Childhood osteoporosis leads to increased propensity to fracture, and thus is an important cause of morbidity, pain and healthcare utilisation. Osteoporosis in children may be caused by a primary bone defect or secondary to an underlying medical condition and/or its treatment. Primary osteoporosis is rare, but there is an increasing number of children with risk factors for secondary osteoporosis. Therefore it is imperative that all paediatricians are aware of the diagnostic criteria and baseline investigations for childhood osteoporosis to enable timely referral to a specialist in paediatric bone health. This review will discuss the approach to diagnosis, investigation and management of childhood osteoporosis, with particular consideration to advances in molecular diagnosis of primary bone disorders, and current and emerging therapies for fracture reduction.

INTRODUCTION: Premature pubarche (PP) is a risk factor for metabolic syndrome (MS). The aim was to evaluate if glucose-insulin metabolism, cardiovascular risk factors, familial cardiovascular risk factors (FCVRF) created a risk for insulin resistance (IR) and if PP was a risk factor alone for MS in normal weight prepubertal girls with PP.
METHODS: Thirty-five prepubertal, non-obese girls with PP with normal birth weight and 35 age-matched control girls were evaluated for FCVRF, anthropometric measurements, blood pressure, lipid profile, fasting blood glucose-insulin, hemoglobin A1c (HbA1c), sex hormone binding globulin (SHBG), leptin, adiponectin, tumor necrosis factor-alpha (TNF-α), androgen levels, and bone age. Oral glucose tolerance test was performed in PP participants. Homeostasis model of assessment of IR (HOMA-IR), fasting glucose/insulin ratio, atherogenic index (AI), and free androgen index (FAI) were calculated. PP participants were further stratified by FCVRF.
RESULTS: HbA1c, lipid profile, testosterone, leptin, adiponectin, TNF-α, HOMA-IR, glucose/insulin ratio, AI, and fasting glucose-insulin levels were similar. In the PP group FAI was significantly higher (p=0.001), whereas SHBG was significantly lower (p=0.010) than the control group. Leptin levels of FCVRF+ and FCVRF- subgroups were 15.2±9.1 and 9.7±7.2 ng/mL, respectively and the difference was significant (p=0.016).
DISCUSSION AND CONCLUSION: As PP does not appear to be a risk factor alone for impaired glucose metabolism and IR in prepubertal non-obese girls with normal birth weight, it is our opinion that it is unnecessary to examine in detail such cases before puberty. Low SHBG levels in the PP group and high leptin levels in FCVRF+ subgroup might suggest that these may be predictive for MS in the future.

INTRODUCTION: Oncologic treatment can affect the adrenal glands, which in stressful situations may lead to life threatening adrenal crisis. The aim of the study was to assess adrenal function in pediatric acute lymphoblastic leukemia (ALL) survivors and to identify the best markers for this assessment.
METHODS: Forty-three ALL survivors, mean age 8.5±3.6 years and 45 age and sex-matched healthy controls were recruited to the study. ALL patients were assessed once within five years following oncological treatment completion. Fasting blood samples were collected from all participants to measure: fasting blood glucose (FBG); cortisol; aldosterone; plasma renin activity (PRA); dehydroepiandrostendione-sulfate (DHEA-S); and adrenocorticotropic hormone (ACTH). Moreover, diurnal profile of cortisol levels and 24-hour urinary free cortisol (UFC) were assessed. ALL survivors underwent a test with 1 ug of synthetic ACTH.
RESULTS: The study revealed lower level of PRA (1.94±0.98 ng/mL/h vs 3.61±4.85 ng/mL/h, p=0.029) and higher FBG (4.6±0.38 mmol/L vs 4.41±0.39 mmol/L, p=0.018) in the ALL group compared to controls. UFC correlated with evening cortisol (p=0.015, r=0.26), midnight cortisol (p=0.002, r=0.33), and DHEA-S (p=0.004, r=0.32). UFC also correlated with systolic and diastolic blood pressure (p=0.033, r=0.23 and p=0.005, r=0.31, respectively). The ACTH test confirmed impaired adrenal function in 4/43 ALL survivors (9%). Two of the patients who needed permanent hydrocortisone replacement had low UFC, midnight cortisol and DHEA-S levels.
DISCUSSION AND CONCLUSION: These results highlight the importance of reviewing adrenal gland functionality after chemo/radiotherapy in ALL survivors. DHEA-S proved to be a good marker to assess the adrenal glands after oncological therapy. Post-treatment disturbances of the adrenal axis could be associated with metabolic complications.

