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.

Nonsurgical hypoparathyroidism is associated with skeletal muscle dysfunction and restrictive lung disease.

CONTEXT: Systematic assessment of skeletal muscle function is lacking in patients with nonsurgical hypoparathyroidism (HP). Whether muscle dysfunction involves respiratory muscles and results in restrictive lung disease (RLD) is not studied. OBJECTIVE: To assess skeletal muscle and pulmonary functions in patients with HP. DESIGN: Observational case-control study. METHODS: Thirty patients with HP (mean age 37.7 years, 60% males) and 40 age-, sex-, and body mass index (BMI)-matched healthy controls were assessed for skeletal muscle function by handgrip strength, the short physical performance battery (SPPB) test, dual-energy X-ray absorptiometry (DXA), and electromyography (EMG). Pulmonary function was assessed by spirometry, body plethysmography, diffusion lung capacity for carbon monoxide, and diaphragmatic ultrasound (DUS). RESULTS: Patients with HP had lower serum calcium (2.25 ± 0.15 vs 2.4 ± 0.12 mmol/L, P < .001), serum magnesium (median [interquartile range] 0.74 [0.69-0.82] vs 0.78 [0.69-0.90] mmol/L, P = .04), handgrip strength (18.08 ± 8.36 vs 22.90 ± 7.77 kg, P = .01), and composite SPPB scores (9.5 [7-10] vs 12 [12-12], P < .001) compared to healthy controls. Electromyographic evidence of myopathy was seen in 23% (5 of 22) of patients with HP but in none of the controls (P = .08). The prevalence of RLD was higher in the HP cohort compared to that in controls (24% vs 0%, P = .01). Diaphragmatic excursion (DE) (4.22 ± 1.38 vs 5.18 ± 1.53 cm, P = .01) and diaphragmatic thickness (DT) (3.79 ± 1.18 vs 4.28 ± 0.94 mm, P = .05) on deep inspiration were reduced in patients with HP. CONCLUSION: Detailed testing of patients with HP without overt muscle and lung diseases revealed significant impairment in parameters of skeletal muscle function. Myopathy and RLD were observed in a considerable proportion of patients with HP.

Etiology, clinical characteristics and mortality among Indian patients with Addison's disease.

The etiology, presentation and mortality of patients with primary adrenal insufficiency (PAI) in developing countries may differ from economically developed nations. However, information in this regard is scanty. The aim of this study was to determine the etiology and compare the clinical characteristics and mortality in infectious and autoimmune causes of PAI in Indian patients. All eligible (n = 89) patients (ages 15-83 years) diagnosed with PAI between 2006 and 2019 were studied. Patients were followed for a median duration of 5.9 (range 0.1-15.7) years. Eighty-six subjects underwent an abdominal computerized tomography scan or ultrasonography, and adrenal biopsy was performed in 60 patients. The most frequent etiologies of PAI were adrenal histoplasmosis (AH, 45%), adrenal tuberculosis (AT, 15%), autoimmunity (AI, 25%) and primary lymphoma (6%). Forty-two percent of patients presented with an acute adrenal crisis. AH and AT could not be differentiated on the basis of clinical features, except for a greater frequency of hepatomegaly-splenomegaly and type 2 diabetes mellitus (63% vs 15%, P < 0.01) in the former. Patients with an autoimmune etiology had a higher frequency of 21-hydroxylase antibodies (41% vs 3%) and autoimmune thyroid disease (46% vs 5%) vs those with infectious etiologies. Mortality was significantly higher in AH (45%) compared with AT (8%) or AI (5%) (P = 0.001). Causes of death included adrenal crises, progressive AH and unexplained acute events occurring at home. In conclusion, infections, especially AH, were the most frequent cause of PAI in north India. Despite appropriate therapy, AH had very high mortality as compared with AT and AI.

