Volume 34, Issue 7

Postnatal thyroid hormone changes enable the neonate to be adapted for postnatal life. Several factors can affect this adaption. In this review, we summarized the studies that reported the association among the delivery factors and neonatal thyroid hormones and thyroid stimulating hormone. A comprehensive literature search was performed in PubMed, Web of Science, and Scopus up to March 2020, to identify the studies investigating the relationship between delivery factors, especially the mode of delivery and labor pain, and neonatal thyroid hormones and TSH. Finally, in this review study, of 157 articles obtained in the initial search, 25 eligible studies were reviewed. Various maternal, fetal/neonatal, and obstetric factors affected neonatal TSH and thyroid hormones. Among various influencing factors, mode of delivery, labor pains, and duration of labor have a strong relationship with neonatal thyroid hormones and need to be considered for interpretation of neonatal thyroid status. The majority of the studies revealed that vaginal deliveries (instrumental or natural) lead to higher levels of cord TSH compared to elective cesarean section. This can be explained by the increased secretion of catecholamine during labor. It has been suggested that blood TSH and thyroid hormone levels are affected by perinatal stress events such as maternal anxiety, labor pains, fetal distress, and other stimulants of the catecholamine response. These changes may act as the trigger to increase thyroid hormone levels for adapting of neonates in the first hours after birth. This assumption needs to be re-evaluated by performing comprehensive and well-designed studies.

Background Tetrahydrobiopterin deficiency (BH4D), a less common form of hyperphenylalaninemia (HPA), can lead to severe developmental retardation if untreated. Little has been reported on the prevalence of BH4D among live births worldwide. This study examined its prevalence across China and between geographical areas within the country. Methods We analyzed data from the Chinese national screening program for HPA in newborns between 2013 and 2019. BH4D prevalence was examined by province, region and the entire country. Provincial-level prevalence was estimated from the number of confirmed BH4D cases and screened newborns, after adjusting for HPA-positive recall rate. Regional- and national-level prevalences were estimated by summing provincial-level prevalences after weighting them by the number of live births. A Poisson distribution was assumed in order to calculate 95% confidence intervals (CIs) for prevalence. Results Among 107,078,115 newborns screened for HPA in China, 380 with BH4D were identified, corresponding to a total prevalence of 3.8 per 1,000,000 live births. Prevalence was higher in eastern regions (5.9 per 1,000,000) and northern regions (4.1 per 1,000,000) of China than in southern regions (1.6 per 1,000,000) or northwestern regions (1.7 per 1,000,000). Across the entire country, 3.9% cases of HPA were diagnosed as BH4D, and this proportion reached as high as 15.1% in the southern part of the country. Conclusions These first insights into BH4D prevalence across China suggest slightly higher prevalence than in other countries, and it varies substantially by region. More attention should be paid to early diagnosis and timely treatment of BH4D.

Objectives Cryptorchidism is the most common genitourinary birth defect in live newborn males and is considered as an important risk factor for testicular germ cell tumors and infertility. The Androgen Receptor gene is important in this pathology due to its participation, mainly, in the inguinoscrotal phase of testicular descent. We determine the length of the CAG tract in the Androgen Receptor ( AR ) gene in Mexican patients with nonsyndromic cryptorchidism. Methods One hundred and 15 males were included; of these, 62 had nonsyndromic cryptorchidism and 53 were healthy volunteers. DNA was extracted from a peripheral blood samples, subsequently, the CAG tract in exon 1 of AR gene was amplified by PCR and sequenced. Results Mexican patients with nonsyndromic cryptorchidism presented 25.03 ± 2.58 repeats of CAG tract in the AR gene compared to 22.72 ± 3.17 repeats of CAG tract in Mexican healthy individuals (p≤0.0001; t value of 4.3). Furthermore, the deletion of codon 57 that corresponds to the deletion of a leucine residue at position 57 (Del L57) in the AR gene was found for the first time in a nonsyndromic cryptorchidism patient. This molecular alteration has been related previously to testicular germ cell tumor (TGCT). Conclusions The CAG tract in the AR gene is longer in patients with nonsyndromic cryptorchidism than in healthy individuals, supporting the association between this polymorphism of the AR gene and nonsyndromic cryptorchidism in the Mexican population.

