Clinical and molecular characterisation of children with monogenic obesity: a case series.

INTRODUCTION: To study the clinical profile and molecular diagnosis of children with severe early-onset non-syndromic monogenic obesity. METHODS: The clinical and molecular data (performed using whole exome sequencing) of 7 children with early-onset (< 5 years) non-syndromic monogenic obesity were extracted from the Obesity Clinic files and analysed retrospectively. RESULTS: The median (IQR) age at presentation was 18 (10.5-27) months. Of the 7 patients, 5 were boys, 3 had a history of parental consanguinity, and 4 had a family history of severe early-onset obesity. All patients exhibited hyperphagia and showed signs of insulin resistance. Dyslipidaemia and fatty liver were observed in 4. The variants identified in 6 patients included 2 in leptin receptor, and one each in melanocortin 4 receptor, pro-opiomelanocortin, leptin, and neurotrophic tyrosine kinase receptor type 2 genes. Notably, 4 of these variants were novel. CONCLUSIONS: This case series provides valuable insights into the spectrum of genetic mutations associated with non-syndromic monogenic obesity in North Indian children. The findings underscore the significance of next-generation sequencing in identifying the aetiology of severe early-onset obesity.

Tolvaptan for Treatment of Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) in a Child with Corpus Callosum Agenesis.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is one of the common causes of euvolemic hyponatremia (serum Na+ < 135 mEq/L) in hospitalized children. It is characterized by increased serum ADH, leading to water retention via its action on V2 receptors in the distal renal tubules. Various conditions such as pain, the postoperative state, drugs, central nervous system infections, tumors, malformations, and pneumonia can predispose a person to SIADH. The conventional treatment of SIADH includes fluid restriction and salt supplementation. Occasionally, this may fail to control hyponatremia, mandating pharmacological therapy. V2-receptor antagonists are an FDA-approved therapy for adults with euvolemic and hypervolemic hyponatremia. However, there is limited experience with their use in the pediatric population. Here, the authors present a girl with corpus callosum agenesis with severe symptomatic hyponatremia due to SIADH who was successfully managed with the V2-receptor antagonist tolvaptan.

Cognitive Function in Early Onset Type 1 Diabetes in Children.

OBJECTIVES: To assess cognitive function and factors affecting it in Indian children with early-onset type 1 diabetes (T1D) (less than 6 y). METHODS: This cross-sectional, single-centre study recruited children diagnosed with T1D before 6 y of age and having a disease duration of at least 2 y, as cases. Controls were age- and sex-matched apparently healthy children or siblings. Children with birth asphyxia, intellectual disability, syndromic children, or pre-existing psychiatric illness were excluded. Enrolled children underwent cognitive assessment using Malin's Intelligence Scale for Indian Children (MISIC), and scores in various subtests were compared between cases and controls. RESULTS: A total of 60 children were enrolled in each group. When compared to controls, cases had significantly lower scores on most subtests, verbal, performance and overall Intelligence Quotient (IQ- 100.62 ± 3.26 vs. 103.23 ± 1.22). HbA1c >9%, severe hypoglycemia and lesser duration since the last diabetic ketoacidosis (DKA) episode significantly correlated with lower neurocognitive scores. CONCLUSIONS: Children with early onset T1D showed significant deficits in various cognitive domains and IQ. Poor glycemic control, higher glycemic variability and exposure to severe hypoglycemia are risk factors for poor cognitive outcomes in these children. Further longitudinal studies could potentially aid in a finer understanding of factors affecting cognitive functioning in T1D children in developing countries.

Estimation of Reference Values for External Genitalia Parameters in North Indian Preterm and Term Female Newborns.

OBJECTIVES: To establish gestation-wise normative data of external genitalia measurements in North Indian term and preterm female newborns. METHODS: In this cross-sectional descriptive study, institutionally-born female neonates between 28-42 wk gestation were consecutively enrolled between 24-72 h of life. Newborns with major congenital malformations, chromosomal anomalies, multifetal gestation and birth injuries were excluded. Data on various genital measurements were collected [Clitoral length (CL), clitoral width (CW), ano-clitoral distance (AGDAC), ano-fourchette distance (AGDAF) and anogenital ratio (AGR)]. RESULTS: One hundred ninety-eight of 508 neonates (39%) were preterm and 310 (61%) were term. Mean (± SD) CL and CW were 4.6 ± 1.8 mm and 3.9 ± 1.6 mm, respectively. Mean (± SD) values for AGDAF, AGDAC and AGR were 9.3 ± 1.8 mm, 30.2 ± 3.9 mm, and 0.31 ± 0.05, respectively. According to these results, term female newborns with CL more than 7 mm and/or CW more than 6 mm (95th centile) warrant evaluation for clitoromegaly. An anogenital ratio greater than 0.45 should be considered as a sign of virilization in a female neonate. Gestation-wise percentile charts for CL, CW, AGDAF, AGDAC and AGR were generated. CONCLUSIONS: The percentile values defined in the study can serve as local normative data for accurate interpretation of genital measurements in North Indian female newborns and enable health care professionals for early identification of genital virilization.

