Volume 37, Issue 1

Patients with congenital hypogonadism will encounter many health care professionals during their lives managing their health needs; from antenatal and infantile periods, through childhood and adolescence, into adult life and then old age. The pubertal transition from childhood to adult life raises particular challenges for diagnosis, therapy and psychological support, and patients encounter many pitfalls. Many patients with congenital hypogonadism and delayed or absent puberty are only diagnosed and treated after long diagnostic journeys, and their management across different centres and countries is not well standardised. Here we reconsider the management of pubertal delay, whilst addressing problematic diagnostic issues and highlighting the limitations of historic pubertal induction protocols – from the perspective of both an adult and a paediatric endocrinologist, dealing in our everyday work with the long-term adverse consequences to our hypogonadal patients of an incorrect and/or late diagnosis and treatment in childhood.

Objectives Although AVP and its surrogate, copeptin, are mainly regulated by osmotic and volume stimuli, their secretion is also elicited by stress and growth hormone (GH) stimulating agents. The aim of this report is to describe unusual patterns of copeptin response in a subset of children undergoing GH stimulation tests (GH-ST). Methods We conducted a secondary analysis of a cohort of 93 healthy short children with no polydipsia, polyuria or fluid/electrolyte abnormalities, undergoing GH-ST with intravenous arginine, insulin, oral clonidine, or L-Dopa/carbidopa in various combinations. Serum copeptin concentrations were measured 1–3 min after phlebotomy (0 min) and at 60, 90, 120 min during GH-ST. Results In 85 subjects (normal response group, NRG) serum copeptin concentrations increased from a 0 min median of 9 pmol/L (IQR 6, 11.5) (all values ≤21) to a median peak between 60 and 120 min of 22 (IQR15, 38) pmol/L, which varied depending on the stimulating agent. Conversely, in the eight outliers, copeptin concentrations decreased gradually from a median of 154 (IQR 61, 439) pmol/L (all ≥40 pmol/L) to values as low as 14 % of the basal value, by 120 min. Test-associated anxiety was described in 17 subjects in the NRG (20 %) and five of the outliers (63 %). Conclusions A distinctive pattern of very elevated serum copeptin concentrations occurred in 9 % of children undergoing GH-ST, similar to reports in previous pediatric studies. Etiology may include pain or stress of phlebotomy. This phenomenon should be recognized for proper interpretation of copeptin values in children.

Objectives This study aimed to evaluate the efficacy and safety of 3-month leuprorelin acetate (3-month LA, 11.25 mg) for the treatment of idiopathic central precocious puberty (ICPP) in Chinese girls. Methods We conducted a single-center retrospective study in China on 28 girls with ICPP who received at least one year of 3-month LA treatment. Data from anthropometry, biochemistry, bone age (BA), and pelvic ultrasonography were assessed before and every 6 months during medication. Results At CPP diagnosis, the mean chronological age (CA) was 7.8±0.8 years, with bone age advancement (BA–CA) of 1.5±0.8 years. After treatment initiation, growth velocity decreased significantly from 8.5±1.6 cm/year to 5.8±1.1 cm/year at month 12 (p<0.001). GnRH-stimulated peak LH ≤3IU/L, the primary efficacy criterion, was observed in 27 out of 28 (96.4 %) children at month 3. Basal estradiol <20 pg/mL was achieved by all 28 girls (100 %) at month 6 and remained stable at month 12. Basal follicle-stimulating hormone (FSH) decreased from 4.1±3.5 to 1.7±0.9 (p<0.001), and basal LH was also significantly reduced from 3.3±6.5 to 0.7±0.8 (p=0.035) at month 12. The mean predicted adult height (PAH) at treatment initiation was 152.7±5.8 cm, it increased significantly to 157.5±5.5 cm (p=0.007) after one-year treatment. Pubertal development was slowed in most patients, and in some cases, it was even reversed. Only one patient (3.6 %) reported local intolerance. Conclusions Three-month leuprorelin acetate is a safe and effective treatment for suppressing the pituitary–gonadal axis and restoring impaired adult height in Chinese girls.