Association of hyperglycaemia at-admission & diabetes mellitus with 28 day mortality in patients admitted with moderate-severe SARS-CoV-2 infection: A retrospective study.

Background & objectives: The association between hyperglycaemia at admission, diabetes mellitus (DM) status and mortality in hospitalized SARS-CoV-2 infected patients is not clear. The purpose of this study was to determine the relationship between DM, at-admission hyperglycaemia and 28 day mortality in patients admitted with moderate-severe SARS-CoV-2 infection requiring intensive care. Methods: All consecutive moderate-to-severe patients with SARS-CoV-2 infection admitted to the intensive care units (ICUs) over six months were enrolled in this single-centre, retrospective study. The predicators for 28 day mortality were analysed from the independent variables including DM status and hyperglycaemia at-admission. Results: Four hundred and fifty two patients with SARS-CoV-2 were admitted to the ICU, with a mean age of 58.5±13.4 yr, 78.5 per cent being male, HbA1c of 7.2 per cent (6.3-8.8) and 63.7 per cent having DM. Overall, 28 day mortality was 48.9 per cent. In univariate analysis, mortality in diabetes patients was comparable with non-diabetes (47.9 vs. 50.6%, P=0.58), while it was significantly higher in hyperglycaemic group (60.4 vs. 35.8%, P<0.001). In multivariate Cox regression analysis, after adjusting for age, sex and comorbidities, hyperglycaemia at-admission was an independent risk factor of mortality [hazard ratio (HR) 1.45, 95% confidence interval (CI) (1.06-1.99), P<0.05]. Interpretation & conclusions: This study showed that the presence of hyperglycaemia at-admission in critically ill SARS-CoV-2 patients was an independent predictor of 28 day mortality. However, the findings may be susceptible to unmeasured confounding, and more research from prospective studies is required.

Low Diagnostic Utility of Overnight High-Dose Dexamethasone Suppression Test in ACTH-Dependent Cushing's Syndrome.

OBJECTIVE: Overnight high-dose dexamethasone suppression test (ON-HDDST) is a simple test to localize the source of ACTH in patients with ACTH-dependent Cushing's syndrome (CS). However, previous studies have reported its varying accuracy. We studied the utility of ON-HDDST in diagnosing Cushing's disease (CD) in a series of patients with CD and ectopic ACTH syndrome (EAS). METHODS: We conducted a retrospective study of 88 patients with ACTH-dependent CS (plasma ACTH > 20.0 pg/mL), who underwent an ON-HDDST. CD and EAS were diagnosed in 68 and 20 patients, respectively. Patients were investigated using MRI of the sellar region, CT of the thorax/abdomen, Gallium-68-DOTANOC PET scan, and bilateral inferior petrosal sinus sampling as required. RESULTS: Patients with EAS had a significantly higher serum cortisol after ON-HDDST than patients with CD (median [IQR], 19.9 [12.4-31.1] µg/dL vs 9.9 [5.1-25.0] µg/dL, P <.01). A suppressed ON-HDDST (≥50% fall from baseline) was noted in 44 (65%) patients with CD and 3 (15%) patients with EAS (P <.0001). Among patients with CD, cortisol suppression >50% was noted in 35 (76%) of patients with microadenoma and 7 (44%) with macroadenoma. Among patients with EAS, ON-HDDST was suppressed in 1 of 6 patients (17%) with an occult tumor and 2 of 14 patients (14%) with a localized tumor. The ROC curve plotted for the percentage suppression of cortisol had an area under the curve (AUC) of 0.72 (P =.01). The best test parameters, with 65% sensitivity, 85% specificity, 94% positive predictive value, 42% negative predictive value, and 69% accuracy, were at 50% cutoff level. CONCLUSION: The ON-HDDST had a poor diagnostic value in differentiating CD and EAS.

Hereditary Medullary Thyroid Carcinoma: Genotype, Phenotype and Outcomes in a North Indian Cohort.

