The Case with Short Stature and Intellectual Disability Caused by a Novel 2q12 Duplication.

Copy number variation (CNV) is a kind of malfunction of DNA polymerase to produce extra genetic material which leads to more number of repeats in genes. The CNVs have been associated with different clinical phenotypes such as learning disabilities, short stature, and intellectual disability. The chromosomal microarray analysis is an effective diagnostic method for identifying new CNVs and understanding their clinical effects. In this case report, a variation that has not been reported previously in the literature is presented. This case report will contribute to increasing the knowledge. The CNV (arr [hg19] 2q12.1q12.3 (103,368,824-107,946,062) x3) detected in the index case was also detected in her father and male sibling. Key Words: DNA, Copy number variation, Chromosomal duplication, Intellectual disabilities.

Catecholamine-induced Myocarditis in a Child with Pheochromocytoma

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors. The clinical presentation of pediatric PPGLs is highly variable. In cases with pheochromocytoma (PCC), excess catecholamine may stimulate myocytes and cause structural changes, leading to life-threatening complications ranging from stress cardiomyopathy (CM) to dilated CM. Herein, we report the case of catecholamine-induced myocarditis in a child with asymptomatic PCC. A 12-year-and-2-month-old male patient with a known diagnosis of type-1 neurofibromatosis was brought to the emergency department due to palpitations and vomiting. On physical examination, arterial blood pressure was 113/81 mmHg, pulse was 125/min, and body temperature was 36.5 °C. Laboratory tests showed a leucocyte count of 12.8x103 µL/L and a serum C-reactive protein level of 1.1 mg/dL (Normal range: 0-0.5). Thyroid function tests were normal, while cardiac enzymes were elevated. Electrocardiogram revealed no pathological findings other than sinus tachycardia. The patient was diagnosed with and treated for myocarditis as echocardiography revealed a left ventricular ejection fraction of 48%. Viral and bacterial agents that may cause myocarditis were excluded via serological tests and blood cultures. Blood pressure, normal at the time of admission, was elevated (140/90 mmHg) on the 5th day of hospitalization. Magnetic resonance imaging revealed a 41x46x45 mm solid adrenal mass. The diagnosis of PCC was confirmed by elevated urinary and plasma metanephrines. The patient underwent surgery. Histopathology of the excised mass was compatible with PCC. It should be kept in mind that, even if there are no signs and symptoms of catecholamine elevation, CM may be the first sign of PCC.

The Significance of Thiol/Disulfide Homeostasis and Ischemia-modified Albumin Levels in Assessing Oxidative Stress in Obese Children and Adolescents

Objective: There is an association between obesity and several inflammatory and oxidative markers in children. In this study, we analyzed thiol/disulfide homeostasis and serum ischemia-modified albumin (IMA) levels for the first time in order to clarify and determine the oxidant/antioxidant balance in metabolically healthy and unhealthy children. Methods: This study included obese children and healthy volunteers between 4-18 years of age. The obese patients were divided into two groups: metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO). Biochemical parameters including thiol/disulfide homeostasis, and IMA concentrations were analyzed. Results: There were 301 recruits of whom 168 (55.8%) were females. The obese children numbered 196 (MHO n=58 and MUO n=138) and healthy controls numbered 105. No statistically significant difference could be found in ages and genders of the patients among all groups (p>0.05, for all). Native thiol (SH), total thiol (SH+SS), and native thiol/total thiol (SH/SH+SS) ratio were statistically significantly lower in the MUO group than the control group (p<0.001, p=0.005, and p=0.005; respectively). Disulfide (SS), disulfide/native thiol (SS/SH), disulfide/total thiol (SS/SH+SS) and IMA levels were statistically significantly higher in the MUO group than the control group (p=0.002, p<0.001, p<0.001, and p=0.001, respectively). Conclusion: Chronic inflammation due to oxidative stress induced by impaired metabolic parameters in MUO children caused impairment in thiol redox homeostasis. Our data suggested that the degree of oxidant imbalance in obese children worsened as obesity and metabolic abnormalities increased. It is hypothesized that thiol/disulfide homeostasis and high serum IMA levels may be reliable indicators of oxidant-antioxidant status in MUO children.

