A comparison of bone age assessments using automated and manual methods in children of Indian ethnicity.

BACKGROUND: Bone age is useful for pediatric endocrinologists in evaluating various disorders related to growth and puberty. Traditional methods of bone age assessment, namely Greulich and Pyle (GP) and Tanner-Whitehouse (TW), have intra- and interobserver variations. Use of computer-automated methods like BoneXpert might overcome these subjective variations. OBJECTIVE: The aim of our study was to assess the validity of BoneXpert in comparison to manual GP and TW methods for assessing bone age in children of Asian Indian ethnicity. MATERIALS AND METHODS: We extracted from a previous study the deidentified left hand radiographs of 920 healthy children aged 2-19 years. We compared bone age as determined by four well-trained manual raters using GP and TW methods with the BoneXpert ratings. We computed accuracy using root mean square error (RMSE) to assess how close the bone age estimated by BoneXpert was to the reference rating. RESULTS: The standard deviations (SDs) of rating among the four manual raters were 0.52 years, 0.52 years and 0.47 years for GP, TW2 and TW3 methods, respectively. The RMSEs between the automated bone age estimates and the true ratings were 0.39 years, 0.41 years and 0.36 years, respectively, for the same methods. The RMSE values were significantly lower in girls than in boys (0.53, 0.5 and 0.47 vs. 0.39, 0.47 and 0.4) by all the methods; however, no such difference was noted in classification by body mass index. The best agreement between BoneXpert and manual rating was obtained by using 50% weight on carpals (GP50). The carpal bone age was retarded in Indian children, more so in boys. CONCLUSION: BoneXpert was accurate and performed well in estimating bone age by both GP and TW methods in healthy Asian Indian children; the error was larger in boys. The GP50 establishes "backward compatibility" with manual rating.

Development of a simplified new method of bone age estimation using three bones of the hand and wrist.

Though the Greulich and Pyle (GP) method is easy, inter-observer variability, differential maturation of hand bones influences ratings. The Tanner-Whitehouse (TW) method is more accurate, but cumbersome. A simpler method combining the above, such that it utilizes fewer bones without affecting accuracy, would be widely used and more applicable in clinical practice. OBJECTIVES: 1. Devising a simplified method utilizing three bones of the hand and wrist for bone age (BA) assessment. 2. Testing whether the 3 bone method gives comparable results to standard methods (GP,TW2,TW3) in Indian children. METHODS: Developmental stages and corresponding BA for radius, hamate, terminal phalanx (left middle finger) epiphyses combining stages from GP,TW3 atlases were described; BA were rated by two blinded observers. 3 bone method ratings were compared with the same dataset analyzed earlier using GP,TW2,TW3 (4 raters). RESULTS: Radiographs analysed:493 (Girls=226). Mean chronological age:9.4 ± 4.6 yrs, mean BA 3 bone:9.8 ± 4.8 yrs, GP:9.6 ± 4.8 yrs, TW3:9.3 ± 4.5 yrs, TW2:9.9 ± 5.0 yrs. The 3 bone method demonstrated no significant inter-observer variability (p = 0.3, mean difference = 0.02 ± 0.6 yrs); a strong positive correlation (p < 0.0001) with GP (r = 0.985), TW3 (r = 0.983) and TW2 (r = 0.982) was noted. Bland-Altman plots demonstrated good agreement; the root mean square errors between 3 bone and GP,TW3,TW2 ratings were 0.6,0.7,0.6 years; mean differences were 0.19,0.49,-0.14 years respectively. Greatest proportion of outliers (beyond ±1.96 SD of mean difference) was between 6 and 8 years age for difference in 3 bone and GP, and between 4-6 years for difference in 3 bone and TW3,TW2. CONCLUSION: The 3 bone method has multiple advantages; it is easier, tackles differential maturation of wrist and hand bones, has good reproducibility, without compromising on accuracy rendering it suitable for office practice.

Rare case of central congenital hypothyroidism due to a TSHß mutation presenting with macro-orchidism.

A male infant was brought to our paediatric endocrine unit with typical clinical features of congenital hypothyroidism (CH) and striking macro-orchidism. On evaluation, free T3, free T4 and thyroid stimulating hormone (TSH) were found to be low, suggestive of congenital CH. Cortisol was within reference range and prolactin was mildly elevated. No suspicious lesions were encountered on neurosonography. On commencing treatment with thyroxine, clinical features of hypothyroidism showed dramatic improvement with regression of testicular enlargement. Genetic analysis revealed deletion of the TSHß gene.Our case highlights a rare presentation of central CH with macro-orchidism in a genetically proven deletion of TSHß gene. Macro-orchidism has been widely reported in IGSF-1 mutations leading to central CH; however, central CH and macro-orchidism have not been reported in association with TSHß deletions.

