Volume 37, Issue 2

Background Polycystic ovary syndrome (PCOS) treatment in adolescents currently focuses on lifestyle interventions, with pharmacological treatment options often limited to hormonal contraceptives. Several of these carry broad side-effect profiles and are not always accepted by young girls. There is growing interest in non-hormonal therapies for PCOS. We aimed to collate the evidence on the use of myoinositol or D-chiro-inositol in the improvement of PCOS symptoms in symptomatic adolescents. Content A systematic literature review identifying key articles from inception to March 2023. Participants: Female adolescents (aged 12–19 years) with PCOS or PCOS-like features. Intervention: Myoinositol or D-chiro-inositol with or without additional interventions. Comparison: Any other treatment, including lifestyle interventions, hormonal therapy, metformin or no treatment. The main outcome measure were improvement in symptoms, quality of life and adverse effects. Summary Eight studies were included: two randomised open-label trials, one quasi-randomised and three non-randomised interventional studies, one case-control study and one cohort study. All studies showed improvements in some biochemical markers, metabolic parameters or clinical symptoms, but these were not reproducible across all studies. Outlook The benefit of myoinositol in adolescents with PCOS remains unclear, with limited high-quality evidence. This review highlights the need for robustly conducted research to inform clinical practice.

Central precocious puberty (CPP) is the premature activation of the hypothalamus–pituitary–gonadal axis, resulting in the early development of secondary sexual characteristics. CPP classically occurs before the age of 8 years in girls and 9 years in boys. The aetiology of this precocious onset of puberty is governed by complex mechanistic interactions between genetic and environmental factors. The rates of CPP have been documented to have been rising before the COVID-19 pandemic; despite this, the incidence of CPP has increased exponentially since the start of the pandemic. There are multiple theories potentially explaining this change in incidence of CPP over COVID-19. These include the direct effect of SARS-coV-2 infection, increasing body mass index of adolescents over sequential lockdowns, changes in sleep patterns, increased use of electronic devices and levels of stress, and additionally potential earlier detection of signs of CPP by parents and carers. Whilst there is evidence from observational cohorts, case studies and animal models for each of these factors, it is difficult to definitively prove which has had the greatest impact due to the mainly retrospective nature of the human research that has been conducted. Moreover, studies set in diverse settings with varying population make comparison complex. Additionally, each country responded differently to the COVID-19 pandemic and the lockdowns varied between locations, hence the effect of lockdown was not equal or universal. Despite this, similar trends have been identified, with various lifestyle changes that occurred over the pandemic being potentially influential factors on the development of CPP.

Objectives This study aims to explore the effects of fat mass obesity-associated (FTO) (rs9939609) and melanocortin 4 receptor (MC4R) (rs17782313) gene polymorphisms in children with type 1 diabetes (T1D) and their relation to obesity. Methods Fat mass obesity-associated (FTO) (rs9939609) and melanocortin 4 receptor (MC4R) (rs17782313) gene polymorphisms were evaluated in 164 patients and 100 controls, and genotypes, alleles, and haplotype frequencies were compared between cases and controls. Results A significant association with T1D development was found with the TC, CC , and TC+CC genotypes and the C allele of MC4R rs17782313. In addition, TA, AA, and TA+AA genotypes and the A allele of FTO rs9939609 may also be risky for T1D development. While the TC and TC+CC genotypes of  MC4R rs17782313 may be protective against obesity development, the AA genotype and A allele of FTO rs9939609 may also be protective against obesity development. Regarding obese subjects, comparing diabetics vs. non-diabetic studied subjects, FTO rs9939609, TA, AA , and TA+AA genotypes and the A allele had significantly higher frequencies in T1D with a higher risk of developing T1D. However, conducting multivariable analysis using significant covariates in univariable analysis revealed that only earlier age of T1D onset, lower C-peptide, and the MC4R dominant model were considered independent predictors of obesity within T1D. Conclusions The role of both genes’ polymorphisms on the pathogenesis and the outcome of T1D and obesity can help in understanding the pathogenesis of both diseases and their associations with each other’s and may be used as novel therapeutic targets for both diseases.

