Type A insulin resistance syndrome due to a novel heterozygous c.3486_3503del (p.Arg1163_Ala1168del) INSR gene mutation in an adolescent girl and her mother.

Mutations in the insulin receptor (INSR) gene may present with variable clinical phenotypes. We report herein a novel heterozygous INSR mutation in an adolescent girl with type A insulin resistance syndrome and her mother.The index case was a 12-year-old girl without obesity who presented with excessive hair growth, especially in the chest and back area, and hyperpigmentation on the back of the neck (acanthosis nigricans). Acanthosis nigricans was first observed at the age of 11 years. On physical examination, the patient had acanthosis nigricans and hypertrichosis with no acne. Systolic and diastolic blood pressure measurement was within the normal range for age and sex. Laboratory tests revealed fasting hyperglycemia, fasting and postprandial hyperinsulinemia, elevated HbA1c level, and biochemical hyperandrogenemia. Fasting plasma lipids were normal. A diagnosis of type A insulin resistance syndrome was considered, and INSR gene mutation analysis was performed. Next generation sequence analysis was performed with the use of primers containing exon/exon-intron junctions in the INSR gene, and a novel heterozygous c.3486_3503delGAGAAACTGCATGGTCGC/p.Arg1163_Ala1168del change was detected in exon 19 of the INSR gene. In segregation analysis, the same variant was detected in the patient's mother, who had a milder clinical phenotype.We reported a novel, heterozygous, p.Arg1163_Ala1168del mutation in exon 19 of the INSR gene in a patient with type A insulin resistance syndrome, expanding the mutation database. The same mutation was associated with variable phenotypical severity in two subjects within the same family.

Type A insulin resistance syndrome due to a novel heterozygous c.3486_3503del (p. Arg1163_Ala1168del) INSR gene mutation in an adolescent girl and her mother

SUMMARY Mutations in the insulin receptor (INSR) gene may present with variable clinical phenotypes. We report herein a novel heterozygous INSR mutation in an adolescent girl with type A insulin resistance syndrome and her mother. The index case was a 12-year-old girl without obesity who presented with excessive hair growth, especially in the chest and back area, and hyperpigmentation on the back of the neck (acanthosis nigricans). Acanthosis nigricans was first observed at the age of 11 years. On physical examination, the patient had acanthosis nigricans and hypertrichosis with no acne. Systolic and diastolic blood pressure measurement was within the normal range for age and sex. Laboratory tests revealed fasting hyperglycemia, fasting and postprandial hyperinsulinemia, elevated HbA1c level, and biochemical hyperandrogenemia. Fasting plasma lipids were normal. A diagnosis of type A insulin resistance syndrome was considered, and INSR gene mutation analysis was performed. Next-generation sequence analysis was performed with the use of primers containing exon/exon-intron junctions in the INSR gene, and a novel heterozygous c.3486_3503delGAGAAACTGCATGGTCGC/p. Arg1163_Ala1168del change was detected in exon 19 of the INSR gene. In segregation analysis, the same variant was detected in the patient's mother, who had a milder clinical phenotype. We reported a novel, heterozygous, p. Arg1163_Ala1168del mutation in exon 19 of the INSR gene in a patient with type A insulin resistance syndrome, expanding the mutation database. The same mutation was associated with variable phenotypical severity in two subjects within the same family.

Cinacalcet therapy in a child with novel homozygous CASR p.Glu353Lys mutation causing familial hypocalciuric hypercalcemia type 1: case report and review of the literature.

