A novel variant in LCHGR gene in 3 siblings with type 1 Leydig cell hypoplasia.

INTRODUCTION: Leydig cell hypoplasia (LCH) is an autosomal recessive disease that causes 46, XY sex development disorder. The patients with LCH are usually in the female phenotype and are presented with the complaints of no breast development and primary amenorrhea. In this article, the cases of three siblings who presented with primary amenorrhea and who had LCH were presented. CASE: A 16-year-old patient with female phenotype is presented with primary amenorrhea. Breast development was at Tanner stage 1, the external genitalia were completely in female phenotype. The karyotype was determined as 46, XY. The hormonal analyses revealed that the testosterone synthesis was insufficient despite the high level of luteinizing hormone (LH). Cortisol, ACTH, 17-Hydroxyprogesterone, and AMH levels were normal. LCH diagnosis was considered in the patient with elevated LH and no testosterone synthesis. A new mutation of homozygous c.161 + 4A > G was detected in LHCGR gene. The same mutation was detected in the patient's two siblings with female phenotype and 46, XY karyotype. CONCLUSION: In patients presenting with primary amenorrhea and karyotype 46, XY, there is no testosterone synthesis and if there is LH elevation, LCH should be considered. We found a novel variant in the LHCGR gene in three siblings with karyotype 46, XY and female phenotype.

A rare cause of delayed puberty in two cases with 46,XX and 46,XY karyotype: 17 α-hydroxylase deficiency due to a novel variant in CYP17A1 gene.

Aims: 17α-hydroxylase deficiency is a rare form of congenital adrenal hyperplasia (CAH) which is inherited autosomal recessive. It occurs result of a mutations in gene cytochrome (CYP)17A1, which encodes both 17α-hydroxylase and 17,20-lyase enzymes. The main clinical findings of the disease are delayed puberty, primary amenorrhea in females, and disorders of sex development (DSD) in males. Also, hypertension and hypokalemia can be seen in both sexes. In this paper, we describe the clinical and genetic changes of two patients with 46,XY and 46,XX karyotypes from two different families who were diagnosed with complete 17α-hydroxylase enzyme deficiency.Methods: In this study various methods including clinical, hormonal, radiological and genetic analyzes were used. Blood samples were obtained for genetic tests. Genomic DNA was extracted from peripheral blood leukocytes, and coding sequence abnormalities of the CYP17 gene were assessed by polymerase chain reaction and direct sequencing analysis.Results: 17α-hydroxylase deficiency was diagnosed in 2 patients with 46,XX and 46,XY karyotype who presented with hypertension and delayed puberty. The pQ80 * (c.238C > T) mutation detected in both cases was evaluated as a novel variant.

Evaluation of QT dispersion and Tp-e interval in children with subclinical hypothyroidism.

BACKGROUND: Studies on adults have shown increased dispersion of QT and corrected QT (QTc), peak-to-end interval of the T wave (Tp-e), Tp-e/QT ratio, and Tp-e/QTc ratio in subclinical hypothyroidism (SH), but there have been no pediatric studies. MATERIALS AND METHODS: A total of 40 SH patients were compared with 40 healthy children in respect to serum thyroid-stimulating hormone (TSH), serum-free level of triiodothyronine, and free level of thyroxine (fT4). SH diagnosis was accepted as TSH above the laboratory accepted upper limit (>4.2 mU/L) and normal fT4 values. The patient and control group data were compared by calculating the QT interval, QTc, QT dispersion (QTd), QTc dispersion (QTcd), Tp-e, Tp-e/QT ratio, and Tp-e/QTc ratio on 12-lead surface electrocardiogram. RESULTS: The mean age was 7.91 ± 3.6 years in the SH group and 8.8 ± 2.4 years in the control group. In the SH group, the minimum QT (QTmin) was determined to be statistically significantly lower (P < 0.001) and maximum QT (QTmax), QTd, QTcd, Tp-e, Tp-e/QT ratio, and Tp-e/QTc ratio were statistically significantly higher (P = 0.028, P < 0.001, P = 0.003, P < 0.001, P = 0.001, P < 0.001, respectively). A positive correlation was determined between TSH and QTmax (r: +0.331, P = 0.037). CONCLUSIONS: The current study is the first to have shown significantly increased QTd, QTcd, Tp-e, Tp-e/QT ratio, and Tp-e/QTc ratio in children diagnosed with SH. A positive correlation was determined between TSH and maximum QT values, Tp-e, Tp-e/QT ratio, and Tp-e/QTc ratio. These results suggest the need to further assess the long-term risks of prolonged QT dispersion in the setting of subclinical hypothyroidism.

