Novel Mutations in Obesity-related Genes in Turkish Children with Non-syndromic Early Onset Severe Obesity: A Multicentre Study

Objective: Non syndromic monogenic obesity is a rare cause of early onset severe obesity in the childhood period. This form may not be distinguishable from other forms of severe obesity without genetic analysis, particularly if patients do not exibit any physical abnormalities or developmental delay. The aim of this study was to screen 41 different obesity-related genes in children with non-syndromic early onset severe obesity. Methods: Children with severe (body mass index-standard deviation score >3) and early onset (<7 years) obesity were screened by next-generation sequencing based, targeted DNA custom panel for 41 known-obesity-related genes and the results were confirmed by Sanger technique. Results: Six novel variants were identified in five candidate genes in seven out of 105 children with severe obesity; two in SIM1 (p.W306C and p.Q36X), one in POMC (p.Y160H), one in PCSK1 (p.W130G fs Ter8), two in MC4R (p.D126E) and one in LEPR (p.Q4H). Additionally, two previously known variations in MC4R were identified in four patients (p.R165W in three, and p.V166I in one). Conclusion: We identified six novel and four previously described variants in six obesity-related genes in 11 out of 105 childrens with early onset severe obesity. The prevalence of monogenic obesity was 10.4% in our cohort.

Intrathyroidal Ectopic Thymus in Children: Retrospective Analysis of Grayscale and Doppler Sonographic Features.

OBJECTIVES: The purpose of this study was to define grayscale and color Doppler sonographic features of an ectopic intrathyroidal thymus and to differentiate it from other thyroid nodule etiologies. METHODS: We retrospectively reviewed imaging findings from 30 children who had a diagnosis of an ectopic intrathyroidal thymus from November 2005 to January 2013. Nodular thyroid lesions that were enclosed by the thyroid parenchyma and showed a typical echo pattern consistent with the thymus were accepted as the enclosed form of an intrathyroidal ectopic thymus. Eleven of these 30 children had an intrathyroidal ectopic thymus enclosed by the thyroid parenchyma, and they were enrolled in the study. The recorded sonograms were reviewed according to side, location, size, shape, echo pattern, internal content, and vascularization. RESULTS: The enclosed forms of ectopic intrathyroidal thymuses were unilateral in all children and located in the mid portion (n = 10) or lower portion (n = 1). All lesions were well demarcated, and the most common shape was fusiform (n = 8). Nine lesions showed a typical hypoechoic echo pattern with internal linear and punctate echoes resembling a mediastinal thymus. On color Doppler imaging, 6 lesions showed hypovascularity compared to the thyroid parenchyma, and 5 lesions showed internal vascularity. CONCLUSIONS: Unique sonographic features of the enclosed form of an ectopic intrathyroidal thymus, including a hypoechoic echo pattern with multiple linear and punctate echoes, a fusiform shape, a well-demarcated contour, and a mid- or low-lying location with hypovascularity or internal vascularity, can help radiologists differentiate it from other thyroid nodule etiologies.

Oxidative stress in obese children and its relation with insulin resistance.

BACKGROUND: In obese populations, oxidative stress plays a major role in the pathogenesis of serious diseases such as diabetes, coronary heart disease, and atherosclerosis. In this study, we investigated the status of oxidative stress in obese children as to nitrite/nitrate and glutathione peroxidase levels, and their relation with insulin resistance (IR). METHODS: A total of 63 obese children were enrolled in the study. Each was relegated to one of three groups: 20 obese children without IR (11 adolescents, 9 prepubertal; mean age 10.27 +/- 2.36 years; 10 males, 10 females), 22 obese children with IR (13 adolescents, 9 prepubertal; mean age 11.26 +/- 2.52 years; 10 males, 12 females), and a control group of 21 children (14 adolescents, 7 prepubertal; mean age 11.41 +/- 2.00 years; 10 males, 11 females). RESULTS: Glutathione peroxidase levels were lower in the obese group with IR than in either the control group or the obese group without IR (0.032 +/- 0.01 vs. 0.048 +/- 0.01 and 0.042 +/- 0.01, respectively). Nitrite/nitrate levels were higher in the obese group with IR than in the control group or the obese group without IR (89.83 +/- 25.00 vs. 66.00 +/- 21.75, and 68.65 +/- 28.98, respectively) and compared by pubertal status, adolescents' results were similar. However, in prepubertal children, nitrite/nitrate and glutathione peroxidase levels were not significantly different between groups. Multiple regression analysis revealed that nitrite/nitrate levels were positively correlated with the homeostasis model assessment of IR (HOMA-IR) independent of body mass index, age, gender, serum lipids, and pubertal stages, and that glutathione peroxidase levels were negatively correlated with body mass index and HOMA-IR independent of age, gender, pubertal status, and serum lipids. CONCLUSION: This study demonstrates that oxidative stress exists even in populations of obese children, and that oxidative stress markers have a relation with the HOMA-IR, which was used as a surrogate marker of IR.

