Growth and endocrinopathies among children with ß-Thalassemia major treated at Dubai Thalassemia centre.

BACKGROUND: ß-Thalassemia major (BTM) is one of the most common hereditary anemias worldwide. Patients suffer from iron overload that results from repeated blood transfusion This in turn leads to multiple organ damage and endocrinopathies. This study aims to assess the prevalence of growth retardation, hypothyroidism, and diabetes mellitus in children and adolescents with BTM treated at Dubai Thalassemia Centre. METHODS: A total of 105 children and adolescents were included in this retrospective observational study. RESULTS: 39 children and 66 adolescents' data were analyzed. Females composed 51.3% (n = 20) of children and 53.0% (n = 35) of adolescents. Pretransfusion hemoglobin below 9 gm/dl was observed in 10.8% (n = 4) and 10.6% (n = 7) in children and adolescents, respectively. The mean age of menarche was 13.5 years. Among all study participants, 22.6% (n = 14) had normal height velocity whereas 37.1% (n = 23) had reduced height velocity in one year and 40.3% (n = 25) had reduced height velocity in two consecutive years. The proportion of children and adolescents showing reduced height velocity was significantly higher in females compared to the males (90.6% versus 63.3%, respectively, Chi-square = 6.597, p-value = 0.010). Although none of the study participants had diabetes mellitus, 26.1% (n = 12/46) had pre-diabetes. Elevated TSH was observed in 14.7% (n = 5) children and 8.1% (n = 5) adolescents while low FT4 was reported in one child and one adolescent. CONCLUSION: Of all endocrinopathies seen among children and adolescents with BTM, growth delay remains the main concern for this group of patients. Effective treatment is key to further reducing endocrinopathies. Although the sample size is limited, we postulate that the low percentage of endocrinopathies among children with BTM treated at Dubai thalassemia center and the low level of pretransfusion anemia reflect the effective transfusion and chelation at the center.

High carrier frequency of CYP21A2 gene mutations in Southern India - underscoring the need for genetic testing in Congenital Adrenal Hyperplasia.

PURPOSE: Congenital Adrenal Hyperplasia (CAH) is one of the highly prevalent autosomal recessive endocrine disorders. The majority of CAH cases result from mutations in the CYP21A2 gene, leading to 21-hydroxylase deficiency. However, with the pseudogene-associated challenges in CYP21A2 gene analysis, routine genetic diagnostics and carrier screening in CAH are not a part of the first-tier investigations in a clinical setting. Furthermore, there is a lack of data on the carrier frequency for 21-OH deficiency. Therefore, this study is aimed at investigating the carrier frequency of common pseudogene derived CYP21A2 mutations in Southern India. METHODS: Recently, a cost-effective Allele-specific PCR based genotyping for CYP21A2 hotspot mutations has been demonstrated to be a highly specific and sensitive assay at the authors' center. Leveraging this approach, a total of 1034 healthy individuals from South India underwent screening to identify the carrier frequency of nine hotspot mutations in the CYP21A2 gene. RESULTS: In this study, it was observed that 9.76% of the subjects were carriers for one or more of the nine different CYP21A2 mutations. Among the carriers, the most common was the large 30 kb deletion, followed by II72N, E6 CLUS, and I2G mutations. CONCLUSION: We have identified a high prevalence of CYP21A2 mutation carriers in Southern India. These findings emphasize the importance of implementing and expanding cost-effective genetic diagnostics and carrier screening throughout India. Such initiatives would play a crucial role in managing the disease burden, enabling early intervention, and establishing guidelines for CAH newborn genetic screening in the country. This study represents the first carrier screening data on CYP21A2 hotspot mutations from India and is the largest study conducted till date in this context.

Bone Mineral Density and Serum Bone Turnover Markers among Post-Menarchal Girls from Rural South India.

