Volume 30, Issue 7

Background: Type 1 diabetes (T1D) is frequently associated with other autoimmune conditions such as autoimmune thyroiditis, coeliac disease (CD) and Addison’s disease. There are sparse data on the prevalence of antibodies against these conditions in Indian patients with T1D. This study aims to evaluate prevalence of these T1D associated autoantibodies in Indian patients. Methods: Two hundred and fifty-eight patients with T1D were recruited from the Bangalore Diabetes Hospital and the Vydehi Institute of Medical Sciences and Research Centre (VIMS) for the study. Participants diagnosed with diabetes before the age of 18 years, as per the American Diabetes Association (ADA) criteria, and who were classified as T1D based on clinical grounds were recruited for the study. Anti-thyroid peroxidase antibody (TPO) and IgA tissue transglutaminase antibody (tTG) were estimated in all the patients. 21-Hydroxylase antibody (21-OHAb) were estimated in 170 patients. All assays were done by commercial immunoassay. Eighty-eight unrelated age-matched healthy controls were chosen for comparison. Results: The mean age of T1D patients was 14.33 years. The mean duration of diabetes was 4.88 years. Anti-TPO was positive in 43 (16.7%) patients with T1D as compared to 3 (3.4%) in controls. IgA tTG was positive in 12 (4.65%) patients with T1D and was absent in controls. 21-OHAb was positive in two (1.1%) patients with T1D and was absent in controls. Both patients who had positive 21-OHab had the other two antibodies. Five patients had positive anti-TPO and IgA-tTG antibodies. Conclusions: Anti-TPO antibody was the most prevalent antibody in patients with T1D. Anti-TPO and IgA-tTG antibodies were significantly higher than in the control population. Further studies will be required to assess the clinical significance of these positive antibodies.

Background: Phenylketonuria (PKU) often requires a lifelong phenylalanine (Phe)-restricted diet. Introduction of 6R-tetrahydrobiopterin (BH4) has made a huge difference in the diets of patients with PKU. BH4 is the co-factor of the enzyme phenylalanine hydroxylase (PAH) and improves PAH activity and, thus, Phe tolerance in the diet. A limited number of published studies suggest a pharmacodynamic profile of BH4 more suitable to be administered in divided daily doses. Methods: After a 72-h BH4 loading test, sapropterin was initiated in 50 responsive patients. This case-control study was conducted by administering the same daily dose of sapropterin in group 1 (n=24) as a customary single dose or in two divided doses in group 2 (n=26) over 1 year. Results: Mean daily consumption of Phe increased significantly after the first year of BH4 treatment in group 2 compared to group 1 (p<0.05). At the end of the first year of treatment with BH4, another dramatic difference observed between the two groups was the ability to transition to a Phe-free diet. Eight patients from group 2 and two from group 1 could quit dietary restriction. Conclusions: When given in two divided daily doses, BH4 was more efficacious than a single daily dose in increasing daily Phe consumption, Phe tolerance and the ability to transition to a Phe-unrestricted diet at the end of the first year of treatment.

Background: Breastfeeding is recommended as the best source of nutrition in the first months of life and observational studies have associated exclusive breastfeeding with decreased weight gain and a protective effect against obesity in childhood. The objective of this study was to describe the characteristics of a cohort of exclusively breastfed obese infants to determine factors that may lead to this unusual weight gain. Methods: Infants seen between 2003 and 2015 who were exclusively breastfed and showed excessive weight gain in the first year of life were followed with a focus on features of the mother, the child, feeding patterns and the presence of concomitant factors that influence nutritional status. Additionally, in a subset of the sample, macronutrients of the maternal breast milk were analyzed. A descriptive, prospective cross-sectional study was conducted. Results: Of 73 patients, 63% were girls. At 3 months of life, 64% had a weight-for-height standard deviation score (SDS) >2. At 6 and at 12 months, 100% of the patients had a weight-for-height >2 SDS. The mean age at semisolid-food introduction was 7 months. The mean age at weaning was 15.8 months. The babies were fed on demand and no hunger-satiety pattern was observed. In the breast milk samples analyzed, a significantly lower fat content was found. Conclusions: The results of our study lead to the assumption that inter-individual variations in mother’s milk composition may affect the growth patterns of children.