Objectives Congenital idiopathic growth hormone deficiency (GHD) is associated with various MRI abnormalities, including sellar and extrasellar abnormalities. However, it remains contentious whether MRI brain findings could provide an additional avenue for precisely predicting the differentiation of GHD based on severity and type {isolated GHD or multiple pituitary hormone deficiencies (MPHD)}. This study aimed to ascertain the abnormality that is the best predictor of severity and type of GHD amongst the different MRI findings. Methods We conducted an analytical cross-sectional study, including 100 subjects diagnosed with idiopathic GHD. Patients were grouped into severe GHD, partial GHD, and MPHD and into groups based on the presence of pituitary hypoplasia, extrasellar brain abnormalities (EBA), and presence of ectopic posterior pituitary or pituitary stalk abnormalities (EPP/PSA) or both. Results Sixty six percentage of subjects had isolated GHD, 34% had MPHD, 71% had severe GHD, and 29% had partial GHD. Pituitary hypoplasia was the most common finding, observed in 53% of patients, while 23% had EBA, and 25% had EPP/PSA. Pituitary hypoplasia was observed to be the best predictor of severity of GHD with an odds ratio (OR) of 10.8, followed by EPP/PSA (OR=2.8), and EBA was the weakest predictor (OR=1.8). Pituitary hypoplasia was the only finding to predict MPHD (OR=9.2) significantly. On ROC analysis, a Pituitary height SDS of −2.03 had the best detection threshold for both severe GHD and MPHD. Conclusions We observed Pituitary hypoplasia to be not only the most frequent MRI abnormality but also the best predictor of severe GHD and MPHD amongst various sellar and extrasellar abnormalities.

Objectives Determination of LH in urine has proved to be a reliable method for evaluation of pubertal development. The human LH assay based on time-resolved immunofluorometric (IFMA) technology (AutoDELFIA, PerkinElmer, Wallac) has been found to be suitable for this purpose thanks to its high sensitivity but other assays have not been evaluated. We have analyzed our data obtained by another potentially sensitive detection technique, enhanced luminometric assay (LIA) with the objective of finding a viable alternative to IFMA since these may not be available in the future. Methods LIA was used to measure LH and FSH in serum and urine samples from 100 healthy subjects of each Tanner stage and both genders, whose pubertal development has been determined. Results Urinary gonodotropin concentrations measured by LIA correlated well with Tanner stage [(r=0.93 for girls, r=0.81 for boys; p<0.01 for LH) and (r=0.81 for girls, r=0.73 for boys; p<0.01 for FSH)]. LIA determinations revealed the increase in U-LH concentrations during the transition from Tanner stage 1–2 in both girls and boys (p<0.001), whereas U-FSH and S-LH were able to detect the increase from Tanner stage 1–2 only in boys or girls, respectively (both p<0.001). Conclusions Measurement of urinary gonadotropin concentrations by LIA may be useful for the evaluation of overall pubertal development and also in the detection of transition from prepuberty to puberty.