Background: The data on the bone mineral density (BMD) and bone turnover markers (BTMs) in Indian adolescents are limited. Objectives: To assess BMD at lumbar spine (LS, L1-L4) and femoral neck (FN) in South Indian post-menarchal girls and correlate it with dietary calcium intake (mg/day), physical activity score and post-menarchal years. The study also assessed serum BTMs and their correlation with chronological age in the study population. Methods: This cross-sectional study included apparently healthy post-menarchal adolescent girls aged 12-16 years randomly selected from the community. Participants with vitamin D deficiency were excluded. The data on calcium intake and physical activity were obtained using validated questionnaires. All participants were evaluated with serum calcium, 25-hydroxy vitamin D, parathyroid hormone, N-terminal propeptide of type 1 collagen (P1NP) and Beta-CrossLaps (CTx) and BMD at LS and FN using dual X-ray absorptiometry (DXA). Statistical Analysis: EpiData version 3.1 was used for the data entry. The data analysis was done using Statistical Package for Social Sciences (SPSS) version 21. Continuous variables were expressed as mean ± SD. Pearson's correlation coefficient (r) was calculated, and two-tailed Kendall's tau-b test was used for assessing correlation of all nonparametric measures. Results: A total of 103 participants were screened, and data from 77 were analysed. There was a significant positive correlation of BMD at LS with chronological age (r: +0.235, P = 0.036), but not at FN. Positive correlation of BMD with increase in post-menarchal years was also noted at LS (r: +0.276, P = 0.015). There was no significant association of BMD with calcium intake and physical activity scores at both sites. There was a significant negative correlation of serum BTMs with age CTx (r: -0.596, P = 0.0001) and P1NP (r: -0.505, P = 0.0001). Conclusion: This study provides insight into the reference BMD range at LS spine and FN in South Indian rural post-menarchal adolescent girls. BMD positively correlated, whereas BTMs negatively correlated with age. The study also provides the first Indian reference range for serum BTMs in this age group.

International Consensus Guideline on Small for Gestational Age: Etiology and Management From Infancy to Early Adulthood.

This International Consensus Guideline was developed by experts in the field of small for gestational age (SGA) of 10 pediatric endocrine societies worldwide. A consensus meeting was held and 1300 articles formed the basis for discussions. All experts voted about the strengths of the recommendations. The guideline gives new and clinically relevant insights into the etiology of short stature after SGA birth, including novel knowledge about (epi)genetic causes. Further, it presents long-term consequences of SGA birth and also reviews new treatment options, including treatment with gonadotropin-releasing hormone agonist (GnRHa) in addition to growth hormone (GH) treatment, as well as the metabolic and cardiovascular health of young adults born SGA after cessation of childhood GH treatment in comparison with appropriate control groups. To diagnose SGA, accurate anthropometry and use of national growth charts are recommended. Follow-up in early life is warranted and neurodevelopment evaluation in those at risk. Excessive postnatal weight gain should be avoided, as this is associated with an unfavorable cardiometabolic health profile in adulthood. Children born SGA with persistent short stature < -2.5 SDS at age 2 years or < -2 SDS at 3 to 4 years of age, should be referred for diagnostic workup. In case of dysmorphic features, major malformations, microcephaly, developmental delay, intellectual disability, and/or signs of skeletal dysplasia, genetic testing should be considered. Treatment with 0.033 to 0.067 mg GH/kg/day is recommended in case of persistent short stature at age of 3 to 4 years. Adding GnRHa treatment could be considered when short adult height is expected at pubertal onset. All young adults born SGA require counseling to adopt a healthy lifestyle.

Upfront adjuvant irradiation versus postoperative surveillance following incomplete surgical resection of craniopharyngiomas in children and young adults.