INTRODUCTION: Multisystem inflammatory syndrome in children (MIS-C), associated with Coronavirus disease-2019, is defined as the presence of documented fever, inflammation, and at least two signs of multisystem involvement and lack of an alternative microbial diagnosis in children who have recent or current Severe acute respiratory syndrome-Coronavirus-2 infection or exposure. In this study, we evaluated thyroid function tests in pediatric cases with MIS-C in order to understand how the hypothalamus-pituitary-thyroid axis was affected and to examine the relationship between disease severity and thyroid function.
METHODS: This case-control study was conducted between January 2021 and September 2021. The patient group consisted of 36 MIS-C cases, the control group included 72 healthy children. Demographic features, clinical findings, inflammatory markers, thyroid function tests, and thyroid antibody levels in cases of MIS-C were recorded. Thyroid function tests were recorded in the healthy control group.
RESULTS: When MIS-C and healthy control groups were compared, free triiodothyronine (fT3) level was lower in MIS-C cases, while free thyroxine (fT4) level was found to be lower in the healthy group (p<0.001, p=0.001, respectively). Although the fT4 level was significantly lower in controls, no significant difference was found compared with the age-appropriate reference intervals (p=0.318). When MIS-C cases were stratified by intensive care requirement, fT3 levels were also lower in those admitted to intensive care and also in those who received steroid treatment (p=0.043, p<0.001, respectively).
DISCUSSION AND CONCLUSION: Since the endocrine system critically coordinates and regulates important metabolic and biochemical pathways, investigation of endocrine function in MIS-C may be beneficial. These results show an association between low fT3 levels and both diagnosis of MIS-C and requirement for intensive care. Further studies are needed to predict the prognosis and develop a long-term follow-up management plan.

INTRODUCTION: A close relationship has been suggested between Celiac disease (CD) and glandular autoimmunity. The aim of this study was to determine the predictive factors for autoimmune glandular disease (AGD) in children with CD.
METHODS: The study included 228 pediatric patients, diagnosed with CD between 2010 and 2019. The cases with AGD (Group 1) and those without AGD (Group 2) and the patients with type 1 diabetes mellitus (T1DM) (Group A) and those without T1DM (Group B) were retrospectively reviewed and compared in terms of clinical and laboratory features.
RESULTS: AGD was detected in 8.8% (n=20) of the patients: T1DM in 13 (65%), T1DM and Hashimoto’s thyroiditis (HT) in 3 (15%), HT only in 2 (10%), T1DM and Graves disease (GD) in 1 (5%), and GD only in 1(5%). The mean age at the diagnosis of CD was significantly higher in Group 1 (10.93±4.15 years) compared to Group 2 (8.10±4.19 years) (p<0.05) and also was significantly higher in Group A compared to Group B (p<0.05). Most of the diagnoses of AGD were made before the diagnosis of CD and age was an effective factor. There was no difference between Group 1 and Group 2 and Group A and Group B in terms of gender, typical/atypical CD ratio, tissue transglutaminase IgA (TTGA) level, human leucocyte antigen (HLA)-DQ2 and/or HLA-DQ8 positivity rate, and histopathological stage.
DISCUSSION AND CONCLUSION: Although patients with a diagnosis of co-existent CD and AGD were significantly older than patients with isolated CD, gender, celiac symptoms, TTGA level, HLA type, and histopathological stage had no predictive value for the coexistence of AGD in patients with CD.