Objectives Seasonal environment at birth may influence diabetes incidence in later life. We sought evidence for this effect and analyzed the association between the month of birth and the risk of developing type 1 diabetes mellitus (T1DM). Methods This was a cohort study carried out with 814 patients diagnosed with T1DM in the region of Bauru – São Paulo State, Brazil, receiving medical care in a private Endocrinology clinic or in the public Brazilian National Health Care System, from 1981 to 2021. All live births that occurred in São Paulo State between 1974 and 2020 were classified by month of birth and were considered as the control group. Results We found no statistically significant difference (χ 2 =16.31, critical 19.68) between the month of birth and risk of developing T1DM, when comparing our patients with the background population of the region. There was no association between the month of birth, sex, age at diagnosis, duration of symptoms before diagnosis, self-reported color, and socioeconomic status. Conclusions We found no association between month of birth and the risk of developing T1DM in this highly admixed South American population. Our data suggest that our population heterogeneity and geographic location may be important factors in the development of T1DM. Future prospective studies, evaluating environmental factors that may confer risk or protection to the disease, are warranted.

Objectives Obesity and type 2 diabetes mellitus (T2DM) are growing health concerns. Since 2005, Student Health Service (SHS) and Hong Kong Paediatric Society formulated a protocol on urine glucose screening (UGS) for early diagnosis of T2DM in students with obesity in Hong Kong. This study reviews students with T2DM captured by this screening program and compare the data with the Hong Kong Children Diabetes Registry (HKCDR) database, to see if the UGS program facilitates early diagnosis of T2DM. Methods Students between the ages of 10–18 years old with age- and sex-specific body mass index (BMI) >97th percentile who attended SHS between the school years from 2005/06 to 2017/18 were recruited for UGS. Those tested positive for random urine glucose underwent diagnostic testing for T2DM according to ADA guidelines. Demographic data and investigatory results from UGS and HKCDR within the same time period were compared. Results A total of 216,526 students completed UGS in the said period; 415 (0.19 %) students were tested positive for urine glucose of which 121 students were diagnosed with T2DM. UGS picked up 23 % of the newly diagnosed T2DM cases. When compared to the HKCDR database, students diagnosed via UGS were significantly younger, less obese, and had fewer diabetic related complications. The negative predictive value of UGS is high and can effectively rule out T2DM. Conclusions Urine glucose screening is an inexpensive and simple test that allows for early diagnosis of T2DM among obese school students. Other methods including POCT HbA 1c can be explored to improve program effectiveness.

Objectives To assess the effect of daily zinc supplementation for 12 weeks on thyroid auto-antibodies – thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb), and oxidative stress in children with autoimmune thyroid disease (AITD) compared to standard therapy. Methods This open-labeled, parallel, randomized controlled trial was done in a tertiary care teaching institute in south India. Children aged 3–18 years with AITD were randomized to receive 25 mg elemental zinc daily for 12 weeks or standard therapy alone. The change in thyroid function tests (thyroid stimulating hormone, free T3, free T4), thyroid auto-antibody (TPOAb, TgAb) titers, oxidative stress markers (glutathione peroxidase, malondialdehyde, superoxide dismutase, and total antioxidant capacity) were compared. Results Forty children, 20 in each arm, were recruited in the study. We observed a female-to-male ratio of 7:1. Median duration of disease was 2 (0.25, 4.25) years. A total of 37 (92.5 %) children were hypothyroid, two hyperthyroid, and one euthyroid at enrolment. A total of 13 children (32.5 %) had associated co-morbidities, most commonly type 1 diabetes mellitus and systemic lupus erythematosus, three (7.5 %) each. We did not find any significant change in thyroid function tests, thyroid auto-antibody titers, and oxidative stress markers. However, the requirement of levothyroxine dose was significantly increased in the control arm, compared to the zinc group (p=0.03). Only four (20 %) children had minor adverse effects like nausea, metallic taste, and body ache. Conclusions Zinc supplementation did not have any effect on thyroid auto-antibodies and oxidative stress. Zinc-supplemented children did not require escalation in levothyroxine dose.

Objectives Investigate serum vitamin D (vit D) levels’ relation to uterine volume in idiopathic central precocious puberty (ICPP) girls and compare findings with normal peers. Methods Analyzed 278 ICPP cases from January 2017 to September 2022 alongside 239 normally developing girls. Collected clinical data and lab markers and performed subgroup analysis based on vit D levels. Correlation and regression analyses were conducted. Results The ICPP group exhibited elevated uterine volume and lower serum vit D compared to controls (p<0.05). A weak negative correlation was noted between vit D and uterine volume in ICPP (r=−0.193, p=0.004), and no such correlation in controls (r=−0.073, p=0.319). The ICPP vit D deficiency subgroup displayed higher uterine volume than the insufficiency and sufficiency subgroups (p<0.05). Uterine volume in the insufficiency subgroup exceeded the sufficiency subgroup (p<0.05). After adjusting for confounders, lower vit D is linked to increased ICPP uterine volume (non-standardized regression coefficient β=−25.55, 95 % CI= −46.23, −4.87, p=0.016). A Limited correlation between vit D and uterine volume was seen in girls with normal pubertal timing. Conclusions We demonstrated a correlation between vit D and uterine volume in ICPP girls, absent in normal peers. ICPP girls often exhibit lower vit D levels and increased uterine volume. Further research is vital for understanding vit D’s role in ICPP pathogenesis and guiding prevention and treatment strategies.