BACKGROUND: Aggressiveness of hereditary medullary thyroid carcinoma (hMTC) has been conventionally described to correlate with American Thyroid Association (ATA) risk groups based on RET mutations. Recent evidence increasingly contradicts this notion. We studied the RET genotype and its correlation with disease phenotype and survival outcomes in a cohort of hMTC patients. METHODS: In a retrospective cohort of 55 hMTC patients from 23 families treated at a north Indian tertiary care institute over 15-years, RET genotype was correlated with disease phenotype (clinical, biochemical, and pathological attributes) and outcomes in terms of biochemical cure (normalization of serum calcitonin), structural cure, overall survival (OS) and disease specific survival (DSS). RESULTS: Forty-nine patients had Multiple Endocrine Neoplasia (MEN)-type 2A syndrome, 02 had MEN-2B, and 4 had familial MTC. Two patients belonged to highest ATA risk, 41 to high-risk, and 12 to moderate risk categories. Age of the patients or stage of disease at presentation did not differ significantly between the ATA risk groups. Though the baseline serum calcitonin was significantly higher in highest risk category, the biochemical cure rates were not significantly different. At a median follow up of 48 months (Inter-quartile range 18-84, range 12-192) structural cure rates in ATA moderate and high risk groups were significantly higher than highest risk group (p = 0.04). No significant difference in OS between the three ATA groups of hMTC among the patients who underwent surgical treatment was observed (p = 0.098). CONCLUSIONS: The ATA moderate and high risk groups have better structural cure rates compared to ATA highest risk group. The biochemical cure and overall survival rates did not significantly differ between ATA risk-groups, and were impacted by the disease stage at presentation. The current ATA risk-groups do not reliably predict the outcomes in terms of biochemical cure and survival in hMTC patients.

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.

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.

Results of Percutaneous Computed Tomography-Guided Biopsy of Adrenal Lesions and Spectrum of Computed Tomography Findings.

OBJECTIVE: Adrenal enlargement occurs in various conditions such as infections, benign, and malignant neoplasms. Percutaneous computed tomography (CT)-guided adrenal biopsy is a safe method for obtaining tissue specimen in cases where diagnosis cannot be established on imaging and biochemical grounds. The study aims to evaluate diagnostic yield, accuracy, and complications of percutaneous CT-guided adrenal biopsies. Furthermore, CT findings of various adrenal lesions have been described. MATERIALS AND METHODS: Data of CT-guided adrenal biopsies performed from September 2009 to May 2019 were analyzed. Biopsies were performed on a 64-slice or a 128-slice multidetector CT scanner using a coaxial technique. Pathological and microbiological reports were retrieved from the hospital information system. Clinical details were obtained from clinical case records. RESULTS: CT-guided adrenal biopsies were performed in 48 patients, 37 males and 11 females. Adrenal insufficiency was present in 31 (64%) cases and bilateral adrenal glands were affected in 35 (73%). Biopsy yielded a diagnosis in 35 cases (72.9%). The final diagnosis was achieved in 43 (90%) cases. Combined accuracy of CT-guided biopsy for identifying malignancy and infection was 88.3%. Adrenal histoplasmosis (AH) was the most common entity diagnosed (44%). After combining histopathology and microbiology results, the sensitivity for diagnosing AH was 100%. One (2%) patient had a major complication in the form of intra-abdominal hemorrhage requiring transfusion. Local hematoma and mild stable pneumothorax were noted in one patient each. CONCLUSION: Percutaneous CT-guided biopsy is a safe procedure for the diagnosis of adrenal lesions. It has good accuracy for diagnosing adrenal conditions such as infections and malignancies. However, the specific diagnosis of benign adrenal lesions was difficult to make. AH, tuberculosis, and metastasis have overlapping imaging findings.

Coronary artery calcification, carotid intima-media thickness and cardiac dysfunction in young adults with type 2 diabetes mellitus.