Objectives This study was conducted to study the expression of both microRNA-29a and microRNA-122, and serum levels of sestrin-2, interleukin-6 (IL-6), and other inflammatory markers among obese children with/and without diabetes mellitus. Methods One hundred obese children with diabetes in addition to 100 age- and sex-matched obese children without diabetes, and 100 age- and sex-matched apparently healthy children were included in the study. Expressions of both microRNA-29a and microRNA-122, and serum levels of sestrin-2, IL-6, tumor necrosis factor-α (TNF-α), and high sensitive-CRP (hsCRP) were measured for all included study populations. Results Study results showed that the expressions of both microRNA-29a and microRNA-122, serum levels of IL-6, TNF-α, and hsCRP were significantly higher among obese children with diabetes in comparison to both obese children without diabetes and healthy children. In contrast, serum sestrin level was significantly low among obese children with diabetes in comparison to the other study populations. Expressions of both microRNA-29a and microRNA-122 were correlated with waist circumference, BMI, total cholesterol, triglycerides, LDL-cholesterol, HbA 1c , c-peptide, glucose, insulin, homeostatic model assessment-insulin resistance (HOMA-IR), IL-6, hsCRP, and TNF-α among obese children with diabetes. However, serum sestrin-2 level was correlated inversely with these parameters. Higher expressions of both microRNA-29a and microRNA-122 among obese children either with or without diabetes mellitus (DM) can suggest their roles in the development of obesity among children. Conclusions The study results can hypothesize that down-regulation of these micro-RNAs may solve this health problem with its sequelae, a hypothesis that needs more studies.

Objectives The association between obesity and gastroesophageal reflux disease (GERD) is well-established in adults; however, data in pediatric population is scarce. Our study aimed to assess the association between GERD and health-related quality of life (HRQoL) in overweight children. Methods From April to August of 2020, we included children aged 7–18 years who attended the Endocrinological Outpatient Clinic at the Paediatric Institute, University of Debrecen, Hungary. The participants completed two questionnaires: the Pediatric Gastroesophageal Reflux Disease Symptom Questionnaire (PGSQ) and the HRQoL questionnaire (PedsQL). Based on the criteria of the World Health Organization (WHO), the patients were categorized into two groups: an overweight or obese group and a group with normal weight. Results A total of 107 children (51 % female, mean age 13.2 years, 46 % overweight or obese) completed the questionnaires. The median PGSQ score was similar in both groups (4.0 (IQR: 1.0–7.8) vs. 3.0 (IQR: 1.0–7.0), p=0.6). However, the total PedsQL score was significantly lower in the children with overweight or obesity compared to those with normal weight (80.1 (71.1–91.0) vs. 88.0 (76.1–94.6), p=0.031). The PedsQL score was lower among overweight patients with GERD symptoms than that of normal-weight patients without GERD symptoms. Conclusions Our findings highlight the importance of raising awareness about GERD to enhance the HRQoL and prevent long-term complications in obese children.

Objectives Carnitine palmitoyltransferase II (CPT II) deficiency is an autosomal recessive disorder of long-chain fatty acid oxidation. Three clinical phenotypes, lethal neonatal form, severe infantile hepatocardiomuscular form, and myopathic form, have been described in CPT II deficiency. The myopathic form is usually mild and can manifest from infancy to adulthood, characterised by recurrent rhabdomyolysis episodes. The study aimed to investigate the clinical features, biochemical, histopathological, and genetic findings of 13 patients diagnosed with the myopathic form of CPT II deficiency at Ege University Hospital. Methods A retrospective study was conducted with 13 patients with the myopathic form of CPT II deficiency. Our study considered demographic data, triggers of recurrent rhabdomyolysis attacks, biochemical metabolic screening, and molecular analysis. Results Ten patients were examined for rhabdomyolysis of unknown causes. Two patients were diagnosed during family screening, and one was diagnosed during investigations due to increased liver function tests. Acylcarnitine profiles were normal in five patients during rhabdomyolysis. Genetic studies have identified a c.338C>T (p.Ser113Leu) variant homozygous in 10 patients. One patient showed a novel frameshift variant compound heterozygous with c.338C>T (p.Ser113Leu). Conclusions Plasma acylcarnitine analysis should be preferred as it is superior to DBS acylcarnitine analysis in diagnosing CPT II deficiency. Even if plasma acylcarnitine analysis is impossible, CPT2 gene analysis should be performed. Our study emphasizes that CPT II deficiency should be considered in the differential diagnosis of recurrent rhabdomyolysis, even if typical acylcarnitine elevation does not accompany it.

Objectives Gender-related differences in oxidative stress, nitric oxide bioavailability, and cardiometabolic risk factors were examined in a cross-sectional study involving 313 prepubertal children (8–9 years old) from the generation XXI birth-cohort. Methods Anthropometric measurements, cardiometabolic variables, and redox markers were assessed, including plasma and urinary isoprostanes (P-Isop, U-Isop), plasma total antioxidant status (P-TAS), serum myeloperoxidase (MPO), plasma and urinary nitrates and nitrites (P-NOX, U-NOX), and urinary hydrogen peroxide (U-H 2 O 2 ). Results Girls showed higher levels of total/non-HDL cholesterol, triglycerides, and insulin resistance (HOMA-IR) compared to boys. Notably, U-H 2 O 2 values were lower in girls. When stratifying by body mass index (BMI) and gender, both girls and boys exhibited higher MPO concentration and U-Isop values. Uric acid concentration was higher in overweight and obese girls than in normal weight girls, while no significant differences were observed among boys across BMI categories. Furthermore, U-NOX values differed only in boys, with higher levels observed in overweight and obese individuals compared to those with normal weight. Multivariate analysis, adjusted for age and BMI z-score, demonstrated inverse associations between U-H 2 O 2 and pulse wave velocity values, as well as between U-NOX and total or non-HDL cholesterol, exclusively in boys. In girls, a positive association between U-Isop and HOMA-IR values was observed. Conclusions In conclusion, gender differentially impacts oxidative stress, nitric oxide bioavailability, and cardiometabolic risk factors in prepubertal children. Prepubertal girls appear more susceptible to oxidative stress-induced metabolic dysfunction, while in boys, elevated levels of redox and nitric oxide bioavailability markers seem to provide protection against arterial stiffness and lipid homeostasis.