Objectives The GnRH stimulation test has been used as the gold standard for the diagnosis of central precocious puberty (CPP), but it has some practical barriers. This study intends to build a diagnostic model of CPP in girls based on the population in northern China. Methods A total of 163 girls with precocious puberty (PP) were included from December 2018 to December 2019. Multifactor logistic regression analysis was conducted. Based on the results of multivariate logistic regression analysis, a nomogram was established for clinical application. Results A multi logistic regression model showed that LH (OR=1.238, 95 % CI: 1.067–1.436, p=0.005), inhibin B (OR=1.066, 95 % CI: 1.032–1.100, p<0.001), bone age (OR=1.563, 95 % CI: 1.037–2.358, p=0.033), and uterine length (OR=1.180, 95 % CI: 1.034–1.348, p=0.014) were diagnostic factors for CPP. The prediction model AUC was 0.906 (95 % CI: 0.852–0.959, p<0.001). Conclusions We successfully developed a nomogram model for CPP patients based on clinical data. The diagnostic prediction model included four indicators: basal LH, inhibin B, bone age, and uterine body length.

Objectives The current paper presents the steps considered for validation of a questionnaire for assessment of sexual maturity among Iranian adolescent girls. Methods This cross-sectional study was performed in 2022 in Isfahan, Iran. Based on the Growth and Development Questionnaire that included both the Pubertal Development Scale (PDS) and Sexual Maturation Scale (SMS), two Persian questionnaires were prepared. The face validity, content validity, criterion validity, and reliability of the questionnaire were assessed. We compared agreement of two parent-reported measures of puberty, SMS and PDS, with clinical Tanner stages (TSs) as the gold standard. Percent agreement, Cohen’s kappa coefficient, and Kendall’s τ b were used to assess the agreement between maternal assessments with clinical TS. The intraclass correlation coefficient (ICC) and the Cronbach’s α coefficient were also calculated to evaluate the reliability of the questionnaire. Results A total of 150 students aged 6–17 years with mean (SD) age of 10 (2.04) completed this study. The percentages of agreement for the mother-reported SMS in relation to clinical TS for breast stage and pubic hair stage were 60 % and 53.8 %, respectively. The percentages of agreement of the mother-reported PDS in relation to clinical TS for breast stage and pubic hair stage were 55.8 and 66 %, respectively. The weighted kappa coefficients showed moderate agreement, with weighted kappa ranging from 0.52 to 0.61. The mother-reported SMS and PDS showed high reliability. The Cronbach’s alpha of the PDS and the SMS was 0.88 and 0.83, respectively. The ICC of the mother-reported SMS and the mother-reported PDS was 0.95 (0.92–0.98) and 0.97 (0.94–0.98), respectively. Conclusions This study indicated that a maternal assessment of sexual maturity using the PDS or SMS can reliably estimate pubertal development in adolescent girls in an Iranian population.

Objectives Newborn screening (NBS) for primary carnitine deficiency (PCD) exhibits suboptimal performance. This study proposes a strategy to enhance the efficacy of second-tier genetic screening by adjusting the cutoff value for free carnitine (C0). Methods Between January 2021 and December 2022, we screened 119,898 neonates for inborn metabolic disorders. Neonates with C0 levels below 12 μmol/L were randomly selected for second-tier genetic screening, employing a novel matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) assay. Results In total, 2,515 neonates with C0 <12 μmol/L underwent further screening, including 206 neonates with C0 <8.5 μmol/L and 320 neonates with 8.5<C0<12 μmol/L. Genetic screening identified positive results in 12.36 % (65) of neonates, with one being homozygous, 10 compound heterozygotes, and 54 heterozygotes. Sanger sequencing revealed a second SLC22A5 variant in three of the 54 neonates. Ultimately, 14 patients were diagnosed with PCD; all 14 patients exhibited low C0 levels, though two had normal C0 levels during the recall review. The MALDI-TOF MS assay demonstrated detection and diagnostic rates of 89.29 % and 78.57 %, respectively. Eleven distinct SLC22A5 variants were identified, with the most common variant being c.51C>G, accounting for 25 % (7/28) of allelic frequencies. Conclusions A novel MALDI-TOF MS assay targeting 21 SLC22A5 variants in a Chinese population was successfully established. This assay exhibits a high detection and diagnostic rate, making it suitable for population-based genetic screening. Combined genetic screening is recommended to enhance the efficiency of PCD–NBS.