Background: A number of factors influence sexual maturation in adolescents, including chronic illnesses like HIV. Marshall and Tanner devised a method of classifying the adolescent based on the level of sexual maturation into five stages. This study compared the Tanner staging of HIV-infected and uninfected girls. Methods: This was a cross-sectional study of 100 HIV-infected girls aged 8–18 years and 100 uninfected counterparts matched for age and social class. Using standard photographs as a guide, stages of sexual maturation were determined according to the method proposed by Marshall and Tanner. Data analysis was done with SPSS version 20. p-values <0.05 were regarded as significant. Results: The study participants were aged 8–17 years. Fifty-five subjects compared to 39 controls were still in pre-pubertal breast developmental stages while 45 subjects (45%) compared to 61 controls (61%) have commenced breast development (p=0.024). Similarly, 52 subjects compared to 31 controls were in the pre-pubertal pubic hair developmental stages, while 48 subjects (48%) compared to 69 controls (69%) had commenced pubic hair development (p=0.003). Conclusions: Perinatal HIV infection affected the onset of pubic hair and breast development but did not significantly affect the attainment of sexual maturation.

Background: This study aims to assess the joint association of screen time (ST) and physical activity (PA) with anthropometric indices among Iranian children and adolescents. Methods: In this national study, 23,183 school students, aged 6–18 years, were studied. By using a multi-stage cluster sampling method, they were selected from rural and urban areas of 30 provinces of Iran. ST and PA were assessed by self-administered validated questionnaires. Height, weight, hip and waist circumferences (WC) were measured according to standard protocols, and body mass index (BMI) was calculated. ST of <2 h per day was categorized as “low” and ≥2 h per day as “high”. PA levels were obtained by a 7-day recall of sports or activities that made participants sweat or make their legs feel tired, or games that made them breathe heavily. Using this questionnaire, the score of 1–1.9 was categorized as “low” and scores between 2 and 5 as “high” PA. Logistic regression analyses were used to evaluate the joint association of PA and ST categories with odds of anthropometric measures. Results: In both genders, those students categorized as “Low PA & High ST” had the highest levels of BMI z-scores (boys: 0.15±1.12, girls: 0.17±1.08), WC (boys: 69.93±13.89 cm, girls: 67.30±11.26 cm), and hip circumference (boys: 82.41±13.90 cm, girls: 84.05±13.7 cm), as well as the highest prevalence of overweight (boys: 15.32%, girls: 14.04%) (p<0.001 in all comparisons). In linear multivariate model, students with “High PA & High ST” had significant increased levels of z-scores for BMI, WC and hip circumference (p<0.05). Conclusions: The current findings underscore the importance of reducing ST along with increasing PA for prevention and control of excess weight in children and adolescents.

Background: Population specific data and influence of sub-clinical hypothyroidism on insulin like growth factor-1 (IGF-1) and its binding protein-3 (IGFBP-3) in Indian children is lacking. This study was undertaken to evaluate serum IGF-1 and IGFBP-3 and their correlation with age, gender, pubertal status and thyroid functions. Methods: A total of 840 apparently healthy school girls aged 6–18 years, were recruited for the study and underwent assessment of height, weight, body mass index, pubertal status and serum T3, T4, TSH, IGF-1, IGFBP-3 and IGF-1/IGFBP-3 molar ratio. Results: The mean serum levels of IGF-1, IGFBP-3 levels and IGF-1/IGFBP-3 molar ratio were 381.8±240.5 ng/mL, 4.19±2.08 μg/mL and 40.5±37.2%, respectively. The serum IGF-1 and IGF-1/IGFBP-3 molar ratio increased significantly (p<0.0001) at 11 years followed by a steady yet non-significant rise till 16 years of age. A similar pattern was observed for IGFBP-3 showing a steep rise at 12 years and peaking at 16 years. Likewise, serum levels of IGF-1 and molar ratio of IGF-1/IGFBP-3 increased significantly with pubertal maturation from stage 1 to 3 and were higher in overweight girls compared to normal weight and obese girls. The growth factors were no different in girls with or without subclinical hypothyroidism. Conclusions: There was no significant impact of age on IGF-1 and IGFBP-3 in pre-pubertal girls. A sudden marked increase at 11 years followed by a gradual rise in growth factors till 16 years is indicative of pubertal initiation and maturation. Subclinical hypothyroidism did not influence growth factors in girls.

