Volume 33, Issue 9

Background PHKG2-related liver phosphorylase kinase deficiency is inherited in autosomal recessive pattern and is a rare type of liver glycogenosis. We demonstrated the clinical presentation and genetic determinants involved in children with PHKG2- related liver phosphorylase kinase deficiency. Methodology Ten Pakistani children with liver phosphorylase kinase from seven different families, were enrolled over a period of 18 months. All regions of the PHKG2 gene spanning exons and splicing sites were evaluated through targeted exome sequencing. Variants were analyzed using different bioinformatics tools. Novel variants were reconfirmed by direct sequencing. Results Seven different variants were identified in PHKG2 gene including five novel variants: three stop codons (c.226C>T [p.R76*], c.454C>T [p.R152*] and c.958C>T [p.R320*]), one missense variant c.107C>T (p.S36F) and one splice site variant (c.557-3C>G). All five novel variants were predicted to be damaging by in Silico analysis. The variants are being transmitted through recessive pattern of inheritance except one family (two siblings) has compound heterozygotes. Laboratory data revealed elevated transaminases and triglycerides, normal creatinine phosphokinase and uric acid levels but with glycogen loaded hepatocytes on liver histology. Conclusion PHKG2 related liver phosphorylase kinase deficiency can mimic both liver glycogenosis type I (glucose-6-phosphatase deficiency) & III(amylo-1,6 glucosidase) and characterized by early childhood onset of hepatomegaly, growth restriction, elevated liver enzymes and triglycerides. Molecular analysis would be helpful in accurate diagnosis and proper treatment. The symptoms and biochemical abnormalities in liver glycogenosis due phosphorylase kinase deficiency tend to improve with proper dietary restrictions but need to be monitored for long-term complications such as liver fibrosis and cirrhosis.

Objectives Established reference intervals of thyroid function in neonates are important; however, studies often consist of a small sample size or lack of clinical information. We aim to define reference intervals for thyroid-stimulating hormone (TSH) and free thyroxine (FT4) for infants aged 14–30 days. We also reviewed follow-up TSH for infants with initial values 10–20 mIU/L. Methods Venous TSH and FT4 of term babies aged 14–30 days with breast milk jaundice that had thyroid function test performed as part of a prolonged jaundice workout from September 2016 to March 2017 were analyzed. Electronic medical records were reviewed to ensure only well babies with no pathological causes of jaundice or conditions that may affect thyroid function were included. TSH and FT4 were analyzed using immunoassay analyzer Dxl 800, Beckman Coulter. Results There were no correlations between FT4 and TSH with gender, birth weight and ethnicity. Correlation coefficient between FT4 and total bilirubin was weak at 0.138 (p=0.001). No association was found between TSH and bilirubin levels. Mean FT4 was higher in the younger age group day 14–21 (p<0.01). There was no significant difference in TSH values between the age groups. Infants with mildly elevated TSH 10–20 mIU/L had normalized values on follow-up (mean, 11.41 vs. 4.42 mIU/L; p<0.01; 95%CI, 5.88–8.09). The following reference intervals (2.5–97.5th percentile) were derived: FT4 day 14–21 (n=513): 11.59–21.00 pmoL/L; FT4 day 22–30 (n=66): 10.14–19.60 pmoL/L; TSH day 14–30 (n=579): 1.90–10.34 mIU/L. Comparison between studies showed variations of reference intervals with different manufacturer assays, age and methodology. Conclusions Our reference intervals would be useful in the clinical setting. Infants with mildly elevated TSH could be monitored first instead of immediate treatment.

