INTRODUCTION: Recent reports have indicated the role of the prokineticin receptor 2 gene (PROKR2) in the etiology of pituitary hormone deficiencies, suggesting a potential role for the PROK2 pathway in pituitary development, in addition to its role in gonadotropin releasing hormone-expressing neuron development. Here, we present the clinical and molecular findings of four patients with PROKR2 mutations.
METHODS: Next-generation targeted sequencing was used to screen 25 genes in 59 unrelated patients with multiple pituitary hormone deficiency (MPHD), isolated growth hormone (GH) deficiency, or idiopathic short stature.
RESULTS: Two different, very rare PROKR2 missense alterations classified as pathogenic (NM_144773.4: c.518T>G; NP_658986.1: p. (Leu173Arg)) and likely pathogenic (NM_144773.4: c.254G>A; NP_658986.1: p.(Arg85His)) were identified in four patients in heterozygous form. Patient 1 and Patient 2 presented with short stature and were diagnosed as GH deficiency. Patient 3 and Patient 4 presented with central hypothyroidism and cryptorchidism and were diagnosed as MPHD. No other pathogenic alterations were detected in the remaining 24 genes related to short stature, MPHD, and hypogonadotropic hypogonadism. Segregation analysis revealed asymptomatic or mildly affected carriers in the families.
DISCUSSION AND CONCLUSION: PROKR2 dominance should be kept in mind as a very rare cause of GH deficiency and MPHD. Expressional variation or lack of penetrance may imply oligogenic inheritance or other environmental modifiers in individuals who are heterozygous carriers.

INTRODUCTION: The aim of the present study was to investigate islet autoimmunity and susceptibility to type 1 diabetes (T1D) in children/ adolescents with autoimmune thyroid disease (AITD, and in family members of AITD patients with islet autoimmunity.
METHODS: Islet-cell cytoplasmic, glutamic-acid decarboxylase, and tyrosine-phosphatase autoantibodies (AAbs) were measured in 161 AITD patients [127 with autoimmune thyroiditis (AT); 34 with Graves’ disease (GD)], 20 family members of AITD patients with islet autoimmunity, and 155 age-matched controls.
RESULTS: Islet autoimmunity was found in 10.6% of AITD patients, significantly more frequent than in controls (1.9%; p=0.002). A higher prevalence of islet AAbs was found in females with AITD (p=0.011) but not in males (p=0.16) and in AT (p=0.013) but not in GD patients (p=0.19), compared to corresponding controls. Two or three islet AAbs were found concurrently in six AITD patients with islet autoimmunity. They all developed T1D and had significantly higher islet AAbs titers (p=0.01) than AITD patients with single islet AAbs but normal glucose metabolism. T1D was found in 3.7% of AITD patients compared to 0.2% of the age-matched, general Croatian population. Islet AAbs were found in 5/20 family members of AITD patients with islet autoimmunity, among whom two developed T1D. None of the controls was positive for more than one islet AAb or developed T1D.
DISCUSSION AND CONCLUSION: Children/adolescents with AITD, particularly females and patients with AT, appear to represent a risk group for islet autoimmunity and T1D, as do family members of AITD patients with positive islet AAbs. However, these findings should be validated in larger studies.

INTRODUCTION: To estimate the incidence rates (IR) and analyse the trend in type 1 diabetes (T1D) among children aged 0-14 years in the West, South, and Tripoli regions of Libya.
METHODS: A retrospective study was conducted on Libyan children aged 0-14 years with a new diagnosis of T1D who were admitted and/or had their follow-up at Tripoli Children’s Hospital during the period 2004 to 2018. The data were used to estimate the IR and the age-standardized IR per 100,000 population in the studied region for the years 2009-2018. The IRs by sex and age group (0-4, 5-9, 10-14 years) for every calendar year were assessed.
RESULTS: A total of 1,213 children were diagnosed during the study period (2004-2018), 49.1% were males with a male-to-female ratio of 1: 1.03. The mean age (±standard deviation) at diagnosis was 6.3±3.8 years. The distribution of incident cases according to age group 0-4, 5-9, and 10-14 years was 38.2%, 37.8%, and 24.1%, respectively. Poisson regression modelling in the period 2009-2018 revealed an overall trend of a 2.1% increase per annum. In the period 2014-2018, the overall age-adjusted IR was 31.7 (95% confidence interval: 29.2-34.2) per 100,000 population, the IRs of age groups 0-4, 5-9, and 10-14 years were 36.0, 37.4, and 21.6 per 100,000, respectively
DISCUSSION AND CONCLUSION: The incidence of T1D in Libyan children in the West, South, and Tripoli regions appears to be rising, with a higher rate in the 0-4 and 5-9 year age groups.