Field Testing of Synthetic Growth Charts in 1-60-Month-Old Indian Children.

Background: Malnutrition among under-five children (U5C) in India is a major public health problem due to double burden caused by nutritional transition. WHO cut-offs are adopted as global growth standards which define how children should grow in condition of optimal nutrition and health. Growth references which are representative of population-specific existing growth patterns need to be updated regularly which is cumbersome; hence, the author's group published 'synthetic growth references' for Indian children of age 0-18 years. Objectives: The objective of this study is to field test the new synthetic growth references in U5C for height-for-age, weight-for-age and body mass index (BMI)-for-age against WHO charts in urban and rural Indian children to estimate prevalence of various indices of malnutrition. Methods: A cross-sectional anthropometric assessment of apparently healthy rural and urban Indian U5C attending vaccination centre was performed using standard protocols. They were converted to Z-scores using WHO and Indian synthetic growth references. The equality of proportion of parameters of malnutrition was tested by McNemar's test and P value <0.05 was considered significant. Results: WHO charts significantly overestimated stunting and malnutrition as compared to synthetic references with difference in sensitivity of 7.2% and 8.5%, respectively, and converse for over-nutrition by 2.1%. The most commonly affected parameter of malnutrition was underweight. Stunting was significantly higher in rural population using both cut-offs (P < 0.05). Conclusion: The synthetic references limit the spread of weight and BMI and do not overestimate stunting and wasting. They may be more useful for identification of malnutrition and may thus be recommended for routine screening in Indian U5C.

Comparison of insulin sensitivity indices for detection of double diabetes in Indian adolescents with type 1 diabetes.

OBJECTIVES: The role of insulin sensitivity (IS) in the development and progression of metabolic syndrome (MS) in subjects with type-1 diabetes (T1D) is being increasingly recognized. As patients with T1D lack endogenous insulin secretion, measurement of insulin concentration by immunoassay or by indices such as homeostasis model of assessment for insulin resistance (HOMA-IR) is not helpful in assessing IS. Hence, some equations have been developed and validated against data from euglycemic-hyper-insulinemic clamp tests (the gold standard) to estimate IS. 1) To assess IS using available equations (EDC, SEARCH and CACTI) and relationship of IS with MS and microalbuminuria in adolescents with T1D, (2) To compare the predictive value of these equations for detection of MS and derive a cut-off to predict the future risk of development of MS and microalbuminuria and (3) To identify the most accurate non-invasive and easy-to-use equation for detecting patients with double diabetes (DD) in a clinical setting. METHODS: This cross-sectional study included 181 adolescents aged 12-18 years with T1D. Demographic data and laboratory measurements were performed using standard protocols. IS was calculated using following equations:(1) EDC=24.31-12.22×(WHR)-3.29×(hypertension)-0.57×(HbA1c), (2) SEARCH=exp(4.64725-0.02032(waist)-0.09779(HbA1c)-0.00235(Triglycerides), (3)CACTI-exA=exp(4.1075-0.01299×(waist)-1.05819×(insulin dose)-0.00354×(Triglycerides)-0.00802×(DBP)). RESULTS: IS determined by all three methods had significant negative correlation (p<0.05) with MS as well as with microalbuminuria. The cut-off value of 5.485 mg/kg/min by SEARCH method for determining IS had the highest sensitivity and specificity in identifying MS. CONCLUSIONS: IS by SEARCH equation may be used in routine clinical practice to detect DD in Indian adolescents with T1D at risk of developing metabolic as well as microvascular complications.

Rare case of renal Ewing sarcoma presenting as ectopic Cushing syndrome in a 12-year-old girl.

We present a 12-year-old girl with recent onset weight gain and purple striae over the abdomen. Examination revealed her to be hypertensive. On evaluation for Cushing syndrome (CS), her cortisol and adrenocorticotropic hormone (ACTH) were found to be high. MRI brain showed a suspicious lesion (thought to be pituitary microadenoma). Inferior petrosal sinus sampling was not conclusive of pituitary source of ACTH. High dose dexamethasone suppression test confirmed an ectopic source of ACTH secretion and CT scan revealed a mass in the right kidney which was laparoscopically excised. Histopathology and immunohistochemistry confirmed Ewing sarcoma. Our case highlights the rare presentation of renal Ewing sarcoma (RES) as CS. To the best of our knowledge, this is only the second case report of RES/primitive neuroectodermal tumour of the kidney presenting as CS in paediatric age group and first with a concomitant pituitary incidentaloma.