Objectives Recently, several studies have reported the association between elevation of thyroid-stimulating hormone (TSH) levels and liver disease, especially, non‐alcoholic fatty liver disease (NAFLD). We aimed to evaluate the incidence and risk factors of TSH elevation in patients with liver disease. Methods We retrospectively reviewed the data of patients aged <18 years who were diagnosed with liver disease between January 2015 and March 2019. Results Among the 77 patients, 17 (22.1%) had subclinical hypothyroidism and 3 (17.6%) progressed to overt hypothyroidism. A total of 26 (33.8%) patients had NAFLD, and 6 (23.1%) had subclinical hypothyroidism. The ultrasound grade of liver steatosis was not related to the elevation of TSH levels. The median age was significantly younger in patients with TSH elevation (5 vs. 9 years, p = 0.017). Albumin levels were significantly decreased (3.9 vs. 4.3 g/dL, p = 0.007), and total bilirubin levels were elevated (2.2 vs. 0.6 mg/dL, p = 0.001) in patients with subclinical hypothyroidism. Conclusions TSH elevation commonly occurs in patients with liver disease, especially those with younger age. The cause of liver disease was not a risk factor for TSH elevation.

Objectives To define thyroid gland vascularity index (VI) values in healthy children with the superb microvascular imaging (SMI) method and to assess whether or not there is a correlation with potential factors that may affect these values. Methods This prospective study included a total of 138 children, their ages varying from 3–17 years. Cases were divided into three subgroups according to age: 3–6, 7–12 and 13–17 years. Gender, age, height, weight, body mass index (BMI), thyroid-stimulating hormone (TSH) and free thyroxine (fT4) values were recorded. Volume and SMI measurements were performed with a 14 L5 mHz linear transducer. VI measurements were performed in the transverse and longitudinal planes and correlation with basic descriptive data was researched. Results Mean age was 11.14 ± 3.34 years and BMI was 19.95 ± 4.92. VI values were 4.59 ± 2.34 in the right lobe and 4.23 ± 2.73 for the left lobe, with no significant difference identified. There were no significant differences in mean VI for all parenchyma regarding gender and age groups. While there was no correlation identified with mean VI for all parenchyma with TSH and fT4, there was, however, a negative correlation with BMI. Conclusions Reference VI values for normal thyroid glands in healthy children and adolescents were defined with the SMI method. There was no correlation between the VI values and age, gender, volume, TSH and fT4 values, while there was a negative significant correlation with BMI.

Objectives We evaluated the spectrum of diseases accompanying congenital hypothyroidism (CH) in the United Arab Emirates and compared them with internationally studied patterns. Methods The presented retrospective cross-sectional study took place in two government tertiary care centres. In total, 204 patients with a confirmed diagnosis of CH and a minimum period of follow-up of 1 year were included. Patients with Down syndrome, infants born at <35 weeks of gestation, and babies with TORCH ( Toxoplasma gondii , Other viruses [HIV, measles, etc.], Rubella, Cytomegalovirus, and Herpes simplex) infections were subsequently excluded from the study. Results Of the subjects with CH, 39% had associated extrathyroidal anomalies (ETAs); among these, 25% had a single anomaly. A significant proportion of Arab males were affected by CH as compared to other ethnic groups. Dyshormonogenesis was the commonest aetiological cause (55%) of CH. Males with an ectopic lingual thyroid gland had significant ETAs as compared to females of the same cohort. The most common ETAs were congenital heart disease (16%), followed by urogenital tract anomalies (14%). Conclusions Detection of a high rate and variability of ETAs associated with CH necessitates the formulation of a structured screening programme including appropriate clinical, laboratory, and imaging tools to detect ETAs at an earlier stage.