Objectives Transient hyperinsulinism (THI) is a hypoglycemia disorder which resolves spontaneously within the first weeks or months of life. The pathomechanism of THI is not elucidated yet; however, it is known that perinatal stress predisposes for THI. We aimed to characterize the clinical phenotype and treatment of children with THI, and to identify options for improved management. Methods A retrospective analysis of 36 children with THI treated at the University Children’s Hospital Düsseldorf between 2007 and 2019 was performed. Results All children had risk factors for neonatal hypoglycemia or indicators of perinatal stress. Eighty three percent were diagnosed with hypoglycemia on day of life (DOL)1. None of the six diagnosed later had routine blood glucose screening and showed significantly lower blood glucose levels at the time of first blood glucose measurement compared to the children diagnosed on DOL1. Ninety seven percent of all children received intravenous glucose, 42% received continuous glucagon and 81% were started on diazoxide. Diazoxide withdrawal and subsequent fasting tests lacked standardization and were based on clinical experience. Three patients had a subsequent episode of hypoglycemia, after fasting studies only demonstrated “clinical” remission without proving the ability to ketogenesis. Conclusions Any kind of perinatal stress might pose a risk to develop THI, and postnatal monitoring for hypoglycemia still needs to be improved. Diazoxide is effective in children with THI; however, further studies are needed to guide the development of criteria and procedures for the initiation and discontinuation of treatment. Furthermore, establishing consensus diagnostic criteria/definitions for THI would improve comparability between studies.

Objectives Fasting plasma glucose or oral glucose tolerance test (OGTT) is the traditional diagnostic tool for type 2 diabetes (T2DM). However, fasting is required and implementation in all overweight/obese subjects is not practical. This study aimed to formulate a clinical pathway to stratify subjects according to their risk of abnormal OGTT. Methods This retrospective study included patients with overweight or obesity who had undergone OGTT in a tertiary paediatric unit from 2012 to 2018. The optimal haemoglobin A1c (HbA1c) cutoff that predicts abnormal OGTT was evaluated. Other non-fasting parameters, in combination with this HbA1c cutoff, were also explored as predictors of abnormal OGTT. Results Three hundred and thirty-two patients (boys: 54.2%, Chinese: 97.3%) were included for analysis, of which, 272 (81.9%) patients had normal OGTT while 60 (18.0%) patients had abnormal OGTT (prediabetes or T2DM). Optimal HbA1c predicting abnormal OGTT was 5.5% (AUC 0.71; sensitivity of 66.7% and specificity of 71%). When HbA1c≥5.5% was combined with positive family history and abnormal alanine transaminase (ALT) level, the positive predictive value for abnormal OGTT was increased from 33.6 to 61.6%. Conclusions HbA1c, family history of T2DM and ALT level could be used to derive a clinical pathway to stratify children who have high risk of abnormal OGTT.

Objectives The objective of this study is to investigate the cardiovascular risk factors associated with metabolic syndrome (MetS), which is increasingly becoming prevalent in childhood obesity. Methods A total of 113 patients, 76 of whom were between the ages of 10 and 17 (mean age: 14.5 ± 1.8 years) and diagnosed with obesity (30 non-MetS and 46 MetS using IDF) and 37 of whom constituted the control group, participated in the study. Echocardiographic examination and atherogenicity parameters (Atherogenic index of plasma [AIP: logTG/HDL], total cholesterol/HDL, and TG/HDL ratio and non-HDL) were evaluated. Results The most common component accompanying obese MetS was found to be hypertension and low HDL. While obesity duration, body mass index (BMI), blood pressure, fasting insulin, insulin resistance, atherogenicity parameters were determined to be significantly higher in the obese-MetS group. Echocardiography showed that while the thickness, volume, and diameter of LV end-diastolic wall, left ventricular mass (LVM), LVM index (LVMI g/m 2 ) and relative wall thickness (RWT) were significantly high in the MetS group, however, mitral E/A ratio was significantly lower (p<0.05). Change in LV geometry consistent with concentric remodeling (increased RWT, normal LVMI) was visible in obese groups. LVM were positively significantly related to BMI, waist circumference, insulin resistance, blood pressure, LDL level, and negative to mitral E/A ratio. In the obese-MetS group, LVMI was positively correlated to office systolic BP, left atrium end-diastolic volume/index. Conclusions LVMI and atherogenicity parameters that were found to be significantly higher in obese MetS exhibit increased cardiovascular risk in childhood.