OBJECTIVE: Incomplete surgical removal of craniopharyngiomas frequently results in suboptimal oncological control. Radiation therapy is usually offered in these cases to prevent local recurrence of disease; however, the efficacy of radiation is limited by its potential adverse effect, particularly in younger patients. This study was undertaken to compare long-term outcomes and rates of postoperative obesity and endocrinopathy in patients undergoing either upfront adjuvant radiation after surgery, or postoperative surveillance with progression-contingent intervention. METHODS: Thirty-seven patients aged <25 years who had undergone primary incomplete surgical resection of craniopharyngiomas were retrospectively identified and categorized according to the prescribed treatment strategy. Recurrence rates, functional status, neuro-ophthalmologic, and endocrine outcomes were studied in both groups of patients. RESULTS: Twenty-three patients received upfront adjuvant radiation, and 14 patients underwent postoperative surveillance. Adjuvant radiation in the former group was delivered using either conventional (n=10), 3D-conformal (n=4), or fractionated stereotactic (n=9) techniques using a linear accelerator. The mean follow-up duration was 64.7 months (range 14-134 months). Disease progression was significantly higher in patients undergoing surveillance as compared to those undergoing upfront adjuvant radiation (71.4 versus 17.4%; p=0.002). Median progression-free survival times were 129 months and 27 months in the upfront adjuvant radiation and surveillance groups, respectively (p=0.007). In patients undergoing surveillance, 50% ultimately required irradiation, and the median radiation-free survival time in this subgroup was 57 months. Two children in the adjuvant radiation group developed asymptomatic radiation-related vasculopathies on follow-up; however, there were no statistically significant differences between the two groups in terms of visual, functional, or pituitary-hypothalamic function at last follow-up. CONCLUSIONS: In comparison to upfront adjuvant radiation following incomplete craniopharyngioma resection significantly, a strategy of postoperative surveillance resulted in less durable disease control but allowed radiation therapy to be delayed by a median time of 57 months, without significant detriment to global functional, visual, and neuro-endocrinological outcomes. The merits and demerits of either strategy should be carefully considered in the post-surgical management of these patients.

Genetic Heterogeneity and Challenges in the Management of Permanent Neonatal Diabetes Mellitus: A Single-Centre Study from South India.

Aim and Objectives: 1. To study the clinical outcome, growth and glycaemic control, 2. To study the frequency and type of genetic mutations. Methods: This is a retrospective study with a review of data of medical records from 2008 till date. Results: Twelve patients (six males) with neonatal diabetes mellitus (NDM) were identified. Median (interquartile range - (IQR)) age at diagnosis was 72 (31-95) days with a history of consanguinity in 75%. The median birth weight (range) was 2345 (900-3300) g. Follow-up data were available for eight patients with a median age at (IQR) follow-up of 3.3 (3-5.3) years. At follow-up, the mean annual HbA1c was 8.2% at a mean insulin dose of 1.1 U/kg/d. One patient with Wolcott-Rallison syndrome (WRS) and 21α-hydroxylase deficiency had poor growth and intellectual difficulty. The rest demonstrated satisfactory growth with an increase of mean weight centile from 2nd to 13th, height centile from 6.5th to 20th and normal neuro-cognitive development. Eleven patients underwent genetic testing with a molecular diagnosis in 54% (6/11): EIF2AK3 (n = 2) and one each in INS, PDX1, IL2RA and FOXP3. None had variants in ABCC8 or KCNJ11. One with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome underwent haematopoietic stem cell transplant (HSCT) and later succumbed. Conclusion: Our study demonstrates good clinical outcomes among NDM patients without immune dysfunction. Molecular diagnosis was attained only in around half of the patients (54%) with a great genetic heterogeneity.

A Comparison of Long-Term Treatment Outcomes Between Giant and Nongiant Craniopharyngiomas.

BACKGROUND: There is limited literature on outcomes after surgical treatment of giant craniopharyngiomas in adult and pediatric patients. METHODS: A retrospective review of 159 patients undergoing surgery for craniopharyngiomas at a single institution was performed. Patients with giant craniopharyngiomas (maximum dimension ≥4.5 cm) were compared with nongiant tumors in terms of various clinical and radiological parameters and long-term surgical outcomes. Extent of resection was determined by postoperative magnetic resonance imaging. Factors associated with post-treatment obesity were also analyzed. RESULTS: Giant craniopharyngiomas (n = 66) were characterized by higher rates of childhood presentation, visual impairment, neurological deficits, multicompartmental involvement, and hydrocephalus as compared with nongiant tumors (n = 139). Giant tumors also were less likely to undergo transsphenoidal resection and were associated with a higher rate of postoperative neurological morbidity. There were no significant differences between the 2 groups in terms of extent of resection, use of postoperative radiation therapy, and long-term endocrinological outcomes. Overall recurrence rates over a mean follow-up period of 4.1 years were similar between giant and nongiant tumors; however, recurrences after presumed gross total resection/near total resection were significantly higher in the former subgroup versus the latter (39.4% vs. 18.4%; P = 0.044). Risk factors for post-treatment obesity in giant craniopharyngiomas included adult age (P = 0.001), preoperative obesity (P = 0.003), and hypothalamic involvement (P = 0.012). CONCLUSION: Gross total resection/near total resection of giant craniopharyngiomas can be achieved at rates comparable to nongiant tumors. However, there remains a greater risk of postoperative neurological morbidity. Radiation therapy mitigates the risk of recurrence on long-term follow-up.

