Clinical features, diagnosis and treatment outcomes of Cushing's disease in children: A multicenter study.

OBJECTIVE: Since Cushing's disease (CD) is less common in the paediatric age group than in adults, data on this subject are relatively limited in children. Herein, we aim to share the clinical, diagnostic and therapeutic features of paediatric CD cases. DESIGN: National, multicenter and retrospective study. PATIENTS: All centres were asked to complete a form including questions regarding initial complaints, physical examination findings, diagnostic tests, treatment modalities and follow-up data of the children with CD between December 2015 and March 2017. MEASUREMENTS: Diagnostic tests of CD and tumour size. RESULTS: Thirty-four patients (M:F = 16:18) from 15 tertiary centres were enroled. The most frequent complaint and physical examination finding were rapid weight gain, and round face with plethora, respectively. Late-night serum cortisol level was the most sensitive test for the diagnosis of hypercortisolism and morning adrenocorticotropic hormone (ACTH) level to demonstrate the pituitary origin (100% and 96.8%, respectively). Adenoma was detected on magnetic resonance imaging (MRI) in 70.5% of the patients. Transsphenoidal adenomectomy (TSA) was the most preferred treatment (78.1%). At follow-up, 6 (24%) of the patients who underwent TSA were reoperated due to recurrence or surgical failure. CONCLUSIONS: Herein, national data of the clinical experience on paediatric CD have been presented. Our findings highlight that presenting complaints may be subtle in children, the sensitivities of the diagnostic tests are very variable and require a careful interpretation, and MRI fails to detect adenoma in approximately one-third of cases. Finally, clinicians should be aware of the recurrence of the disease during the follow-up after surgery.

Plasma leucine-rich α-2-glycoprotein 1 - a novel marker of diabetic kidney disease in children and adolescents with type 1 diabetes mellitus?

BACKGROUND: Glomerular endothelial dysfunction and neoangiogenesis play a significant role in the pathogenesis of diabetic kidney disease (DKD). Leucine-rich α-2 glycoprotein 1 (LRG1) is a recently discovered protein that participates in the molecular pathway of inflammation and angiogenesis. We aimed to investigate efficacy of LRG1 to predict estimated glomerular filtration rate (eGFR) decrease in children and adolescents with type 1 diabetes mellitus (T1DM). METHODS: The study comprised 72 participants with diabetes duration for ≥ 2 years. At study initiation, LRG1, urine albumin, eGFR (cystatin C-based, and Schwartz), HbA1c, and lipid values were evaluated and diabetes-related clinical features and anthropometric measurements were collected. These results were compared with final control values after ≥ 1 year. Patients were divided into subgroups according to presence of albuminuria progression, eGFR decrease, and metabolic control parameters. RESULTS: There was positive correlation between LRG1 level and Schwartz and cystatin C-based eGFR decline (r = 0.360, p = 0.003; r = 0.447, p = 0.001, respectively), and negative correlation between final cystatin C-based eGFR and LRG1 (p = 0.01, r = -0.345). Patients with cystatin C-based eGFR decrease > 10% had significantly higher LRG1 levels (p = 0.03), however, LRG1 was not different between albuminuria progression subgroups. A 0.282 µg/ml increase in LRG1 correlated with a 1% decrease in eGFR in simple linear regression analysis (ß = 0.282, %CI 0.11-0.45, p = 0.001) and LRG1 was an independent predictor of GFR decline even in the presence of covariates. CONCLUSIONS: Our study supports the relationship between plasma LRG1 and eGFR decline and suggests LRG1 may be an early marker of DKD progression in children with T1DM. A higher resolution version of the Graphical abstract is available as Supplementary information.

Clinical Characteristics of Children with Combined Pituitary Hormone Deficiency and the Effects of Growth Hormone Treatment.