INTRODUCTION: This study was designed to examine the effect of blue light exposure and exposure time on puberty in an animal model.
METHODS: Eighteen 21-day-old female Sprague Dawley rats were divided into three equal groups which were: control group (CG); blue light-6 hours (BL-6); and blue light-12 hours (BL-12). CG rats were maintained with 12/12-hour light-dark cycles. The animals in BL-6 and BL-12 were exposed to blue light of wavelength 450-470 nm and intensity of 0.03 uW/cm2 for 6 and 12 hours, respectively. Exposure to blue light continued until the first signs of puberty. Serum follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol, testosterone, dehydroepiandrosterone sulfate (DHEA-S), leptin and melatonin were measured. Subsequently the ovaries and uterus were examined histomorphologically.
RESULTS: The median day of puberty start was 38, 32 and 30 for the CG, BL-6, and BL-12 groups, respectively (p=0.001). FSH, testosterone, DHEA-S, and leptin concentrations of all groups were similar. However, LH and estradiol concentrations in BL-6 were higher compared to CG (p=0.02). There was a negative correlation between blue light exposure, exposure time, and melatonin concentrations (r=-0.537, p=0.048). Ovarian tissue was compatible with puberty in all groups. As blue light exposure time increased, capillary dilatation and edema in the ovarian tissue increased. Prolonged exposure was associated with polycystic ovary-like (PCO) morphological changes and apoptosis in granulosa cells.
DISCUSSION AND CONCLUSION: These results suggest that exposure to blue light and the duration of exposure induced earlier puberty in female rats. As the duration of blue light exposure increased, PCO-like inflammation, and apoptosis were detected in the ovaries.

INTRODUCTION: Current peak serum cortisol cutoffs for the diagnosis of adrenal insufficiency (AI) after Cosyntropin stimulation have been established using polyclonal antibody (pAb) immunoassays. However, new and highly specific cortisol monoclonal antibody (mAb) immunoassays are being used more widely, which can potentially yield higher false positive rates. Thus, this study aimed to redefine the biochemical diagnostic cutoff points for AI in children when using a highly specific cortisol mAb immunoassay and liquid chromatography tandem mass spectrometry (LC/MS) to avoid unnecessary steroid use.
METHODS: Cortisol levels from 36 children undergoing 1 mcg Cosyntropin stimulation tests to rule out AI were measured using pAb immunoassay (Roche Elecsys Cortisol I), mAB immunoassay (Roche Elecsys Cortisol II), and LC/MS. Logistic regression was used to predict AI using the pAB as the reference standard. A receiver operator characteristic curve, area under the curve (AUC), sensitivity, specificity, and kappa agreement were also calculated.
RESULTS: Using a peak serum cortisol cutoff value of 12.5 μg/dL for the mAb immunoassay provided 99% sensitivity and 94% specificity for diagnosing AI, when compared to the historical pAb immunoassay cutoff of 18 μg/dL (AUC=0.997). Likewise, a cutoff of value of 14 μg/dL using the LC/MS, provided 99% sensitivity and 88% specificity when compared to the pAb immunoassay (AUC=0.995).
DISCUSSION AND CONCLUSION: To prevent overdiagnosis of AI in children undergoing 1 mcg Cosyntropin stimulation test, our data support using a new peak serum cortisol cutoff of 12.5 μg/dL and 14 μg/dL to diagnose AI when using mAb immunoassays and LC/MS in children, respectively.

