Beyond HbA1c: Identifying Gaps in Glycemic Control Among Children and Young People with Type 1 Diabetes Using Continuous Glucose Monitoring.

OBJECTIVES: To describe continuous glucose monitoring (CGM) derived glycemic variables, and study their association with HbA1c and socio-economic factors in young people with Type 1 diabetes mellitus (T1DM). METHODS: Ninety-two participants [age 15.7 ± 5.0 y (mean ± SD), HbA1c 8.0 ± 1.5% (mean ± SD)] wore a professional CGM sensor for 14 d. RESULTS: Median (IQR) time in range (TIR) was 41 (18)%. Participants spent 41 ± 20% of their day in hyperglycemia (>180 mg/dl), and 14 (13)% in hypoglycemia (<70 mg/dl). High glycemic variability (percent CV >36%) was seen in 92% participants. Older age at diagnosis was associated with higher TIR (ß = 0.267, p = 0.01), lower time above range (TAR) (ß = -0.352, p <0.001), but higher time below range (TBR) (ß = 0.274, p = 0.006). The use of NPH vs. glargine basal insulin was associated with higher TBR (ß = -0.262, p = 0.009) but lower TAR (ß = 0.202, p = 0.041). HbA1c showed negative correlation with TIR (r = -0.449, p <0.001) and TBR (r = -0.466, p <0.001) and positive correlation with TAR (r = 0.580, p <0.001) and mean glucose (r = 0.589, p <0.001). CONCLUSIONS: These data demonstrate wide gaps between the recommended vs. real world glycemic variables in patients with T1DM in this region on multiple daily insulin injections. CGM identifies glycemic variability and complements HbA1c in improving glycemic control.

Clinico-pathologic profile and outcomes of pediatric endocrine patients managed by endocrine surgeons: Experience over three decades in a tertiary center in India.

BACKGROUND: Pediatric endocrine disorders requiring surgical intervention are rare and so are experienced surgeons dealing with these. The aim of the current study was to investigate disease profile and perioperative outcome of pediatric patients with surgical endocrine disorders in an endocrine surgery unit. METHODS: This retrospective study (Sep 1989-Aug 2019) consisted of pediatric endocrine surgery patients (<18 years) who were managed by a team of pediatric endocrinologists and endocrine surgeons at our center. Patients were divided into three cohorts consisting of a decade each. Clinico-pathologic variables, perioperative events operative and follow-up details were recorded. RESULTS: A total of 332 children were included and their mean age was 14.6 ± 3.9 years (M:F = 1:1.6). Thyroid disorders were most prevalent (59.8%), followed by adrenal (28.2%), parathyroid (10.4%), and pancreas (1.5%). Incidence of benign, malignant, and congenital/developmental disorders were 65.4, 28.1 and 8.3, respectively. Familial association was observed in 8.9% children, which is highest among pheochromocytoma patients. Overall, 201 thyroidectomies + associated procedures, 35 parathyroidectomies, 96 adrenal and paraganglioma resections, and 5 pancreatic procedures were performed. Median hospital stay was 5.6 ± 4.1 days. The number of cases increased significantly over 3 decades. Clinical profile and outcome did not vary except for significant decrease in incidence of malignant pathology (p = 0.04) and increase in VHL cases (p = 0.04) in the last decade though overall increase in familial cases was nonsignificant (p = 0.11). No perioperative mortality was observed except for 3% after adrenalectomy. CONCLUSION: A team of dedicated endocrine surgeons and pediatric endocrinologists is effective in management of pediatric endocrine surgery.

Basic carbohydrate counting and glycemia in young people with type 1 diabetes in India: A randomized controlled trial.