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.

Allele-specific PCR and Next-generation sequencing based genetic screening for Congenital Adrenal Hyperplasia in India.

Genetic screening of Congenital Adrenal Hyperplasia (CAH) is known to be challenging due to the complexities in CYP21A2 genotyping and has not been the first-tier diagnostic tool in routine clinical practice. Also, with the advent of massive parallel sequencing technology, there is a need for investigating its utility in screening extended panel of genes implicated in CAH. In this study, we have established and utilized an Allele-Specific Polymerase Chain Reaction (ASPCR) based approach for screening eight common mutations in CYP21A2 gene followed by targeted Next Generation Sequencing (NGS) of CYP21A2, CYP11B1, CYP17A1, POR, and CYP19A1 genes in 72 clinically diagnosed CAH subjects from India. Through these investigations, 88.7% of the subjects with 21 hydroxylase deficiency were positive for eight CYP21A2 mutations with ASPCR. The targeted NGS assay was sensitive to pick up all the mutations identified by ASPCR. Utilizing NGS in subjects negative for ASPCR, five study subjects were homozygous positive for other CYP21A2 variants: one with a novel c.1274G>T, three with c.1451G>C and one with c.143A>G variant. One subject was compound heterozygous for c.955C>T and c.1042G>A variants identified using ASPCR and NGS. One subject suspected for a Simple Virilizing (SV) 21 hydroxylase deficiency was positive for a CYP19A1:c.1142A>T variant. CYP11B1 variants (c.1201-1G>A, c.1200+1del, c.412C>T, c.1024C>T, c.1012dup, c.623G>A) were identified in all six subjects suspected for 11 beta-hydroxylase deficiency. The overall mutation positivity was 97.2%. Our results suggest that ASPCR followed by targeted NGS is a cost-effective and comprehensive strategy for screening common CYP21A2 mutations and the CAH panel of genes in a clinical setting.

Phenotypic variability of a TREX1 variant in Aicardi-Goutieres type 1 patients from the Indian subcontinent.

Aicardi-Goutieres Syndrome (AGS) is a heterogeneous genetic syndrome, manifesting early as encephalopathy and is associated with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, thrombocytopenia and intracranial calcification. The most severe neonatal type, AGS1, is caused by biallelic disease-causing variants in TREX1. In this study, we describe four patients with TREX1-related AGS1 whose phenotype overlaps with intra-uterine infections and neonatal lupus. Exome sequencing identified a previously reported TREX1 variant, c.223dup (NM_016381.5; p. Glu75GlyfsTer82) in all the four patients belonging to the Indian subcontinent. The functional consequence of the disease-causing variant was predicted by using a new combination of bioinformatics softwares. The recurrence of this pathogenic variant indicates a possible founder effect in TREX1 for AGS1 in this population. The phenotypic variability in those with this founder mutation can mimic intrauterine infections and neonatal lupus, thereby leading to misdiagnosis warranting a targeted genetic testing approach to be a part of the diagnostic workup to obtain a definite, early and cost-effective diagnosis in patients from Indian subcontinent with early onset encephalopathy.

Clinicogenetic Profile, Treatment Modalities, and Mortality Predictors of Gaucher Disease: A 15-Year Retrospective Study.

