Clinical, radiological and molecular studies in 24 individuals with Dyggve-Melchior-Clausen dysplasia and Smith-McCort dysplasia from India.

BACKGROUND: Dyggve-Melchior-Clausen dysplasia (DMC) and Smith-McCort dysplasia (SMC types 1 and 2) are rare spondyloepimetaphyseal dysplasias with identical radiological findings. The presence of intellectual disability in DMC and normal intellect in SMC differentiates the two. DMC and SMC1 are allelic and caused by homozygous or compound heterozygous variants in DYM. SMC2 is caused by variations in RAB33B. Both DYM and RAB33B are important in intravesicular transport and function in the Golgi apparatus. METHODS: Detailed clinical phenotyping and skeletal radiography followed by molecular testing were performed in all affected individuals. Next-generation sequencing and Sanger sequencing were used to confirm DYM and RAB33B variants. Sanger sequencing of familial variants was done in all parents. RESULTS: 24 affected individuals from seven centres are described. 18 had DMC and 6 had SMC2. Parental consanguinity was present in 15 of 19 (79%). Height <3 SD and gait abnormalities were seen in 20 and 14 individuals, respectively. The characteristic radiological findings of lacy iliac crests and double-humped vertebral bodies were seen in 96% and 88% of the affected. Radiological findings became attenuated with age. 23 individuals harboured biallelic variants in either DYM or RAB33B. Fourteen different variants were identified, out of which 10 were novel. The most frequently occurring variants in this group were c.719 C>A (3), c.1488_1489del (2), c.1484dup (2) and c.1563+2T>C (2) in DYM and c.400C>T (2) and c.186del (2) in RAB33B. The majority of these have not been reported previously. CONCLUSION: This large cohort from India contributes to the increasing knowledge of clinical and molecular findings in these rare 'Golgipathies'.

Genotype-phenotype correlation of KATP channel gene defects causing permanent neonatal diabetes in Indian patients.

BACKGROUND: There are very few reports pertaining to Indian patients with neonatal diabetes mellitus (NDM). Activating or gain of function mutations of KATP channel genes namely KCNJ11 and ABCC8 are most predominant cause of permanent neonatal diabetes mellitus (PNDM). OBJECTIVES: To identify the genotype-phenotype correlation of KATP channel gene defects in a large series of (n = 181) Indian PNDM patients. METHODS: Direct sequencing of all exons of KCNJ11 and ABCC8 genes in all 181 patients with PNDM were performed. Clinical and biochemical data were collected. RESULTS: We have identified the molecular basis of KATP -NDM in 39 out of 181 patients (22%). Of these, 20 had KCNJ11 mutations and 19 had ABCC8 mutations, thus comprising 51% of KCNJ11 and 49% of ABCC8. There were four novel mutations (D1128Tfs*16, Y1287C, S1422T, and H1537R) in ABCC8 gene. Three patients with KCNJ11 mutations had developmental delay with DEND syndrome. In patients with ABCC8 mutations developmental delay was seen in seven out of 19 (36.8%). Of this, three patients (15.7%) had DEND phenotype and four (21%) had iDEND. Of the 39 patients, 33 (84%) patients were shifted to sulfonylurea therapy (glibenclamide). Of this, 19(57.5%) patients harbored KCNJ11 mutations and 14(42.1%) ABCC8 mutations. CONCLUSIONS: This is the first largest study in NDM patients in India demonstrating the importance of KATP channel gene mutation screening in PNDM and efficacy of glibenclamide for Indian patients with KATP -PNDM. The success rate of transfer is more in patients with KCNJ11 mutations compared with those with ABCC8 mutations.

Use of Continuous Glucose Monitoring System in Children with Type 1 Diabetes Mellitus in a Resource Limited Setting.

Background: Regular self-monitoring of blood glucose (SMBG) remains the mainstay method for diabetes monitoring. The major limitation of SMBG is poor compliance and it only provides a snapshot of glucose values at that point of time. Continuous glucose monitors (CGMs) are non-invasive devices which measure subcutaneous interstitial glucose for every five minutes and provide glucose variability throughout the day. Aim and Objective: To assess the effectiveness of intermittent continuous blood glucose monitoring in comparison with SMBG on the percentage reduction in HbA1c level in children with type 1 diabetes mellitus (DM). Methods: Children diagnosed with type 1 DM of age group 3-18 years were enlisted into the study. Participants were randomised to the study arm (CGMs+SMBG) or the control arm (SMBG alone). Subjects in the study group were given CGM along with regular SMBG for 14 days. The control group was asked to perform SMBG. HbA1c levels were measured in both groups after three months of intervention. Results: There were 62 children in each group. After three months, in the intervention group HbA1c level dropped from 11.23% ± 1.53% (Mean ± SD) to 10.14% ± 1.99%, in control group HbA1c level dropped from 11.62% ± 1.62% to 11.32% ± 1.57%. The fall in HbA1c level in intervention group is significant (p value -0.01). Conclusion: In a resource-limited setting, intermittent use of CGMs atleast once every two to three months will help in understanding the factors influencing glucose variation throughout the day and, with appropriate therapeutic modifications, will aid in achieving optimal glycaemic control.