The Effects of Risk Behaviors and Orthorexic Behavior on Glycemic Control in Adolescents with Type 1 Diabetes

Objective: Adolescents with chronic disease are as likely to exhibit risk-taking behavior as their peers. The aim was to investigate the risk behaviors of adolescents with type 1 diabetes (T1D) and the effect of orthorexic eating behaviors (OEB) on glycemic control (GC). Methods: This cross-sectional study was conducted with 107 adolescents with T1D, aged between 13-18 years and attending high school. The Risk Behavior Scale (RBS) and Orthorexic Behavior Scale (ORTO-11) were administered. A high RBS score indicates risky behavior; a low ORTO-11 score suggests a tendency to OEB. Participants hemoglobin A1c (HbA1c) status was used to assess GC: optimal GC (HbA1c ≤7%); or poor GC (HbA1c >7%). Results: Among females, those with poor GC had significantly lower (p=0.031) ORTO-11 scores than those with optimal GC, which was not the case in males. A significant correlation (r=0.358, p<0.001) was found between HbA1c and total RBS, eating habits subscale, and suicidal tendency subscale scores. Participants with poor GC had significantly higher eating habits subscale, alcohol use, and tobacco use subscale scores (p<0.05). Among females, total RBS and suicidal tendency subscale score was found to be significantly higher in those with poor GC; among males, alcohol subscale score was found to be significantly higher in those with poor GC. Conclusion: This study is the first to show the effect of the tendency for OEB on GC among female adolescents with T1D. The study showed that, along with inappropriate eating behaviors, adolescents with T1D should also be assessed for other risk behaviors to help achieve optimal GC.

A Duplication Upstream of SOX9 Associated with SRY Negative 46,XX Ovotesticular Disorder of Sex Development: A Case Report

The 46,XX ovotesticular disorder of sex development (DSD) is rarely observed in humans. This disorder is generally described as ambiguous genitalia with the presence of ovarian and testicular tissues in different gonads or in the same gonad. Almost no subjects with 46,XX ovotesticular DSD have sex-determining region of the Y chromosome (SRY) gene. It is known that excessive expression of SRY-related high mobility group box 9 (SOX9) is the cause of SRY-negative 46,XX ovotesticular DSD in the absence of SRY. Here, we analyzed our SRY-negative case with 46,XX ovotesticular DSD. In an array comparative genomic hybridization study using a peripheral blood sample from the patient, a duplication of 1114 kb (Hg19 coordinates: chr17:69006280-70120619) in the region of 17q24.3 containing SOX9 was detected. This is the first case reported from Turkey, exhibiting SOX9 duplication in SRY-negative 46,XX ovotesticular DSD.

Evaluation of Renal Function in Obese Children and Adolescents Using Serum Cystatin C Levels, Estimated Glomerular Filtration Rate Formulae and Proteinuria: Which is most Useful?