AIMS: Cardiovascular diseases (CVD) are the major causes of mortality in patients with type 2 diabetes mellitus (T2DM). There is paucity of information on prevalence of subclinical atherosclerosis and cardiac dysfunction in young adults with T2DM. This study aimed to assess the prevalence of subclinical atherosclerosis and cardiac dysfunction in young adults with T2DM, asymptomatic for CVD. METHODS: Sixty-two patients with T2DM, age between 30 and 50 years were evaluated for coronary artery calcium (CAC) score, carotid intima-media thickness (CIMT) and flow-mediated dilatation (FMD) at the brachial artery. All were subjected to 2D-color Doppler echocardiography, electrocardiography and testing for serum N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitivity C-reactive protein (hsCRP). The results were compared with those in 60 age, sex and BMI-matched healthy controls. RESULTS: Prevalence of a positive CAC score was comparable among subjects with and without T2DM (14.5% vs 11.7%). Patients with T2DM had a significantly higher CIMT (0.54 ±â€¯0.15 vs 0.49 ±â€¯0.10 mm, p = 0.01), left ventricular (LV) mass (170 ±â€¯36 vs 147 ±â€¯23 g, p < 0.001), heart rate (83 ±â€¯13 vs 74 ±â€¯11, p < 0.001) and QTc interval (402 ±â€¯20 vs 382 ±â€¯21 ms, p < 0.001) compared to controls. FMD was lower in patients with T2DM compared to controls (9.1 ±â€¯4.4% vs 10.7 ±â€¯3.9%, p = 0.04). There was a higher prevalence of LV hypertrophy (37% vs 7%, p < 0.001) and diastolic dysfunction (7% vs 0) in patients with T2DM compared to controls. None of the participants had systolic dysfunction. Hypertension (42 vs 7%, p < 0.001) and metabolic syndrome (76 vs 35%, p < 0.001) were more prevalent in the patient group. In the multivariate analysis, age was the lone predictor of CIMT and FMD; while T2DM and male gender were the independent predictors of LV mass. CONCLUSIONS: Young adults with T2DM, asymptomatic for CVD had a higher prevalence of CVD risk factors, LV hypertrophy and diastolic dysfunction. A higher CIMT and LV mass, and a lower FMD were noted in patients with T2DM. CAC score was comparable between the groups and thus may not be a useful tool for assessment of subclinical atherosclerosis in this cohort, where CIMT and FMD may be more appropriate.

Genetic Profile of Indian Pheochromocytoma and Paraganglioma Patients - A Single Institutional Study.

BACKGROUND AND AIMS: Pheochromocytomas (PCCs) and Paragangliomas (PGL) are rare catecholamine producing tumors that may present in sporadic or familial settings. Despite vast strides in understanding of PCC/PGL genetics in the last two decades, there is a dearth of information from India. The aim here is to study the prevalence of genetic mutations in Indian PCC/PGL patients. SETTINGS AND DESIGN: Tertiary care academic hospital; prospective study. METHODS: 50 histopathologically diagnosed PCC/PGL patients formed the study group. Clinical, biochemical, pathological attributes and outcomes were documented and the phenotype was compared to the genotype. Succinyl dehydrogenase (SDH), Re-Arranged during Transfection (RET), Von-Hippel-Lindau (VHL) and NeuroFibromatosis-1 (NF1) mutations were studied. Additionally, immunohistochemisty for SDHB was also done, and the results compared to mutational analysis of SDH by MLPA (Multiplex Ligation-dependent Probe Activation). STATISTICAL ANALYSIS: Independent samples t-test and Fisher's exact test were used as appropriate. P values ≤0.05 were considered statistically significant. RESULTS: The mean age was 34.3 years. Of the 50 patients, 27 were males and 23 females. 10 patients (20%) in all were detected to have a genetic mutation. 6 patients possessed a RET mutation, while two had VHL mutations. No patient presented with a NF1 mutation. 2 patients had a SDH mutation, and Immunohistochemistry for SDHB correlated with mutational analysis for these patients. CONCLUSIONS: The proportion of patients with a familial variant of PCC/PGL is more than what the historic "Rule of Ten" suggests. Our study found that one in five patients have a genetic mutation. PCC/PGL patients with genetic mutations not only require more stringent follow-up, but also screening of family members.

