Weight Gain and Height Growth during Infancy, Childhood, and Adolescence as Predictors of Adult Cardiovascular Risk.

OBJECTIVES: To investigate independent relationships of childhood linear growth (height gain) and relative weight gain to adult cardiovascular disease (CVD) risk traits in Asian Indians. STUDY DESIGN: Data from 2218 adults from the Vellore Birth Cohort were examined for associations of cross-sectional height and body mass index (BMI) and longitudinal growth (independent conditional measures of height and weight gain) in infancy, childhood, adolescence, and adulthood with adult waist circumference (WC), blood pressure (BP), insulin resistance (homeostatic model assessment-insulin resistance [HOMA-IR]), and plasma glucose and lipid concentrations. RESULTS: Higher BMI/greater conditional relative weight gain at all ages was associated with higher adult WC, after 3 months with higher adult BP, HOMA-IR, and lipids, and after 15 years with higher glucose concentrations. Taller adult height was associated with higher WC (men ß = 2.32 cm per SD, women ß = 1.63, both P < .001), BP (men ß = 2.10 mm Hg per SD, women ß = 1.21, both P ≤ .001), and HOMA-IR (men ß = 0.08 log units per SD, women ß = 0.12, both P ≤ .05) but lower glucose concentrations (women ß = -0.03 log mmol/L per SD P = .003). Greater height or height gain at all earlier ages were associated with higher adult CVD risk traits. These positive associations were attenuated when adjusted for adult BMI and height. Shorter length and lower BMI at birth were associated with higher glucose concentration in women. CONCLUSIONS: Greater height or weight gain relative to height during childhood or adolescence was associated with a more adverse adult CVD risk marker profile, and this was mostly attributable to larger adult size.

Clinical and molecular characterization of neonatal diabetes and monogenic syndromic diabetes in Asian Indian children.

Mutations in the pancreatic ATP sensitive K(+) channel proteins [sulfonyluea receptor 1 (SUR1) and inward rectifier K(+) channel Kir6.2 (Kir6.2), encoded by ATP-binding cassette transporter subfamily C member 8 (ABCC8) and potassium channel J11 (KCNJ11), respectively], are the most common cause of neonatal diabetes. We describe the clinical presentation and molecular characterization of Asian Indian children with neonatal diabetes mellitus and monogenic syndromes of diabetes. We sequenced KCNJ11, ABCC8 and insulin (INS) genes in 33 unrelated Indian probands with onset of diabetes below one year of age. A total of 12 mutations were identified which included ABCC8 mutations in seven, KCNJ11 mutations in three and INS mutations in two children. The Asp212Tyr mutation in ABCC8 was novel. We also detected two novel mutations (Val67Met and Leu19Arg) in children with syndromic forms of diabetes like Berardinelli Seip syndrome [1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2)] and Fanconi Bickel syndrome [solute carrier family 2A2 (SLC2A2)]. Children carrying the KCNJ11 (Cys42Arg, Arg201Cys) and ABCC8 (Val86Ala, Asp212Tyr) mutations have been successfully switched over from insulin therapy to oral sulfonylurea. Our study is the first large genetic screening study of neonatal diabetes in India.

Clinical application of a novel next generation sequencing assay for CYP21A2 gene in 310 cases of 21- hydroxylase congenital adrenal hyperplasia from India.

PURPOSE: Accurate diagnosis is required for management of Congenital adrenal hyperplasia (CAH). The conventional method for detection of mutations in the CYP21A2 gene is targeted capillary sequencing which is labor intensive and has limited multiplexing capability. Next generation sequencing (NGS) provides data with high sequence coverage and depth. Our objective was to develop an accurate NGS-based assay to characterize the mutation spectrum in CYP21A2 gene in Indian patients suspected to have 21-OH CAH. METHODS: Cases with 21-OH CAH from 12 endocrine units across India were studied. DNA was extracted from proband's and parent's(subset) blood. Locus-specific long-range PCR and gel electrophoresis of amplicons was followed by NGS where no visible 30 kb homozygous/whole gene deletion was observed. Orthogonal confirmation was performed by capillary sequencing (ABI 3500) and Multiplex Ligation-dependent Probe Amplification (MLPA, MRC-Holland). PCR products were purified and individual libraries were pooled and sequenced (Illumina). RESULTS: Of the 310 CAH cases, biallelic mutations (pathogenic/ likely pathogenic variants involving both CYP21A2 gene copies) were detected in 256 (82.6%), heterozygous mutations in 13 (4.2 %), and none in 41 (13.2%). Most common mutation was c.293-13A/C>G (29.03%), followed by 30 kb deletion (18.24%). Thirty samples tested orthogonally (by capillary sequencing or MLPA) showed 100% concordance with NGS assay. Nine novel variants were identified. CONCLUSIONS: We have developed and validated a comprehensive NGS-based assay for detection of variants in CYP21A2 gene in patients with 21-OH CAH. We describe CYP21A2 mutation spectrum and novel variants in a large cohort of Indian patients with CAH.