OBJECTIVES: The aim of this study was to evaluate the effect on glycemic control and acceptability of basic carbohydrate counting (BCC) in children and young adults with type 1 diabetes (T1DM). METHODS: Ninety-two children and young adults (6-25 y of age) with T1DM were randomized to receive either routine nutrition education (RNE), which addressed food groups, glycemic index, and effects of food and exercise on glycemia, or learn BCC with personalized portion size education. A continuous glucose monitoring study and glycosylated hemoglobin (HbA1c) were performed at baseline and after 12 wk. The primary outcome was a change in time-in-range from baseline through 12 wk. A questionnaire on the acceptability of BCC was administered. RESULTS: At 12 wk, there was no significant difference in change in time-in-range between the two groups (BCC group: 1.2 ± 12.2; RNE group: 1.9 ± 12.3; P = 0.786). No significant changes were observed in the percentage of time that blood glucose was >180 or >250 mg/dL; <70 or <54 mg/dL; glycemic variability, percentage of nights with hypoglycemia and HbA1c. In subgroup analysis, there was a significant decrease in HbA1c in the BCC group among participants with higher maternal education (-0.5 versus 0.2, P = 0.042). The total score on the acceptability questionnaire was higher in the BCC group (P = 0.022). CONCLUSION: Among children and young adults in our region with T1DM, BCC provided flexibility in food choices and perception of greater ease of insulin adjustment. Although BCC was equivalent to RNE in terms of glycemic control, larger studies may reveal benefit in outcomes in certain subgroups.

School-time Hyperglycemia and Prolonged Night-Time Hypoglycemia on Continuous Glucose Monitoring in Children With Type 1 Diabetes.

OBJECTIVE: To document glycemic patterns during school and sleep by continuous glucose monitoring system (CGMS) in school-going children with type 1 diabetes. To correlate glycemia with meal composition. METHODS: Patients with type 1 diabetes (n = 22) aged 4 to 19 years were enrolled. Food recording was taught, and a retrospective CGMS sensor was worn by them for 6 to 14 days. Dietary composition and glycemic patterns during school and sleep were analyzed. RESULTS: The mean (SD) of dietary carbohydrate was 62.9 (9.2)% of daily calories (high) and protein 13 (2.5) % (low). Sensor glucose > 180 mg/dL (hyperglycemia) was detected on 73% of 139 school day CGMS records and involved 58 % of the school time. Sensor glucose < 70 mg/dL (hypoglycemia) was present on 45% of 172 nights. Time below range was 20 (25) %. Mean (SD) protein content (g) of dinner was significantly higher when it included lentil (dal) than without [20.4 (9.7) vs 15.3 (8.3); P < 0.001]. Hypoglycemia occurred less often on nights with vs without dal for dinner (42.1% vs 51.7%; P = 0.048). CONCLUSIONS: Hyperglycemia during school hours was notable. The inclusion of lentil (dal) in the night meal in the traditional diet may reduce nocturnal hypoglycemia.

High Frequency of Recessive WFS1 Mutations Among Indian Children With Islet Antibody-negative Type 1 Diabetes.

BACKGROUND: While the frequency of islet antibody-negative (idiopathic) type 1 diabetes mellitus (T1DM) is reported to be increased in Indian children, its aetiology has not been studied. We investigated the role of monogenic diabetes in the causation of islet antibody-negative T1DM. METHODS: We conducted a multicenter, prospective, observational study of 169 Indian children (age 1-18 years) with recent-onset T1DM. All were tested for antibodies against GAD65, islet antigen-2, and zinc transporter 8 using validated ELISA. Thirty-four islet antibody-negative children underwent targeted next-generation sequencing for 31 genes implicated in monogenic diabetes using the Illumina platform. All mutations were confirmed by Sanger sequencing. RESULTS: Thirty-five (21%) children were negative for all islet antibodies. Twelve patients (7% of entire cohort, 34% of patients with islet antibody-negative T1DM) were detected to have pathogenic or likely pathogenic genetic variants. The most frequently affected locus was WFS1, with 9 patients (5% of entire cohort, 26% of islet antibody-negative). These included 7 children with homozygous and 1 patient each with a compound heterozygous and heterozygous mutation. Children with Wolfram syndrome 1 (WS) presented with severe insulin-requiring diabetes (including 3 patients with ketoacidosis), but other syndromic manifestations were not detected. In 3 patients, heterozygous mutations in HNF4A, ABCC8, and PTF1A loci were detected. CONCLUSION: Nearly one-quarter of Indian children with islet antibody-negative T1DM had recessive mutations in the WFS1 gene. These patients did not exhibit other features of WS at the time of diagnosis. Testing for monogenic diabetes, especially WS, should be considered in Indian children with antibody-negative T1DM.