Elevated FGF23 in a patient with hypophosphatemic osteomalacia associated with neurofibromatosis type 1.

CONTEXT: The mechanism behind hypophosphatemia in the setting of neurofibromatosis type 1 (NF1) is not known. We describe a possible role of fibroblast growth factor-23 (FGF23) in the pathophysiology of hypophosphatemia in a patient with NF1. CASE DESCRIPTION: A 34-year woman with NF1 presented with severe hypophosphatemia, osteomalacia, and elevated plasma FGF23. The patient had considerable improvement on replacement of oral phosphate. Two Ga68 DOTANOC PET-CT scans over a period of 2 years failed to detect any localized uptake. Immuno-staining for FGF23 was absent in the neural-derived tumour cells of the neurofibromas in the proband. CONCLUSION: The patient with NF1 had elevated circulating FGF23. Tumour cells in the neurofibroma tissues did not stain for FGF23 on IHC. It is unlikely for neurofibromas to contribute to high circulating FGF23 levels in the proband.

Heterogeneity in the aetiology of diabetes mellitus in young adults: A prospective study from north India.

Background & objectives: In contrast to Caucasians of European origin, the aetiology of diabetes mellitus (DM) in young adults in other ethnic groups, including Indians is likely to be heterogeneous and difficult to determine. This study was undertaken to determine the aetiology of diabetes in young Indian adults using a protocol-based set of simple clinical and investigation tools. Methods: In this prospective study, 105 Indian young adults with diabetes (age at onset 18-35 yr; duration <2 yr) were studied for a period of 1-3 years. Pancreatic imaging, fasting C-peptide, islet antibodies (against glutamic acid decarboxylase, tyrosine phosphatase and zinc transporter-8) and mitochondrial A3243G mutational analysis were performed in all patients. Four patients were screened for maturity-onset diabetes of the young (MODY) using next-generation sequencing. Results: Type 1 and type 2 diabetes mellitus (T1DM and T2DM) were equally frequent (40% each), followed by fibrocalculous pancreatic diabetes (FCPD, 15%). Less common aetiologies included MODY (2%), mitochondrial diabetes (1%) and Flatbush diabetes (2%). There was considerable phenotypic overlap between the main aetiological subtypes. Elevated islet antibodies were noted in 62 per cent of T1DM patients [positive predictive value (PPV) 84%; negative predictive value (NPV) 78%] while low plasma C-peptide (<250 pmol/l) was present in 56 per cent of T1DM patients [PPV 96% (after excluding FCPD), NPV 72%]. Using these tests and observing the clinical course over one year, a final diagnosis was made in 103 (99%) patients, while the diagnosis at recruitment changed in 23 per cent of patients. Interpretation & conclusions: The aetiology of diabetes in young adults was heterogeneous, with T1DM and T2DM being equally common. FCPD was also frequent, warranting its screening in Indian patients. Testing for islet antibodies and C-peptide in this age group had good PPV for diagnosis of T1DM.

Novel mutations and spectrum of the disease of NR0B1 (DAX1)-related adrenal insufficiency in Indian children.