A rare cause of delayed puberty and primary amenorrhea: 17α-hydroxylase enzyme deficiency.

AIM: 17α-hydroxylase enzyme deficiency is a rare form of congenital adrenal hyperplasia (CAH) and is caused by mutations in the CYP17A1 gene. The main clinical findings are delayed puberty and primary amenorrhea in girls, and disorders of sex development in boys. It can also cause hypertension and hypokalemia in both genders. In this study, we aimed to present the clinical, laboratory and genetic results of 13 patients from eight different families who were diagnosed with complete 17α-hydroxylase enzyme deficiency. METHODS: The age, symptoms, anthropometric measurements, blood pressure, Tanner stages, and hormonal and chromosome analysis results at the time of admission were recorded from the medical records of the patients. Whole gene next-generation sequencing of CYP17A1 gene was performed to detect mutations. Multiplex ligation dependent probe amplification (MLPA) method were used to detect deletions in the seven patients who had no point mutation were detected in the CYP17A1 gene. RESULTS: The average age of the patients at the time of admission was 14.8 (range: 12.9-16.6) years. Also at this time, all patients were in adolescence and were raised as females. The karyotypes of eight patients were 46,XY, and of five patients were 46,XX. Ten patients presented with delayed puberty and primary amenorrhea, one patient with delayed puberty and hypertension, and two patients with hypertension and/or hypokalemia. Hypertension and hypokalemia were detected in nine and seven patients, respectively. CONCLUSIONS: P450c17 enzyme deficiency should be considered in patients presenting with delayed puberty or primary amenorrhea in the adolescence period and diagnosed with hypergonadotropic hypogonadism, if hypertension and hypokalemia accompany. Early diagnosis prevents the occurrence of important health problems such as hypertension, psychological problems, and gender identity disorders, which affect the majority of these patients.

Evaluation of anterior segment parameters with Pentacam in children with poorly-controlled type 1 Diabetes Mellitus without diabetic retinopathy.

PURPOSE: To determine the effect of abnormal glucose metabolism on the cornea, lens, anterior chamber volume (ACV), and anterior chamber depth (ACD) in children with poorly-controlled type 1 diabetes mellitus (DM) without diabetic retinopathy (DR). METHODS: After the complete ophthalmologic examination of children with poorly-controlled (glycosylated hemoglobin [HbA1c] >7.0 %) type 1 DM without DR and age-matched healthy subjects (control group), the central corneal thickness (CCT), keratometry (K) values (Kmean front and back, and Kmax), radius (R) values (Rmin front and back), corneal volume (CV), ACD, ACV, pupil diameter, mean lens density (MLD), lens density standard deviation (LD SD), and maximum lens density (LD max) were measured using Pentacam High Resolution. Endothelial cell density was measured using a specular microscope. The results were assessed and compared between the two groups. RESULTS: There were 60 patients (38 boys and 22 girls) in the DM group and 30 (14 boys, 16 girls) in the control group. There were considerable differences between the groups in terms of CCT, CV, ACD, MLD, LD SD and LD max, and Kmean back. Further, there was a positive correlation between HbA1c and MLD, LD SD, CV, and CCT in patients with DM. CONCLUSION: The results of our study demonstrate that poorly-controlled type 1 DM without DR affects the cornea, ACD, and LD based on anterior segment measurements taken with a Scheimpflug camera. CCT, CV, LD SD, and MLD values may be parameters that can be used to follow-up patients with type 1 DM.

Left and right ventricular functions may be impaired in children diagnosed with subclinical hypothyroidism.