Objective: There is a growing interest in the relationship between obesity and renal damage. The effect of obesity on renal function in children and adolescents has not been adequately investigated. In addition, there is no complete consensus on the reliability of various renal function parameters. The primary goal of this study was to evaluate renal function in obese children and adolescents using glomerular filtration rate (GFR), cystatin C, and creatinine (Cr)-derived formulas. We also compared classical GFR measurement methods with methods based on bioimpedance analysis-derived body cell mass (BCM). Methods: We enrolled 108 obese and 46 healthy subjects aged 6-18 years. Serum cystatin C, serum Cr, 24-hour proteinuria, Cr clearance, and GFR were evaluated in both groups. Estimated GFR was measured with Cr-based, cystatin C-based, combined (cystatin C and Cr) and BCM-based formulae. Both actual and fat-free mass body surface areas (BSA) were used when required. Metabolic parameters (blood glucose, insulin, and lipids) were analyzed in the obese subjects. International Diabetes Federation criteria were used to identify metabolic syndrome (MetS). Results: We did not detect statistically significant differences between the obese and control groups for mean Cr (p=0.658) and mean cystatin C (p=0.126). Mean cystatin C levels of MetS patients were significantly higher than those of non-MetS obese participants (p<0.001). Cr-based GFR measurements, BCM-based measurements and a combined Cr and cystatin C measurement showed a statistically significant increase in the GFR of obese subjects compared to controls (p=0.002 and p<0.001). This increase was negatively correlated with duration of obesity. Estimations based on actual or fat-free mass BSA did not differ either. Only the Filler equation showed a statistically significant decrease in eGFR in MetS patients. There were no statistically significant differences between the obese and control groups for proteinuria (p=0.994) and fat-free mass proteinuria (p=0.476). Conclusion: We conclude that cystatin C could be used as an earlier biomarker than Cr in the detection of impaired renal function in obese children, especially those with MetS. Cr-based formulae reveal hyperfiltration as the first change in renal function. Decreasing eGFR seen in MetS patients with cystatin C-based formulae, but not Cr-based formulae, may represent the early stages of renal damage. Using fat-free mass or BCM for eGFR formulae in obese children seems to provide no additional information.

Evaluation of Efficacy of Long-term Growth Hormone Therapy in Patients with Hypochondroplasia

Hypochondroplasia is a cause of disproportionate short stature and characterized by minor clinical manifestations. The aim of this study was to evaluate the efficacy of long-term growth hormone (GH) therapy in hypochondroplastic cases with inadequate response to GH stimulation tests. In this study, six patients who had a height standard deviation score of -3.43 before the treatment and a mean age of 7.42 years and who had received GH treatment at a dose of 0.2 mg/kg/week for a mean period of 4.45 years were evaluated. A good response was found in the first year of treatment, but this increase was not found to be sufficient for the patients to achieve an adequate final height.

The Diagnostic Value of Anti-Müllerian Hormone in Early Post Menarche Adolescent Girls with Polycystic Ovarian Syndrome.

STUDY OBJECTIVE: Polycystic ovarian syndrome (PCOS) is a common endocrine disorder characterized by hyperandrogenism and chronic anovulation, which affects 5%-10% of reproductive-age women. Diagnosis of adult patients with PCOS is made easily with clinical and laboratory methods and the anti-Müllerian hormone (AMH) level are accepted as a good indicator. However, there is still no complete consensus on the diagnosis of PCOS in adolescents. DESIGN AND SETTING: Prospective cohort study, December 2013 to November 2014. PARTICIPANTS: The study was conducted on adolescent girls with oligomenorrhea, with at least 2 years since menarche. The study group consisted of adolescent girls with complete PCOS and incomplete PCOS. A control group was formed of healthy adolescent girls. Complete PCOS was diagnosed according to the Rotterdam criteria, as the presence of all the following characteristics: oligomenorrhea, hyperandrogenism, and polycystic ovarian morphology on ultrasound image. Incomplete PCOS was accepted as "oligomenorrhea and polycystic ovarian morphology," or "oligomenorrhea and hyperandrogenism." INTERVENTIONS AND MAIN OUTCOME MEASURES: All patients underwent a physical examination and the anthropometric assessments, insulin resistance, and acanthosis nigricans were recorded. It was also noted whether or not the patient had an acne score. The Ferriman-Gallwey score was applied to evaluate hirsutism. RESULTS: The results of this study showed that no statistically significant difference was found between the PCOS and incomplete PCOS groups and the control group with respect to AMH levels. CONCLUSION: The use of adult-specific diagnostic methods in adolescence might result in an incomplete diagnosis and inadequate treatment plan. Although the serum AMH level clearly facilitates the diagnosis of PCOS, the use of the AMH level in adolescence in PCOS diagnosis is still controversial and further studies are needed.