BACKGROUND: Familial hypocalciuric hypercalcemia (FHH) is one of the conditions that should be considered in the differential diagnosis of hypercalcemia and normo-hypophosphatemia in childhood. Heterozygous Calcium-sensing receptor (CASR) gene mutations cause FHH, and homozygous CASR gene mutations cause neonatal severe primary hyperparathyroidism (NSHPT). Cinacalcet is an allosteric modulator of Calciumsensing receptor (CaSR), and has been used in the treatment of these clinical entities in recent years. CASE: A 26-month-old boy was examined for a recurrent rash. During the evaluation, hypercalcemia (13.3 mg/ dL), hypophosphatemia (2.3 mg/dL) and inappropriately normal PTH level (67 pg/mL) were observed. Neck and renal ultrasonography were normal. The parathyroid scintigraphy was unremarkable. The patient`s family members were also evaluated, and hypocalciuria (fractional excretion of calcium were 0.01%, 0.04% on two separate tests) was detected concurrently with the patient`s hypercalcemia. The mother`s serum calcium was 10.2 mg/dL, the father`s was 10.6 mg/dL, and the brother`s was 12.8 mg/dL. CASR gene sequencing showed a novel homozygous mutation in exon 4 (c.1057G > A), which had generated a substitution of the amino acid glutamate to lysine at codon 353 (p.Glu353Lys). This mutation was homozygous in the children and heterozygous in the parents. Fluid hydration, furosemide, oral phosphorus, prednisolone, pamidronate and cinacalcet treatments were used in the management of hypercalcemia of the proband. A longer and more effective control was achieved with cinacalcet treatment. CONCLUSIONS: FHH can be seen in heterozygous as well as homozygous CASR gene mutations. Different clinical findings may occur in different individuals from the same family. Cinacalcet therapy can be used successfully in the treatment of individuals with FHH.

Body mass index evolution and ovarian function in adolescent girls who received GnRH agonist treatment for central precocious puberty or early and fast puberty.

OBJECTIVES: Gonadotropin-releasing hormone agonist (GnRHa) has been used for central precocious puberty (CPP) or early and fast puberty. It was aimed to assess changes in body mass index (BMI), polycystic ovary syndrome (PCOS) frequency, and anti-Müllerian hormone (AMH) in girls who had been treated with GnRHa. METHODS: Fifty-eight adolescent girls treated with GnRHa for CPP or early and fast puberty (3.75 mg/28 days), between 2011 and 2015, were re-evaluated in 2020-2022 at least 2 years after menstruation. Hormonal analyses were compared with 51 healthy adolescents. RESULTS: In the GnRHa-treated group, a statistically significant increase was observed when the BMI standard deviation score (SDS) at the beginning of the treatment was compared with the BMI SDS at the end of the treatment (p=0.038). A statistically significant decrease was observed when the BMI SDS at the end of the treatment was compared with the BMI SDS in late adolescence (p=0.012). When the BMI SDS at the beginning of the treatment was compared with the BMI SDS in late adolescence, it was observed that there was no statistically significant difference (p=0.196). Of the 58 girls in the GnRHa-treated group, 8 (14 %) had PCOS. Serum AMH levels did not differ between the GnRHa-treated and the control group. CONCLUSIONS: GnRHa treatment causes no adverse effect on BMI, at least in late adolescence. Girls treated with GnRHa were not found to be prone to developing PCOS. AMH levels were similar in the GnRHa-treated group as in the control group.

Depression, anxiety, eating problems, and diabulimia risk in adolescents with type 1 diabetes: a case-control study.

OBJECTIVES: Type 1 diabetes (T1D) causes psychological distress, negatively impacting normal childhood activities. Depression, anxiety disorders, and eating problems are commonly observed in this population. METHODS: The study population consisted of 40 adolescents (22 females and 18 males) who had been diagnosed with T1D and 41 healthy adolescents (21 females and 20 males). The aim of this study was to compare adolescents with T1D to healthy controls in terms of depression, anxiety, and eating problems and subsequently examine the T1D group in relation to the risk of diabetes-specific eating disorders. Eating Attitudes Test (EAT-40), Revised Children's Anxiety and Depression Scale (RCADS), and Diabetes Eating Problem Survey - Revised (DEPS-R) scales were used to compare the case and control groups. RESULTS: The case group exhibited significantly higher scores in EAT-40 total score, RCADS parent form major depressive disorder (MDD), social anxiety disorder (SAD), generalized anxiety disorder (GAD), panic disorder (PD), total anxiety score, total scale scores, RCADS child form MDD, PD, and total scale scores compared to the control group. Individuals at high risk of diabetes-specific eating disorder within the case group demonstrated significantly higher RCADS (child and parent form) MDD scores and RCADS parent form separation anxiety (SA) and total scale scores. Binary logistic regression analysis revealed that the RCADS parent form total scale score could predict DEPS-R. CONCLUSIONS: Routine screening of children and adolescents diagnosed with T1D for depression, anxiety, and eating disorder risk may facilitate early detection of possible psychopathologies, allowing for early intervention to address factors that may disrupt treatment adherence. Further longitudinal studies with larger samples are needed to investigate psychopathologies, particularly eating disorders, in children and adolescents with T1D.