Background X-linked adrenal hypoplasia congenita (AHC), due to mutations in the nuclear receptor superfamily 0, group B, member 1 (NR0B1)/dosage-sensitive sex reversal, AHC, critical region on the X chromosome, gene 1 (DAX1) gene, usually presents with a salt-wasting adrenal crisis in infancy and hypogonadotropic hypogonadism (HH) in adolescents. Genetic reports in the literature from patients of diverse ethnicity are limited. We describe the atypical clinical characteristics and molecular genetic results in six Indian patients. Methods Both exons and flanking intronic sequences of the NR0B1 gene were amplified and sequenced in five patients. In the sixth patient, suspected to have a large deletion, multiplex ligation-dependent probe amplification (MLPA) and chromosomal microarray analysis were performed. Results Sequencing revealed three novel mutations: a nonsense mutation (c.776C > A), a deletion (c.298del), both causing loss of domains which are highly conserved among nuclear receptor families, and a missense mutation (c.1112T > C). In-silico analysis by structure-based protein modeling predicted a de-stabilizing effect of the novel missense mutation. Two previously reported mutations were seen in patients with atypical manifestations such as late-onset adrenal insufficiency and precocious puberty. One patient had a 7.15-Mb contiguous deletion involving the NR0B1, Duchenne muscular dystrophy (DMD), glycerol kinase (GK) and melanoma antigen, family B, 16 (MAGEB16) genes. Conclusions Our report emphasizes the wide clinical spectrum of AHC, including rare manifestations, and enumerates unique mutations in the NR0B1 gene.

Glycemic Control and Long-term Complications in Pediatric Onset Type 1 Diabetes Mellitus: A Single-center Experience from Northern India.

OBJECTIVE: To study glycemic control, mortality and long-term complications in children with type 1 diabetes (T1D). DESIGN: Cross-sectional study. SETTING: Referral centre at a government teaching hospital. PARTICIPANTS: Patients with T1D with age £18 years at onset. METHODS: We retrospectively collected demographic data from computer records from 1991 to 2015. Prospective study for outcomes was conducted between 2012 and 2016. MAIN OUTCOME MEASURES: Mortality rate, glycosylated hemoglobin (HbA1c), and microvascular complication rate. RESULTS: The proportion of T1D patients (n=512) <5 years of age at onset was 18.6% between 1995 and 2004, and 24.2% in 2005-2014 (P<0.001). Twenty eight patients had died out of 334 whose living status was known (mortality 1.1 per 100 patient-years over 2549 patient-years follow up). Median (range) HbA1c (n=257) was 8.3% (5.1-15.0%). At least one episode of severe hypoglycemia (coma/seizure/inability to assist self) had occurred in 22.8% patients over two years. Hypertension was present in 11.7% patients. Microvascular complications screen in 164 eligible patients [median (range) age 20 (8-45) y and duration of diabetes 9.1 (5-30) y] showed diabetic nephropathy in 3.0%, proliferative retinopathy in 3.6% and LDL cholesterol >100 mg/dL in 34% patients. CONCLUSIONS: The mortality rate and prevalence of hypertension were high, given the short duration of diabetes of the patients. The proportion of patients with age ≤5 years at onset of diabetes has increased at our center.

The impact of free medical supplies and regular telephonic contact on glycemic control in Indian children and adolescents with type 1 diabetes.

BACKGROUND/OBJECTIVE: The effect of economic assistance to underprivileged families with type 1 diabetes has never been described. Such a study is relevant as logistic and cultural factors may preclude an anticipated good outcome. The objective of the study is to determine the impact of economic and educational intervention on hemoglobin A1c (HbA1c) and diabetes knowledge. METHODS: Eighty-five consecutive participants were prospectively provided insulin and glucose strips for 1 year. From the 6th to 12th month, patients were randomized such that half of them (telephone group) received proactive telephonic advice by a diabetes educator, while the non-telephone group received usual care. HbA1c and diabetes knowledge were measured at baseline, 6 and 12 months. RESULTS: Significant improvement was seen in HbA1c with provision of free diabetes supplies, when patients were compared with their own HbA1c values during the prior 36 months (baseline [8.38 ± 2.0%], at 3 months [8.0 ± 1.6%] and at 6 months [8.1 ± 1.5%, P = 0.0106]). Knowledge score increased from baseline (48 ± 15) to 6 months (58 ± 13, P < 0.001). No difference was seen between the telephone and non-telephone groups in HbA1c from the 6th to 9th and 12th month. The knowledge score showed significant improvement in the telephone group during the proactive telephonic advice study compared with the non-telephone group (P = 0.002). CONCLUSIONS: The provision of free medical supplies improved HbA1c and diabetes knowledge. Intensive telephone contact improved knowledge, not HbA1c. These results provide important background for policy makers and diabetes management teams.