Response to Anastrozole Treatment in a Case with Peutz-Jeghers Syndrome and a Large Cell Calcifying Sertoli Cell Tumor.

Peutz-Jeghers syndrome (PJS) is inherited as an autosomal dominant trait characterized by multiple gastrointestinal hamartomatous polyps, mucocutaneous pigmentation, and an increased risk of neoplasm. Large-cell calcifying Sertoli cell tumor (LCCSCT) is a kind of sex cord-stromal tumor which may co-exist with PJS and which is characterized radiologically by calcification foci within the testes. Surgical treatment options for this tumor range from testis-preserving surgery to radical orchiectomy. Not with standing this invasive approach, recently, there are some case reports demonstrating the efficacy of aromatase inhibitors in avoiding orchiectomy and its associated complications. In this paper, we have presented a LCCSCT case diagnosed in a boy with PJS and his response to anastrozole treatment.

Acute reversible cardiomyopathy and heart failure in a child with acute adrenal crisis.

Acute adrenal crisis is a life-threatening disorder. Cardiovascular complications of the condition are usually limited to hypovolaemic hypotension and shock. An acute reversible cardiomyopathy and heart failure in association with acute adrenal crisis is rarely reported, particularly in children. A 6-year-old girl with adrenal crisis which was complicated by acute reversible cardiomyopathy is reported. Inotropic and ventilatory support in addition to intravenous hydrocortisone and furosemide therapy were required to achieve cardiovascular stability. The cardiomyopathy resolved over 5 days and she was discharged with normal cardiac and intellectual functions. Cardiomyopathy should be considered in patients with acute adrenal crisis demonstrating any symptoms or signs of heart failure.

Delayed Diagnosis of a 17-Hydroxylase/17,20-Lyase Deficient Patient Presenting as a 46,XY Female: A Low Normal Potassium Level Can Be an Alerting Diagnostic Sign.

17-hydroxylase/17,20-lyase deficiency (17-OHD), a rare autosomal recessive defect in adrenal and gonadal steroidogenesis, causes absence of secondary sexual characteristics and frequently associated with hypertension and hypokalemia. Here, we report a 46,XY case who had normal potassium levels and no hypertension. Our patient was a 2.5-year-old female admitted with female external genitalia and inguinal swelling. Pathology of biopsy revealed that this gonad was a testis. Karyotype was 46,XY. She had no hypertension and no hypokalemia. Serum luteinizing hormone and follicle-stimulating hormone levels were high; testosterone, dehydroepiandrosterone sulfate, and androstenedione were low. Human chorionic gonadotrophin stimulation resulted in partial testosterone response. She was initially diagnosed as partial gonadal dysgenesis or testosterone synthesis defect. In her follow-up after noticing low normal potassium levels at age 9 years, progesterone level was measured and detected to be high. Adrenocorticotropic hormone-stimulated steroid measurements were consistent with 17-OHD. Genetic analyses revealed p. R96Q (c.287G>A) homozygous mutation on exon 1 of CYP17A1 gene. In conclusion, evaluation of 46,XY disorder of sex development patients must include serum potassium levels, and near low levels of potassium levels should also suggest 17-OHD despite absence of hypertension or remarkable hypokalemia. Testosterone synthesis defects must be excluded before establishing the diagnosis of partial gonadal dysgenesis.

Coexistence of Mosaic Uniparental Isodisomy and a KCNJ11 Mutation Presenting as Diffuse Congenital Hyperinsulinism and Hemihypertrophy.

BACKGROUND: Isolated hyperinsulinaemic hypoglycaemia (HH) commonly results from recessively inherited mutations in the ABCC8 and KCNJ11 genes that are located on chromosome 11p15.1. More rarely, HH can feature in patients with Beckwith-Wiedemann syndrome (BWS), a congenital overgrowth disorder, resulting from defects at a differentially methylated region telomeric to the K-ATP channel genes at chromosome 11p15.5. SUBJECT: We undertook genetic testing in a patient with diazoxide-unresponsive HH diagnosed at birth. Physical examination later revealed hemihypertrophy of the right arm, a feature of BWS. RESULTS: We identified a novel mosaic, paternally-inherited KCNJ11 mutation(s) in the patient. Further analysis confirmed uniparental disomy (UPD) of chromosome 11, which extended across the KCNJ11 gene at 11p15.1 and the BWS locus at 11p15.5. CONCLUSION: These results highlight the importance of considering UPD as a mechanism of disease in patients with HH and a paternally inherited K-ATP channel mutation, especially when additional syndromic features are present.