Tuberculous meningitis associated with diabetic ketoacidosis.

Diabetic ketoacidosis (DKA) is a life-threatening acute complication of type 1 diabetes mellitus. Infections are the leading cause of DKA, but trauma, myocardial infarction, or surgery may also precipitate this condition. In patients with DKA, although cerebral edema is the most common cause of neurological symptoms, other possibilities such as meningitis or encephalitis should also be considered. Herein, we present the case of an 8-year-old girl with DKA and tuberculous meningitis.

Efficiency of fluid treatments with different sodium concentration in children with type 1 diabetic ketoacidosis.

OBJECTIVE: The management of children with diabetic ketoacidosis (DKA) continues to be a controversial issue with regard to amount of intravenous fluid to be given, rate of delivery of fluid, and type of fluid to be used. We aimed to analyze the results obtained by administration of rehydration fluids of two different sodium (Na) concentrations (75 mEq/L vs. 100 mEq/L) in the treatment of children with DKA. METHODS: Thirty-two children with DKA were assessed for efficacy and safety of fluid treatment. After an initial rehydration time, intravenous fluids were switched to a 5% dextrose solution with a Na content of 75 mEq/L (Group I, n=19) or 100 mEq/L (Group II, n=13). Venous blood samples were collected from all subjects at diagnosis and at the 4th, 8th, 16th and 24th hours of treatment. RESULTS: Changes in blood glucose levels did not differ significantly between the two groups at the 4th, 8th, 16th and 24th hours of the follow-up. Nadir effective plasma osmolality (Peff osm) and Peff osm levels also did not show statistically significant differences. Plasma sodium (PNa) level did not drop lower than the level at diagnosis in both groups. The changes in PNa concentrations in the two groups were not statistically significant at diagnosis or in follow-up samples (p=0.74). pH, anion gap, pCO2 and HCO3 levels were also similar in Group I and Group II. The duration of a pH level of <7.3 was shorter in Group II, but this was not statistically significant (p=0.65). None of the patients enrolled in this study developed cerebral edema. CONCLUSION: The efficacy and safety of rehydration fluids with Na concentrations of 75 or 100 mEq/L did not reveal any differences in children with DKA.

Case report: two patients with partial DiGeorge syndrome presenting with attention disorder and learning difficulties.

DiGeorge syndrome (DGS) has classically been characterized by the triad of clinical features including congenital cardiac defects, immune deficiencies secondary to aplasia or hypoplasia of the thymus, and hypocalcaemia due to small or absent parathyroid glands. The phenotypic features of these patients are much more variable and extensive than previously recognized. The acknowledgement of similarities and phenotypic overlap of DGS with other disorders associated with genetic defects in 22q11 has led to an expanded description of the phenotypic features of DGS including palatal/speech abnormalities, as well as cognitive, neurological and psychiatric disorders. Here, we report the cases of two DGS patients with dysmorphic facial features who were initially admitted to the Psychiatry Department for attention disorder and learning difficulties.

The effect of gonadotropin-releasing hormone analog treatment (leuprolide) on body fat distribution in idiopathic central precocious puberty.

Gonadotropin-releasing hormone analog (GnRHa) therapy is used in idiopathic central precocious puberty (ICPP) worldwide. It has also been shown that during this therapy, body mass index (BMI) increases slightly as a side effect. We investigated the side effects of GnRHa treatment in ICPP on body composition and insulin resistance (IR). Twenty girls (7.55 +/- 1.02 y) with ICPP were treated with GnRHa (leuprolide) for an average of 20.83 +/- 4.8 months. Bioelectrical Impedance Analysis (BIA) was used to measure the body's fat balance. Nine patients out of 20 (45%) had significant gain weight. We showed a significant elevation in trunk fat mass compare to baseline values (p < 0.01). These nine patients had high homeostasis model assessment (HOMA)-IR and low glucose/insulin (G/I) index. This study showed a slight increase in BMI, moderate increase in total body fat, and exaggerated elevation in trunk fat mass and IR in GnRHa-treated ICPP children.

Evaluation of thyroid functions with respect to iodine status and TRH test in chronic autoimmune thyroiditis.

OBJECTIVE: Chronic autoimmune thyroiditis (CAT) is the most common form of thyroiditis in childhood and a frequent cause of acquired hypothyroidism. The objective of this study was to evaluate the thyroid status of children and adolescents with CAT with respect to iodine status and diagnostic values of thyrotropin-releasing hormone (TRH) test. METHODS: Seventy-one children (mean age: 11.6 years) were studied in a retrospective analysis. Free thyroxine (T4), thyrotropin (TSH), TSH response to TRH test, thyroid autoantibodies, thyroid sonography, and urinary iodine excretion (UIE) were evaluated. RESULTS: At diagnosis, 8.5% of patients had overt hypothyroidisim and 36.6% subclinical hypothyroidism; 5.6% had overt hyperthyroidisim and 8.5% had subclinical hyperthyroidism. Of them, 40.8% were euthyroid. Median UIE was 51 mg/L in overt hypothyroidism and 84 mg/L in subclinical hypothyroidism. The values were 316 mg/L and 221 mg/L in overt and subclinical hyperthyroidism, respectively. Basal TSH showed a strong correlation with peak TSH level on TRH test. Thirty-four percent of patients with normal basal TSH level showed an exaggerated TSH response. CONCLUSION: Iodine deficiency was seen more in cases with hypothyroidism, while excess of iodine was observed to be more frequent in hyperthyroid patients. Iodine status was a strong predictorof the thyroid status in CAT. TRH test may be helpful in further delineating patients with subclinical hypothyroidism.