INTRODUCTION: Nutrition and exposure to various chemicals, including environmental pollution, insecticides, and plant phytoestrogens (having oestrogen-like effects), are environmental factors that affect puberty onset. The aim of this study was to identify the effects of propolis, which has been reported to have oestrogenic effects, on precocious puberty and the reproductive system in prepubertal female rats (ovary, endometrium, breast).
METHODS: Thirty-four 25-day-old, prepubertal, female Sprague-Dawley rats were included. Rats were randomly divided into the propolis (n=17) and control groups (n=17). The primary endpoint was the number of rats that developed vaginal opening, a sign of puberty, at 12-day follow-up. In addition, the effect of propolis on ovary, uterus and breast tissue was evaluated histologically.
RESULTS: Vaginal patency occurred earlier (about 7.5 days sooner) in the propolis group and all animals in the propolis group had vaginal patency by day 12. The number of ovarian follicles (in all follicles), endometrial thickness, and mammary gland secretory gland area were significantly higher in the propolis group than in the control group (all p<0.001). In addition, Ki-67 activity in the endometrium, breast tissue and ovary was more intense in the propolis group compared to the control group (all p<0.001).
DISCUSSION AND CONCLUSION: Propolis triggers precocious puberty in female rats, possibly by interacting with the oestrogen receptor. The mechanism of action of propolis should be considered before prescribing it. In addition, further studies are needed to explore the mechanism of action of propolis and to determine the component of propolis that triggers puberty.

INTRODUCTION: Cardiac involvement is common in Noonan syndrome (NS). Concerns have been raised regarding the effect of recombinant growth hormone (rGH) use on ventricular wall thickness and a possible increased risk of cardiac side effects. This study aimed to investigate the effect of rGH on the development of hypertrophic cardiomyopathy and other cardiac findings in NS.
METHODS: Patients under the age of 18 years and diagnosed with NS according to the Van der Burgt criteria, were included. Patients were divided into two groups according to those receiving rGH or not at the time of obtaining cardiac measurements. Before and after the treatment, electrocardiographic and echocardiographic (ECHO) assessments were made, including interventricular septal thickness, left ventricular internal diameter, and left ventricular posterior thickness. Results were expressed as Z scores.
RESULTS: Twenty-four NS subjects (16 boys, eight girls) were included. At the beginning of the follow up, the overall height standard deviation score was -2.56±0.94. Sixteen were on rGH. The mean rGH treatment duration was 8.3±3.8 years, and the mean dose was 0.22±0.04 mg/kg/week. The final height was 169±8.2 cm, and 10 of 11 patients who reached the final height received rGH. There was no difference between the rGH and non-rGH groups in terms of ECHO parameters pre-and post-treatment.
DISCUSSION AND CONCLUSION: In this cohort, there was no change in ECHO parameters on rGH and during follow-up. These results suggest that rGH is safe in NS patients with cardiac pathology under close follow-up.

INTRODUCTION: The harmful or beneficial effect of obesity on bone mineral density (BMD) remains controversial in children and adolescents. Fibroblast growth factor 21 (FGF21) is a metabolic factor that plays a specific role in the regulation of carbohydrate and lipid metabolism. However, the role of FGF21 in bone metabolism appears paradoxical and is complex. To determine whether serum FGF21 level was associated with BMD in obese children and adolescents.
METHODS: The study was conducted with the participation of children and adolescents aged 8-18 years. Ninety-eight obese children were included in the study group and 44 children were included in the control group. BMD, in addition to the routine obesity workup, which includes fasting blood glucose, fasting insulin levels, lipid profile, and liver enzymes; serum FGF21 levels have been analyzed.
RESULTS: The mean age of the obese group (n=98) was 13.34±2.24 years and the mean age of controls (n=44) was 13.48±2.87 years. Based on International Diabetes Federation criteria, 15 of 98 (15.3%) patients were metabolically unhealthy. FGF21 levels were 193.54±139.62 mg/dL in the obese group and 158.69±151.81 mg/dL in the control group (p=0.06). There was no difference between the FGF21 and BMD z-score values of girls and boys in the obese and control groups (p>0.05).
DISCUSSION AND CONCLUSION: BMD-z-score was increased in obese children compared to healthy control. Moreover, BMD-z-score tended to be higher when more metabolic risk factors were present. However, there was no significant relationship between FGF21 levels and BMD z-score values in obese children.