Objectives To evaluate if the parental origin of X-chromosome has an impact on the phenotype and biochemical profile in Turner syndrome (TS). Result of the previous studies have been equivocal and could be attributable to the multicentric study design with different experts examining heterogeneous TS population of various ethnic background. Methods A cross-sectional single center study from Northern India. Fifty nine diagnosed subjects of TS and their parents participated in the study. Parental origin of intact X-chromosome was determined using 12 highly polymorphic short tandem repeats (STR) on X-chromosome. For the evaluation of parent-of-origin effects, typical phenotypic traits including congenital malformations, anthropometry, body composition by dual energy X-ray absorptiometry (DXA) and biochemical profile were compared. Clinical stigmata of TS in all subjects were examined by a single expert. Results The intact X-chromosome was of maternal origin (X m ) in 49.1% subjects while 50.9% had paternal origin (X p ). Skeletal anomalies were more common in X m group, out of which prevalence of short neck and short fourth metatarsal reached statistical significance (p=0.04 and 0.01 respectively). A strong correlation was observed between subject’s baseline height standard deviation score (Ht SDS) and paternal height (r=0.593, p<0.001), maternal height (r=0.564, p<0.001) and mid-parental height (MPH) (r=0.372, p=0.047) in X p group. This effect was not seen in X m subjects whose baseline Ht SDS showed no significant correlation with maternal height, paternal height or MPH. No differences were detected between the groups with regard to biochemical profile or body composition. Conclusions We speculate that the differences in skeletal anomalies and height correlations between X m and X p groups could be due to the modifying effect of epigenetic signature on short stature homeobox ( SHO X) gene of X m . SHO X gene is not modified on X p thereby explaining the paucity of skeletal changes and height correlations in X p subjects.

Objectives Turner syndrome (TS) is a complex and chronic medical condition that requires lifelong subspecialty care. Effective transition preparation is needed for successful transfer from pediatric to adult care in order to avoid lapses in medical care, explore health issues such as fertility, and prepare caregivers as adolescents take over responsibility for their own care. The objective of this study was to evaluate accuracy of knowledge of personal medical history and screening guidelines in adolescents and young adults (AYA) with TS. Methods This was a prospective cross-sectional study of 35 AYA with TS of ages 13–22 years recruited from a tertiary care center. AYA completed questionnaires on personal medical history, knowledge of screening guidelines for TS, and the Transition Readiness Assessment Questionnaire (TRAQ). Results Eighty percent of AYA with TS were 100% accurate in reporting their personal medical history. Only one-third of AYA with TS were accurate about knowing screening guidelines for individuals with TS. Accuracy about knowing screening guidelines was significantly associated with TRAQ sum scores (r = 0.45, p < 0.05). However, there was no association between knowledge of personal medical history and TRAQ sum scores. Conclusions Transition readiness skills, TS-specific knowledge, and accurate awareness of health-care recommendations are related, yet distinct, constructs. Understanding of one’s personal medical history is not an adequate surrogate for transition readiness. Validated tools for general transition, like the TRAQ, can be used but need to be complemented by TS-specific assessments and content. Providers are encouraged to identify opportunities for clinical and educational interventions well in advance of starting transfer to adult care.

Objectives Growth references of today traditionally describe growth in relation to chronological age. Despite the broad variation in age of pubertal maturation, references related to biological age are lacking. To fill this knowledge gap, we aimed to develop a new type of pubertal height reference for improved growth evaluation during puberty, considering individual variation in pubertal timing. Methods Longitudinal length/height measures were obtained from birth to adult height in 1,572 healthy Swedish children (763 girls) born at term ∼1990 to nonsmoking mothers and Nordic parents, a subgroup of GrowUp 1990 Gothenburg cohort. A total height reference was constructed from Quadratic-Exponential-Puberty-Stop (QEPS)-function-estimated heights from individual height curves that had been aligned for time/age at onset of pubertal growth (5% of P-function growth). References that separated growth into specific pubertal height SDS (P-function growth) and basic height SDS (QES-function growth) were also generated. Results References (cm and SDS) are presented for total height, and height subdivided into that specific to puberty and to basic growth arising independently of puberty. The usefulness of the new pubertal growth reference was explored by identifying differences in the underlying growth functions that translate into differences in pubertal height gain for children of varying body mass, height, and with different pubertal timings. Conclusions A new type of height reference allowing alignment of individual growth curves, based on the timing of the pubertal growth spurt was developed using QEPS-model functions. This represents a paradigm shift in pubertal growth research and growth monitoring during the adolescent period.