Estimation of Reference Values for External Genitalia Parameters in North Indian Preterm and Term Male Newborns.

OBJECTIVES: To generate gestation-wise normative data of external genitalia measurements in North Indian term and preterm male newborns. METHODS: This was a hospital-based cross-sectional observational study. Male neonates born between 28-42 wk of gestation (at 24-72 h of life) were consecutively recruited in the study. Newborns with major congenital malformations, chromosomal anomalies, multifetal gestation and birth injuries were excluded. Data on various genital measurements were collected [Stretched penile length (SPL), penile width (PW), upper anogenital distance (AGDu), lower anogenital distance (AGDl) and anogenital ratio (AGR)]. RESULTS: Out of 532 newborns, 208 (39.1%) were preterm. Mean (± SD) SPL and PW were 27.9 ± 3.6 mm and 10.6 ± 1.3 mm respectively. The mean values for AGDl, AGDu and AGR were 20.13 ± 4.04 mm, 39.2 ± 5.59 mm, and 0.51 ± 0.07, respectively. SPL less than 21 mm in a term male newborn and 17.5 mm in preterm should be considered micropenis (<2.5 SD) in our population. Gestation-wise percentile charts for SPL, PW, AGDl, AGDu and AGR were generated. CONCLUSIONS: The reference values and percentile charts generated can serve as local normative data for accurate interpretation of genital measurements in North Indian newborns, assessment of ambiguous genitalia and avoiding diagnostic errors.

Stem cell therapy for type 1 diabetes: a scientometric assessment of global research during the twenty-first century.

Purpose: We aimed to provide a scientometric assessment of global research in stem cell therapy (SCT) for type 1 diabetes (T1D) during 1999-2020. Methods: The published data on SCT in T1D were retrieved from Elsevier's Scopus database and analyzed using select bibliometric tools. We used VOSviewer software and the Biblioshiny app to construct and visualize bibliometric networks. Results: The global yield totaled 1806 publications in the 22-year study period, registering a 17.7% annual growth peaking at 196.9% in the last 11 years. The average citations per publication (CPP) decreased from 62.0 during 1999-2009 to 24.3 during 2010-2020. The funded publications were 727 (40.2%). Randomized controlled trials (RCTs) were only 2.4% (45). Amongst 70 participating countries, the USA led with a 38.6% share. Of the 388 global organizations, Harvard Medical School, USA, San Raffaele Scientific Institute, Italy, and the University of Florida, USA were the topmost contributors. Florina, Couri, and Trucco were the top productive authors, whereas Melton, Abdi, and Simoes were the most impactful. Only 129 (3.1%) publications were highly-cited; their total and average CPP were 31,228 and 214.0 (range 101-1841), respectively. Conclusions: The quantity of research in SCT for T1D has increased during the last two decades while the quality has dipped. The research landscape is dominated by high-income North-American and Western-European countries. There is a need for conducting large-scale RCTs and promoting research collaborations between high- and low-income countries for long-term sustainability and global impact.

Glycaemic control and factors affecting it in type 1 diabetes in children: experience from a tertiary care centre in India.

INTRODUCTION: Optimal glycaemic control is essential for the prevention of future micro- and macrovascular complications in type 1 diabetes (T1D). The type of insulin, the type of insulin delivery device, the caregiver's knowledge, the patient's age, duration of diabetes, and self-monitoring of blood glucose affect glycaemic control in type 1 diabetes. In the present study, we analysed glycaemic control and factors affecting it at a tertiary care centre in northern India. MATERIAL AND METHODS: A retrospective review of records of patients registered between 2015 and 2018 was done. The data on demographic and disease-related factors were collected from the records. The different groups were compared with the t-test, one-way ANOVA, or Kruskal-Wallis test. RESULTS: The mean age at the time of evaluation was 10.43 ±4.04 years (2-21 years), and the mean disease duration was 46.61 ±28.49 months (16-141 months). Most of the patients were prepubertal and using a basal-bolus regimen. The mean glycated haemoglobin (HbA1c ) was 7.96 ±1.46%, but only 24% had HbA1c below the International Society of Paediatric and Adolescent Diabetes (ISPAD) recommended desirable level of below 7%. Forty-six patients suffered one or more micro-macrovascular complications, and dyslipidaemia was the most common complication. Children with a longer duration of disease (8.39 ±1.42% vs. 7.59 ±1.65%), an episode of DKA (diabetes ketoacidosis) within a year of evaluation (9.19 ±2.54% vs. 7.93 ±1.39%), lower maternal (8.22 ±1.37% vs. 7.56 ±1.45%) and paternal education (8.26 ±1.67% vs. 7.78 ±1.30%), and hyperthyroid state (9.43 ±2.28% vs. 7.91 ±1.45%) had higher HbA1c. CONCLUSIONS: Better diabetes education focusing on parents with lower education strata and children with longer disease duration and poor compliance can help improve glycaemic control in developing countries like India.