Background: While the main role of growth hormone (GH) replacement therapy in children is to promote linear growth, GH has also an effect on lipids and body composition. There is an ongoing discussion whether discontinuation of GH treatment is associated with deterioration of lipids. Methods: We analyzed weight status [as body mass index-standard deviation score (BMI-SDS)], insulin like growth factor (IGF)-1, triglycerides, total, low-density liporptoein (LDL)- and high-density lipoprotein (HDL)-cholesterol at the end of GH treatment and in mean 6 months later in 90 adolescents (53 with GH deficiency, 16 with Turner syndrome [TS] and 21 born small-for-gestational age [SGA]). Results: After stopping GH treatment, total cholesterol (+10±24 mg/dL vs. −4±13 mg/dL) and LDL-cholesterol (+15±20 mg/dL vs. −6±12 mg/dL) increased significantly higher in severe (defined by GH peak in stimulation test <3 ng/mL) compared to moderate GHD. In patients with TS, total cholesterol (+19±9 mg/dL), LDL-cholesterol (+9±12 mg/dL) and HDL-cholesterol (+4.3±3.5 mg/dL) increased significantly. In adolescents born SGA, triglycerides increased (+34±51 mg/dL) and HDL-cholesterol decreased significantly (−3.8±7.1 mg/dL). In multiple linear regression analyses, changes of total and LDL-cholesterol were significantly negatively related to peak GH in stimulation tests, but not to gender, age at GH start, duration of GH treatment, observation time, changes of BMI-SDS or IGF-1 after the end of GH treatment. The BMI-SDS did not change after the end of GH treatment. Conclusions: Discontinuation of GH treatment leads to a deterioration of lipids in TS, SGA and severe but not moderate GHD.

Background: The clinical, laboratory, genetic properties and final height of a large cohort of patients with nonclassical 21-hydroxylase deficiency (NC21OHD) in Turkey were analyzed. Methods: This multicenter, nationwide web-based study collected data. Results: The mean age was 9.79±4.35 years (229 girls, 29 boys). The most common symptoms were premature pubarche (54.6%) and hirsutism (28.6%). The peak cortisol was found below 18 μg/dL in three (15.45%) patients. A mutation was detected in the CYP21A2 gene of 182 (87.5%) patients. The most common mutation was V281L . Final height in female patients who were diagnosed and treated before attaining final height or near final height was found to be shorter than the final height in female patients who were diagnosed after attaining final height or near final height. Conclusions: The final height of the patients who were treated during childhood was found to be shorter than the final height of patients during the adolescent period.

Background: The interpretation of individual laboratory test results requires the availability of population-based reference intervals. In children, reference interval estimation has to consider frequently the strong age-dependency. Generally, for the construction of reference intervals, a sufficiently large number of independent measurement values is required. Data selections from hospitals or cohort studies often comprise dependencies violating the independence assumption. Methods: In this article, we propose a combination of LMS-like (mean, M; coefficient of variation, S; skewness, λ or L) and resampling methods to overcome this drawback. The former is recommended by the World Health Organization (WHO) for the construction of continuous reference intervals of anthropometric measurements in children. The approach allows the inclusion of dependent measurements, for example, repeated measurements per subject. It also provides pointwise confidence envelopes as a measure of reliability. Results and conclusions: The combination of LMS-type methods and resampling provides a feasible approach to estimate age-dependent percentiles and reference intervals using unbalanced longitudinal data.

Background: Deficiencies of galactokinase (GALK) and UDP-epimerase (GALE) are implicated with galactose metabolic disorders. The aim of the study was the identification of mutations in GALK and GALE genes and clinical evaluation of patients. Methods: Five patients with GALK and five with GALE deficiency were picked up via the Neonatal Screening Program. Additionally, two females, 4 years old, were referred with late diagnosed galactosemia, as rare cases. Mutational analysis was conducted via Sanger sequencing, while in silico analysis tools were utilized for the novel mutation. Psychomotor and speech development tests were performed, as well. Results: The mutation p.Pro28Thr was identified in both alleles in GALK-deficient patients of Roma (gypsy) origin, whereas the novel p.Asn39Ser was detected in two non-Roma patients. In GALE-deficient patients benign and/or likely benign mutations were found. Psychomotor and speech delay were determined in the Roma GALK patients. In each of the late diagnosed females, four mutations were identified in all galactosemia-related genes. Conclusions: The mutational spectrums of GALE- and GALK-deficient patients in Greece are presented for the first time along with a clinical evaluation. Mutational analysis in all galactosemia-related genes of symptomatic patients is highly recommended for future cases.