Variable presentations of GCK gene mutation in a family.

We describe siblings born from non-consanguineous parents, with older sibling having asymptomatic hyperglycaemia while younger sibling presented with low birth weight and persistent hyperglycaemia from first month of life. Our case, the older sibling was heterozygous for paternally inherited GCK pathogenic variant resulting in diabetes of maturity-onset in the young (MODY) manifested as mild fasting hyperglycaemia. GCK gene sequencing revealed that the younger sibling was compound heterozygous for missense mutations (two) combined in a novel GCK-permanent neonatal diabetes mellitus (PNDM) genotype. Thus, heterozygous inactivating GCK mutations are likely to lead to maturity-onset diabetes of the young type 2 (MODY 2) and the homozygous inactivating or compound heterozygous GCK mutations are a cause of PNDM.

A pilot study to determine association of parental metabolic syndrome with development of metabolic risk in Indian children, adolescents and youth with Type-1 diabetes.

BACKGROUND AND AIMS: Prevalence of metabolic syndrome (MS) is increasing in children with type-1 diabetes (T1D). Genetic and environmental factors shared among family members are considered significant risk factors. We conducted this study to assess the association of parental MS with development of metabolic risk (MR) in patients with T1D. METHOD: This cross-sectional study included 29 patients with T1D along with their parents (29 triads). Demographic data, anthropometry, blood pressure, biochemical measurements and body composition measurements were performed using standard protocols. Insulin resistance was calculated using estimated glucose disposal rate (eGDR) in patients and using HOMA-IR in their parents. MS was diagnosed using International Diabetes Federation Consensus Definition, 2017. RESULTS: Of total study participants, 44.8% patients with T1D had MR while 25.3% of parents had MS. Low HDL was identified as the most common component of MS. 64.3% patients with T1D, who had parents with MS, had MR. The odds ratio (OR) for development of MR in patients with T1D with parents affected by MS was 4.9 (95% confidence interval 1.0-24.1) while relative risk (RR) was 2.4 (95% confidence interval 0.9-6.1). MR in patients with T1D was found to have a strong correlation with parental MS and also with development of double diabetes (DD). CONCLUSION: In conclusion, parental MS increases the risk of development of metabolic abnormalities in patients with T1D. Thus, positive family history may serve as a useful indicator for targeted screening to detect DD.

Prevalence of nephropathy in Indian children and youth with type 1 diabetes mellitus.

OBJECTIVES: Children with type 1 diabetes (T1D) having diabetic nephropathy (DN) are at increased risk of developing end stage renal disease. The present study aimed to determine the prevalence of DN and its predictors in Indian children and youth with T1D. METHODS: This cross-sectional study included 319 children and youth (2.6-21 years) with T1D having disease duration of at least 2 years. Demographic data and laboratory findings were obtained using standard questionnaires and protocols. Diagnosis of diabetic nephropathy was based on albuminuria on two occasions within a period of 3 months. RESULTS: The prevalence of DN in our study subjects was 13.4%. 7.5% subjects were known cases of diabetic nephropathy on treatment with enalapril. Hypertension was found in 14.3% subjects with DN in contrast to 4.1% without DN (p<0.05). Duration of diabetes and estimated glucose disposal rate were the important predictors of DN. Interestingly, of the 43 children with DN, 11.3% (n=8) were under 10 years age. CONCLUSIONS: We found a high prevalence of DN in children and youth with T1D including in children under the age of 10 years. Early screening and timely intervention are required to retard the disease progression and avoid end stage renal disease.

Prevalence of metabolic syndrome and predictors of metabolic risk in Indian children, adolescents and youth with type 1 diabetes mellitus.

INTRODUCTION: Children with type 1 diabetes (T1D) are at the same risk of developing metabolic syndrome (MS) as the general population. Several environmental factors such as lifestyle, exogenous insulin therapy (over-insulinization) and genetic/familial factors are thought to underlie the phenotype of 'double diabetes' (co-existence of MS components in patients with T1D). OBJECTIVES: To determine the prevalence of overweight/obesity and MS and to identify its predictors in Indian children, adolescents and young adults with T1D. METHODS: This cross-sectional study included 355 children and youth aged 6-23 years with T1D. Demographic data were obtained from patients using questionnaires. Anthropometry, blood pressure, sexual maturity rating, biochemical measurements and body composition measurements were performed using standard protocols. Insulin resistance (IR) was calculated using estimated glucose disposal rate (eGDR) and MS was diagnosed using the international diabetes federation (IDF) consensus definition 2017. RESULTS: The prevalence of overweight/obesity and MS in our study was 15.5% and 4.5%, respectively. Abnormal HDL-cholesterol was the most common component of MS (55.6%) among children with T1D. Age, gender, body mass index (BMI) and eGDR were identified as significant predictors of the likelihood of MS. CONCLUSIONS: We found a similar prevalence of MS in children with T1D as compared to other healthy children, which emphasises the need for monitoring of eGDR to determine IR in these children.