INTRODUCTION: Patients with congenital adrenal hyperplasia (CAH) require lifelong therapy with glucocorticoids to suppress androgen excess and substitute for deficient cortisol. An important aspect of care is the prevention of metabolic sequelae. In infants, potentially lethal nocturnal hypoglycaemia has been described. In adolescence, visceral obesity, hypertension, hyperinsulinism and insulin resistance are reported. To date, systematic studies of glucose profiles in this age group with CAH are lacking.
METHODS: This was a monocentric, prospective, observational study to determine the glucose profiles under different treatment regimens in a cohort of young patients with CAH. The continuous glucose monitoring device used was the latest generation FreeStyle Libre 3® sensor in blinded mode. Therapeutic and auxological data were obtained.
RESULTS: The cohort consisted of 10 children/adolescents with a mean age of 11 years. Three patients exhibited morning fasting hyperglycaemia. Overall, 6 out of 10 patients had unacceptably few total values in the desired range of 70-120 mg/dL. Tissue glucose values above 140-180 mg/dL were found in 5 of 10 patients. The mean value for glycosylated haemoglobin for the cohort was of 5.8%. All pubertal adolescents with reverse circadian regimens had significantly higher glucose levels at night. Two adolescents showed asymptomatic nocturnal hypoglycaemia.
DISCUSSION AND CONCLUSION: Most of the patients exhibited abnormalities in glucose metabolism. Two-thirds had elevated total 24h glucose values outside the age-appropriate reference values. Thus, this aspect may need to be addressed early in life by adjusting the doses, treatment regimen or dietary measures. Consequently, reverse circadian therapy regimens should be critically indicated and closely monitored due to the potential metabolic risk.

INTRODUCTION: The aim of this study was to compare the development of early diabetic retinopathy (DR) findings, a microvascular complication, between patients with isolated type 1 diabetes mellitus (T1DM) (Group 1), concurrent T1DM and autoimmune thyroiditis (AT) (Group 2), and healthy controls (Group 3), who were matched for age, sex, number, and body mass index for comparison.
METHODS: This was a prospective observational study that included individuals aged 10-20 years, and patients in Groups 1 and 2 had been followed up for ≥5 years. None of them developed clinical DR during the follow-up period. Optical coherence tomography angiography (OCTA) was used to evaluate the foveal avascular zone (FAZ) and parafoveal vascular density (PVD) for the development of early DR. OCTA findings were compared between patients and healthy controls.
RESULTS: Thirty-five individuals were included in each of the groups. The mean FAZ and PVD differed significantly between the three groups (FAZ, p=0.016; PVD, p=0.006). The mean FAZ was higher in Groups 1 and 2 than in Group 3 (p=0.013 and p=0.119, respectively). The mean PVD was lower in Groups 1 and 2 than in Group 3 (p=0.007, respectively). No significant difference was found between Groups 1 and 2 in terms of the mean FAZ and PVD (p=0.832 and p=0.653, respectively). The mean glycated hemoglobin (HbA1c) level was significantly correlated with FAZ and PVD (FAZ: r=0.496, p<0.001; PVD: r=-0.36, p=0.001).
DISCUSSION AND CONCLUSION: In patients with T1DM who did not develop clinical DR, OCTA findings revealed an increase in FAZ, which was associated with higher HbA1c levels. The mean PVD was significantly lower in the group with coexisting AT and T1DM than in the control group. These results suggest that the coexistence of AT and T1DM can contribute to the development of microvascular complications. However, studies with larger patient series are required.