Objectives Pediatric thyroid cancer represents 2.3 % of thyroid cancers, and its long-term outcome data are sparse. There have not been studies in the UAE delineating its epidemiology, clinical and histological characteristics, and follow-up outcomes. We aimed to evaluate the clinical–pathological behavior, recurrence and survival rates in pediatrics with all types of thyroid cancer in the UAE. Methods Multicentre retrospective chart review analysis of pediatric patients with thyroid carcinoma from January 2010 to December 2020 in Abu Dhabi, UAE. Results Thirty-four patients were included, 85 % being females. Papillary thyroid carcinoma (PTC) was the commonest type of thyroid cancer (88 %) vs. follicular thyroid carcinoma (FTC) (11.8 %). Almost half of our patients had a multifocal disease, 26 % had lymphovascular invasion (LVI), and 21 % had extrathyroidal extension (ETE). There were no mortalities during follow-up. 85 % of patients exhibited complete remission, while 15 % of patients showed evidence of progressive residual or recurrent disease. One patient had metastasis to lymph nodes and lungs. Conclusions There were similar trends of incidence, sex prevalence, and histopathological patterns as the ones observed internationally. Potential risk factors in our population include a family history of thyroid cancer and obesity. The lower rate of ETE, LVI, metastasis, and recurrence indicates a possibly less aggressive disease.

Objectives To assess auxological parameters, adult height outcome and its determinants in Indian girls with idiopathic central precocious puberty (iCPP) treated with gonadotropin-releasing hormone analogues (GnRHa). Methods Retrospective study. Inclusion: data on girls with iCPP from initiation to stopping GnRHa (n=179). Exclusion: boys, peripheral, organic central precocity. Results Mean age of starting GnRHa: 8.2± 1.1 years, duration: 2.8± 1.2 years. 11.7 % had attained menarche at first presentation. The difference between bone (BA) and chronological (CA) ages reduced significantly from 2.6± 0.9 years (onset) to 1.6± 0.8 years (cessation). Weight, BMI Z-scores increased (p<0.01), height Z-scores decreased (0.8 vs. 0.6; p<0.01), predicted adult height (PAH) and Z-scores improved by 3.5 cm, 0.5 SDS following treatment (p<0.01). Overweight/obese girls (vs. normal BMI) were taller, with more advanced BA at starting (height Z-score: 0.7 vs. 1.0, BA-CA: 2.2 vs. 2.9 years), stopping (height Z-score: 0.5 vs. 0.9, BA–CA: 1.4 vs. 1.9 years) treatment, but showed no difference in PAH at starting, stopping treatment. Adult height data (n=58) revealed 1.9 cm gain above target height. Adult height Z-scores significantly exceeded target height Z-scores (p<0.01). Mean adult height (157.1± 5.8 cm) crossed PAH at starting treatment (155.9± 6.4 cm) but remained 1.6 cm lesser than PAH at cessation. Adult weight, BMI Z-scores (−0.2± 1.3, −0.1± 1.2) were significantly lower (p<0.01) than those at stopping GnRHa. Height gain adjusted for age at starting GnRHa correlated negatively with height, weight, BMI, Tanner-staging, BA, FSH, Estradiol at treatment onset, BA at cessation, and correlated positively with treatment duration. Conclusions GnRHa treatment in Indian girls with iCPP resulted in improved PAH, decelerated bone age advancement and growth velocity. Most girls achieved adult height within target range, surpassing PAH at treatment initiation. Lesser anthropometric, sexual, skeletal maturity, lower baseline FSH, estradiol, longer treatment duration, less advanced BA at stopping GnRHa may translate into better adult height outcomes.