The Effectiveness of Thyroid Elastography in Evaluating Thyroiditis in Children with Type 1 Diabetes.

OBJECTIVE: Shear wave elastography can detect inflammation and fibrosis in the thyroid tissue. It can be used to evaluate Hashimoto's thyroiditis or in the assessment of thyroid diseases accompanying type 1 diabetes mellitus. Our aim was to examine whether there is a difference between the shear wave elastography scores as kilopascals of individuals with type 1 diabetes mellitus and healthy children, and the relationship between diabetes-related parameters and shear wave elastography scores. MATERIALS AND METHODS: A total of 77 type 1 diabetes mellitus children and 53 healthy controls were compared. Serum thyroid-stimulating hormone, free thyroxine, free tri-iodothyronine, antibodies against thyroid peroxidase and thyroglobulin, average of the last 2 control plasma glycosylated hemoglobin A1c, duration of diabetes and daily insulin dose in diabetic individuals, thyroiditis staging by ultrasound, and shear wave elastography scores were also recorded. RESULTS: In terms of shear wave elastography scores, no significant difference was found between the healthy control group and the group with type 1 diabetes mellitus without Hashimoto's thyroiditis (7.9 ± 2.8 kPa vs. 8.4 ± 3.3 kPa, P = .772). The score of the group with type 1 diabetes mellitus accompanied by Hashimoto's thyroiditis (15.1 ± 6.6 kPa) was found to be higher than the group with type 1 diabetes mellitus without Hashimoto's thyroiditis and the healthy control group (P = .022 and P = .015, respectively). CONCLUSIONS: This is the first study to compare children with type 1 diabetes mellitus and healthy controls in terms of shear wave elastography scores. We found that there was no significant difference between the shear wave elastography scores of children with type 1 diabetes mellitus without Hashimoto's thyroiditis compared to healthy controls.

Comparison of internet usage and internet addiction scores in healthy children and children with type 1 diabetes mellitus.

OBJECTIVES: The Internet, an integral part of modern life, can lead to internet addiction, which negatively affects academic performance, family relationships, and emotional development. This study aimed to evaluate the Internet addiction scores (IAS) during COVID-19 in children with type 1 diabetes mellitus (T1DM) compared with healthy controls. METHODS: Children with T1DM and healthy controls aged 8-18, were evaluated with the Parent-Child Internet Addiction Test (PCIAT20). Internet addiction scores of the participants were assessed. The relationship between diabetes duration, mean HbA1c level and IAS were also examined in children with T1DM. RESULTS: The study included 139 patients with T1DM and 273 controls. The IAS were significantly lower in patients compared with controls (25.28 ± 15.52 vs. 29.69 ± 19.08, p=0.019). There was a weak negative correlation between the duration of diabetes and IAS in children with diabetes (r=-0.21, p=0.021). There was no significant association between IAS and mean HbA1c (r=0.14, p=0.128) or age (r=0.08, p=0.115). Furthermore, there was no statistically significant difference in IAS between children with well-controlled diabetes (n=17) and those with poorly-controlled diabetes (n=122) (IAS: 27.1 ± 17.2; 24.8 ± 15.5, p=0.672, respectively). CONCLUSIONS: Internet addiction scores were lower in patients with T1DM compared with their healthy peers. Unlike previous studies reporting an increase in problematic internet use, the results of the present study did not confirm internet use as a real challenge in front of the diabetes management for the majority of children with T1DM. This result may be attributed to the important role played by families in the management of T1DM.