INTRODUCTION: To compare pulse wave analysis (PWA) of obese children with and without metabolic syndrome (MS) with healthy, non-obese children and to evaluate the association between PWA findings and additional risk factors present in children with MS and obesity.
METHODS: From the obese patients examined between June 2019 and June 2021, 41 patients with MS, 36 obese patients without MS, and 34 healthy non-obese children of similar age and gender were evaluated retrospectively. Anthropometric measurements, biochemical evaluation, 24-hour ambulatory blood pressure (BP) measurement (ABPM), left ventricular mass index (LVMI) and PWA measurements were compared.
RESULTS: When the three groups were compared, weight standard deviation score (SDS), height SDS and body mass index SDS were all significantly higher in the MS group (p<0.05). The following measurements were significantly higher in both MS and non-MS obese patients compared to the control group: from ABPM measures, the systolic and mean arterial pressure BP SDSs load; from PWA, the night central systolic BP, 24-hour, day and night pulse pressure values and 24-hour, day and night pulse wave velocity (PWV) rates; and from cardiac evaluations, the LVMI and relative wall thickness measurements (all p<0.05). Furthermore, the 24-hour and daytime central systolic (cSBP) and diastolic BP (cDBP) values were significantly different between the three groups, being the highest in the MS group (p<0.05).
DISCUSSION AND CONCLUSION: Obesity causes higher office, ambulatory and central BP, PWV and LVMI. However our results suggest that additional risk factors associated with MS do not contribute to these parameters, except for 24-hour and daytime cSBP and cDBP values.

INTRODUCTION: Congenital adrenal hyperplasia (CAH) is an inherited condition in which individuals require multiple daily doses of medication and are at risk for life-threatening adrenal crisis. The chronic nature and severity of CAH place children at risk for psychiatric morbidity. The aim was to assess the degree of anxiety and depressive symptoms in children with CAH.
METHODS: A cross-sectional cohort study of children (7-17 years) with CAH and their caregivers were recruited between May and December 2021. Children with hypothyroidism (HT) and their caregivers served as unaffected controls. Validated mental health questionnaires [Children’s Depression Inventory 2 Self Report-Short (CDI-2), Screen for Child Anxiety Related Disorders (SCARED), Patient Health Questionnaire modified for Adolescents (PHQ-A); self and proxy] were completed by participants at one clinic visit. Higher scores indicated greater symptoms of anxiety and depression.
RESULTS: A total of 60 children and 56 parents participated. Among the children 34 had CAH (68% female, mean age 11.41±2.5, CAH duration 8.5±4.1) and 26 had HT (73% female, mean age 12.7±2.9 years, HT duration 6.0±4.2 years). There was no increase in anxiety and depression symptoms in children with CAH compared to controls. In sub-analyses, children with CAH and controls reported a greater number of anxiety and depression symptoms than their caregivers on the SCARED and CDI-2, respectively. There was no association between adrenal control and the degree of anxiety or depression symptoms.
DISCUSSION AND CONCLUSION: Children with CAH do not have more symptoms of anxiety or depression compared to controls. Child and caregiver-proxy responses lack agreement, suggesting that children with CAH may continue to benefit from routine mental health evaluation, regardless of voiced caregiver concern.

Glucose 6 phosphate dehydrogenase (G6PD) is expressed in all tissues and is necessary to maintain oxidant stress capacity of cells. G6PD deficiency is the most common enzymopathy in humans and is among the important causes of hemolytic anemia. It has been reported that severe hemolytic anemia due to G6PD deficiency may develop in newly diagnosed diabetes, especially during the correction of hyperglycemia. To date, nine cases have been published. Genetic analysis was not performed for G6PD deficiency in these published patients. We present a case of hemolytic anemia due to G6PD deficiency secondary to newly diagnosed type 1 diabetes mellitus. Genetic testing was performed for the index patient and revealed a previously reported missense pathogenic variant (c.653C>T; p.Ser218Phe) in the G6PD gene.

Tumor-induced osteomalacia (TIO) is a rare, paraneoplastic disorder of hypophosphatemia associated with elevated tumor-produced fibroblast growth factor 23 (FGF23). Maxillofacial tumors are rarely involved in TIO, especially maxillary TIO in children. We present a 14-year-old boy with osteomalacia and high serum levels of FGF23, a hormone associated with decreased phosphate resorption, due to a maxillary tumor. The patient was treated with oral phosphorus and calcitriol, and surgical removal of the tumor was performed. After 21 months follow-up, he was pain free and had returned to full activity. We review the reported pediatric cases of TIO in the maxillofacial and oral region and discuss the management of these patients considering the published evidence.