Feminizing adrenocortical oncocytoma presenting as precocious puberty: a case report and literature review.

OBJECTIVES: Feminizing adrenal tumors are rare in childhood. We present a case of a special category of adrenal tumor, an oncocytoma, causing isosexual peripheral precocity. CASE PRESENTATION: A 4-year old girl presented with breast development and menstrual bleeding over a period of 3-4 months. Her SMR staging was breast stage 4, pubic hair stage 3. Her bone age was advanced (6 year 10 months), stimulated LH 0.7 IU/L, estradiol 206 pmol/L and DHEAS >27.1 micromol/L. CT scan revealed a right adrenal mass with features of atypical adrenal adenoma. Laparoscopic adrenalectomy was done and histopathology revealed oncocytoma. Lin-Weiss-Bisceglia criteria classified it as likely benign, borne out till a 2 year follow up. CONCLUSIONS: Adrenal oncocytoma can be a cause of isosexual peripheral precocity in a young girl. Recognition and correct classification of this histological variant, which is more often benign, is important for prognostication and choice of therapy after surgery.

Vitamin D Status in Children on Anticonvulsant Therapy.

OBJECTIVE: To assess vitamin D status of children on long-term anticonvulsants, including the less studied widely used levetiracetam, and the potential risk factors for deficiency. METHOD: Children on antiepileptic drugs (cases, n = 269) were compared with controls (n = 295) for serum biochemistry, 25OHD, parathormone (PTH), sun exposure, dietary calcium, and vitamin D intake. RESULTS: Cases had lower serum 25OHD [median (IQR) 18.4 (11.5-24.1) ng/mL] compared to controls [20.8 (15.4-26.2] ng/mL, p < 0.001), as well as more frequent vitamin D deficiency (25OHD < 12 ng/mL, 27.1%) and insufficiency (25OHD < 20 ng/mL, 57.6%) than did controls (11.2% and 46.1%, respectively). Significantly lower median (IQR) serum calcium [8.8 (8.1-9.4) vs. 9.2 (8.5-10.0) mg/dL], phosphorous [3.8 (3.3-4.2) vs. 4.7 (4.0-5.3) mg/dL), and higher PTH [58.4 (42.9-85.8) vs. 38.9 (24.6-55.5) pg/mL, p < 0.001 for all] and proportion of elevated alkaline phosphatase (11.2% vs. 5.1%, p < 0.01) was seen in cases versus controls. Vitamin D deficiency was present in 53.4% of children with cerebral palsy (CP) versus 19.9% in those without CP (p < 0.001). Serum 25OHD did not differ between patients on cytochrome P450 inducers versus noninducers, neither among the 3 major groups, users of carbamazepine, valproate, and levetiracetam. Logistic regression analysis showed serum 25OHD < 12 ng/mL to be independently influenced by case or control status, presence of CP, and season of sampling. CONCLUSION: Vitamin D deficiency is common with anticonvulsant therapy, especially in those having CP. In Kerala, the hot, dry season from March to May is protective.

Relative Adrenal Insufficiency in Decompensated Cirrhotic Children: Does It Affect Outcome?

INTRODUCTION: Relative adrenal insufficiency (RAI) is associated with poor outcome in adult cirrhotics. So far, pediatric studies are not available on the same. We aimed to prospectively study the presence and outcome of RAI in children with decompensated cirrhosis over 180 days. METHODS: Hemodynamically stable children with decompensated cirrhosis were sampled for serum basal cortisol and peak cortisol (after 30 minutes of 1-µg intravenous Synacthen) at day 1 and day 21. RAI was diagnosed as peak cortisol <500 nmol/L. Serum cytokines (interleukin-6 and tumor necrosis factor-α) and lipid profile were correlated with RAI. Cohort was followed up for outcomes over 180 days for complications and survival. With the identified risk factors, prognostic models were derived and compared with pediatric end-stage liver disease (PELD) and Child-Turcotte-Pugh scores. RESULTS: Prevalence of RAI was 54% at baseline and 61% at day 21 in the enrolled patients (n = 63, aged 128 ± 48 months, male 78%). No significant differences in cytokines and serum lipid levels were seen between RAI and normal adrenal function groups. Patients with RAI at baseline (D1-RAI) developed higher complications at follow-up as compared to the normal adrenal function group (53% vs 24%, P = 0.02). The PELD score (odds ratio 1.08, confidence interval 1.05-1.12, P < 0.01) and D1-RAI (odds ratio 3.19, confidence interval 1.32-7.73, P = 0.01) were independent predictors of follow-up complications. The PELD-delta cortisol model (area under the receiver operating curve 0.84, P < 0.001, 92% sensitivity; 60% specificity) predicted morbidity better than isolated PELD or Child-Turcotte-Pugh scores. DISCUSSION: RAI is a risk factor for development of complications in pediatric cirrhosis over short-term follow-up. The PELD-delta cortisol score is a promising prognostic model for predicting follow-up complications.