Molecular Characterization and Management of Congenital Hyperinsulinism: A Tertiary Centre Experience.

BACKGROUND: There is limited data from India regarding medical management of congenital hyperinsulinism (CHI). OBJECTIVE: To study the molecular diagnosis, medical management and outcomes of children with CHI. STUDY DESIGN: Ambispective. PARTICIPANTS: Children with CHI admitted in from December, 2011 till March, 2020 at a tertiary care referral hospital. OUTCOMES: Clinical and genetic profile, treatment, and response. RESULTS: 42 children with a median age of 3 days (range 1 day to 6 years) were enrolled, of which 23 (54.7%) were diazoxide-responsive. Mutations were identified in 28 out of 41 (68.2%) patients. The commonest gene affected was ABCC8 in 22 patients. The pathogenic variant c.331G>A in ABCC8 gene was identified in 6 unrelated cases from one community. Good response to daily octreotide was seen in 13 of the 19 (68.4%) diazoxide-unresponsive patients. Monthly long-acting octreotide was initiated and daily octreotide could be stopped or tapered in 9 patients. Sirolimus was tried with variable response in 6 patients but was discontinued in 5 due to adverse effects. Four patients had focal CHI, of which one underwent partial pancreatic resection. The disease severity reduced with age and neurodevelopment was good in the patients with identifiable genetic defects who were optimally managed. CONCLUSIONS: Medical management of CHI is effective, if compliance can be ensured, with good quality of life and neurological outcomes.

Bartter syndrome and hypothyroidism masquerading cystinosis in a 3-year-old girl: rare manifestation of a rare disease.

Cystinosis is a multisystem disorder with varied presentations secondary to deposition of cystine crystals in different organ systems. Children with cystinosis typically present with renal tubular acidosis and failure to thrive. We report a 3-year-old girl, born to a third-degree consanguineous couple, who presented with failure to thrive and polyuria. Laboratory investigations showed metabolic alkalosis suggestive of a Bartter-like syndrome and acquired hypothyroidism. Although metabolic alkalosis is a rare manifestation of cystinosis, the presence of renal tubular dysfunction and hypothyroidism prompted consideration of a probable diagnosis of cystinosis in the index child. Slit-lamp examination revealed cystine crystals in the cornea and genetic analysis showed a mutation in exon 9 of the CTNS (cystinosin, lysosomal cystine transporter) gene on chromosome 17. We highlight the importance of considering cystinosis as a differential diagnosis for Bartter syndrome and hypothyroidism.

Role of Intrapleural Urokinase in Empyema Thoracis.

OBJECTIVE: To study the role of fibrinolytic therapy in pediatric empyema in relation to duration of hospital stay, need for surgical intervention and survival to discharge. METHODS: Retrospective analysis of case records of children <16 y of age admitted in a tertiary care hospital during January 2013 - December 2017 with diagnosis as empyema thoracis was done. Clinico-laboratory characteristics and the primary and secondary outcomes between the group which received intrapleural urokinase (IPU) and the group which did not (non IPU), were compared. RESULTS: Of the 84 cases, 40 children received IPU. Mean duration of hospital stay in IPU group (17.51 + 4.57 d) was significantly less than non IPU group (24.32 + 10.18 d, CI -10.19 to -3.64, p < 0.001), so was the duration of intercostal drain (ICD) insertion (9.08 + 3.12 d - IPU group vs. 11.20 + 3.95 d - non IPU group, CI -3.68 to -0.50, p < 0.01). No statistically significant difference was found between the groups with regard to need for surgical intervention [IPU - 4 (10%), non IPU - 9 (20.4%), p = 0.23]. There was no mortality or adverse reaction to urokinase in either group. CONCLUSIONS: IPU holds promising results in terms of reduction of hospital stay and duration of ICD insertion. It may be the initial choice of treatment in septated empyema where surgical options are not easily available or cost-effective especially in resource limited settings.