The Relationship Between Internet Usage Style and Internet Addiction and Food Addiction in Obese Children Compared to Healthy Children.

OBJECTIVE: The frequency of using the internet and social media increases in childhood, which leads to a decrease in physical activity. We aimed to investigate the effects of such technological applications on the internet and food addiction in obese and nonobese children. MATERIALS AND METHODS: A total of 180 obese and 180 nonobese children were included in this study. Turkish version of the Parent-Child Internet Addiction Scale and Dimensional Yale Food Addiction Scale Version 2.0 for Children were applied. RESULTS: The frequency of internet addiction in the sample was 1.7%. The mean internet addiction scores of males were found to be significantly higher than females (34.9 ± 20.6, 26 ± 17.2; P < .001). Children, who used the internet for information and homework had significantly lower internet addiction scores and food addiction scores, respectively (P = .002, P = .009). Watching movies, TV series, or sports events (P < .001, P = .009); following food recipes, campaigns, or advertisements (P = .04, P < .001); and eating snacks in front of the screen (P < .001, P < .001) were found to cause higher internet addiction scores and food addiction scores. It was observed that body mass index showed a positive and significant correlation with internet addiction scores and food addiction scores. CONCLUSIONS: Internet addiction and social media applications were found to be significantly related. Considering the relationship between body mass index and addiction, the effect of internet usage style and internet addiction and food addiction on obesity is striking.

Can thyroid elastography with ultrasound be used to stage children with Hashimoto's thyroiditis?

OBJECTIVES: We aimed to evaluate the stiffness of the thyroid parenchyma with Shear wave elastography (SWE) in children with Hashimoto's thyroiditis (HT) and healthy controls. METHODS: A total of 130 children with HT and 46 healthy controls were included in this study. The clinical and laboratory characteristics of the groups, thyroiditis stages in thyroid ultrasonography, and SWE scores which was obtained as kilopascal (kPa), were analysed. RESULTS: We observed that SWE scores were significantly higher in children with HT compared to healthy controls, and SWE scores increased significantly in HT group, as the thyroiditis stage increased (p<0.001). Median, 1st (Q1) and 3rd (Q3) quartiles of SWE scores were as follows; healthy control: 7.4 kPa (6-10.6), stage 1 HT: 9.6 kPa (7.4-11.2), stage 2 HT: 15.2 kPa (10.8-19.9), stage 3 HT: 17.9 kPa (13.7-25.8), (p<0.001). Children with HT were divided into subgroups according to serum TSH and free T4 levels as euthyroid (103; 79.2% of children), euthyroid but subclinical TSH elevation (7; 5.4% of children), hypothyroidism (11; 8.5% of children) and hyperthyroidism (9; 6.9% of children). The SWE scores were significantly higher in children with hypothyroidism with HT compared to healthy controls 17.9 kPa (13.6-27.5) vs. 7.4 kPa (6-10.6), and in euthyroid children with HT compared to healthy controls 11.5 kPa (9.2-15.6) vs. 7.4 kPa (6-10.6), (p=0.006 and p<0.001, respectively). CONCLUSIONS: The SWE scores increase as the thyroiditis stage increases in children with HT. There was no significant difference in SWE scores between stage 2 and stage 3 thyroiditis.