AIM: We aimed to describe the clinical characteristics of patients with congenital combined pituitary hormone deficiency (CPHD) and evaluate the first-year growth responses of individuals with CPHD and isolated growth hormone deficiency (IGHD) in order to establish the influence of other hormone deficiencies on growth response. PATIENTS AND METHODS: This retrospective study was conducted in four tertiary care centers in Turkey. The records of patients diagnosed with CPHD (n=39) and severe IGHD (n=50) were collected. Cases with acquired lesions or chronic diseases were not included in the study. Data are presented as median (interquartile range). RESULTS: Among 39 patients (13 females; 33%) with a diagnosis of CPHD, the majority of patients (64%) presented initially with combined deficits at baseline examination, whereas isolated deficiencies (36%) were less prevalent. Among all patients with GH deficiency, TSH, ACTH, FSH/LH, and ADH deficiencies were present in 94%, 74%, 44%, and 9% of patients, respectively. Patients with CPHD were diagnosed at a younger age (4.9 (8.4) vs. 11.6 (4.1), p<0.001, respectively) and had lower peak GH concentrations (0.4 (1.8) vs. 3.7 (2.9), p<0.001, respectively) than patients with IGHD. Patients with IGHD and CPHD had similar first-year growth responses (Δheight SD score of 0.55 (0.63) vs. 0.76 (0.71), respectively, p=0.45). CONCLUSIONS: We established the nature and timing of numerous hormonal deficits emerging over time. We also identified that the existence of CPHD did not hinder growth response.

Does fludrocortisone treatment cause hypomagnesemia in children with primary adrenal insufficiency?

Background/aim: Aldosterone is a mineralocorticoid that secreted from adrenal glands and a known factor to increase magnesium excretion by direct and indirect effects on renal tubular cells. Although the frequency of hypomagnesemia was found to be approximately 5% in adult studies, there is no study in the literature investigating the frequency of hypomagnesemia in children by using fludrocortisone, which has a mineralocorticoid activity. Materials and methods: A multi-center retrospective study was conducted, including children who were under fludrocortisone treatment for primary adrenal insufficiency and applied to participant pediatric endocrinology outpatient clinics. Results: Forty-three patients (58.1% male, 41.9% prepubertal) included in the study, whose median age was 9.18 (0.61-19) years, and the most common diagnosis among the patients was a salt-wasting form of congenital adrenal hyperplasia (67.4%). Mean serum magnesium level was 2.05 (±0.13) mg/dL, and hypomagnesemia was not observed in any of the patients treated with fludrocortisone. None of the patients had increased urinary excretion of magnesium. Conclusion: Unlike the studies performed in adults, we could not find any evidence of magnesium wasting effect of fludrocortisone treatment with normal or even high doses in children and adolescents.

Anthropometric findings from birth to adulthood and their relation with karyotpye distribution in Turkish girls with Turner syndrome.

To evaluate the anthropometric features of girls with Turner syndrome (TS) at birth and presentation and the effect of karyotype on these parameters. Data were collected from 842 patients with TS from 35 different centers, who were followed-up between 1984 and 2014 and whose diagnosis age ranged from birth to 18 years. Of the 842 patients, 122 girls who received growth hormone, estrogen or oxandrolone were excluded, and 720 girls were included in the study. In this cohort, the frequency of small for gestational age (SGA) birth was 33%. The frequency of SGA birth was 4.2% (2/48) in preterm and 36% (174/483) in term neonates (P < 0.001). The mean birth length was 1.3 cm shorter and mean birth weight was 0.36 kg lower than that of the normal population. The mean age at diagnosis was 10.1 ± 4.4 years. Mean height, weight and body mass index standard deviation scores at presentation were -3.1 ± 1.7, -1.4 ± 1.5, and 0.4 ± 1.7, respectively. Patients with isochromosome Xq were significantly heavier than those with other karyotype groups (P = 0.007). Age at presentation was negatively correlated and mid-parental height was positively correlated with height at presentation. Mid-parental height and age at presentation were the only parameters that were associated with height of children with TS. The frequency of SGA birth was found higher in preterm than term neonates but the mechanism could not be clarified. We found no effect of karyotype on height of girls with TS, whereas weight was greater in 46,X,i(Xq) and 45,X/46,X,i(Xq) karyotype groups.

Primary hypothyroidism: an unusual manifestation of Wolcott-Rallison syndrome.