Prevalence and epidemiological profile of celiac disease in children with type 1 diabetes mellitus: Experience from a tertiary care center of India.

BACKGROUND: The HLA associations of celiac disease (CD) in north Indians differ from that in Europeans. Our dietary gluten is among the highest in the world. Data on CD in people with diabetes (PWD) in north India is scant. OBJECTIVE: To estimate the prevalence and clinical profile of CD in children with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: Retrospective review of case records of PWD with onset ≤18 years of age, registered between 2009 and 2020, having at least one anti tissue-transglutaminase (anti-tTG) serology report. RESULTS: Of 583 registered PWD, 398 (68.2%) had celiac serology screening. A positive report was obtained in 66 (16.6%). Of 51 biopsied people, 22 (5.5%) were diagnosed to have CD, 12 in the first 2 years of diabetes onset. Symptomatic CD at diagnosis was seen in 63% (14/22). Age at diabetes onset (median [IQR] age 5.5 years, [2-12]) was lower in PWD and CD compared to PWD alone (10 years, [7-14], p < 0.016). Of 36 biopsied children with anti-tTG >100 au/ml, 20 (55.5%) had CD, while 2 out of 15 (13.3%) of those with lower anti-tTG titer had histopathology suggestive of CD. Of 23 seropositive children not diagnosed with CD, 5 of 8 with anti tTG >100 au/ml, and all 15 with lower anti-tTG, had normalization of titers over the 24 (10-41) months. CONCLUSIONS: Our prevalence of CD is comparable to international data. Celiac disease was common with younger age at onset of T1D and higher titer of celiac serology. A high proportion was symptomatic of CD at diagnosis.

Vitamin D Status of School-Age Children in North India.

Information on vitamin D deficiency in prepubertal children is scarce. The authors studied calcium intake, sunlight exposure, serum calcium, alkaline phosphatase, 25-hydroxyvitamin (25OHD), and intact parathormone (iPTH) in the children (N = 135) attending the pediatric endocrinology clinic (declared normal after evaluation) and their healthy siblings. Serum 25OHD < 12 ng/mL was frequent (55.6%) and median (IQR) 25OHD lower [10.1 (11.4) ng/mL] in pubertal (n = 36) versus prepubertal (n = 99) children [36.4% (p < 0.05), 15.5 (13.2) ng/mL (p < 0.001)]. Girls had lower 25OHD [12.33 (10.32)] vs. [15.83 (13.37) ng/mL, p < 0.05], calcium intake [517.20 (405.5) vs. 623.6 (430.5) mg, p < 0.05], and minutes of sunlight exposure [MSE, 38.55 (42.86) vs. 63.4 (66.8) min, p < 0.01] than boys. MSE and body surface area (BSA) exposed were significant associations of 25OHD in a multivariate model. Vitamin D deficiency in children, both pubertal and prepubertal, assumes public health importance in the authors' region. Girls are at higher risk. Duration of sunlight exposure and BSA are modifiable factors.

Neonatal Diabetes Mellitus: Novel Mutations.