Impact of decreased physical activity due to COVID restrictions on cardio-metabolic risk parameters in Indian children and youth with type 1 diabetes.

BACKGROUND AND AIMS: Implementation of COVID restrictions following lockdown led to changes in routines of subjects with type 1 diabetes due to closure of schools and outdoor activities. The aim of this study was to assess the impact of decreased physical activity due to COVID restrictions on cardio-metabolic risk parameters (waist circumference, laboratory and body composition parameters) in Indian children and youth with T1D. METHODS: This observational study included 312 participants (2-21 years) with T1DM having disease duration of ≥6 months. Demographic, anthropometric, body composition data and investigations were recorded at two time points (during COVID restrictions when children came for follow up, pre COVID restriction data from medical and electronic records). RESULTS: Glycemic control improved during COVID restrictions (Hba1c: 9.8 ± 2.0%) as compared to pre COVID restrictions (Hba1C: 10.0 ± 1.9%) (p < 0.05). However, due to significant reduction in physical activity (p < 0.05) there was significant increase in waist circumference z-scores (-0.9 ± 1.1 vs -1.6 ± 1.1), body fat percentage z-scores (-0.2 ± 1.0 vs -0.3 ± 0.9) and lipid parameters like cholesterol, low density lipid cholesterol and triglyceride concentrations (p < 0.05) without any significant change in body mass index z-scores (p > 0.05). CONCLUSIONS: Prolonged COVID restrictions, although led to modest improvement in glycemic control, there was worsening of cardio-metabolic risk factors or indices of adiposity like waist circumference, body fat percentage and lipid parameters which could be attributed to decreased time spent in physical activity.

Low bone mineral density on DXA and slipped capital femoral epiphysis as rare presentation in a child with Rubinstein-Taybi syndrome.

We present a 7-year-old girl with Rubinstein-Taybi syndrome (RTS) and slipped capital femoral epiphysis (SCFE). She underwent bilateral arthroscopy with implant fixation for the SCFE and the symptoms resolved. This was followed by fracture of the femur after minor trauma. Dual energy X-ray absorptiometry (DXA) scan done to evaluate her bone health revealed a low bone mineral density (BMD). Our case highlights the finding of low BMD on DXA and rare association of SCFE in a child with RTS. The conundrum in this case is whether this child can be labelled to have osteoporosis as defined by the criteria given by the International Society for Clinical Densitometry guidelines.

Long-term follow-up of a child with Wolcott-Rallison syndrome.

Wolcott-Rallison syndrome (WRS), the most common cause of permanent neonatal diabetes mellitus (DM) in consanguineous families, has a poor prognosis, with a mean survival of 5.8 years. Majority of children with WRS succumb to the disease in the first decade of life. We present the long-term follow-up of an 8-year-2-month-old girl with genetically proven WRS who was born to a non-consanguineous parentage. She is on basal bolus regimen of insulin therapy for DM. In addition, she was noted to have features of skeletal dysplasia at 3 years and 3 months of age, which has led to her short stature. Surprisingly, she has had no episodes of hepatitis or liver dysfunction so far, which is frequently seen in children with WRS. To the best of our knowledge, she is the oldest surviving patient with WRS reported in India and South Asia.

Extended growth charts for Indian children.

OBJECTIVES: While growth charts depicting 7 percentile lines for height and weight are useful for healthcare workers and pediatricians, endocrinologists need indication-specific z score cutoffs to plan investigations and treatment. The current Indian charts do not offer lower percentile/z scores (-2.25, -2.5, and -3 z score) lines. Also, increasing prevalence of childhood overweight and obesity necessitates a quick screening of nutritional status without calculations while using the same growth chart. Our objectives were to produce extended and user-friendly growth charts for 0-18-year-old Indian children that depict -2.25, -2.5, and -3 z score height lines in addition to the standard 7 lines and to add a quick BMI assessment tool as an inset. METHODS: LMS values from IAP 2015 growth charts (5-18 years) and WHO 2006 MGRS charts (<5 years) were used to generate -2.25, -2.5, and -3 z score height lines (1.2, 0.6, and 0.1 percentiles, respectively) from 0-18 year for boys and girls. These newly generated lines were added to standard 7 (3, 10, 25, 50, 75, 90, 97) percentile lines for height charts. In addition, modified BMI quick screening tool was incorporated as an inset. RESULTS: The extended height charts (with 10 lines), standard (7 lines) weight charts, and quick BMI assessment tool are presented in a single unified chart for use by endocrinologists. CONCLUSIONS: These charts will help in defining specific height z score cutoffs as well as screen for overweight and obesity without any calculations in Asian Indian children.