Wolcott-Rallison syndrome has been reported to be associated with early-onset diabetes, epiphyseal dysplasia, hepatic and renal dysfunction, mental retardation, severe growth retardation, neutropenia, exocrine pancreatic dysfunction, and central hypothyroidism. We report on primary hypothyroidism, which has not been previously described, of a patient with Wolcott-Rallison syndrome due to novel mutation (W521X), who showed improved growth after thyroid hormone treatment.

Frequency of hematological findings associated with severe plasma vitamin B12 deficiency in infants and adolescents.

BACKGROUND: The aim of this study was to determine the hematological status of severe vitamin B12 deficiency in infants and adolescents. METHODS: This study involved 95 infants and 117 adolescents with severe plasma vitamin B12 deficiency (< 120 pg/ mL) and normal plasma folate and ferritin. Infants were aged between one and 24 months. Adolescents were aged between 11 and 17 years. RESULTS: Macrocytic anemia was associated with nine (9.5%) out of 95 infants with severe vitamin B12 deficiency. Neutropenia was found in 16 (16.8%) out of 95 infants with severe vitamin B12 deficiency. Thrombocytopenia was not found in 95 infants with severe vitamin B12 deficiency. Macrocytic anemia was found in two (1.7%) out of 117 adolescents with a severe vitamin B12 deficiency. Neutropenia was associated in one (0.8%) out of 117 adolescents with severe vitamin B12 deficiency. Thrombocytopenia was not found in 117 adolescents with severe vitamin B12 deficiency. CONCLUSIONS: Low clinical or hematological findings for B12 deficiency in infants and adolescents living in regions at risk, such as those with low consumption of meat and other animal products warrant the measurement of vitamin B12 level.

HIIT serves as an efficient training strategy for basketball players by improving blood fluidity and decreasing oxidative stress.

BACKGROUND: A challenge for coaches and athletes is to find the best combination of exercises during training. Considering its favorable effects, HIIT has been very popular recently. OBJECTIVE: The goal of this study was to investigate anthropometric features, performance, erythrocyte deformability, plasma viscosity (PV) and oxidative stress in response to acute and long-term (6 weeks) HIIT in adolescent basketball players. METHODS: 22 sportsmen between the ages of 14-16 were included. Tabata protocol was applied to the HIIT group in addition to their routine training program 3 days/week, for 6 weeks. Erythrocyte deformability was determined using an ectacytometer (LORCA), PV with a rotational viscometer. Total oxidant status (TOS), total antioxidant status (TAS) were measured by kits. RESULTS: HIIT for 6 weeks induced an improvement in performance tests and waist circumference. 6 weeks of HIIT resulted in a decrement, while the last exercise session yielded an increment in RBC deformability. PV and TOS of HIIT groups were decreased on the 6th week. CONCLUSIONS: Our results demonstrate that, HIIT in addition to the routine exercise program is beneficial for improving performance and blood fluidity as well as decreasing oxidative stress in basketball players. Therefore, HIIT seems as an efficient training strategy for highly-trained individuals.

Elevated glucose level at 30 minutes during an oral glucose tolerance test in obese adolescents: a new disorder of glucose tolerance.

We observed glucose levels >140 mg/dL measured at 30 minutes (min) during an oral glucose tolerance test (OGTT) in some obese patients. We aimed to investigate the significance of this finding by comparing lipid profiles, insulin resistance indices, and systemic inflammatory mediators between obese adolescents with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and elevated glucose levels at 30 min. The study involved 80 obese (body mass index >95(th) percentile for age and sex) adolescents (48 female, 32 male) between 11 and 16 years of age. Depending on OGTT results, patients were divided into NGT and IGT groups. The third group was recruited from the NGT group as having glucose levels > 140 mg/dL at 30 minutes. Lipid profiles, [interleukin-6 (IL-6)], neopterin, and lipoprotein associated phospholipase A2 (Lp-PLA2)] were assessed. Neopterin and Lp-PLA2 levels were significantly higher in obese adolescents with elevated glucose levels at 30 min. compared with those in both NGT and IGT groups (p=0.013, and 0.004, respectively). In these adolescents, IL-6 levels were significantly higher only than the NGT group (p=0.01). In logistic regression analysis, IL-6, neopterin and Lp-PLA2 levels were detected to be related to high blood glucose levels at 30 min (OR 1.11, p=0.01; OR 9.03, p=0.013; OR 1.01, p=0.004 respectively). Obese adolescents with elevated glucose levels at 30 min. demonstrated higher inflammatory mediators levels, which were atherosclerotic indicators, than obese adolescents with NGT and IGT. These results suggest that glucose levels >140 mg/dL measured at 30 min during an OGTT may be a new disorder of glucose tolerance in obesity.