Objectives Abdominal pain is a common presentation in patients of diabetic ketoacidosis (DKA). However, this pain generally resolves with resolution of dehydration and acidosis. Persistence of abdominal pain even after resolution of ketosis and acidosis should warrant careful reassessment to find evidence of sepsis and concomitant abdominal pathology. Case presentation We report a rare case of type 1 diabetes mellitus in a 15 year old girl diagnosed 6 months ago who presented with mild DKA (pH 7.24, HCO 3 − 13.5 mmol/L). Her hospital course was extremely stormy and despite best of our efforts she succumbed due to colonic ischemia and perforation peritonitis. Conclusions A high index of suspicion for gut ischemia or perforation should be kept if DKA is associated with septic shock and there is suboptimal response to standard treatment. Mesenteric ischemia can occur in pediatric patients even with mild DKA having very poor diabetes control.

Objectives Graves’ disease (GD) is a rare auto-immune disorder in pediatric population. The association between GD and thymic hyperplasia was rarely reported in children. Diagnosis and management of GD are challenging in children. Case presentation This report presents the case of a 5-year-old girl with a personal history of asthma and congenital bilateral isolated clinical anophthalmia who presented with acute congestive heart failure, sinus tachycardia and atypical signs of orbitopathy with edema and erythema of the lower right eyelid and excessive tearing. The diagnosis of GD was based on detecting a suppression of serum TSH level and the presence of high titers of TRAbs. Relapse occurred after 10 months of antithyroid drugs with chief complaints of palpitations, dyspnea and dysphagia. Computed tomography showed heterogeneous anterior mediastinal mass with no invasion into the surrounding tissue. The marked shrinkage of the mass after radioiodine therapy supported the diagnosis of thymic hyperplasia associated with GD. Conclusions The presence of clinical anophthalmia may be a confusing factor for the diagnosis of Gravesʼ ophthalmopathy. Recognition of the association between GD and thymic hyperplasia would avoid invasive diagnostic procedures and unnecessary surgical resection. Radioiodine therapy may be used in young children with repeated relapses of GD.

Objectives Resistance to thyroid hormone (RTH) is a genetic condition, caused by mutations in the thyroid hormone receptor gene and characterized by impaired end organ responsiveness to thyroid hormone. Here we describe a novel case of THR associated with large goiter mimicking infiltrative c. Case presentation A 13-year-old male with a hyperthyroid phenotype of RTH diagnosed as a toddler, on methimazole and nadolol therapies presented with an increase in goiter size and possible nodule. Thyroid ultrasound was concerning for a diffuse infiltrative process or malignancy. Methimazole was discontinued and he underwent further imaging, fine needle aspiration and core biopsies. Biopsy results were reassuring and imaging findings were subsequently attributed to RTH rather than malignancy. He started every other day liothyronine therapy, which led to a decrease in goiter size, thyroglobulin level, and improvement of hyperthyroid symptoms. Conclusions This is the first case to our knowledge describing the above thyroid imaging findings in association with RTH. It also adds important information to the pediatric literature regarding management of the hyperthyroid phenotype of RTH, including the role of liothyronine therapy.

Objectives Hereditary hypomagnesemia with secondary hypocalcemia (HSH), which results from variations in the transient receptor potential melastatin 6 ( TRPM6 ) genes, is a rare hereditary cause of extremely low serum magnesium levels. We describe an infant with triggered seizures due to hypomagnesemia and a novel mutation in TRPM6 gene was identified. Case presentation A 10-month-old boy presented with multidrug resistant seizures, and axial hypotonia due to severe hypomagnesemia. Electroencephalography and neuroimaging of the patient was normal. He had a favorable outcome with magnesium supplement. In this study, the patient underwent clinical exome sequencing (CES) which detected a novel homozygous variant in the TRPM6 gene: NM_017662.5: c.5571-3C>G. After replacing his magnesium orally, he was free from seizures and had an encouraging outcome at the twelfth-month follow-up. Conclusions HSH often presents with developmental issues, treatment-resistant seizures, and increased neuromuscular excitability. Untreated hypomagnesemia can potentially be fatal and severely impair cognitive function. Clinical suspicion is essential for early diagnosis and treatment.