Objectives Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in the pediatric population at global level. Present study aims to assess the effect of l -carnitine supplementation on the NAFLD in children and adolescents. Methods This randomized, triple-blind, placebo-controlled clinical trial was conducted in 2018–2019. Study was carried out in NAFLD participants (5–15 years). They were randomly assigned to receive either 50 mg/kg/day l -carnitine twice a day or identical placebo per day for three months. Liver enzymes and liver ultrasonography were assessed before and after the intervention. Both groups received similar consultation for lifestyle changes. Results Overall, 55 participants completed the study, 30 patients in the l -carnitine group and 25 patients in placebo group. Mean changes of anthropometric measurements did not have significant differences between groups (p>0.05). No significant differences in the mean changes of aspartate aminotransferase (AST) (p=0.82) and alanine aminotransferase (ALT) (p=0.76) levels were documented between two groups. Based on within-group analysis, there were significant changes in AST and ALT levels before and after the intervention in both groups. The sonographic grades of fatty liver were not significantly different between two groups before (p=0.94) and after intervention (p=0.93). Conclusions In the present clinical trial, L-carnitine did not have significant effect on improving biochemical and sonographic markers of NAFLD in children and adolescents. Future studies are necessary to evaluate the applicability and efficacy of long-term l -carnitine supplementation to treatment of NAFLD in pediatric population. Trial registration IRCT20170628034786N2.

Objectives To identify a safe pathway for management and treatment of patients with X-linked hypophosphatemic rickets (XLH) during Covid-19 pandemic lockdown. Methods Twenty-six patients with XLH (age 3.1–25.7 years) were enrolled in Pediatric Endocrine Unit; nine of them were receiving human monoclonal anti-fibroblast growth factor 23 antibody (burosumab) and 17 (pediatric patients, age 9.5–17.9 years, n=7; young-adult patients, age 20.1–25.7 years, n=10) received conventional treatment with inorganic oral phosphate salts and active vitamin D metabolites. A Covid-19 free pathway was addressed for XLH patients receiving burosumab treatment in hospital. XLH patients receiving conventional treatment were followed by phone calls, e-mails, or telemedicine. Results All XLH patients receiving burosumab continued the scheduled follow-up and treatment; none of them was infected by Covid-19. Seven XLH patients out of 17 (41%) receiving conventional treatment showed some complication related to the disease itself or its treatment: periapical abscess with gingival fistula was diagnosed in five patients (three children and two young-adults) and treated with antibiotics with complete resolution; one child showed abdominal pain due to the administration of high doses of inorganic oral phosphate salts solved by reducing the dosage, and one child had severe legs pain during deambulation after orthopedic surgery solved with common analgesics. Conclusions Covid-19 free pathway was safe and effective to manage XLH patients receiving burosumab. E-health technologies were useful methods to follow XLH patients receiving conventional treatment during Covid-19 pandemic lockdown.

Objectives Polycystic ovary syndrome (PCOS) is an endocrinopathy, in which hyperandrogenism and hyperinsulinism have both occurred. Fetuin-A, a natural inhibitor of tyrosine kinase, leads to insulin resistance. The aim was to evaluate the relationship between fetuin-A and hyperandrogenism and hyperinsulinism and the role of fetuin-A in the pathophysiology of PCOS. Methods Thirty-eight cases with PCOS and 40 healthy adolescents were included in the study. PCOS and controls were divided into obese/non-obese subgroups. LH, FSH, total and free testosterone (TT, FT), SHBG, androstenedione, DHEAS were measured in patients with PCOS. Fasting glucose, insulin, lipid profile, AST, ALT, HsCRP, and fetuin levels of PCOS patients and healthy controls were also measured. Results Fetuin-A levels were higher in PCOS patients than in controls. In the obese-PCOS group, when compared to non-obese PCOS patients; the levels of SHBG and HDL were low while cholesterol, LDL, triglyceride, HOMA-IR, FT, FAI, and HSCRP levels were high, but Fetuin-A levels were similar. In the obese-PCOS group, fetuin-A levels were higher than in obese-controls. HOMA-IR and fetuin-A levels were higher in non-obese PCOS patients than in non-obese controls. In the PCOS group, fetuin-A was positively correlated with TT, FT, FAI and androstenedione and negatively correlated with SHBG. Regression analysis demonstrated that FT, SHBG, and androstenedione significantly predicted fetuin-A levels (R2=54%). In non-obese PCOS patients and controls, fetuin-A was positively correlated with insulin and HOMA-IR. Conclusions These results suggest a relationship between androgen levels and fetuin-A in PCOS cases, independent of insulin resistance, and may shed light on further studies.