Safety and reactogenicity of a low dose diphtheria tetanus acellular pertussis vaccine (Boostrix) in pre-school Indian children.

OBJECTIVE: To evaluate the safety and reactogenicity of a reduced-antigen-content combined Diphtheria Tetanus Acellular Pertussis (dTpa) vaccine in Indian preschool children. METHODS: GlaxoSmithKline Biologicals combination dTpa vaccine was administered as a single booster dose to 347 children aged 46 years in seven centers across India. All children were subsequently followed up for two weeks for safety and reactogenicity assessment. RESULTS: A total of 345 subjects completed the study and two subjects were lost to follow-up. One serious adverse event (head injury) unrelated to vaccination was reported. Otherwise, all subjects were in good health throughout the study period. Three subjects (0.9%) reported transient general symptoms (such as irritability and drowsiness), which prevented normal activity. Pain at injection site, swelling and redness was reported in 31.1%, 18.2% and 8.9% subjects respectively. Five subjects (1.4%) reported severe pain preventing normal movement. This resolved within 48 hours in all cases. There were no other severe local reactions including large injection site reactions. CONCLUSION: The reduced antigen content combined dTpa vaccine is safe and well tolerated in Indian pre-school children.

Current Indicators of Nutritional Care in Children with Type 1 Diabetes in India: Do we Need a National Nutritional Guideline?

BACKGROUND: Nutrition is an important pillar of management in children with type 1 diabetes. Indian food is heavily influenced by region, religion, traditions, seasons, and cultural choices. This survey was done to assess current practices and the need for India specific nutritional guidelines for children with type 1 diabetes. MATERIALS AND METHODS: Two 12-item questionnaires were administered to forty health-care professionals across India. The first questionnaire evaluated current clinical practice indicators for nutrition in these children and second assessed practices for counseling a child on dietary habits. RESULTS: There is great heterogeneity across the country with regard to dietary advice offered to children with type 1 diabetes. 97.5% of the respondents feel there is a need for an Indian dietary guideline for children with type 1 diabetes. CONCLUSION: There is need of India specific nutritional guidelines that should be made considering key variants such as age, region, cultural preference, economic burden and psychosocial beliefs, to offer guidance to diabetes care professionals.

Clinical and Molecular Characterization of Prader-Willi Syndrome.

OBJECTIVES: To describe the clinical presentations and molecular diagnosis to aid the clinicians in early diagnosis and appropriate management of Prader-Willi syndrome (PWS). METHODS: Thirty-four clinically diagnosed PWS cases were enrolled after obtaining informed consent/assent. Demographic details, clinical data and anthropometry were recorded using structured proforma. The facial dysmorphology was evaluated. Appropriate genetic testing was performed to confirm the diagnosis. RESULTS: At diagnosis, the most common clinical features included obesity (59%) and short stature (53%). Distinct dysmorphic features were observed in 67%. Neonatal hypotonia with feeding difficulty, delayed development in infancy and childhood behavioral problems were reported in 94%, 94% and 74% respectively. Food seeking behavior and hyperphagia was reported in 67%. Seizures were reported in 47%. All children had underdeveloped external genitalia. Growth hormone (GH) deficiency and impaired glucose tolerance were found in 56% and 50% respectively. Sleep related problems were seen in 67%. Skin and rectal picking were reported in 67%. FISH confirmed micro-deletion was found in 64.7% and abnormal methylation in 35%, of which uniparental disomy was confirmed in 14.7%. CONCLUSIONS: Clinical suspicion is vital for early detection of PWS. Confirmation of the diagnosis requires complex multi-tier molecular genetic testing.

Efficacy of zinc in the treatment of severe pneumonia in hospitalized children <2 y old.