Gonadotropin-Releasing Hormone Analogue Treatment in Females with Moderately Early Puberty: No Effect on Final Height.

OBJECTIVE: To investigate the effects of treatment with gonadotropin-releasing hormone analog (GnRHa) on final height in girls who experienced moderately early puberty with symptoms beginning at 7-8.5 years of age. METHODS: Female cases diagnosed with moderately early puberty which had started between ages 7 to 8.5 years were included in the study. In the treatment groups, all cases with a bone age ≤10.5 years constituted group 1 (n=18) and those with a bone age >10.5 years constituted group 2 (n=23). The 8 patients for which treatment approval could not be obtained constituted group 3. The 49 cases in all three groups were observed until they reached their final height. RESULTS: Target height, target height standard deviation score (SDS), final height, and final height SDS values were similar in all 3 groups. Final height showed a significant positive correlation with target height (p=0.000, r=0.54) and height at diagnosis (p=0.003, r=0.467) in all groups. Linear regression analysis revealed that a 1 cm longer height at diagnosis increased the final height 0.213 fold, and a 1 cm longer target height at diagnosis increased the final height 0.459 fold. CONCLUSION: We found that GnRHa did not make a positive contribution to final height in cases of moderately early puberty.

A Deep Intronic HADH Splicing Mutation (c.636+471G>T) in a Congenital Hyperinsulinemic Hypoglycemia Case: Long Term Clinical Course.

Unlike other congenital fatty acid oxidation defects, short-chain L-3-hydroxyacyl-CoA (SCHAD, HADH) deficiency is characterised by hypoglycemia with hyperinsulinism in the neonatal or infancy periods. The long-term and detailed clinical progression of the disease is largely unknown with almost 40 patients reported and only a few patients described clinically. We present clinical and laboratory findings together with the long-term clinical course of a case with a deep intronic HADH splicing mutation (c.636+471G>T) causing neonatal-onset hyperinsulinemic hypoglycemia with mild progression.

Diagnostic characteristics and metabolic risk factors of cases with polycystic ovary syndrome during adolescence.

STUDY OBJECTIVE: Polycystic ovary syndrome (PCOS) is a disorder without definite consensus on its diagnosis and management during adolescence. According to Amsterdam-2012 consensus, as physiological characteristics of adolescence may overlap with PCOS signs, it has been indicated that all Rotterdam criteria should be met. In this present study, characteristics of adolescents with different phenotypes who were diagnosed with PCOS were evaluated; and presence of differences for metabolic risk factors between phenotypes were investigated. DESIGN: The study was performed on adolescent females. According to phenotypic application models, individuals with all Rotterdam diagnostic criteria [hyperandrogenism (HA), polycystic ovarian morphology (PCOM), and chronic anovulation (CA) on the ultrasonography] were in Group 1 (n = 26); with HA and CA were in Group 2 (n = 10); with HA and PCOM were in Group 3 (n = 7); and with CA and PCOM were in Group 4 (n = 10). RESULTS: The most common application complaint (87%) among 53 cases enrolled in the study was menstrual irregularities, and 57% of cases were not obese. When PCOS was evaluated according to phenotypes, it was realized that cases that meet all 3 diagnostic Rotterdam criteria according to the current recommendation in adolescents. (Group 1) was the most common phenotype. Hyperandrogenism was associated with more metabolic abnormalities. CONCLUSION: The close monitoring of adolescents, who have 2 diagnostic criteria is advisable among PCOS phenotypes. Potentially Groups 2 and 3 which have hyperandrogenism, in particular should warrant closer follow-up although they do not meet current diagnostic criteria for adolescents.