Objectives To study the effect of combined gonadotropin therapy (CGT) on testicular descent ± spermatogenesis in congenital hypogonadotropic hypogonadism (CHH) patients with cryptorchidism beyond infancy. Methods This retrospective cohort study included CHH patients with cryptorchidism [bilateral (n=5) or unilateral (n=1)] treated with CGT for testicular descent ± pubertal induction. All participants were treated with CGT [human menopausal gonadotropin (hMG) and human chorionic gonadotropin (hCG)] with hMG pretreatment in three and monitored for changes in testicular volume (TV), serum total testosterone (T), serum inhibin-B, and sperm concentration. Results Complete testicular descent to the scrotal position was achieved in 5/6 patients (10/11 testes) after 4.7 ± 1.6 months of treatment. There was 44 ± 18%, 97.5% (IQR: 44–195), 10-fold (IQR: 3–19.6), and two-fold (IQR: 1.7–9.3) increase in stretched penile length, ultrasound measured TV, T level, and serum inhibin-B from baseline, respectively. In two pediatric cases, testicular descent occurred with isolated hMG therapy. At the last follow up (median: 23.5, IQR: 10.5–38.7 months), all the descended testes remained in scrotal position. In four pubertal/postpubertal age patients, continuous CGT (18–60 months) yielded T and inhibin-B levels of 16.64 ± 1.46 nmol/l and 106 ± 32.6 pg/mL, respectively. All the three patients with available semen analysis had sperm concentration of ≥5 million/mL and one of them achieved paternity. Conclusions A trial of CGT before orchiopexy may be considered in CHH males with cryptorchidism even beyond the narrow age-window of infancy. CGT may also have beneficial effects on future spermatogenesis and fertility outcomes in these patients.

Objectives COVID-19 pandemic significantly impacted the diagnosis of type 1 diabetes and its acute complications. Thus, the study aimed to evaluate the characteristics of pediatric patients with type 1 diabetes hospitalized during the first wave of the pandemic and the prevalence of new onset diabetes among patients with evidence of COVID-19 infection. Methods A single-center surveillance study included all patients with diabetes admitted to Children’s Hospital, Ain Shams University, in Egypt between May to August 2020. Data were collected to evaluate patients’ clinical and laboratory characteristics as well as their outcomes. Results Thirty-six patients were admitted during the study period. The mean age was 8.4 ± 3.8 years. Patients presented late to the emergency department with a mean delay of 3.05 ± 1.19 days from onset of symptoms. 34/36 patients presented in diabetic ketoacidosis (DKA), 50% presenting in severe DKA. Almost 81% of the patients were newly diagnosed. During the study period, SARS-CoV-2 PCR was found positive in four patients, COVID Ig M antibodies were positive in another two patients; all were symptomatic requiring ICU admission. Four patients showed a picture suggestive of the multi-inflammatory syndrome (MIS-C); cardiac affection was a constant feature. Conclusions The pandemic affected both the prevalence and severity of DKA among pediatric patients. The increased prevalence of severe DKA could be partly related to delayed hospital admission or the effect of COVID-19 in triggering DKA. Efforts should be done to continuously raise awareness about diabetes in children as well as the importance of seeking timely medical guidance.