BACKGROUND: Severe pneumonia remains a leading cause of morbidity and mortality in undernourished young children in developing countries. OBJECTIVE: This study evaluated the effect of adjuvant zinc therapy on recovery from severe pneumonia by hospitalized children in southern India who were receiving standard antibiotic therapy. DESIGN: This randomized, double-blind, placebo-controlled clinical trial was conducted at the Christian Medical College Hospital, an 1800-bed teaching hospital in Tamilnadu, India. Enrollment and follow-up occurred between September 2003 and August 2004. Children aged 2-23 mo (n = 299) who were hospitalized with severe pneumonia were randomly assigned to receive 10-mg tablets of zinc sulfate or placebo twice a day during hospitalization, along with standard therapy for severe pneumonia. All clinical signs and symptoms of pneumonia were assessed and recorded at 8-h intervals. RESULTS: There were no clinical or statistically significant differences in the duration of tachypnea, hypoxia, chest indrawing, inability to feed, lethargy, severe illness, or hospitalization. Zinc supplementation was associated with a significantly longer duration of pneumonia in the hot season (P = 0.015). CONCLUSIONS: Zinc supplementation had no overall effect on the duration of hospitalization or of clinical signs associated with severe infection in young children hospitalized for severe pneumonia in southern India. This finding differs from the results of 2 previously reported trials wherein zinc supplementation was associated with a shorter period of recovery from severe pneumonia. Given the conflicting results, further research in representative settings is required to help clarify the role of zinc in the treatment of severe pneumonia.

Massive powder aspiration in a toddler.

We report a case of aspiration of calcium carbonate powder by a toddler. Bronchoscopic removal of aspirated contents resulted in favourable outcome.

Diabetic ketoacidosis in children and adolescents.

Diabetic ketoacidosis (DKA) is considered to be a common presentation of both type 1 diabetes mellitus and type 2 diabetes mellitus in children and adolescents. DKA arises due to lack of adequate insulin in the body. Insulin stops the use of fat as an energy source by inhibiting the peptide hormone glucagon. Without insulin, glucagon levels rise resulting in the release of free fatty acids from adipose tissue, as well as amino acids from muscle cells. Neurological observations should be made for warning signs and symptoms of cerebral edema, and capillary blood glucose concentration should be measured on an hourly basis. Every 2-4 h electrolytes, blood gases, and beta-hydroxybutyrate should be measured. Cerebral edema occurs in 0.5-0.9% of all episodes of DKA. It is considered to be a major cause of death in childhood DKA. Treatment of cerebral edema should be prompt and immediate. Successful DKA management in children depends upon swift diagnosis, meticulous monitoring of clinical and biochemical parameters with prompt intervention.

Type 1 diabetes: Awareness, management and challenges: Current scenario in India.

Type 1 diabetes mellitus (T1DM) has a wide presence in children and has a high mortality rates. The disease, if left unmanaged, poses various challenges to the patient and healthcare providers, including development of diabetic complications and thus decreasing the life expectancy of the affected child. The challenges of T1DM include awareness of the disease that is very poor among the general public and also in parents of T1DM children along with the health care professionals. The challenge of lack of awareness of T1DM can be met by increasing public awareness programs, conducting workshops for diabetes educators regarding T1DM in children, newsletters, CMEs, online courses, and by structured teaching modules for diabetes educators. Diagnosis of T1DM was a challenge a few decades ago but the situation has improved today with diagnostic tests and facilities, made available even in villages. Investigation facilities and infrastructure, however, are very poor at the primary care level, especially in rural areas. Insulin availability, acceptability, and affordability are also major problems, compounded by the various types of insulin that are available in the market with a varied price range. But effective use of insulin remains a matter of utmost importance.

Haemophilus influenzae disease in children in India: a hospital perspective.

We review and summarize published information on diseases caused by Haemophilus influenzae in India and unpublished data from our center covering more than three decades. Since the mid-1950s H. influenzae has been the most common cause of pyogenic meningitis in children admitted to our hospital, accounting for one-third to one-half of cases. Information from other centers in India has been scanty; the lower frequency of isolation of Haemophilus in studies in some centers may be caused by unsatisfactory media and culture methods. The annual numbers of admissions for pyogenic meningitis in our hospital have been quite similar to the numbers of cases of poliomyelitis. Assuming that the similar numbers of children hospitalized with these two diseases indicate similar incidence rates in the community and taking into account the frequency of Haemophilus isolations in pyogenic meningitis, we estimate that there may be as many as 75 to 100 cases of meningitis caused by this organism per year per 100000 children <5 years of age. Although pneumonia caused by H. influenzae has been recognized in a few studies, information is too scanty to attempt the estimation of incidence. Pus-producing infections caused by Haemophilus are rare. Epiglottitis caused by Haemophilus does not seem to occur in India. In recent years we have found that most invasive Haemophilus infections are caused by H. influenzae type b (Hib); other types or untypable strains are infrequent. An increasing prevalence of resistance to chloramphenicol and ampicillin has been recognized in our center and elsewhere. Thus from a hospital perspective, primary prevention by using Hib vaccine seems to be a rational and beneficial intervention. Community-based studies to measure the disease burden of Hib are urgently needed for a more satisfactory assessment of the need for, and cost benefit of, Hib immunization of all infants.