Factors Affecting Thyroid Elastography in Healthy Children and Patients with Hashimoto's Thyroiditis

Objective: Hashimoto's thyroiditis (HT) is the most common form of thyroiditis in childhood. In addition to thyroid ultrasonography, shear-wave elastography (SWE) can evaluate thyroid parenchyma tissue stiffness, and more detailed findings can be obtained with this method. We aimed to evaluate the relationship between SWE values and clinical, biochemical and hormonal parameters of patients with HT and in healthy individuals. Methods: We compared 46 newly diagnosed HT cases with 46 healthy controls. We examined the effect of all metabolic parameters and thyroid-related markers on SWE values. Results: The mean SWE values in those patients with euthyroid HT were 12.5±5.1 kilopascal (kPa), whereas it was 8.2±2.82 kPa in healthy controls (p<0.001). Although the clinical [age, gender and body mass index (BMI)] and laboratory parameters (such as thyroid function tests, homeostasis model assessment of insulin resistance, insulin-like growth factor-1 values, which we think may affect SWE scores) of those children with HT and the healthy controls were statistically similar (p>0.05), except for their thyroid autoantibodies and thyroglobulin, SWE values and thyroid volume were significantly higher in those individuals with HT (p<0.001). Multiple linear regression analysis was performed to evaluate the direction and degree of the effect of the variables on thyroid elasticity scores. It was observed that age (p=0.002), BMI standard deviation score (SDS) (p=0.04) and anti-thyroid peroxidase (p=0.008) levels were effective on the thyroid elasticity score in the regression model. We detected a SWE cut-off value of 9.68 kPa with 68% sensitivity and 72% specificity, a 70% positive predictive value, and a 69% negative predictive value in thyroid elastography when differentiating between cases with HT and healthy controls. Conclusion: Our results show that no metabolic factor other than BMI SDS has any effect on SWE scores, especially in healthy children. There was a positive correlation between BMI SDS and SWE in healthy children (r=0.353; p=0.02), but not in those patients with HT (r=0.196; p=0.19). Likewise, age is another factor affecting SWE only in healthy children. We do not recommend routine evaluation of any laboratory parameters other than thyroid functions before thyroid elastography.

Ocular findings in central precocious puberty.

PURPOSE: To evaluate ocular findings in central precocious puberty (PP). METHODS: This prospective study included 38 children with PP and 34 healthy control children. All participants were evaluated in terms of refractive error, axial length (AL), and anterior segment parameters, including keratometry (K), corneal volume (CV), anterior chamber depth (ACD), anterior chamber volume (ACV), and iridocorneal angle (ICA). Central macular thickness (CMT), retinal nerve fiber layer (RNFL) thickness and central subfoveal choroidal thickness (ChT) were also analyzed. The correlation of these parameters with Tanner stage was also investigated in the PP group. RESULTS: Compared with the control group, spherical refraction was less hyperopic (P = 0.017) and AL was significantly higher (P = 0.001) in the PP group. Spherical value and AL were significantly associated with the Tanner stage. None of the anterior segment parameters obtained by Pentacam was different in the PP group compared with controls. In PP cases, CMT and RNFL thicknesses in all sectors did not differ from controls. Subfoveal ChT was significantly higher in the PP group, regardless of Tanner stage (P < 0.001). CONCLUSIONS: In our cohort of children with central PP, AL and ChT were higher than in children without PP.

Ocular surface alterations and changes of meibomian glands with meibography in type 1 diabetic children.