Neonatal diabetes and congenital hypothyroidism (CH) syndrome is a rare condition caused by homozygous or compound heterozygous mutations in the GLIS3 gene. Small for gestational age, congenital glaucoma, polycystic kidney disease, cholestatic hepatic fibrosis, pancreatic exocrine insufficiency, developmental delay, dysmorphic facial features, sensorineural deafness, osteopenia, and skeletal anomalies are other accompanying phenotypic features in the 22 cases described so far. We present a male patient with neonatal diabetes, CH, congenital glaucoma, developmental delay, and facial dysmorphism. During the patient’s 17-year follow-up, no signs of exocrine pancreatic insufficiency, liver and kidney diseases, deafness, osteopenia, and bone fracture were observed. A homozygous exon 10-11 deletion was detected in the GLIS3 gene. We report one of the oldest surviving GLIS3 mutation case with main findings of neonatal diabetes and CH syndrome to contribute to the characterization of the genotypic and phenotypic spectra of the syndrome.

IGSF1 deficiency is a rare X-linked condition characterized by central hypothyroidism and a wide variety of other clinical features with variable prevalence, including a delayed pubertal testosterone rise and growth spurt in the context of normal or accelerated testicular growth, and adult macroorchidism with relatively low serum testosterone concentrations. Other features include increased waist circumference, attention deficit, prolactin deficiency and transient partial growth hormone (GH) deficiency in childhood, contrasting with an increased GH secretion in adulthood. Patients with this disorder are not detected shortly after birth if neonatal screening programs are based on thyroid-stimulating hormone (TSH) concentrations. A 13.2-year-old male patient was referred to pediatric endocrinology for evaluation of short stature. He was born large for gestational age into a nonconsanguineous family. During work-up for short stature, deficiencies of TSH, prolactin and GH were detected, leading to treatment with levothyroxine and GH. At 16.9 years, GH treatment was stopped and during transition to adult care, his insulin-like growth factor 1 level was above the normal range. This prompted an analysis of IGSF1, in which a novel hemizygous variant causing a stop codon at c.3559C>T (p.Q1187*) was found, confirming the diagnosis of IGSF1 deficiency syndrome. In this report, we describe his clinical and hormonal characteristics at presentation and during long-term follow-up.

Neurofibromatosis-Noonan syndrome (NFNS), a rare autosomal-dominant hereditary disease, is characterized by clinical manifestations of both neurofibromatosis type 1 (NF1) and NS. We present a case of NFNS with short stature caused by a heterozygous nonsense variant of the NF1 gene. A 12-year-old boy was admitted because of short stature, numerous café-au-lait spots, low-set and posteriorly rotated ears, sparse eyebrows, broad forehead, and inverted triangular face. Cranial and spinal magnetic resonance imaging showed abnormal nodular lesions. Molecular analysis revealed a novel heterozygous c.6189 C > G (p.(Tyr2063*)) variant in the NF1 gene. The patient was not prescribed recombinant growth hormone (GH) therapy because exogenous GH may have enlarged the abnormal skeletal lesions. During follow-up, Lisch nodules were found in the ophthalmologic examination. NFNS, a variant form of NF1, is caused by heterozygous mutations in the NF1 gene. The mechanism of GH deficiency caused by NF1 is still unclear. Whether NFNS patients should be treated with exogenous GH remains controversial.

A balanced and healthy diet is very important in type 1 diabetes mellitus (T1DM) in childhood. In addition to regulating blood glucose with diet, diet should also support optimal growth. Low-carbohydrate diet aims to provide daily energy from fats and was originally used for childhood epilepsy. We present a patient with T1DM who experienced unfavorable effects when on a low-carbohydrate diet.