Objectives Childhood obesity is an important cause of end-stage renal disease. To date, available markers do not characterize kidney changes, especially in the early stages. kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) are already detected before the onset of proteinuria or alterations of glomerular filtration rate and thus might represent biomarkers that directly reflect kidney injury. Methods We characterize kidney injury in a group of 40 obese-prepubertal children compared to 29-healthy age- and gender matched-peers. Anthropometric measurements and body composition were determined. Fasting blood samples were collected for measurement of insulin, glucose, lipid profile, transaminases, cystatin C and creatinine. Urine samples were collected to assess urinary NGAL, KIM-1 and urinary isoprostanes. Kidney length was measured with ultrasound evaluation. Differences between the two groups were evaluated by Mann–Whitney U test, and Spearman correlation analysis was used to explore relationship between variables. Results Triglycerides, alanine transaminase (ALT), glucose, insulin, homeostasis model assessment insulin resistance, triglycerides/high-density lipoprotein (HDL)-cholesterol ratio and cystatin C values were significantly higher in obese children than normal weight peers. Creatinine values were normal and similar between the two groups, while isoprostanes were higher in obese. Obese children had larger kidney sizes, indicating organ hypertrophy. NGAL and KIM-1 were increased in obese children compared to controls. A significant association between NGAL and KIM-1 with adiposity indices, insulin status and markers of oxidative stress postulated a possible effect of obesity in inducing kidney abnormalities. KIM-1 and NGAL are directly related respectively to cystatin C and isoprostanes, supporting the ability of these biomarkers in reflecting early kidney damages in obese subjects. Conclusions These findings suggest that obese subjects exhibit a certain degree of renal damage before kidney function loss.

Objectives Staging sexual maturation is an integral component of adolescent research. The Pubertal Development Scale (PDS) is commonly used as a puberty self-assessment tool because it avoids the use of images. Among the youth living in rural Pakistan, we determined the accuracy of self-reported pubertal assessments using a modified PDS compared to the ‘gold standard’ of physically assessed Tanner stages by a physician. Methods The strength of agreement between self-assessed puberty using a modified PDS and the ‘gold’ standard of physician-assessed Tanner stages was reported using weighted kappa ( κ w ) for girls (n = 723) of 9.0–14.9 years of age or boys (n = 662) of 10.0–15.9 years of age living in the rural District of Matiari. Results Agreement between the gold standard and self-assessment for puberty was substantial, with a κ w of 0.73 (95% confidence interval [CI]: 0.67; 0.79) for girls and a κ w of 0.61 (95% CI: 0.55; 0.66) for boys. Substantial agreement was observed for both boys and girls classified as thinness but only for girls with a normal body mass index. Those who were classified as severely thin had moderate agreement. The prevalence of overestimation was 18.5% (95% CI: 15.9–21.5) for girls and 2.7% (95% CI: 1.7–4.3) for boys, while the prevalence of underestimation estimation was 8.0% (95% CI: 6.2–10.2) for girls and 29.0% (95% CI: 25.8–32.6) for boys. Conclusions Most girls and boys assessed their pubertal development with substantial agreement with physician assessment. Girls were better able to assess their puberty, but they were more likely to overestimate. Agreement for boys was also substantial, but they were more likely to underestimate their pubertal development. In this rural Pakistan population, the PDS seems to be a promising tool for self-assessed puberty.