INTRODUCTION: Children born small for gestational age (SGA) are at risk of future obesity and associated comorbidities. Therefore the identification of risk factors and novel biomarkers which are associated with this risk are needed for early detection and to improve preventive strategies. Spexin (SPX), a novel neuropeptide that is involved in the regulation of obesity and fat metabolism, is a candidate biomarker for predicting obesity and related comorbidities at an early age. The aim of this study was to investigate serum levels of SPX in term infants born small, appropriate, and large for gestational age (LGA) and its association with newborn anthropometric measurements.
METHODS: One hundred and twenty term newborn babies classified as SGA, appropriate for gestational age (AGA), or LGA and their mothers were included. SPX, leptin and visfatin were measured in cord blood and maternal serum by enzyme-linked immunosorbent assay.
RESULTS: Fifty-six (46.7%) neonates were girls and 64 (53.3%) were boys. The mean birth weight was 3170.70±663 g, birth length was 48.9±2.79 cm, and head circumference was 34.5±1.67 cm. Birth weights, lengths, and head circumferences of the neonates in the SGA, AGA, and LGA groups were significantly different. Cord blood SPX and leptin levels in the SGA groups were significantly lower than those of both the LGA and AGA groups. Cord blood visfatin levels were significantly lower in the AGA group than the LGA and SGA groups. Maternal SPX levels of SGA babies were significantly lower than those of the mothers in both the LGA and AGA groups, but no significant difference was observed between the SGA and LGA groups. Maternal visfatin levels of the AGA babies were significantly higher than the maternal levels of SGA and LGA groups. There was no difference in terms of maternal leptin levels. Cord blood SPX and leptin levels were positively correlated with birth weight, length and head circumference. Birth weight increased significantly in line with maternal pregestational body mass index.
DISCUSSION AND CONCLUSION: The lowest SPX levels were found in the SGA babies and cord SPX level was significantly correlated with newborn length, weight, and head circumference.

INTRODUCTION: Preterm and low birth weight (LBW) neonates may present with thyroid dysfunction during a critical period for neurodevelopment. These alterations can be missed on routine congenital hypothyroidism (CH) screening which only measures thyroid stimulating hormone (TSH). The objective of this study was to evaluate a protocol for thyroid function screening (TFS) six years after national implementation.
METHODS: Serum TSH and free thyroxine (fT4) were measured during the second week of life in neonates below 31 weeks. Patients with abnormal TFS (fT4 <0.8 ng/dL and/or TSH >5 mU/L) were followed up with repeated tests until normal levels were reported. Patients who were still on levothyroxine (LT4) at three years of age were re-evaluated.
RESULTS: Five-hundred and nine neonates were included. Thyroid dysfunction was detected in 170 neonates (33%); CH n=20 (3.9%) including typical CH n=1; delayed TSH elevation CH n=19; hypothyroxinemia of prematurity (HOP) n=15 (2.9%); and transient hyperthyrotropinemia n=135 (26.5%). Twenty-one neonates (4.1%) were treated (20 for CH and 1 for HOP). At 3-year follow-up only three patients were diagnosed with permanent CH and still need treatment. LBW infants tended to have TSH levels higher than those with adequate weight.
DISCUSSION AND CONCLUSION: This protocol was able to detect thyroid dysfunction in preterm neonates who were not identified by the current program based on TSH determination in whole-blood. This thyroid dysfunction seems to resolve spontaneously in a few months in the great majority of neonates, but in some cases LT4 could be needed. There is a critical need for specific guidelines regarding the follow-up and re-evaluation of transient CH in preterm neonates.

The purpose of this case series was to evaluate menstrual suppression in sex assigned at birth female adolescents identifying as male or gender non-conforming. A retrospective chart review of four gender minority youth (GMY), age 14-17, was performed for gender identity history, type and success of menstrual suppression, method satisfaction, side effects and improvement in menstrual distress. Menstrual suppression was successful in three patients, one patient discontinued use due to side effects that caused an increase in gender dysphoria. Menstrual distress and bleeding pattern improved in the majority of GMY in this series but side effects, as well as contraindications, may limit their use. In conclusion, menstrual dysphoria can be life-threatening for GMY and it is important that clinicians consider menstrual suppression in GMY with menstrual dysphoria. This series emphasizes the importance of individualized treatment plans.