Permanent neonatal diabetes mellitus: clinical presentation and epidemiology in Oman.

AIM: To estimate the accurate incidence and prevalence of permanent neonatal diabetes mellitus, and to determine the clinical profile of this condition in the Sultanate of Oman. METHODS: All children diagnosed as having permanent neonatal diabetes mellitus between 1991 and 1995 in Oman were included in the study. RESULTS: The mean incidence was 2.2 per 100 000 live births/year and the prevalence among under 5s during 1995 was 2.0/100 000. Intrauterine growth retardation was noted in all (mean birthweight 1.86 kg), and diabetic ketoacidosis (mean plasma glucose 34.4 (SD 8.7) mmol/l, mean pH 7.17 (SD 0.09) in 80%. Hypertriglyceridaemia (mean serum triglyceride 19.06 (6.13) mmol/) was constant. No infant had clinical or immunological evidence of congenital viral infections. None had C-peptide excretion or circulating islet cell antibody during diagnosis or follow up. The other important features were parental consanguinity in all, HLA DR3/DR4 association in 80%, development of autoimmune hypothyroidism in one and observation of autoimmune disorders (insulin dependent diabetes mellitus and Hashimoto's thyroiditis) in family members. CONCLUSIONS: These findings strongly suggest an immune mediated aetiology for diabetes mellitus. The reported incidence of permanent insulin dependent neonatal diabetes mellitus in Oman is the highest in the world.

Immune response to measles, mumps & rubella vaccine at 9, 12 & 15 months of age.

Seroconversion rates to measles, mumps and rubella (MMR) in children given MMR vaccine at 9, 12 and 15 months of age were assessed so as to recommend the optimum age for vaccination. A total of 164 infants were recruited, of whom 123 completed the study. Sera were tested pre-immunization and 4 wk after MMR vaccine, for the presence and titres of antibodies by the haemagglutination inhibition (HI) test and by enzyme-linked immunosorbant assay (ELISA). The pre-immunization results showed that levels of maternal antibody detectable by HI had disappeared by 9 months in all infants in the case of measles, but not in the case of mumps or rubella. Evidence for subclinical infection with the three viruses was found in 19 to 31 per cent of infants by 15 months of age. The responses to measles antigen by both HI test and ELISA were better (> 95%) at 12 or 15 months than at 9 months (80%). Vaccine failure was low at 12 or 15 months. The response to mumps antigen by HI antigen was also higher (92%) at 12 months than at 9 months (75%). Vaccine failure was less frequent at 12 months than at 9 months. The ELISA was found to be unreliable for mumps virus antibody testing. Rubella vaccine evoked good seroresponse (> 92%) at 9, 12 and 15 months, both by HI test and ELISA. Thus a better response to the MMR vaccine was obtained at or after 12 months of age than earlier. Hence, a dose of MMR may be given optimally at 12 months for children not previously immunized with measles vaccine. For those already given measles vaccine, the MMR may be given at 12 or 15 months.

Occurrence of multiple antimicrobial resistance among Haemophilus influenzae type b causing meningitis.

Among the 157 children with culture proven pyogenic meningitis who were admitted during 1987-1991, in the Department of Child Health at the Christian Medical College and Hospital, Vellore, 40 had H. influenzae type b (HIB) meningitis; 17 of these had multiantimicrobial resistant HIB (MRHIB) and 23 others had usual susceptibility HIB (USHIB) meningitis. The two groups were compared. Children with MRHIB meningitis who received optimal treatment with cefotaxime had excellent recovery. When cefotaxime therapy was delayed, mortality was noted in all except one child who survived with severe neurological sequelae. MRHIB meningitis treated with drugs other than cefotaxime had 100 per cent mortality. Cefotaxime is therefore recommended in children below 3 yr of age presenting with purulent meningitis, as MRHIB is a possible causative agent in this group.