Objectives There are some variations in the practice of puberty induction between different regions; however, data from Arab countries are lacking. We aimed to survey the practice of pediatric endocrinologists in Arab countries on the timing and regimen for puberty induction in girls and boys with hypogonadism. Methods An online questionnaire was emailed to physicians registered in the Arab Society for Paediatric Endocrinology and Diabetes. Results In total, 106 replies from 17 countries were received. In non Turner syndrome (TS) girls, puberty was induced by 49.4% of participants at 12–13 years and by 32.5% at  ≥14 years. Ethinyl estradiol and conjugated estrogen were the most popular preparations used (29.7 and 16.6%, respectively). Of the participants, 60% introduce progesterone either at 2–3 years after starting estrogen or following a significant breakthrough bleeding on estrogen. In girls with TS, 84.2% of participants prescribed estrogen to those aged 11 years and older (51.5% at 11–12 years) and 5.3% prescribed it to those at the prepubertal age. In boys, 57.3% of participants induce at ≥14 years, 80.6% use intramuscular testosterone and 46.5% start with 50 mg/kg/month. Human chorionic gonadotropin is more used in non-Gulf Arab countries (18.2 vs. 2.9%; p 0.036) with a trend of using oral testosterone undecanoate in Gulf states (12.2 vs. 2.0%; p 0.051). Conclusions We describe the approach to puberty induction in boys and girls among pediatric endocrinologists in Arab countries. The observed variation in practice would be useful in developing regional consensus guidelines on puberty induction in children with hypogonadism.

Background Obesity and obesity-related diseases are one of the common health problems worldwide and have also been proposed to be important predictors of blood pressure and cardiovascular disease risk. The aim of our study is to determine the utility of different anthropometric measurements (body mass index [BMI], skinfold thickness [SFT], waist circumference [WC], mid-upper arm circumference [MUAC], arm circumference-height ratio [AHtR], and waist circumference-height ratio [WHtR]) as markers of hypertension (HT) risk in adolescents. Methods In this cross-sectional study, 544 participants aged between 12 and 13 years were included. Anthropometric measurements and blood pressure of participants were measured. The association of different anthropometric measurements with blood pressure was evaluated. Results The frequency of both elevated blood pressure and HT was 30.2%. Biceps, triceps, and suprailiac SFT have an impact on HT in girls but only suprailiac SFT in boys. WC measurements above the 85th percentile were strongly correlated with HT conditions, and this relationship was stronger in boys than in girls (3.3 vs. 2.6 fold). MUAC, WHtR, and AHtR measurements also have strong correlation with HT in boys but only WHtR has a poor relation in girls. In boys and girls with obesity, there was a positive association between obesity and blood pressures. Conclusions Not only age-related BMI z scores but also a number of other anthropometric measurements, such as WC, SFT, MUAC, WHtR, and AHtR, could have an influence on high blood pressure. The influence changes with gender during adolescence.

Background It remains unclear whether muscle strength, which reduces cardiovascular (CV) risk in adults, is associated with similar protection in Asian adolescents. This study investigated the association between handgrip strength and CV health in a large Korean sample of school-age adolescents. Methods We performed a cross-sectional analysis of adolescents aged 10–18 years (n=4,018) from the Korean National Health and Nutrition Survey between 2014 and 2017. Handgrip strength was measured using a dynamometer. CV risk factors include waist circumference, blood pressure, fasting glucose or hemoglobin A1c, and lipid levels. Logistic regression models were applied with adjustment for potential confounders. Results The mean age of participants was 14.0 years, and 53.6% were boys. Mean handgrip strength was 30.4 kg for boys and 22.0 kg for girls. Boys more frequently had high systolic blood pressure and impaired fasting glucose, whereas girls more frequently had low high-density lipoprotein cholesterol. Multivariate logistic regression analysis revealed that in boys only, handgrip strength was negatively associated with central obesity and hypertriglyceridemia and positively associated with higher systolic blood pressure. Conclusion Handgrip strength is independently associated with some CV risk factors only in boys.

Objectives Objectives Pseudohypoparathyroidism type 1A (PHP1A) is caused by maternal inheritance of GNA S mutations. It is characterized by the resistance to several hormones, primarily the parathyroid hormone (PTH), and the features of Albright’s hereditary osteodystrophy. Case presentation Here, we present a family comprised two affected brothers with PHP1A and identify a novel mutation (c.277C>T) in the GNA S gene. The siblings developed a slightly different presentation in the same clinical condition. Although both patients presented with PTH resistance, which is the hallmark of PHP, the proband showed the thyroid-stimulating hormone resistance with the progression of heterotopic ossification from skin and subcutaneous tissue into deep connective tissue, while the younger brother with normocalcemia did not show the resistance to other hormones. The patients may inherit the mutation from their mother who presumably carries the mutation as a mosaicism. Conclusions Our case highlights the significance of considering mosaicism as an explanation for apparent de novo cases of pseudohypoparathyroidism.