Background: Polycystic thyroid disease (PCTD) is a rare condition and has been described in adults in the setting of subclinical and clinical hypothyroidism. We present the first known case of a pediatric patient with diffuse macrocystic degeneration of the thyroid. Clinical presentation: A 6-year-old previously healthy patient was evaluated after presenting with a 16-month history of an enlarging polycystic thyroid and hyperthyroidism. Markers of autoimmune thyroid disease including thyroid stimulating immunoglobulin (TSI), thyroid stimulating hormone (TSH) receptor antibody, thyroid peroxidase antibody and thyroglobulin antibody were negative. No family history of benign or malignant thyroid or cystic disease was present. The patient underwent a total thyroidectomy without perioperative complication. She remains euthyroid with thyroid hormone replacement therapy. Summary: To our knowledge, this is the first report of PCTD in the pediatric population associated with hyperthyroidism without evidence of autoimmune disease. Somatic activating thyrotropin-receptor gene mutations are known to cause non-autoimmune hyperthyroidism in children, however it is unknown if similar mechanisms are responsible for pediatric PCTD. Conclusions: Polycystic thyroid degeneration can occur in children and may result in a hyperthyroid state.

Background: Krukenberg tumors are ovarian metastatic adenocarcinomas with a primary origin usually located in the stomach, colon, gallbladder, pancreas, or breast. Occasionally, these tumors produce virilization in the affected individual due to androgen production by luteinization of the tumoral stroma. It is believed that during pregnancy these tumors are more likely to increase androgen production due to the elevated levels of human chorionic gonadotropin (hCG). High maternal androgens can cross the placenta producing virilization of the female fetus. Case presentation: A 46,XX newborn female, whose mother was diagnosed with a metastatic ovarian tumor during her second trimester of gestation associated with worsening hirsutism and acne, was found to have ambiguous genitalia at birth. Testosterone levels in both the mother and infant were elevated. Follow-up laboratory tests showed progressive normalization of circulating androgens after delivery. Conclusions: Krukenberg tumors are rare and may produce virilization of the mother and the female fetus when present during pregnancy.

Background: Postprandial hyperinsulinemic hypoglycemia (PHH) is an increasingly recognized complication of gastric bypass surgery in obese adults, distinct from the “dumping syndrome”. Case presentation: Upon birth, primary repair of esophageal atresia was performed, and at the age of 14 months definite esophageal reconstruction was performed. At the age of 3 years, recurrent brief episodes of symptomatic hypoglycemia started. At the age of 5.7 years the girl was admitted to our clinic and investigations indicated hyperinsulinemic hypoglycemia. Oral glucose tolerance test (OGTT) and continuous glucose monitoring results revealed frequent postprandial hypoglycemic events, which were always preceded by early postprandial hyperglycemia. It was concluded that the patient had PHH caused by a delayed and hyperinsulinemic response to carbohydrate intake as a result of esophagogastric surgery. Treatment with acarbose was titrated using flash glucose monitoring, which resulted in satisfactory glucose regulation. Conclusions: This is the first described case of a child with PHH following esophageal reconstruction.

Background: Achondroplasia (ACH), an autosomal dominant skeletal dysplasia, occurs in approximately 1:20,000 births. On the other hand, 47,XXY aneuploidy (Klinefelter syndrome [KS]) is the most common sex chromosome disorder, with a prevalence of approximately 1:600 males. To the best of our knowledge, only five cases of patients presenting both ACH and KS have been reported to date in the international literature. However, none of these cases has been longitudinally followed during the entire childhood. Case presentation: We report a male patient with ACH and KS, diagnosed in early infancy because of his typical phenotype of ACH. The diagnosis was confirmed by molecular analysis revealing a de novo heterozygous 1138 G-to-A mutation of the FGFR3 gene. During his first assessment, a karyotype was performed, which also revealed coexistence of KS. He was followed by our pediatric endocrinology team until the age of 16 years, then he was gradually transferred to adult endocrine care. Conclusions: This is the first reported case with both conditions that was diagnosed in infancy and was longitudinally followed by a pediatric endocrinology team regularly, from infancy to late adolescence. With a typical phenotype of ACH, it is striking and noteworthy that he did not develop the classical endocrine complications of a child with KS, neither did he necessitate testosterone supplementation during his pubertal development, due to his normal virilization and testosterone levels.