PURPOSE: To observe the changes of the ocular surface and meibomian glands by non-contact meibography in patients with type 1 diabetic children. METHODS: A total of forty-three patients with type 1 diabetic children and 43 age-matched healthy subjects were included in the study. The ocular surface disease index (OSDI) questionnaire, invasive tear film break-up time (TF-BUT), fluorescein staining of the ocular surface and Schirmer II test were performed for all participants. Ocular surface and lid margins were evaluated by slit lamp. Non-contact meibography was performed with the Phoenix-Meibography module in Sirius corneal topographic device. RESULTS: Both groups consisted of 25 (58.1%) female and 18 (41.9%) male children and the mean age was 14.4 ± 2.5 years. In the T1DM group, the mean disease duration was 6.8 ± 3.1 years. The mean TF-BUT (p = 0.002) and Schirmer II test (p = 0.007) measurements were lower in the diabetic group than those of in controls. Total eyelid score (p = 0.027) and meibomian gland (MG) secretion score (p = 0.007) were significantly high in diabetic children. MG area loss was also significantly high in both lower and upper eyelid (p < 0.001). In morphological analyses of meibomian glands thinning, shortening and presence of ghost areas (p = 0.05, p = 0.027 and p = 0.000, respectively) were more common in the diabetic group. There was no correlation between both lower and upper eyelid meiboscores and disease duration (p = 0.51 and p = 0.61), BMI (p = 0.08 and p = 0.51), serum HbA1c level (p = 0.06 and p = 0.49) and IGF-1 SDS (p = 0.38 and p = 0.68). CONCLUSION: The study revealed that the MG loss area increases and morphological alterations of meibomian glands occur in type 1 diabetic children. Disease duration and metabolic control of diabetes do not affect meibography measurements. CLINICAL TRIALS REGISTRATION: The study was organized in accordance with the ethical standards settled by the Ethics Committee of Faculty of Medicine, Afyonkarahisar Health Sciences University. TRIAL REGISTRATION NUMBER: 2011-KAEK-2, 2021/106. TRIAL REGISTRATION DATE: 02.05.2021.

Evaluation of early retinal vascular changes by optical coherence tomography angiography in children with type 1 diabetes mellitus without diabetic retinopathy.

PURPOSE: To evaluate macular and peripapillary vascular changes by optical coherence tomography angiography (OCTA) in children with type 1 diabetes mellitus (T1DM) without diabetic retinopathy (DR). METHODS: This study included 46 patients with T1DM and 46 age-sex matched healthy subjects. All participants were evaluated in terms of macular and optic disk parameters by using AngioVue. Foveal avascular zone (FAZ) area, macular and optic disk vessel density (VD) were analyzed. The correlation of these parameters with metabolic factors such as disease duration, mean hemoglobin A1c (HbA1c), insulin-like growth factor 1 (IGF-1) standard deviation score (SDS), homocysteine (Hcy) level, body mass index (BMI) SDS and daily insulin dose was also investigated in T1DM group. RESULTS: No significant difference was found in FAZ area and optic disk radial peripapillary capillary (RPC) VD comparing diabetic and control groups. In all macular regions, VD was significantly lower in T1DM versus control group both in superficial capillary plexus (SCP) and deep capillary plexus (DCP). None of the metabolic parameters was correlated with FAZ area and optic disk RPC-VD. Vascular density in SCP was negatively correlated with mean HbA1c and positively correlated with IGF-1 SDS. Homocysteine level was negatively correlated with DCP-VD in all areas. CONCLUSION: In children with T1DM without clinically apparent DR, VD in SCP and DCP was decreased and OCTA is a valuable imaging technique for detecting early vascular changes. The metabolic parameters such as mean HbA1c, IGF-1 SDS and Hcy affect the macular VD in diabetic children. TRIAL REGISTRATION NUMBER: 2011-KAEK-2, 2021/4, Trial registration date: 02.04.2021.

Optic Nerve Parameters in Obese Children as Measured by Spectral Domain Optical Coherence Tomography.

PURPOSE: To investigate whether an association exists between obesity and optic nerve parameters. METHODS: This was a prospective comparative study including 125 eyes of 63 obese and 122 eyes of 62 healthy pediatric subjects. Optic nerve measurements were performed using the Cirrus spectral domain optical coherence tomograph (SD-OCT). RESULTS: The disc area, cup volume, mean and vertical C/D ratio, inferior and temporal RNFL thickness values were significantly higher in the control group than the obese group; however, age, sex, mean, superior and nasal RNFL thickness and rim area measurements were not statistically significantly different between the two groups. Age was significantly negatively correlated with temporal RNFL thickness in the obese group. Girls had significantly higher rim area, mean and superior RNFL thickness, and lower cup volume and vertical C/D ratio than boys in the obese group. CONCLUSION: These results could be helpful in the diagnosis and follow-up of obese children.