An exceptionally rare case of Cushing's syndrome caused by ectopic ACTH syndrome due to olfactory neuroblastoma in childhood.

OBJECTIVES: Ectopic adrenocorticotropic hormone secretion/syndrome (EAS) is caused by excess secretion of ACTH leading to hypercortisolism by non-pituitary, commonly malignant origins. We present a rare case of esthesioneuroblastoma (ENB) complicated by EAS in the follow-up period. CASE PRESENTATION: A child presented with nasal obstruction at the age of 10 months. Polypoid mass obstructing the right nasal passage was detected. Magnetic resonance imaging (MRI) showed a lesion limited within the nasal cavity. The lesion was completely removed by nasal endoscopic surgery. The pathologic examination revealed a diagnosis of esthesioneuroblastoma. It was confined to the nasal cavity so chemotherapy/radiotherapy was not administered and began to follow up. At 28 months of age, he presented with rapid weight gain. Laboratory data were consistent with Cushing's syndrome (CS). High-dose dexamethasone suppression test and imaging studies led us to think of ectopic ACTH syndrome originated from ENB relapse. After partial resection of the tumor, ketoconazole treatment was started along with chemotherapy. Hypercortisolemia was kept under control with ketoconazole treatment as long as the treatment was maintained. CONCLUSIONS: Cushing syndrome is a rare endocrine disorder. Adrenal sources of hypercortisolism and ectopic sources of ACTH overproduction should be investigated especially in young children.

Cord Blood Levels of Spexin, Leptin, and Visfatin in Term Infants Born Small, Appropriate, and Large for Gestational Age and Their Association with Newborn Anthropometric Measurements

Objective: 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. 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.

Severe hypercalcaemia and acute renal failure in an infant with subcutaneous fat necrosis.

Subcutaneous fat necrosis (SFN) in the newborn is a form of panniculitis which presents with erythematous nodules and indurated plaques. Severe life-threatening hypercalcaemia can occur as a late complication. A 2-month-old girl presented with severe hypercalcaemia and acute renal injury as a complication of SFN. She was admitted to hospital with the chief complaint of failure to thrive. She had a history of therapeutic hypothermia. After successful treatment of the hypercalcaemia with bisphosphonates, the acute renal injury recovered spontaneously. In neonates with SFN, acute renal injury is a rare complication of hypercalcaemia. Timely prevention of the complications of hypercalcaemia in SFN is essential.

Metabolic predictors for early identification of fatty liver using doppler and B-mode ultrasonography in overweight and obese adolescents.

THE AIMS OF OUR STUDY WERE: (1) to evaluate the frequency of asymptomatic fatty liver disease (FLD) using both Doppler and B-mode ultrasound (US) in overweight and obese adolescents; (2) to compare metabolic findings of fatty liver (FL) assessed by two methods; and (3) to evaluate metabolic predictors of FL shown by these methods. Fifty-nine overweight and obese adolescents aged between 9.0 and 17.0 years and 41 non-obese healthy adolescents were included in this study. B-mode and right hepatic vein Doppler ultrasonography (US) were performed and anthropometric indices, lipid profiles, and adiponectin levels were evaluated in all adolescents. HDL-C levels were significantly lower in patients with FL detected by Doppler US compared to patients without FL (p < 0.05). HDL-C levels were inversely correlated with presence of FL assessed by two methods (r = -0.285, p = 0.004; r = -0.328, p = 0.001, respectively) and adiponectin levels were correlated with presence of FL only detected by B-mode US (r = -0.263, p = 0.008). Adiponectin levels were significantly lower in patients with FL than those without FL assessed by B-Mode US (p = 0.049). Multiple regression analysis revealed that HDL-C levels was the most important predictor of FL assessed by Doppler US (p = 0.027), while body mass index was the determinant of FL assessed by two methods (p < 0.001) in asymptomatic overweight and obese adolescents. It was found that FLD, identified by both B-mode and Doppler US, is seen frequently in asymptomatic overweight and obese adolescents. Elevated BMI is associated with increased risk of FL assessed by two ultrasonographic methods. When using Doppler US, low HDL-C levels can be used as a good predictor for presence of FLD in overweight and obese adolescents.