Nutritional Status of Underprivileged Indian Children and Youth with Type-1 Diabetes - A Multicentre Study.

Background: India has the highest number of prevalent type-1 diabetes (T1D) cases in the under-20-year age population. Data on the anthropometry of underprivileged Indian children with T1D are scarce. In economically disadvantaged countries like India, poor growth in patients with T1D is a major concern due to limited accessibility and affordability. Besides, due to the double burden of malnutrition, the prevalence of obesity is increasing mirroring the global trends, which may lead to the development of insulin resistance. Objectives: This study aims to assess the prevalence of malnutrition in Indian children and youth with T1D and to identify the determinants of short stature. Methods: A registry-based cross-sectional analysis of data collected from various centres across India enrolled in the Changing Diabetes in Children (CDiC) programme. Results: We observed that 6.4% were undernourished (3.4% severe undernutrition) and 17.7% (overweight 13.2%) had combined overweight/obesity. 21.2% of participants had short stature (adjusted for mid-parental height) with 7.4% cases of familial short stature. Longer duration of illness and insulin requirement were significant positive predictors of short stature while glycaemic control, insulin regimen and mid-parental height did not have a significant relationship with short stature. Participants on basal-bolus regimen had significantly higher insulin requirements and better glycaemic control than the ones on mixed-split regimen. Conclusion: We report that around one-fifth of children and youth with T1D were overweight/obese and around a fourth were stunted, especially those with longer duration of diabetes and higher insulin requirements. Close monitoring of anthropometric parameters is necessary for all children with T1D to optimize growth and nutrition.

WFS1 Gene-associated Diabetes Phenotypes and Identification of a Founder Mutation in Southern India.

CONTEXT: Wolfram syndrome (WFS) is a rare autosomal recessive disorder characterized by juvenile-onset diabetes, diabetes insipidus, optic atrophy, deafness, and progressive neurodegeneration. However, due to the progressive nature of the disease and a lack of complete clinical manifestations, a confirmed diagnosis of WFS at the time of onset of diabetes is a challenge. OBJECTIVE: With WFS1 rare heterozygous variants reported in diabetes, there is a need for comprehensive genetic screening strategies for the early diagnosis of WFS and delineating the phenotypic spectrum associated with the WFS1 gene variants in young-onset diabetes. METHODS: This case series of 11 patients who were positive for WFS1 variants were identified with next-generation sequencing (NGS)-based screening of 17 genemonogenic diabetes panel. These results were further confirmed with Sanger sequencing. RESULTS: 9 out of 11 patients were homozygous for pathogenic/likely pathogenic variants in the WFS1 gene. Interestingly, 3 of these probands were positive for the novel WFS1 (NM_006005.3): c.1107_1108insA (p.Ala370Serfs*173) variant, and haplotype analysis suggested a founder effect in 3 families from Southern India. Additionally, we identified 2 patients with young-onset diabetes who were heterozygous for a likely pathogenic variant or a variant of uncertain significance in the WFS1 gene. CONCLUSION: These results project the need for NGS-based parallel multigene testing as a tool for early diagnosis of WFS and identify heterozygous WFS1 variants implicated in young-onset diabetes.

Estimating the total incidence of type 1 diabetes in children and adolescents aged 0-19 years from 1990 to 2050: a global simulation-based analysis.