INTRODUCTION: Gaucher disease (GD) is a rare autosomal recessive lysosomal storage disorder, in which biallelic pathogenic variants in the Glucosidase beta acid (GBA) gene result in defective functioning of glucosylceramidase that causes deposition of glucocerebroside in cells. GD has 3 major types namely, non-neuronopathic (type I), acute neuronopathic (type II), and chronic neuronopathic (type III). Definite treatment options are limited and expensive. They succumb early to the disease, if untreated. There is paucity of studies from the Indian subcontinent, which elicit the factors resulting in their premature mortality. MATERIALS AND METHODS: A retrospective study was carried out in a tertiary care setting of South India to assess the clinical profile, mutation spectrum, and various management strategies (only supportive therapy, enzyme replacement therapy [ERT], substrate reduction therapy [SRT] haematopoietic stem cell transplant [HSCT]), and mortality predictors of patients with GD from 2004 to 2019. A Kaplan-Meier survival curve was plotted. In silico predictions were performed for novel variants. RESULTS: There were 60 patients with all types of GD seen over the study period of 15 years. Their median age at diagnosis was 2 years. The median follow-up was for 5 years (interquartile range [IQR] = 2-8). The overall mortality rate was 35%; however, it was only 10% in those receiving definite treatment. Mortality was higher (47.5%) by more than 4 folds in those only on supportive therapy. The median survival from the time of diagnosis was 6.3 years (IQR = 3.5-10.8) in the definite treatment group and 3.5 years (IQR = 1-5) in those on supportive therapy. The Kaplan-Meier survival analysis showed significant (p value 0.001) mortality difference between these groups. The multiple logistic regression analysis found the neuronopathic type (OR = 5) and only supportive therapy (OR = 6.3) to be the independent risk factors for premature mortality. CONCLUSION: GD is a rare disease with a high mortality rate, if left untreated. ERT and SRT are the definitive treatments which increase the survival. In resource-limited settings like India, with higher prevalence of the neuronopathic type, HSCT may be a more suitable definitive treatment option, due to its one-time intervention and cost, assuming similar efficacy to ERT. However, the efficacy and safety of HSCT in GD needs to be established further by substantial patient numbers undergoing it.

Optimizing Cord Blood Thyroid Stimulating Hormone Cutoff for Screening of Congenital Hypothyroidism-Experience from Screening 164,000 Newborns in a Tertiary Hospital in India.

BACKGROUND AND OBJECTIVES: In our institution, we have an ongoing newborn thyroid screening (NBS) program since July 2001. In the initial 9 months, we used cord blood thyroid-stimulating hormone (TSH) (CBTSH) cutoff of 20 mIU/L and thereafter the cutoff was increased to 25 mIU/L. Our objective was to evaluate whether a CBTSH cutoff of 25 mIU/L is sensitive and cost-effective in NBS of congenital hypothyroidism (CH). MATERIALS AND METHODS: All in-born babies are screened and those with CBTSH ≥25 mIU/L are recalled for confirmatory TSH/T4/FT4 tests. CH is confirmed with elevated TSH and low T4/FT4. Those with CBTSH 20-24.99 mIU/L were recalled for confirmatory tests in initial period of our NBS and prospectively between January and August 2017. Statistical analysis was done to derive positive predictive value and sensitivity to diagnose CH for each CBTSH between 20 and 30 mIU/L. RESULTS: A total of 164,163 neonates were screened from July 2001 to August 2017. Of the 2352 babies with CBTSH ≥25-30 mIU/L, 1763 returned for retesting and 5 confirmed as CH (4 gland-in-situ and 1 absent uptake on nuclear scan). Of the 14,742 screened during the study period, 195 of the 293 babies with CBTSH 20-24.99 mIU/L returned for retesting and none diagnosed as CH. A CBTSH of 25 mIU/L has 99.2% sensitivity and 97.5% specificity. A lower screen TSH cutoff 20 mIU/L would result in recall of additional 300 babies/year with no definite improvement in sensitivity. CONCLUSIONS: Our data justify the continuation of using screen TSH cutoff of 25 mIU/L while using cord blood for NBS in our population. With a diverse and large population, it is important that we use feasible regional screen cutoffs for optimal use of our resources.

Long-term outcomes following maximal safe resection in a contemporary series of childhood craniopharyngiomas.