Treatment of autonomous ovarian follicular cyst with long-term anastrozole therapy.

Functional follicular ovarian cysts are frequently reported in girls with peripheral precocious puberty (PP). These cysts are usually self-limiting and resolve spontaneously. Several drugs like antiestrogens (tamoxifen) and new aromatase inhibitors are seldom used for treatment. Here we report a girl with peripheral PP who presented with unilateral enlargement of the ovary and a recurrent autonomous ovarian cyst. No skin pigmentation or bone anomaly was noted. The patient was successfully treated with anastrozole, a highly selective aromatase inhibitor. No adverse reaction was noted. Anastrozole is a safe and tolerable drug especially used to suppress estrogen action.

Combined evaluation of IGF-1 and IGFBP-3 as an index of efficacy and safety in growth hormone treated patients.

OBJECTIVE: Measurement of serum insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) levels has been recommended as a useful index for monitoring of growth hormone (GH) therapy in GH deficient children. In this study we aimed to evaluate IGF-1/IGFBP-3 molar ratio during GH treatment as an index of safety and efficacy. METHODS: Serum IGF-1 and IGFBP-3 levels and molar ratio of IGF-1/IGFBP-3 were evaluated in 50 GH deficienct children, during 3 years of GH therapy and these parameters were compared with the growth response. RESULTS: All patients completed the first year, 38 the second year and 26 the third year of therapy. Although 15 patients in the first year, 5 patients in the second year, and 5 patients in the third year had high IGF-1 SDS values, height increments were similar in the low IGF-1 group and in the normal or high IGF-1 level groups. Molar ratios were also not statistically different between the groups. Molar ratio of IGF-1/IGFBP-3 seemed to be more reliable in evaluating the efficacy than basal IGF-1 level. CONCLUSIONS: Evaluation of the molar ratio of IGF-1/IGFBP-3 may be recommended as a tool to monitor GH treatment and it may be possible to individualize GH treatment accordingly.

Vitamin D deficiency in Turkish mothers and their neonates and in women of reproductive age.

OBJECTIVE: Materno-fetal vitamin D deficiency (VDD) may occur in the early neonatal period. We aimed to evaluate the vitamin D (vitD) status and risk factors for VDD in healthy newborns and their mothers, and also in fertile women. METHODS: Serum 25 hydroxyvitamin D3 (25(OH)D), calcium (Ca), phosphorus (P) and alkaline phosphatase (ALP) levels were measured in 70 mothers (study group) and their newborns, and in umbilical cord samples. 104 nonpregnant fertile women comprised the control group. Demographic factors such as education and clothing habits of the mother, number of pregnancies and month of delivery were recorded. A serum 25(OH)D level below 11 ng/ml was accepted as severe, 11-25 ng/ml as moderate VDD, and a value over 25 ng/ml as normal. RESULTS: Severe VDD was found in 27% of the mothers, and moderate deficiency in 54.3%. Severe VDD was detected in 64.3% of the neonates, and moderate deficiency in 32.9%. Only 18.6% of the mothers and 2.9% of the neonates had normal vitD levels. In the control group, severe VDD was observed in 26.9%, and moderate deficiency in 45.2%. Only 27.8% of the controls had normal vitD levels. In the control group, the 25(OH)D levels of the women dressed in modern clothes were significantly higher than those of the women wearing traditional clothes. This difference was not observed in the study group because 75% of these 70 mothers wore modern clothes. Mothers giving birth during the summer months and their neonates had significantly higher serum 25(OH)D levels than those of the mothers giving birth during the winter months and their neonates. CONCLUSION: The study has shown that in Turkey VDD is an important problem in women of reproductive age, in mothers and their neonates. The 25(OH)D levels obtained from the cord may serve as a guide in the determination of the high risk groups.

Permanent central diabetes insipidus with complete regression of pituitary stalk enlargement after 4 years of follow-up.

A 14 year-old patient was admitted because of a history of polyuria and polydipsia. A diagnosis of central diabetes insipidus (CDI) accompanied by growth hormone (GH) and gonadotropin deficiency was made. Hypophyseal magnetic resonance imaging (MRI) of the patient demonstrated isolated pituitary stalk enlargement. Although GH deficiency and gonadotropin deficiency were transient, CDI was persistent despite the regression of the pituitary stalk enlargement over the 4 years of follow-up.