OBJECTIVE: To describe the spectrum of neonatal diabetes mellitus (NDM), document new mutations, and review published Indian literature on the etiology of NDM. METHODS: Retrospective analysis of the clinical and genetic profile of 12 NDM patients. RESULTS: Eight patients presented with NDM before the age of 6 mo. Three other patients, including 2 siblings presented in later part of infancy. An additional patient was diagnosed at age 5 y with the same etiology as her infant sibling. Four patients had transient diabetes [TNDM:1 each with a mutation in KCNJ11 and INS gene, 2 with ABCC8 mutation], 7 had permanent diabetes [PNDM: 2 siblings with complete glucokinase deficiency, 2 siblings with thiamine responsive megaloblastic anemia (TRMA), 1 with Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome and 2 with Wolcott Rallison syndrome, (WRS)]. Four patients had 5 novel mutations. Genetic etiology could not be established in 1 patient with features of insulin resistance. Poorly controlled blood glucose in the TRMA patient led to hyperglycemia-induced hemichorea-hemiballismus, a rare manifestation in children. CONCLUSIONS: The authors describe 5 novel mutations, in the EIF2AK3, ABCC8, and GCK genes, a homozygous mutation at the ABCC8 locus presenting as TNDM, an obscure phenotype of the GCK gene mutation, and hyperglycemia-induced hemichorea-hemiballismus in a patient with TRMA. In India, PNDM is most commonly due to WRS similar to Middle Eastern countries with high consanguinity rates.

Pediatric Primary Hyperparathyroidism: Experience in a Tertiary Care Referral Center in a Developing Country Over Three Decades.

BACKGROUND: There is limited experience in managing pediatric primary hyperparathyroidism (PHPT). The aim of this study was to analyze the clinical presentation and outcome of surgery in children with PHPT managed at a tertiary referral center. METHODS: This retrospective study (September 1989-August 2019) consisted of 35 pediatric PHPT patients (< 18 years) who underwent parathyroidectomy. Clinico-pathologic profile and outcome were noted. RESULTS: The mean age of cohort was 15.2±2.9 years and girls outnumbered boys (M:F = 1:1.9). Familial and symptomatic disease was noted in 8.5 and 94.3% cases, respectively. Skeletal manifestations (83%) were the commonest followed by renal (29%). Fifty-four percent children had skeletal fractures, and 23% were bed-ridden. Among rare manifestations, hypercalcemic crisis, recurrent pancreatitis and stigmata of rickets were observed in 2.8, 11.4 and 14.2% children, respectively. Mean calcium concentration was 12.1 ± 2.0 mg/dl and PTH 91.8 ± 66.5 pmol/L. The sensitivity of preoperative imaging in parathyroid localization was 91.4%. Minimally invasive parathyroidectomy (MIP) was performed in 40% cases. Parathyroid adenoma was observed in 91.4% patients, whereas remaining had hyperplasia. Thirty-four percent suffered from Hungry bone syndrome in postoperative period. The cure rate following primary surgery was 97%. One child with persistent PHPT had successful re-operation. Median follow-up was 5 (1-17) years, and no recurrence or familial disease was revealed during this period. CONCLUSION: Majority of pediatric patients present with symptomatic PHPT. Despite relatively high incidence of familial disease select pediatric patients can undergo successful MIP.

High prevalence of idiopathic (islet antibody-negative) type 1 diabetes among Indian children and adolescents.

OBJECTIVES: To study the prevalence and clinical characteristics of islet antibody-negative (idiopathic) type 1 diabetes mellitus (T1DM) among Indian children and adolescents at the time of diagnosis of illness. METHODS: In a hospital-based cross-sectional study, we studied 110 patients with T1DM aged ≤18 years. This included 61 patients with duration of diabetes ≤2 weeks (mean ± SD age of onset 9.9 ± 4.4 years) and 49 patients with duration 2 to 12 weeks. Antibodies against GAD65 (GADA), IA-2 (IA-2A) and zinc transporter 8 (ZnT8A), detected by radio-binding assay, were measured in all patients. Insulin autoantibody (IAA) was measured only in subjects with duration ≤2 weeks, using a competitive radio-binding assay. RESULTS: The prevalence of GADA, IA-2A, and ZnT8A was 53%, 34%, and 29% respectively, while IAA (measured in 61 patients) was detected in 31%. All four antibodies were absent in 17 of 61 (28%) patients. The prevalence of islet antibody-negative patients was similar among both sexes and in children with onset younger and older than 10 years. ZnT8A was the only antibody detected in four patients, and its measurement resulted in 6% reduction in islet antibody-negative patients. Patients with idiopathic T1DM did not differ in their clinical features or fasting plasma C-peptide at the onset and after follow-up of 1 year. Compared with idiopathic T1DM, antibody-positive patients had an increased allele frequency of HLA DRB1*0301 (46% vs 14%, OR = 5.10 [confidence interval = 1.61-16.16], P = .003). CONCLUSION: Nearly 30% of Indian patients were negative for all islet antibodies at the onset of T1DM. Patients with idiopathic T1DM had similar clinical features to antibody-positive subjects.