BACKGROUND: The optimal management of pediatric craniopharyngiomas remains controversial. This study aimed to characterize long-term outcomes in a contemporary cohort of children undergoing surgery for craniopharyngiomas. METHODS: This was a retrospective review of 37 consecutive children who underwent surgery for craniopharyngioma with a median follow-up duration of 79 months (range 5-127 months). Patients were stratified by extent of resection (EOR) and need for adjuvant radiation therapy (RT). Imaging studies were reviewed to grade extent of hypothalamic involvement. Data on functional outcomes, pituitary function, and obesity were analyzed. RESULTS: Gross total resection was achieved in 16 patients (43.2%), near total resection in six patients (16.2%), and subtotal resection (STR) in 15 patients (40.5%). The recurrence-free survival rate was 81.1% and 70.3% at 5- and 10-year follow-up, respectively. Survival analysis showed superior disease control in patients undergoing STR + RT (p = 0.008). Functional outcomes were independent of EOR, postoperative RT or recurrence. Diabetes insipidus was present in 75% and 44.4% of patients required >2 hormone replacements at last follow-up. Obesity was present in 36.1% patients after treatment, and was associated with preoperative obesity (p = 0.019), preoperative hypothalamic involvement (p = 0.047) and STR + RT (p = 0.011). CONCLUSIONS: Gross or near total resection may be achieved safely in almost 60% of cases; however, radical surgery does not eliminate the risk of recurrence. Over long-term follow-up, STR + RT offers the best disease control rates. Patients with preoperative hypothalamic involvement, obesity, and those with tumors not amenable to radical resection are at risk for developing obesity on long-term follow-up.

Hepatic Glycogenoses Among Children-Clinical and Biochemical Characterization: Single-Center Study.

BACKGROUND: Glycogen storage disease (GSD) is typified by early morning seizures. Absence of this results in delayed diagnosis, especially the non-GSD 1 group. Data are limited to few patients with unclear outcome. OBJECTIVES: 1. Study the common presentation and types of GSD. 2. Study the clinical and biochemical outcome. 3. Review genetic mutations. METHODS: Observational study from May 2016-April 2019 at metabolic clinic at our center. RESULTS: Total of 30 patients were diagnosed with GSD. Ten were excluded-Fanconi-Bickel (3) and <4 months follow-up (7). Data were analyzed for 20 patients (16 males). Mean age at presentation was 4.3 yrs. All had hepatomegaly, 90% had short stature, and 40% had early morning seizures. Mean follow-up was 22 months. There was a statistically significant improvement in metabolic parameters on treatment (mean)-fasting glucose from 50.4 to 79.5 mg/dl, SGPT from 416 to 199 U/L. Lipid profile showed reduction in triglycerides (318-225 mg/dl) but minimal increase in cholesterol (178-188 mg/dl). Mean weight centile improved from 14.1 to 20.3 and height centile from 2.3 to 7.9. Genetic testing confirmed types VI (3), III (3), IXa (1), IXc (1), and Ia (1). Liver biopsy confirmed GSD in 15/20. All were managed with uncooked corn starch. In addition, omega-3 fatty acid was used in 8/20 and high protein diet in 2 with GSD type III. CONCLUSION: Awareness of GSD needs to improve among pediatricians and hepatologists. The most common symptoms are asymptomatic hepatomegaly and short stature. Dietary therapy with uncooked corn starch remains mainstay of treatment. Mixed hyperlipidemia is difficult to control despite good metabolic improvement. Role of omega-3 fatty acid needs to be explored further. Genetic mutation analysis can assist with tailoring treatment and should get precedence over liver biopsy.

Smartphone App as Motivational Intervention to Improve Glycemic Control in Adolescents with Type 1 Diabetes.

OBJECTIVES: Type 1 diabetes (T1D) adolescents often do not achieve good glycemic control. In the context of growing number of technologically savvy adolescents, this study was done to examine the effectiveness of a motivational smartphone app to improve their glycemic control. METHODS: Eleven to eighteen year old adolescents, treated by Pediatric endocrine team of CMC, Vellore, who had T1D ≥ 1 y duration with poor glycemic control (mean HbA1c ≥ 8.5% in preceding 12 mo) were recruited. An app programmed to provide 3 reminders per day regarding insulin, meals and physical exercise was installed on their phone. Diabetes management was continued as per the standard of care. HbA1C was measured after 3 mo. RESULTS: Thirty seven adolescents were recruited; 3 were excluded as the app became non-functional. Seventeen were boys, mean age was 13.8 y (11-18 y) and mean duration of diabetes was 4.9 y (0.8-16 y). The mean HbA1c levels over preceding 12 mo and at recruitment were 10.75% (1.88) and 10.6% (2.08) respectively. Twenty eight participants returned for repeat HbA1C after 3-4 mo. As compared to baseline there was significant reduction in HbA1c level: 10.6% (2.08) vs. 9.65% (1.6); p = 0.004. Twenty two of twenty eight participants showed reduction in HbA1c after app installation. The magnitude of change in HbA1c levels over a 3 mo period before and after the app use was analyzed. There was significant difference between mean HbA1c levels before and after app use; +0.28 (2.06) vs. -0.914 (1.52); p = 0.019. CONCLUSIONS: Following usage of smartphone app as a motivational intervention in adolescents with Type 1 diabetes, there was significant reduction in HbA1c level after 3 mo. With continued use, this may benefit them to achieve target HbA1c levels. Use of mobile phone apps as motivational interventions is feasible in adolescents with Type 1 diabetes in India.