BACKGROUND: Previous studies of type 1 diabetes in childhood and adolescence have found large variations in reported incidence around the world. However, it is unclear whether these reported incidence levels are impacted by differences in country health systems and possible underdiagnosis and if so, to what degree. The aim of this study was to estimate both the total and diagnosed incidence of type 1 diabetes globally and to project childhood type 1 diabetes incidence indicators from 1990 to 2050 for each country. METHODS: We developed the type 1 diabetes global microsimulation model to simulate the natural history and diagnosis of type 1 diabetes for children and adolescents (aged 0-19 years) in 200 countries and territories, accounting for variability in underlying incidence and health system performance. The model follows an open population of children and adolescents in monthly intervals and simulates type 1 diabetes incidence and progression, as well as health system factors which influence diagnosis. We calibrated the model to published data on type 1 diabetes incidence, autoantibody profiles, and proportion of cases diagnosed with diabetic ketoacidosis from 1990 to 2020 and assessed the predictive accuracy using a randomly sampled test set of data withheld from calibration. FINDINGS: We estimate that in 2021 there were 355 900 (95% UI 334 200-377 300) total new cases of type 1 diabetes globally among children and adolescents, of which 56% (200 400 cases, 95% UI 180 600-219 500) were diagnosed. Estimated underdiagnosis varies substantially by region, with over 95% of new cases diagnosed in Australia and New Zealand, western and northern Europe, and North America, but less than 35% of new cases diagnosed in west Africa, south and southeastern Asia, and Melanesia. The total number of incident childhood cases of type 1 diabetes is projected to increase to 476 700 (95% UI 449 500-504 300) in 2050. INTERPRETATION: Our research indicates that the total global incidence of childhood and adolescent type 1 diabetes is larger than previously estimated, with nearly one-in-two children currently undiagnosed. Policymakers should plan for adequate diagnostic and medical capacity to improve timely type 1 diabetes detection and treatment, particularly as incidence is projected to increase worldwide, with highest numbers of new cases in Africa. FUNDING: Novo Nordisk.

Insulin gene mutations linked to permanent neonatal diabetes mellitus in Indian population.

BACKGROUND AND AIM: Neonatal diabetes mellitus (NDM) is a rare monogenic disorder of pancreatic beta cell mass and/or function. In the present study we aimed to evaluate the INS gene mutations in a cohort of children with Permanent Neonatal Diabetes Mellitus (PNDM) and to explore the clinical and genetic characteristics of PNDM caused by INS mutations. METHODS: Direct sequencing of all exons of INS genes was carried out in 189 children with PNDM. Clinical and biochemical data were collected and correlated. The pathogenicity of mutations was determined based on the American College of Medical Genetics and Genomics and Association of Medical Pathology guidelines. RESULTS: Two novel mutations (His34Pro, Leu35Met) in a compound heterozygous state and seven known mutations (Gly32Ser, Phe48Cys, Arg89Cys, Cys96Tyr, Ser98Ile, Try108Asp and Cys109Phe) in the INS gene were identified in 8 patients out of the total of 189 PNDM children studied. Four mutations were involved in defects with disulphide bond formation and hence were in crucial regions of the gene. All the mutations were de novo in origin. CONCLUSIONS: This is the first comprehensive study from India to investigate the insulin gene mutations in PNDM and to show that INS gene mutations also contribute to the causation of PNDM.

Community effect of Haemophilus influenzae type b vaccination in India.

We assessed the effect of distribution of Haemophilus influenzae type b (Hib) vaccine in the private health care sector on Hib meningitis admissions at a referral hospital in India. The annual mean number of Hib cases was 10.7 before Hib vaccine introduction, falling to 3.8 cases following introduction (P < 0.0001). By contrast, the mean of annual numbers of pneumococcal cases were 3.0 and 4.6, (P = 0.55). Even at relatively low coverage through private sector distribution, Hib vaccine has significant community impact on Hib disease.

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.

High prevalence of glucose intolerance even among young adults in south India.

India is experiencing an epidemic of Type 2 diabetes mellitus (DM) in young adults. This study reports the prevalence of glucose intolerance, and insulin profiles, and their relationship to lifestyle factors in 2218 young adults (aged 26-32 years; 997 urban, 1221 rural) in south India. They were drawn from a cohort of 10,691 individuals born during 1969-1973 in Vellore and nearby villages. Family history, socio-economic status, physical activity and tobacco and alcohol use were recorded. Oral glucose tolerance tests were performed for diagnosis (WHO recommendations). Insulin resistance and secretion were derived from plasma insulin concentrations. Median BMI was 20.0kg/m(2). The prevalence of Type 2 DM and impaired glucose tolerance (IGT) was higher in urban than in rural subjects (3.7% versus 2.1%, p=0.02; 18.9% versus 14.3%, p=0.002, respectively), while prevalence of impaired fasting glycaemia (IFG) was similar in urban and rural populations (3.8% versus 3.4%, p=0.04). Type 2 DM, IGT, IFG or higher insulin resistance and increment were associated with higher socio-economic status (more household possessions) and higher percentage body fat, body mass index and waist/hip ratio. Insulin increment was lower in men with higher alcohol consumption. Our data suggest high levels of glucose intolerance in young rural and urban adults highlighting an urgent need for preventive action to avert a public health catastrophe in India.

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.

Associations of variants in FTO and near MC4R with obesity traits in South Asian Indians.