Objectives Congenital adrenal hyperplasia (CAH) is an autosomal recessive inherited disorder of steroidogenesis.11β-hydroxylase deficiency and 17α-hydroxylase deficiency are two forms of CAH caused by defects of CYP11B1 and CYP17A1 respectively. Case presentation Two rare intronic variants were identified in suspected CAH patients. Though not located at the classic splicing sites, these two variants perturbed splicing based on minigene assays. One variant, NM_000497.4: c.240-157T>G of CYP11B1 identified in subject 1, resulted in the retention of 136 intronic nucleotides. The other variant, NM_000102.4: c.754-6 A>G of CYP17A1 identified in subject 2, leading to the retention of 5 intronic nucleotides. Both variants resulted in out-of-frame alteration of the respective transcript. Conclusion Cryptic splicing variants in the intronic regions contribute to the genetic defects of CAH. Minigene assay is useful to confirm the splice altering effect and make a definitive molecular diagnosis.

Objectives Hypoparathyroidism is a rare disease in children that occurs as a result of autoimmune destruction of the parathyroid glands, a defect in parathyroid gland development or secondary to physical parathyroid gland disturbance. Typical symptoms of hypoparathyroidism present as hypocalcaemia and hyperphosphatemia due to decreased parathyroid hormone secretion and may lead to nerve and muscles disturbances resulting in clinical manifestation of tetany, arrhythmias and epilepsy. Currently, there is no conventional hormone replacement treatment for hypoparathyroidism and therapeutic approaches include normalising mineral levels using an oral calcium supplement and active forms of vitamin D. Case presentation We present the case of a 10-year-old girl with primary hypoparathyroidism who had no prior history of autoimmune disorders, but who subsequently developed systemic lupus erythematosus.

Objectives Congenital hypogonadotropic hypogonadism (CHH) is a rare condition resulting from GnRH deficiency. Gonadotropin Releasing Hormone 1 (GNRH1) homozygous mutations are an extremely rare cause of normosmic CHH (nCHH). Most heterozygous individuals are asymptomatic, with the notable exception of individuals heterozygous for a p.R31C GNRH1 mutation. Case presentation The patient is an index case from a consanguineous family, presenting with severe CHH and his parents presenting with late puberty and normal fertility. The index case is homozygous for a p.R31H GNRH1 variant, both parents being heterozygous. The analysis of a panel of genes implicated in CHH does not show any other clinically relevant variant in any other gene tested. Conclusions GNRH1 mutations are a rare cause of nCHH. Five different mutations have been reported so far in homozygous individuals. Most are frameshift in nature but the one reported here causes an amino acid change in the Gonadotropin-releasing hormone (GnRH) decapeptide. Both independently reported patients with the p.R31H mutation are from Turkish origin. The question of the possible role of this mutation in the late puberty of the heterozygous parents needs further documentation. An analogy is made with the heterozygous individuals carrying the p.R31C and displaying partial CHH. No nonreproductive disorder is noted.

Objectives Recently, World Health Organization has declared coronavirus disease 2019 (COVID-19) infection a pandemic. Patients with diabetes may be at an increased risk of developing COVID-19 infection, as well as increased risk of morbidity and mortality. Although the current data have shown that the coronavirus infection generally has a milder course in children. Case presentation In this case report, we present a teenage patient with severe diabetic ketoacidosis (DKA) as the first manifestation of his diabetes and COVID-19 infection. Conclusions He was treated for DKA and COVID-19 infection, and fortunately, had a good response to the treatment.