An Open-label Randomized Controlled Trial to Compare Weight Gain of Very Low Birth Weight Babies with or without Addition of Coconut Oil to Breast Milk.

Background: Nutritional guidelines involving the feeding of very low birth weight babies (VLBW) recommend addition of Human Milk Fortifiers to breast milk. Owing to financial constraints, it is a practice in low- and middle-income countries (LMIC) to add coconut oil to aid better weight gain. There are inadequate data on improvement of growth parameters with oral coconut oil supplementation of breast milk. Methods: In this randomized controlled trial, we measured growth parameters and body composition of 60 babies who received either breast milk with coconut oil or breast milk alone. Randomization was stratified according to intrauterine growth appropriate for gestational age (n = 30) and small for gestational age (n = 30). Results: There was no difference in weight gain between the two groups. The weight gain velocity was 15 ± 3.6 and 14.4 ± 3.4 g/kg/day (p value = 0.49) in the breast milk alone and in the breast milk with coconut oil group, respectively. There was no difference in increase in head circumference and length. Triceps skinfold thickness (n = 56) was similar in both groups, but subscapular skinfold thickness was significantly more in the coconut oil group. Total body fat percentage did not differ between the groups (25.2 ± 4.3 vs. 25.5 ± 4.3%, p = 0.79). Conclusion: Oral supplementation of coconut oil along with breast milk did not increase growth parameters or result in change in body composition in very low birth weight (VLBW) babies.

Novel mutation in the nuclear receptor subfamily 0, group B, member 1 (NR0B1) gene associated with intrafamilial heterogeneity in three boys with X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism from India.

Background: Nuclear receptor subfamily 0, group B, member 1 (NR0B1) gene previously known as DAX1 is a transcription factor that plays a key role in the development of hypothalamo-pituitary-gonadal and adrenal axis. Primary adrenal failure may result from metabolic, infection, autoimmune or developmental causes resulting in a life-threatening condition needing immediate intervention. This study aimed to analyse NR0B1 (DAX1) gene mutation resulting in adrenal hypoplasia congenita (AHC) in three brothers presenting with hypogonadotropic hypogonadism and primary adrenal failure either in infancy or in early childhood. Methods: We studied three boys with primary adrenal failure and hypogonadotropic hypogonadism presenting at different ages at the Paediatric Endocrinology Clinic. Muta- tional analysis of NR0B1 gene was carried out by bidirectional sequencing. Results: All the three boys had deletion of G in exon 1 at position 189 (c.189_189delG) of the gene resulting in frame shift mutation (Y64Tfs*21). Conclusion: Novel mutation in NR0B1 detected by this study explained the cause ofhypogonadotropic hypogonadism with primary adrenal failure in this Indian family. Intrafamilial variability was seen in this family. Early diagnosis by genetic testing, genetic counselling and family screening can help to manage this life-threatening condition.

Sirolimus therapy for congenital hyperinsulinism in an infant with a novel homozygous KCNJ11 mutation.

BACKGROUND: Congenital hyperinsulinism results in refractory hypoglycemia. If a therapy with diazoxide has been unresponsive this has been treated by subtotal pancreatectomy in the past. This therapeutic option poses an increased risk of developing diabetes at a later stage. There have been a few case reports on the use of sirolimus in such situations in the recent past. CASE PRESENTATION: Our patient was started on sirolimus very early, on day 29 of life and at the age of 14 months is doing well on sirolimus therapy. His growth and development have been good and he has not had any major complications so far. Genetic testing showed a novel KCNJ11 homozygous mutation on next generation sequencing and the parents were heterozygous carriers. CONCLUSIONS: We report the successful use of sirolimus in the management of diazoxide unresponsive congenital hyperinsulinism with diffuse pancreatic involvement. We believe this is the youngest patient to be initiated on sirolimus so far.