Objectives Mucormycosis is a life-threatening condition that can be present in diabetes mellitus. Although the rhino-orbito-cerebral form is the most common, other types may be developed as well. Case presentation The present study reports two children with diabetes who had the cutaneous and pulmonary forms of mucormycosis. The first case was a four-year-old boy without a history of diabetes admitted due to loss of consciousness and a necrotic lesion on his hand. The second was an 11-year-old boy with dyspnea, polyuria, and polydipsia who had developed diabetes two years before, and whose chest X-ray had shown a pulmonary lesion. Both cases were treated with surgical implementation and appropriate antifungal therapy. Conclusions Mucormycosis is a fatal condition that can even be present at the onset of diabetes mellitus. Therefore, any diabetic patient with any presentation of respiratory symptoms such as coughs, or any cutaneous lesion should be examined carefully for mucormycosis after which prompt treatment must begin.

Objectives Type C pyruvate carboxylase (PC) deficiency is extremely rare, and has been described in only a few patients in literature to date. Herein, we present the case of a four-year-old patient admitted with diabetic ketoacidosis and diagnosed with type C PC deficiency based on clinical and biochemical findings. Case presentation A Turkish girl was referred to the intensive care unit at the age of three-years with a three-day history of vomiting and abdominal pain. Upon physical examination, the patient was found to be experiencing lethargy, dehydration, and Kussmaul breathing. Hyperglycemia, metabolic acidosis, and ketonemia were detected. Clinical and laboratory findings pointed to a prediagnosis of diabetic ketoacidosis. Intravenous fluid, bicarbonate, and insulin treatments were initiated. Elevated alanine and proline levels were recorded in plasma amino acid analysis, while urinary organic acid level analysis revealed increased lactate, pyruvate, 3-OH-butyrate, and acetoacetate levels. Whole exome sequencing revealed homozygous c.584C>T (p.Ala195Val) mutation in the PC gene. Conclusions To date, there have been no reports in literature of type C phenotype patients manifesting with DKA. Our case is the first case with the type C phenotype to be admitted with clinical and laboratory findings of DKA.

Objectives To describe the metabolic and endocrine features of a patient with Barth syndrome who showed evidence of growth hormone resistance. Case presentation A male proband deteriorated rapidly with lactic acidosis after a circumcision at age three weeks and was found to have severe dilated cardiomyopathy. A cardiomyopathy gene panel led to the diagnosis of TAZ -deficiency Barth syndrome. He subsequently experienced hypotonia and gross motor delay, feeding difficulties for the first four years, constitutional growth delay and one episode of ketotic hypoglycaemia. Cardiomyopathy resolved on oral anti-failure therapy by age three years. He had a hormonal pattern of growth hormone resistance, and growth hormone treatment was considered, however height velocity improved spontaneously after age 3½ years. He also had biochemical primary hypothyroidism. Conclusions With careful metabolic management with l -arginine supplementation, overnight corn starch, and a prescribed exercise program, our patient’s strength, endurance, level of physical activity and body composition improved significantly by age six years.

Objectives Childhood osteoporosis is often a consequence of a chronic disease or its treatment. Lysinuric protein intolerance (LPI), a rare secondary cause of the osteoporosis, is an autosomal recessive disorder with clinical features ranging from minimal protein intolerance to severe multisystemic involvement. We report a case diagnosed to have LPI using a Next Generation Sequencing (NGS) panel and evaluate the utility of reverse phenotyping. Case presentation A fifteen-year-old-boy with an initial diagnosis of osteogenesis imperfecta, was referred due to a number of atypical findings accompanying to osteoporosis such as splenomegaly and bicytopenia. A NGS panel (TruSight One Sequencing Panel) was performed and a novel homozygous mutation of c.257G>A (p.Gly86Glu) in the SLC7A7 gene (NM_001126106.2), responsible for LPI, was detected. The diagnosis was confirmed via reverse phenotyping. Conclusions Reverse phenotyping using a multigene panel shortens the diagnostic process.