Impact of lockdown for COVID-19 pandemic in Indian children and youth with type 1 diabetes from different socio-economic classes.

OBJECTIVES: In March 2020, lockdown was imposed in India to combat spread of Coronavirus, which was extended till 31st May. Implementation of lockdown and limited outdoor activities resulted in changes in routines of children with diabetes. The aim of this study was to assess the impact of lockdown on glycemic control, weight and body mass index (BMI) patterns of children with type 1 diabetes (T1DM) from different socio-economic (SE) classes. METHODS: This observational study included 77 children and youth (5-20 years) with T1DM having disease duration of ≥6 months. Demographic data and investigations were recorded at two time points (post lockdown when the children came for follow up, pre lockdown data from medical records). RESULTS: Glycemic control improved (pre lockdown HbA1C 79.4±19.2 vs. post lockdown Hba1C 74.5±16.9 mmol/mol, p<0.05) and there was weight gain post lockdown (pre lockdown weight z-score -0.4±0.8 vs. post lockdown weight z-score -0.2±0.8, p<0.05) without any significant change in BMI and insulin requirements. Improved glycemic was seen in the lower SE group control post lockdown (p<0.05), whereas in higher SE group, it remained unchanged. Children whose parents were at home during lockdown showed an improved glycemic control (p<0.05) as compared to children whose parents continued to work during lockdown (p>0.01). CONCLUSIONS: During coronavirus lockdown, glycemic control was adequately maintained in children with T1DM, highlighting importance of stronger family support system leading to more steady daily routine.

Endocrinological Management of Sellar and Supra-Sellar Tumors in Children.

CNS tumours and their treatment commonly lead to endocrinopathies in children. Advances in surgical techniques, chemotherapy and radiotherapy have improved the survival in children with CNS tumours however they have also added to the late effect burden. Since the pituitary and hypothalamus regulate many important bodily functions, loss in their function leads to major derangements in growth and hormonal milieu. This article is a review of clinical presentation, diagnosis and management of endocrinopathies encountered in common sellar and supra-sellar CNS tumours in children. The management is divided into mainly two sections: immediate (peri and post-operative) and long term.

Comprehensive evaluation of bone health using DXA and pQCT in an Indian boy with osteogenesis imperfecta.

We present a 9-year-old male child having history of fractures on trivial trauma with a family history of the same. He was treated for osteogenesis imperfecta (OI; zolendronate, calcium and vitamin D) and showed clinical improvement. On evaluating his bone health using dual energy X-ray absorptiometry and peripheral quantitative CT, we found that the child had bone density within the reference range but a smaller bone mass for his height, low muscle mass and thin bones with a lower strength strain index in comparison with healthy children. Our case suggests that treatment with bisphosphonates results in increase in bone density; however, bones remain thin and the lean body mass in these children may also be low. Controlled physical activity to improve muscle health and newer approaches to improve bone geometry would result in better bone health in children with OI.

Turner Syndrome Growth Charts: A Western India Experience.

BACKGROUND AND OBJECTIVES: Disease specific growth charts are useful to monitor growth and disease progress in specific disorders such as Turner syndrome. As there is a paucity of data on spontaneous growth of Indian girls with Turner syndrome, the objectives were to construct reference curves for height and assess height velocity in Indian girls with Turner syndrome from 5 centers from western India. MATERIAL AND METHODS: Three hundred forty-eight readings of height and weight on 113 genetically proven girls with Turner Syndrome from 5 centers from western India were collected and retrospectively analyzed. Data were collected over the last 2 decades (GH treatment naive girls were included). The method described by Lyon et al. was used to compute smoothed standard deviations and percentiles for height. For computing growth velocities, longitudinal data were used on 104 untreated girls (longitudinal readings for height for a minimum of 3 years were used). Midparental height z scores (MPHZ) were computed. RESULTS: In girls with Turner syndrome, the mean adult height was found to be 140.1 cm. Height velocity was low at all ages compared to normal girls with a notable difference beyond the age of 10 years where normally, a growth spurt is expected. The MPH Z-score correlated positively with the height Z-score. The 3rd, 50th, and 97th height percentiles of Turner girls at all ages were lower than normal girls' charts. CONCLUSION: Turner syndrome charts for height are presented; these charts may be used to monitor growth in girls with Turner syndrome.