whole-body dual-energy x-ray absorptiometry. RESULTS: Insulin sensitivity in SHG children was 20% lower than in controls (8.49 vs 10.60 × 10(-4)·min(-1)·(mU/L); P = .014). SHG children also had higher fasting insulin (6.88 vs 5.04 mIU/L; P = .024) and lower IGF binding protein 1 (11.8 vs 19.0 ng/mL; P = .004) concentrations than controls. Baseline cortisol concentrations were 22% higher in SHG offspring (256 vs 210 nmol/L; P = .021). Children in both groups were anthropometrically similar. CONCLUSION: Children born to mothers who experienced SHG have lower insulin sensitivity, which may increase their long-term risk of developing diabetes mellitus. Follow-up of SHG offspring is essential to determine later risk of metabolic disease.

Pre-pubertal children born post-term have reduced insulin sensitivity and other markers of the metabolic syndrome.

BACKGROUND: There are no data on the metabolic consequences of post-term birth (≥42 weeks gestation). We hypothesized that post-term birth would adversely affect insulin sensitivity, as well as other metabolic parameters and body composition in childhood. METHODS: 77 healthy pre-pubertal children, born appropriate-for-gestational-age were studied in Auckland, New Zealand: 36 born post-term (18 boys) and 41 (27 boys) born at term (38-40 weeks gestation). Primary outcome was insulin sensitivity measured using intravenous glucose tolerance tests and Bergman's minimal model. Other assessments included fasting hormone concentrations and lipid profiles, body composition from whole-body dual-energy X-ray absorptiometry, 24-hour ambulatory blood pressure monitoring, and inflammatory markers. RESULTS: Insulin sensitivity was 34% lower in post-term than in term children (7.7 vs. 11.6 x10⁻4·min⁻¹·(mU/l); p<0.0001). There was a compensatory increase in acute insulin response among post-term children (418 vs 304 mU/l; p=0.037), who also displayed lower glucose effectiveness than those born at term (2.25 vs 3.11 x10⁻²·min⁻¹; p=0.047). Post-term children not only had more body fat (p=0.014) and less fat-free mass (p=0.014), but also had increased central adiposity with more truncal fat (p=0.017) and greater android to gynoid fat ratio (p=0.007) compared to term controls. Further, post-term children displayed other markers of the metabolic syndrome: lower normal nocturnal systolic blood pressure dipping (p=0.027), lower adiponectin concentrations (p=0.005), as well as higher leptin (p=0.008) and uric acid (p=0.033) concentrations. Post-term boys (but not girls) also displayed a less favourable lipid profile, with higher total cholesterol (p=0.018) and LDL-C (p=0.006) concentrations, and total cholesterol to HDL-C ratio (p=0.048). CONCLUSIONS: Post-term children have reduced insulin sensitivity and display a number of early markers of the metabolic syndrome. These findings could have important implications for the management of prolonged pregnancies. Future studies need to examine potential impacts later in life, as well as possible underlying mechanisms.