Subclinical hypothyroidism (SH) may influence both ventricular functions. The aim of this study was to evaluation the findings of Tissue Doppler Imaging (TDI) and other echocardiography modalities in children with SH. We compared left ventricular mass index (LVMI) and TDI parameters of patients with SH and children with euthyroidism. Subclinical hypothyroidism was diagnosed when thyroid stimulating hormone level was higher than the reference value of the laboratory (> 4.2 mIU/L) and free thyroxine level was in normal range. The study included a group of 35 patients with SH and a control group of 38 children with euthyroidism (mean age was 7.6 ± 3.5 years and 9.0 ± 2.4 years, respectively). LVMI was significantly higher in the patient group (p = 0.005). TDI parameters including mitral septal ejection time was lower (p = 0.003) and mitral septal myocardial performance index was higher (p = 0.009) in the patient group. Right ventricular TDI revealed that tricuspid lateral E/Ea and tricuspid septal E/Ea were higher (p = 0.015 and p = 0.024, respectively) and tricuspid septal Ea/Aa and ejection time were lower (p = 0.018 and p = 0.017, respectively) in the patient group. SH may lead to increase LVMI. Left ventricular systolic and diastolic TDI parameters (lower mitral septal ejection time, higher mitral septal myocardial performance index) as well as right ventricular systolic (lower tricuspid septal ejection time) and diastolic (higher tricuspid septal and lateral E/Ea, lower tricuspid septal Ea/Ea) functions may be also impaired in children with subclinical hypothyroidism. TDI is a useful method used for the assessment of the effect of SH on cardiac functions.

A Novel Mutation of AMHR2 in Two Siblings with Persistent Müllerian Duct Syndrome

Persistent Müllerian Duct syndrome (PMDS) develops due to deficiency of anti-Müllerian hormone (AMH) or insensitivity of target organs to AMH in individuals with 46,XY karyotype. PMDS is characterized by normal male phenotype of external genitals, associated with persistence of Müllerian structures. This report includes the presentation of a 2.5 year old male patient due to bilateral undescended testis. His karyotype was 46,XY. The increase in testosterone following human chorionic gonadotropin stimulation test was normal. The patient was referred to our clinic after uterine, fallopian tube and vaginal remnants were recognized during the orchiopexy surgery. The family reported that the eight year old elder brother of the patient was operated on for right inguinal hernia and left undescended testis at the age of one year. A right transverse testicular ectopia was found in the elder brother. Both cases had normal AMH levels. AMHR2 gene was analyzed and a homozygous NM_020547.3:c.233-1G>A mutation was found that was not identified previously. In conclusion, we determined a novel mutation in the AMHR2 gene that was identified for the first time. This presented with different phenotypes in two siblings.

A rare cause of neonatal hypoglycemia in two siblings: TBX19 gene mutation.

Congenital isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) is a rarely seen disease characterized by low serum ACTH and cortisol levels accompanied by normal levels of the other anterior pituitary hormones. In these patients, severe hypoglycemia, convulsions, and prolonged cholestatic jaundice are expected findings in the neonatal period. In this paper, we present two siblings with TBX19 gene mutation. The first case was investigated at the age of 2 months for severe hypoglycemia, recurrent convulsions, and prolonged cholestatic jaundice persisting since the neonatal period. The second sibling presented with hypoglycemia in the neonatal period. In both cases, baseline cortisol and ACTH levels were low and cortisol response to the low-dose ACTH test was inadequate, while all other anterior pituitary hormones were normal. Thus, IAD was suspected. Genetic analysis of the TBX19 gene was performed. Both cases were homozygous for c.856 C>T (p.R286*), and hydrocortisone treatment was initiated. The first patient did not attend the clinic regularly. On attendance at another hospital, hydrocortisone treatment was discontinued and antiepileptic treatment was initiated because of suspected epilepsy. This led to developmental delay, measured with the Denver Developmental Screening Test II (DDST-II), because of cessation of the hydrocortisone therapy. The second sibling had normal development, as measured with the DDST. In conclusion, TBX19 gene analysis must be performed if adrenal insufficiency is associated with isolated ACTH deficiency. Delay in diagnosis may lead to inappropriate diagnoses, such as epilepsy, and thus inappropriate therapy, which may result in neonatal mortality.