An epidemic of dengue haemorrhagic fever & dengue shock syndrome in & around Vellore.

This report describes an epidemic of dengue haemorrhagic fever/dengue shock syndrome (DHF/DSS) in the North Arcot Ambedkar district and the adjoining districts in Tamil Nadu and Andhra Pradesh. Nineteen children who fulfilled the clinical criteria for the diagnosis of DHF/DSS were admitted to the Christian Medical College Hospital, Vellore, during June through November, 1990. The clinical presentation was similar to that described in South-east Asian children and the case fatality rate was 26.3 per cent. Serology was confirmatory or suggestive of recent dengue virus infection in 16 children, uninterpretable in 2 and not consistent with recent dengue virus infection in 1 child. All children over 1 yr of age had very high antibody titres suggesting a secondary response whereas infants had lower titres consistent with primary response. The occurrence of recurrent epidemics in this region in the last few years with associated high case fatality emphasizes the urgent need for public health measures to curtail further epidemics.

Neurologic deterioration in a child with Wilson's disease on penicillamine therapy.

Penicillamine is the standard therapy for Wilson's disease in children. We report an 8-year-old-girl with liver disease due to Wilson's disease who developed extrapyramidal symptoms following administration of penicillamine. Symptoms resolved within 20 hours of stopping the drug but recurred within 24 hours when gradually increasing small doses were recommenced.

Treatment of childhood acute lymphoblastic leukaemia with the BFM regimen.

Thirty-eight children with acute lymphoblastic leukaemia were treated with the BFM regimen. Thirty-six (94.7%) achieved complete remission (CR). Twenty 58.8%) of 34 evaluable patients are in continuous complete remission (CCR) at a median follow-up of 33 (range 19-81) months. Long-term disease-free survival was better in the 2-9 years age group (83%) when compared to the 10-14 years group (43%) (P < .05).

Hereditary factor XIII deficiency.

Twelve cases of hereditary factor XIII (FX III) deficiency diagnosed over five years (1986-1990) at Christian Medical College and Hospital, Vellore are presented here. Although all the cases had a history of umbilical cord bleeding and subsequent frequent bleeding episodes, diagnosis was considerably delayed. All but two patients required transfusions for bleeding episodes. Ten patients had a history of consanguinity in parents. Clinical features and family history are described in detail here. The ease of performing the Urea solubility test and problems in it's interpretation are highlighted. The role of prophylactic transfusion is also discussed.

Safety and immunogenicity of Haemophilus influenzae type B vaccine given in combination with DTwP at 6, 10 and 14 weeks of age.

OBJECTIVE: To assess the immunogenicity and reactogenicity of a tetanus conjugate Haemophilus influenzae type b vaccine (Act-Hib) when extemporaneously mixed and administered as a DTwP-Hib combination using an Indian DTwP vaccine (BE DTwP) in comparison with a licensed DTwP-Hib combination vaccine. METHODS: 378 healthy infants were enrolled and randomly allocated to receive either three doses, at 6, 10 and 14 weeks of age, of Act-Hib in combination with BE DTwP (Group A, n = 160), TetrAct-Hib (Group B, n = 160), or BE DTwP and Act-Hib as separate injections (Group C, n = 58). Sera collected before the first dose and one month after the third dose were tested for antibodies to vaccine antigens. Safety was determined using parental diary cards. RESULTS: Anti-Hib antibody concentrations indicative of short-term protection (> 0.15 g/ml) were elicited in all but one subject in Group A (99.3%), and all subjects in Groups B and C. The concentration of 1 g/ml, considered to provide long-term protection, was achieved in 96.7%, 100% and 98.2% of the infants in Groups A, B and C, respectively. All children displayed satisfactory responses to the three DTwP component antigens, TetrAct-Hib eliciting higher titers against diphtheria and tetanus than BE DTwP. No vaccine-associated serious adverse events occurred. The BE DTwP vaccine was associated with more reports of fever than TetrAct-Hib, but most symptoms were regarded as mild and all resolved without sequelae. CONCLUSIONS: Combining Act-Hib and a local DTwP vaccine did not affect the anti-Hib response. In countries where DTwP vaccine available for use in the EPI program is manufactured by a local or other developing country manufacturer, mixing it with lyophilised Act-Hib is a reasonable option though the immunogenicity may have to be documented before routine use. However, use of TetrAct-Hib combination vaccine would be preferable in view of its lower reactogenicity and superior immunogenicity with respect to diphtheria and tetanus.