Clinical outcomes and cortical reserve in adrenal histoplasmosis-A retrospective follow-up study of 40 patients.

OBJECTIVE: Detailed studies of Addison's disease resulting from disseminated adrenal histoplasmosis (AH) are not available. We describe the presentation and prognosis of AH and cortisol status before and after antifungal therapy. DESIGN: Single-centre retrospective hospital-based study of 40 consecutive adults with AH [39 males; age (mean ± SD) 53 ± 11 years] was conducted between 2006 and 2018. The median duration of follow-up was 2.5 years (range 0.2-12 years). PATIENTS AND METHODS: AH was diagnosed by bilateral adrenal enlargement on CT scan and presence of Histoplasma by histology and/or culture of biopsied adrenal tissue. All patients received oral itraconazole and, if required, amphotericin B as per guidelines. ACTH-stimulated serum cortisol (normal > 500 nmol/L) was measured in 38 patients at diagnosis and re-tested after one year of antifungal therapy in 21 patients. RESULTS: Seventy-three per cent of patients had primary adrenal insufficiency (PAI) and one-third had an adrenal crisis at presentation. HIV antibody was negative in all patients. Of the 29 patients who completed antifungal therapy, 25 (86%) were in remission at last follow-up. Overall, 8 (20%) patients died: three had a sudden death, four had severe histoplasmosis and one died due to adrenal crisis. No patient with PAI became eucortisolemic on re-testing after one year of antifungal therapy. Of the eight patients with normal cortisol at diagnosis, two developed adrenal insufficiency on follow-up. CONCLUSION: All patients with AH tested negative for HIV antibody. While patients achieved a high rate of clinical remission after antifungal therapy, overall mortality was significant. Cortisol insufficiency did not normalize despite treatment.

Decreased bone mineral density in women with Sheehan's syndrome and improvement following oestrogen replacement and nutritional supplementation.

Sheehan's syndrome (SS) is an important cause of pan-hypopituitarism in women. There is scanty information on bone mineral density (BMD) in this condition. We determined BMD and the changes in BMD after oestrogen (E2) replacement and nutritional supplementation in women with SS. In a cross-sectional study, BMD was measured by DEXA in 83 patients [age (mean ± SD) 42 ± 9.2 years] and compared with an equal number of matched controls. In a sub-set of 19 patients, we conducted an open-label, prospective study to determine changes in BMD after 1 year of replacement of E2, and calcium and vitamin D3 supplementation. All patients had low serum IGF-1 and E2, while 98% had ≥ 3 pituitary hormone deficiencies. Compared with Indian reference standards, 47% had decreased bone mass (Z-score ≤ - 2.0). BMD Z-scores were decreased at all sites, being most marked in the lumbar spine and femoral neck. At the lumbar spine, BMD was lowest among the age group 21-30 years. Women with SS also had significantly lower BMD Z-scores at all three sites on comparison with ethnic controls. On multivariate analysis, BMD Z-score was associated with weight, daily calcium intake and age (lumbar spine). In the prospective study, 1 year of therapy improved BMD Z-score at lumbar spine (- 1.4 ± 1.2 vs. - 1.1 ± 1.1, p = 0.02), but not at hip or femoral neck. In conclusion, patients with SS had significantly lower BMD compared to controls at all three sites. Replacement of E2 and supplementation with calcium/vitamin D3 lead to significant improvement in lumbar spine BMD.