Objectives It is safe to use recombinant growth hormone in children. Studies have shown it to be effective and safe, except for a few side effects in the short and long term after treatment. The present study investigated the presence of hypertension in pediatric patients receiving growth hormone treatment using 24 h ambulatory blood pressure monitoring (ABPM). Methods This study is a single-center, retrospective study. Eighty-four patients aged 5–16 years who received growth hormone treatment for at least 3 months, who underwent 24 h ABPM were analyzed. They were compared with 67 patients who had no risk factors for hypertension. Results In the study, 84 rhGH-treated patients (45.2 % male, 54.8 % female) and 67 healthy control groups (49.3 % male, 50.7 % female) were analyzed. The mean age of the patient group was 10.83±2.85 years and the mean age of the healthy control group was 13.1±2.93 years. The diagnostic classification of the patients receiving treatment was as follows: 66.6 % (n=56) partial growth hormone deficiency, 22.6 % (n=19) growth hormone deficiency, 7.1 % (n=6) bioactive growth hormone, 2.3 % (n=2) idiopathic short stature, 1.1 % (n=1) low birth weight for gestational age (SGA). Body mass index was significantly lower in the treated group (p=0.013). The duration of treatment was 6.04±4.9 months. Daytime diastolic blood pressure was significantly lower in the treated group (p=0.001). There was no correlation between BMI and ABPM parameters in the treatment group and the control group. Conclusions The present study shows that growth hormone treatment is safe in terms of high blood pressure.

Objectives This study was performed to investigate the effectiveness of the combination of letrozole and recombinant human growth hormone (rhGH) to improve the predicted adult height (PAH) and final adult height (FAH) of Chinese short pubertal boys. Methods In total, 171 Chinese short pubertal boys were recruited for this study. 96 of them received letrozole (2.5 mg/d) combined with rhGH (33.3–66.6 μg/kg.d), and the others received rhGH alone. Follow-up visits were conducted at 1, 3, 6, 9, and 12 months or regularly after the first treatment. During each visit, plasma samples were collected for clinical tests and biomedical analyses, all of which were performed according to standard protocols. This study was registered at www.chictr.org.cn under ID number ChiCTR1900026142. Results After receiving treatment for at least 3 months, 68 boys (91 %) in the rhGH therapy group and 90 (94 %) in the letrozole combined with rhGH (letrozole+rhGH) therapy group achieved an increase in PAH, with the latter treatment leading to a more effective slowing of bone age (BA) advancement. Moreover, the increased PAH showed a significant positive correlation with treatment time in both groups, and letrozole+rhGH increased the PAH to a greater degree than rhGH alone (p=0.0023). And letrozole+rhGH not only slowed the increase in BA more efficiently than rhGH therapy alone (p=0.0025), but also achieved a higher FAH (p=0.0078). Conclusions Letrozole combined with rhGH treatment is a promising therapy to increase the PAH and FAH of Chinese short pubertal boys.

Objectives Sturge–Weber syndrome (SWS) is a rare neurocutaneous disorder that is characterized by a segmental dermatomal facial port-wine stain birthmark and is frequently accompanied by ipsilateral brain and eye abnormalities. We present a case of a patient with SWS who exhibited hypogonadotropic hypogonadism, growth hormone (GH) deficiency, and central hypothyroidism at the age of 20 despite the absence of radiographic findings in the pituitary and hypothalamus. Case presentation A 20-year-old male with SWS with epilepsy and Klippel–Trenaunay syndrome presents with delayed pubertal development, short stature, and obesity. Upon further examination, he was found to have biochemical and clinical evidence of hypogonadism, hypothyroidism, and GH deficiency. A pituitary MRI displayed no abnormalities of the pituitary or hypothalamus. Treatment with testosterone cypionate and levothyroxine was initiated. Despite successful pubertal induction, IGF-1 levels have remained low and treatment with recombinant human growth hormone (rhGH) is now being considered for metabolic benefits. Conclusions This case emphasizes the importance of endocrine evaluation and treatment of hormonal deficiencies in patients with SWS despite the absence of radiographic findings.

Objectives Pseudohypoparathyroidism (PHP1B) is most commonly caused by epigenetic defects resulting in loss of methylation at the GNAS locus, although deletions of STX16 leading to GNAS methylation abnormalities have been previously reported. The phenotype of this disorder is variable and can include hormonal resistances and severe infantile obesity with hyperphagia. A possible time relationship between the onset of obesity and endocrinopathies has been previously reported but remains unclear. Understanding of the condition’s natural history is limited, partly due to a scarcity of literature, especially in children. Case presentation We report three siblings with autosomal dominant PHP1B caused by a deletion in STX16 who presented with early childhood onset PTH-resistance with normocalcemia with a progressive nature, accompanied by TSH-resistance and severe infantile obesity with hyperphagia in some, not all of the affected individuals. Conclusions PHP1B from a STX16 deletion displays intrafamilial phenotypic variation. It is a novel cause of severe infantile obesity, which is not typically included in commercially available gene panels but must be considered in the genetic work-up. Finally, it does not seem to have a clear time relationship between the onset of obesity and hormonal resistance.