The genetic cause of 46, XY disorder of sex development (DSD) still cannot be determined in about half of the cases. GATA-4 haploinsufficiency is one of the rare causes of DSD in genetic males (46, XY). Twenty-two cases with 46, XY DSD due to GATA-4 haploinsufficiency (nine missense variant, two copy number variation) have been previously reported. In these cases, the phenotype may range from a mild undervirilization to complete female external genitalia. The haploinsufficiency may be caused by a sequence variant or copy number variation (8p23 deletion). The aim of this study was to present two unrelated patients with DSD due to GATA-4 variants and to review the phenotypic and genotypic characteristics of DSD cases related to GATA-4 deficiency.

Odontochondrodysplasia (ODCD, OMIM #184260) is a rare, non-lethal skeletal dysplasia characterized by involvement of the spine and metaphyseal regions of the long bones, pulmonary hypoplasia, short stature, joint hypermobility, and dentinogenesis imperfecta. ODCD is inherited in an autosomal recessive fashion with an unknown frequency caused by mutations of the thyroid hormone receptor interactor 11 gene (TRIP11; OMIM *604505). The TRIP11 gene encodes the Golgi microtubule-associated protein 210 (GMAP-210), which is an indispensable protein for the function of the Golgi apparatus. Mutations in TRIP11 also cause achondrogenesis type 1A (ACG1A). Null mutations of TRIP11 lead to ACG1A, also known as a lethal skeletal dysplasia, while hypomorphic mutations cause ODCD. Here we report a male child diagnosed as ODCD with a novel compound heterozygous mutation who presented with skeletal changes, short stature, dentinogenesis imperfecta, and facial dysmorphism resembling achondroplasia and hypochondroplasia.

ACAN variants can manifest as various clinical features, including short stature, advanced bone age (BA), and skeletal defects. Here, we report rare clinical manifestations of ACAN defects in a 9 year, 5 month-old girl born small for gestational age (SGA), who presented with short stature, and was initially diagnosed with idiopathic growth hormone deficiency. She displayed several dysmorphic features, including genu valgum, cubitus valgus, and recurrent patellar dislocations. She presented with progressive advancement of BA compared with chronological age. Whole exome sequencing confirmed the presence of a novel heterozygous nonsense variant, c.1968C>G, p.(Tyr656*), in ACAN. ACAN variants should be considered in short stature patients born SGA with joint problems, particularly those with recurrent patellar dislocation and genu valgum.

Pseudohypoparathyroidism (PHP) type 1A (PHP1A) is a disorder of multiple hormone resistance, mainly parathyroid hormone. It is associated with Albright hereditary osteodystrophy phenotypes. Patients with PHP1A may initially present with hypothyroidism during infancy and later develop typical PHP1A characteristics during their childhood. Central precocious puberty (CPP) is extremely rare among PHP1A patients in whom gonadotropin resistance is more usual. This is a case report of a 9.5-year-old boy with congenital hypothyroidism who developed hypocalcemia secondary to PHP. He had relatively short stature with height standard deviation score of -0.9. Obesity had been noted since the age of two years. At the presentation of PHP, pubertal-sized testes of 10 mL were observed, and CPP was documented with serum testosterone concentration of 298 ng/dL (normal for Tanner stage III, 100-320), luteinizing hormone of 3.9 IU/L (normal, 0.2-5.0), and follicle stimulating hormone of 4.8 IU/L (normal, 1.2-5.8). Pituitary magnetic resonance imaging was unremarkable. Genetic analysis confirmed the diagnosis of PHP1A with a novel heterozygous missense variant of GNAS gene in exon 13, c.1103A>G (p.Asp368Gly). Awareness of PHP1A diagnosis in patients with congenital hypothyroidism and early childhood-onset obesity is important for early diagnosis. Apart from multiple hormone resistance, CPP may manifest in patients with PHP1A.