Aromatase Deficiency due to a Novel Mutation in CYP19A1 Gene

Aromatase deficiency is a rare autosomal recessive genetic disorder with an unknown incidence. Aromatase converts androgens into estrogen in the gonadal and extra-gonadal tissues. Aromatase deficiency causes ambiguous genitalia in the female fetus and maternal virilization (hirsutism, acne, cliteromegaly, deep voice) during pregnancy due to increased concentration of androgens. A 19 months old girl patient was assessed due to presence of ambiguous genitalia. There were findings of maternal virilization during pregnancy. The karyotype was 46,XX. Congenital adrenal hyperplasia was not considered since adrenocorticotropic hormone, cortisol, and 17-hydroxyprogesterone levels were within normal ranges. At age two months, follicle-stimulating hormone and total testosterone levels were elevated and estradiol level was low. Based on these findings, aromatase deficiency was suspected. A novel homozygous mutation IVS7-2A>G (c.744-2A>G) was identified in the CYP19A1 gene. Pelvic ultrasound showed hypoplasic ovaries rather than large and cystic ovaries. We identified a novel mutation in the CYP19A1 gene in a patient who presented with ambiguous genitalia and maternal virilization during pregnancy. Presence of large and cystic ovaries is not essential in aromatase deficiency.

Association of Subclinical Hypothyroidism with Dyslipidemia and Increased Carotid Intima-Media Thickness in Children.

OBJECTIVE: Subclinical hypothyroidism (SH) is defined as an elevated serum thyroid-stimulating hormone (TSH) level with free thyroxine (fT4) level in the normal range. There are very few studies in the literature reporting on the effect of SH on lipid metabolism and carotid intima-media thickness (CIMT) in children. METHODS: The study included 38 children diagnosed with SH and a control group comprising 38 healthy, euthyroid children. SH was diagnosed based on an elevated TSH level (4.2-20 mIU/L) and normal fT4 level measured in two morning fasting blood samples obtained at an interval of 2 to 6 weeks. Blood samples were collected by venipuncture in the morning after an overnight fast. RESULTS: The patient group included 38 children (16 male, 22 female) with SH and the control group -38 healthy, euthyroid children (20 male, 18 female). Mean age was 8.1±3.6 (range, 3.5-15) years in the patient group and 8.9±2.4 (range, 4.5-15) years in the control group. In the patient group, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), TC/high-density lipoprotein cholesterol (HDL-C), and LDL-C/HDL-C were higher compared to the control group (p=0.049, p=0.014, p=0.002, and 0.003, respectively). In the patient group, CIMT was also significantly higher compared to the control group (p=0.001). The patient group was further divided into two subgroups based on their serum TSH level: (I) patients with mildly elevated TSH (TSH=4.2±10 mIU/L) (n=33) and (II) patients with high TSH (TSH≥10 mIU/L) (n=5). However, no significant difference was found between the patients with mild and severe SH with regard to TC, LDL-C, HDL-C, triglyceride level and CIMT levels (p=0.635, p=0.424, p=0.310, p=0.342, and 0.610, respectively). CONCLUSION: Subclinical hypothyroidism leads to increased dyslipidemia (increased TC and LDL) and increased CIMT, which leads to increased risk of cardiovascular disease. Further studies are needed to substantiate these findings in children with SH.

Use of complementary and alternative medicine in children who have no chronic disease.

AIM: In this study, we aimed to evaluate complementary and alternative methods of medicine, determine the frequencies of usage of these methods and investigate the factors which have an impact on their usage. MATERIAL AND METHODS: The study was conducted between October, the 15(th) and November, the 15(th) 2012. Approval was obtained from the local ethics committee (08.10.2012/732). The study form prepared was applied to the mothers of the children who presented to our general outpatient clinic and had no chronic disease. The data were recorded in SPSS for Windows v.16 program. Descriptive statistics, chi-square, Mann-Whitney U and logistic regression analyses were applied. A p value of <0.05 was considered significant. RESULTS: Two hundred and six children were included in the study. Complementary and alternative medicine was used in 83% of the patients. Wearing an evil eye (45%) bead and prayer (35%) to protect from the evil eye were the most commonly used methods. The most common medical conditions which caused to use of complementary and alternative medicine included anemia, diarrhea, constipation and cough. Belief-based application were being used in 73% of the patients and herbal methods were being used in 57%. In 18% of the patients, interventional methods including cutting had been performed. No difference was found between the patients in whom these methods were used and not used in terms of familial income, education levels of the parents, family type and residence (p>0.05). CONCLUSIONS: Complementary and alternative methods of medicine are applied substantially frequently in children. Physicians should have information about these methods in terms of their effects and side effects and warn families and especially mothers about potential risks.