Recent genome-wide association studies show that loci in FTO and melanocortin 4 receptor (MC4R) associate with obesity-related traits. Outside Western populations the associations between these variants have not always been consistent and in Indians it has been suggested that FTO relates to diabetes without an obvious intermediary obesity phenotype. We investigated the association between genetic variants in FTO (rs9939609) and near MC4R (rs17782313) with obesity- and type 2 diabetes (T2DM)-related traits in a longitudinal birth cohort of 2,151 healthy individuals from the Vellore birth cohort in South India. The FTO locus displayed significant associations with several conventional obesity-related anthropometric traits. The per allele increase is about 1% for BMI, waist circumference (WC), hip circumference (HC), and waist-hip ratio. Consistent associations were observed for adipose tissue-specific measurements such as skinfold thickness reinforcing the association with obesity-related traits. Obesity associations for the MC4R locus were weak or nonsignificant but a signal for height (P < 0.001) was observed. The effect on obesity-related traits for FTO was seen in adulthood, but not at younger ages. The loci also showed nominal associations with increased blood glucose but these associations were lost on BMI adjustment. The effect of FTO on obesity-related traits was driven by an urban environmental influence. We conclude that rs9939609 variant in the FTO locus is associated with measures of adiposity and metabolic consequences in South Indians with an enhanced effect associated with urban living. The detection of these associations in Indians is challenging because conventional anthropometric obesity measures work poorly in the Indian "thin-fat" phenotype.

Absence of birth-weight lowering effect of ADCY5 and near CCNL, but association of impaired glucose-insulin homeostasis with ADCY5 in Asian Indians.

BACKGROUND: A feature of the Asian Indian phenotype is low birth weight with increased adult type 2 diabetes risk. Most populations show consistent associations between low birth weight and adult type 2 diabetes. Recently, two birth weight-lowering loci on chromosome 3 (near CCNL1 and ADCY5) were identified in a genome-wide association study, the latter of which is also a type 2 diabetes locus. We therefore tested the impact of these genetic variants on birth weight and adult glucose/insulin homeostasis in a large Indian birth cohort. METHODOLOGY/PRINCIPAL FINDINGS: Adults (n = 2,151) enrolled in a birth cohort (established 1969-73) were genotyped for rs900400 (near CCNL1) and rs9883204 (ADCY5). Associations were tested for birth weight, anthropometry from infancy to adulthood, and type 2 diabetes related glycemic traits. The average birth weight in this population was 2.79±0.47 kg and was not associated with genetic variation in CCNL1 (p = 0.87) or ADCY5 (p = 0.54). Allele frequencies for the 'birth weight-lowering' variants were similar compared with Western populations. There were no significant associations with growth or adult weight. However, the 'birth weight-lowering' variant of ADCY5 was associated with modest increase in fasting glucose (ß 0.041, p = 0.027), 2-hours glucose (ß 0.127, p = 0.019), and reduced insulinogenic index (ß -0.106, p = 0.050) and 2-hour insulin (ß -0.058, p = 0.010). CONCLUSIONS: The low birth weight in Asian Indians is not even partly explained by genetic variants near CCNL1 and ADCY5 which implies that non-genetic factors may predominate. However, the 'birth-weight-lowering' variant of ADCY5 was associated with elevated glucose and decreased insulin response in early adulthood which argues for a common genetic cause of low birth weight and risk of type 2 diabetes.

Glucose tolerance, insulin resistance and insulin secretion in young south Indian adults: Relationships to parental size, neonatal size and childhood body mass index.

OBJECTIVE: To study the relationship of newborn size and post-natal growth to glucose intolerance in south Indian adults. RESEARCH DESIGN AND METHODS: 2218 men and women (mean age 28 years) were studied from a population-based birth cohort born in a large town and adjacent rural villages. The prevalence of adult diabetes mellitus [DM] and impaired glucose tolerance [IGT], and insulin resistance and insulin secretion (calculated) were examined in relation to BMI and height at birth, and in infancy, childhood and adolescence and changes in BMI and height between these stages. RESULTS: Sixty-two (2.8%) subjects had Type 2 diabetes (DM) and 362 (16.3%) had impaired glucose tolerance (IGT). IGT and DM combined (IGT/DM) and insulin resistance were associated with low childhood body mass index (BMI) (p<0.001 for both) and above-average BMI gain between childhood or adolescence and adult life (p<0.001 for both). There were no direct associations between birthweight or infant size and IGT/DM; however, after adjusting for adult BMI, lower birthweight was associated with an increased risk. CONCLUSIONS: The occurrence of IGT and Type 2 DM is associated with thinness at birth and in childhood followed by accelerated BMI gain through adolescence.