Clinical review of 95 patients with 46,XX disorders of sex development based on the new Chicago classification.

STUDY OBJECTIVE: The aim of our study was to determine the etiologic distribution of 46,XX disorder of sexual development (DSD) according to the new DSD classification system and to evaluate the clinical features of this DSD subgroup in our patient cohort. PARTICIPANTS: The evaluation criteria and clinical findings of 95 46,XX patients were described by clinical presentation, gonadal morphology, genital anatomy, associated dysmorphic features, presence during prenatal period with/without postnatal virilization, hormonal characteristics, and presence or absence of steroidogenic defects among 319 patients with DSD. RESULTS: Types and ratios of each presentation of our 95 patients with 46,XX DSD were as follows: 82 had androgen excess (86.3%): (74 had classical congenital adrenal hyperplasia, 2 had CAH variant possibility of P450-oxidoreductase gene defect), 6 had disorders of ovarian development (6.3%): (1 patient had gonadal dysgenesis with virilization at birth with bilateral streak gonad, 4 patients had complete gonadal dysgenesis, and 1 patient had ovotesticular DSD) and 7 had other 46,XX DSD. Two sisters, who had 46,XX complete gonadal dysgenesis,were diagnosed with Perrault Syndrome with ovarian failure due to streak gonads and associated with sensorineural deafness. CONCLUSION: 46,XX DSD are usually derived from intrauterine virilization and CAH is the most common cause of 46,XX DSD due to fetal androgen exposure.

Three cases of Wolfram syndrome with different clinical aspects.

BACKGROUND: Wolfram syndrome is an autosomal recessive disorder caused by mutations in the WFS1 gene. Clinical heterogeneity has been reported both within and between families with WFS1 mutations. SUBJECTS: The first case was diagnosed with insulin-dependent diabetes mellitus with positive for pancreatic autoantibodies and had a ketoacidotic attack in the follow-up period. The second case presented initially with optic atrophy and was diagnosed with behavioral and psychiatric problems at an early age. The third case had early onset insulin-dependent diabetes with multiple anomalies and congenital hypothyroidism. Many of these features have not been reported previously in patients with Wolfram syndrome. In all three patients homozygous mutations in WFS1 were identified. CONCLUSION: Wolfram syndrome is a disease where the characteristic features may present at different times. A diagnosis of Wolfram syndrome should therefore be considered even in the absence of the full spectrum of clinical features.

The Effect of Recombinant Growth Hormone Treatment in Children with Idiopathic Short Stature and Low Insulin-Like Growth Factor-1 Levels.

OBJECTIVE: Idiopathic short stature (ISS) constitutes a heterogeneous group of short stature which is not associated with an endocrine or other identifiable cause. Some ISS patients may have varying degrees of insulin-like growth factor-1 (IGF-1) deficiency. Recombinant growth hormone (rGH) treatment has been used by some authors with variable results. Reports on long-term rGH treatment are limited. METHODS: In this study, 21 slowly growing, non-GH-deficient ISS children who received rGH treatment for 3.62±0.92 years were evaluated at the end of a 5.42±1.67-year follow-up period. The study group included patients with low IGF-1 levels who also responded well to an IGF generation test. The patients were divided into two groups as good responders [height increment >1 standard deviation (SD)] and poor responders (height increment <1 SD) at the end of the follow-up period. RESULTS: The height of the patients improved from -3.16±0.46 SD score (SDS) to -1.9±0.66 SDS. At the end of the follow-up period, mean height SDS was -1.72. Eleven of the patients showed a good response to treatment. Clinical parameters were essentially similar in the good responders and the poor responders groups. A female preponderance was noted in the good responders group. CONCLUSION: rGH treatment can safely be used in ISS children. Long-term GH treatment will ameliorate the height deficit and almost 40% of patients may reach their target height.