A novel compound heterozygous variant in CYP19A1 resulting in aromatase deficiency with normal ovarian tissue.

BACKGROUND: Aromatase deficiency leading to virilization in mother and female fetuses during pregnancy is a rare disease. It is characterized by impaired estrogen production, increased gonadotropins, and ovarian cysts. CASE: Herein, we report a clinical phenotype of the virilized female due to a novel compound heterozygous variant in CYP19A1 [IVS10 + 1 G > A; c.344 G > A (p.R115Q)], with normal gonadotropin levels at the time of admission and histologically normal ovarian tissues. CONCLUSION: Aromatase deficiency should also be considered even if the initial follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels are normal, and ovarian cysts are lacking.

The frequency of autoimmune thyroid disorders in juvenile idiopathic arthritis.

Few studies have been performed to investigate autoimmune diseases associated with organ non-specific rheumatological disorders in children, such as juvenile idiopathic arthritis (IA). The objective in this study was to determine the frequency of autoimmune diseases of the thyroid gland in children with JIA. Eighty patients with JIA and 81 healthy sex- and age-matched controls were enrolled in the study. Serum free T3, free T4, thyroid stimulating hormone (TSH), anti-thyroglobulin antibodies, and anti-peroxidase antibodies were evaluated. The mean age was 11.5 +/- 5.5 years in the patient group and 10.5 +/- 4.9 years in the control group. Twenty-seven of the cases were classified as oligoarticular, 26 as polyarticular, 17 as enthesitis-related, 6 as systemic, and 4 as psoriatic arthritis. Autoimmune thyroid disease was found in 4 patients in the JIA group (5%). There were no significant differences between the study and control groups regarding the existence of anti-thyroid antibodies (p = 0.17). Girls were more likely to develop autoimmune thyroiditis (3 girls, 1 boy). Autoimmune thyroiditis was more frequent in patients who had a family history of thyroid disease (p = 0.02). There was no statistical correlation between rheumatoid factor (RF) and antinuclear antibody (ANA) positivity and autoimmune thyroiditis (p > 0.05). We conclude that there is no need for routine screening of serum thyroid function tests and thyroid antibody levels in patients with JIA in the absence of clinical symptoms.

Investigation of celiac disease followed by immune thrombocytopenic purpura diagnosis in patients and comparison with literature.

OBJECTIVE: Celiac disease (CD) and Immune thrombocytopenic purpura (ITP) may occur together as a result of similar autoimmune mechanisms. The aim of this study was to assess the frequency of CD in a group of ITP patients and in the literature. METHODS: A total of 29 patients in Pamukkale University Faculty of Medicine Hospital Pediatric Hematology and Oncology Department with ITP were included in the study. Test was performed for the antibodies related to CD. Positive result for celiac antibodies was confirmed with biopsy. The results were compared with the literature. RESULTS: Of the study group, 13 patients (44.8%) were female and 16 (55.2%) were male. The mean age was 7.2±4.7 years and mean platelet count at the time of admission was 13,440±11,110/mm3 (range: 2000-41,000/mm3). Twelve patients (41.4%) were diagnosed as acute ITP, 6 patients (20.7%) as persistent ITP, and 11 patients (37.9%) as chronic ITP, according to the duration of thrombocytopenia. Antibody positivity was detected in 1 patient. Histological evaluation was compatible with CD. Results were compared with studies regarding the prevalence of CD in the population. No significant difference was found. CONCLUSION: Although it is not necessary to perform CD test in every case of ITP, the presence of differential diagnosis of CD is important to prevent unnecessary treatment, especially in ITP patients with growth retardation or malabsorption findings.