Influence of Socio-Economic and Cultural Factors on Type 1 Diabetes Management: Report from a Tertiary Care Multidisciplinary Diabetes Management Center in India.

OBJECTIVE: To study the association of socio-economic (SE) and cultural factors with HbA1c and diabetes knowledge of children, adolescents and young adults with T1DM managed in the authors' centre, as these may be unique to a country or a region. METHODS: Demographic details, SE scoring, body mass index and mean of the last two HbA1c values were recorded, in 173 eligible patients. A diabetes knowledge test (DKT) was administered. RESULTS: Median (range) age was 14.0 (3.25-25.5) y and HbA1c 8.2 ± 1.3%. The patients travelled a median of 124 (range 0.5-850) km and 2.3 (range 0.1-18.3) h each way, to reach the clinic. Only 2 children took insulin at school / college. Insulin adjustment for pre-meal blood glucose was practiced by 88%, but adjustment for meal intake by only 17% patients. Median HbA1c was lower in the participants with age > 18 y [7.7 (5.6-11.0) %] vs. < 10 y [8.3 (6.3-10.6) %, p < 0.02] or 10-18 y [(8.3 (5.9-12.6) %, p < 0.02)]. Overweight /obesity were seen in 35%. On multivariate regression, HbA1c was associated negatively with DKT score (DKTS) and age group, and DKTS was associated positively with urban residence and maternal education > class 12th. HbA1c and DKTS were not associated with income. CONCLUSIONS: Low income may be successfully compensated by other factors to obtain good glycemic control. HbA1c did not deteriorate in adolescence in contrast to world experience. Overweight is a worrisome problem. Improved societal awareness about childhood diabetes is crucial.

Vitamin D status of children in Kerala, southern India.

OBJECTIVE: To study plasma 25-hydroxyvitamin D (25(OH)D) status of children in Kerala, southern India, and its relationship with sociodemographic variables. DESIGN: Cross-sectional observational study. SETTING: Tertiary government hospital. PARTICIPANTS: Children (n 296) with trivial acute illness were enrolled. Sun exposure and Ca and vitamin D intakes (7 d dietary recall) were documented. Serum Ca, P, alkaline phosphatase, plasma 25(OH)D and parathyroid hormone (PTH) were measured. RESULTS: Prevalence of vitamin D deficiency (plasma 25(OH)D <30 nmol/l) was 11·1% (median, interquartile range (IQR): 52·6, 38·4-65·6 nmol/l). Children who ate fish daily had significantly higher plasma 25(OH)D than those who did not (median, IQR: 52·5, 40·8-68·9 v. 49·1, 36·2-60·7 nmol/l; P = 0·02). Those investigated in the months of March-May showed highest 25(OH)D v. those enrolled during other times (median, IQR: 58·7, 45·6-81·4 v. 45·5, 35·6-57·4 nmol/l; P <0·001). Plasma 25(OH)D correlated positively with serum P (r = 0·24, P <0·001) and Ca intake (r = 0·16, P 0·03), negatively with age (r = -0·13, P 0·03) and PTH (r = -0·22, P <0·001.). On linear regression, summer season (March-May), lower age, daily fish intake and higher Ca intake were independently associated with plasma 25(OH)D. CONCLUSIONS: Prevalence of vitamin D deficiency is low in Kerala. The natural fish diet of coastal Kerala and the latitude may be protective. Public health policy in India should take account of this geographical diversity.