Şükran Poyrazoğlu

Distribution of gene mutations associated with familial normosmic idiopathic hypogonadotropic hypogonadism.

Objective: Normosmic idiopathic hypogonadotropic hypogonadism (nIHH) is characterized by failure of initiation or maintenance of puberty due to insufficient gonadotropin release, which is not associated with anosmia/hyposmia. The objective of this study was to determine the distribution of causative mutations in a hereditary form of nIHH. Methods: In this prospective collaborative study, 22 families with more than one affected individual (i.e. multiplex families) with nIHH were recruited and screened for genes known or suspected to be strong candidates for nIHH. Results: Mutations were identified in five genes (GNRHR, TACR3, TAC3, KISS1R, and KISS1) in 77% of families with autosomal recessively inherited nIHH. GNRHR and TACR3 mutations were the most common two causative mutations occurring with about equal frequency. Conclusions: Mutations in these five genes account for about three quarters of the causative mutations in nIHH families with more than one affected individual. This frequency is significantly greater than the previously reported rates in all inclusive (familial plus sporadic) cohorts. GNRHR and TACR3 should be the first two genes to be screened for diagnostic purposes. Identification of causative mutations in the remaining families will shed light on the regulation of puberty. Conflict of interest:None declared.

Increased arterial stiffness in young normotensive patients with Turner syndrome: associations with vascular biomarkers

Factors contributing to arteriopathy in patients with Turner syndrome (TS) remain unclear. We assessed arterial stiffness in young, normotensive patients with TS and correlated arterial stiffness with vascular biomarkers, GH treatment and oestrogen exposure. Sixty‐one patients with TS (mean age, 12·6 years; range 6·6–21·3 years) were matched for age and sex with 61 healthy peers. Associations between arterial stiffness and high‐sensitivity C‐reactive protein (hsCRP), B‐type natriuretic peptide (BNP), atrial NP (ANP), plasma aldosterone/plasma renin activity (PRA), IGF1 and IGFBP3 were examined after adjusting for well‐established confounders of vascular disease.

Associations of Size at Birth and Postnatal Catch-up Growth Status With Clinical and Biomedical Characteristics in Prepubertal Girls With Precocious Adrenarche: Preliminary Results

CONTEXT The causes of polycystic ovarian syndrome (PCOS) in girls with precocious adrenarche (PA) remain unclear. OBJECTIVE Our goal was to compare the clinical, biochemical, and ultrasound characteristics of girls with PA whose size at birth was appropriate for gestational age (AGA) vs those born small for gestational age (SGA). PCOS-associated metabolic and morphological correlates were examined. DESIGN Glucose tolerance, ACTH stimulation, and transabdominal ultrasounds were examined in 56 AGA and 31 SGA girls with PA. Bone age and hormonal profiles were determined. SGA girls were divided into 2 groups by catch-up growth (CUG) status. Subgroups were compared. RESULTS Chronological age, Tanner stage for pubarche, ovarian volume, and uterine volume were similar between the groups. SGA girls had lower body mass index and higher bone age-adjusted post-corticotropin cortisol. We found increased body mass index-adjusted mean serum insulin, reduced insulin sensitivity, and reduced IGF-binding protein-1 in SGA girls. Multicystic ovaries were more common in SGA girls (odds ratio [OR] = 9.69, 95% confidence interval [CI] = 3.34-28.15; P < .001). SGA girls without CUG had a higher incidence of multicystic ovaries than CUG counterparts (OR = 8.4, 95% CI = 1.4-19.3; P = .027). Being born SGA (OR = 43.4, 95% CI = 6.9-84.7; P = .001] and exaggerated 17-hydroxyprogesterone response (OR = 15.8, 95% CI = 1.7-49.8; P = .015) were associated with multicystic ovaries. CONCLUSIONS Significant differences in hormone levels, insulin sensitivity, and ovarian maturity were found in prepubertal girls with PA who were SGA. Longitudinal follow-up will help determine whether these factors contribute to a specific PCOS phenotype in SGA girls with PA.

Are metabolic syndrome antecedents in prepubertal children associated with being born idiopathic large for gestational age

Being born large for gestational age (LGA) is a risk factor for development of metabolic syndrome (MS) in adolescents and adults.

Turner syndrome and associated problems in turkish children: A multicenter study

Objective: Turner syndrome (TS) is a chromosomal disorder caused by complete or partial X chromosome monosomy that manifests various clinical features depending on the karyotype and on the genetic background of affected girls. This study aimed to systematically investigate the key clinical features of TS in relationship to karyotype in a large pediatric Turkish patient population. Methods: Our retrospective study included 842 karyotype-proven TS patients aged 0-18 years who were evaluated in 35 different centers in Turkey in the years 2013-2014. Results: The most common karyotype was 45,X (50.7%), followed by 45,X/46,XX (10.8%), 46,X,i(Xq) (10.1%) and 45,X/46,X,i(Xq) (9.5%). Mean age at diagnosis was 10.2±4.4 years. The most common presenting complaints were short stature and delayed puberty. Among patients diagnosed before age one year, the ratio of karyotype 45,X was significantly higher than that of other karyotype groups. Cardiac defects (bicuspid aortic valve, coarctation of the aorta and aortic stenosis) were the most common congenital anomalies, occurring in 25% of the TS cases. This was followed by urinary system anomalies (horseshoe kidney, double collector duct system and renal rotation) detected in 16.3%. Hashimoto’s thyroiditis was found in 11.1% of patients, gastrointestinal abnormalities in 8.9%, ear nose and throat problems in 22.6%, dermatologic problems in 21.8% and osteoporosis in 15.3%. Learning difficulties and/or psychosocial problems were encountered in 39.1%. Insulin resistance and impaired fasting glucose were detected in 3.4% and 2.2%, respectively. Dyslipidemia prevalence was 11.4%. Conclusion: This comprehensive study systematically evaluated the largest group of karyotype-proven TS girls to date. The karyotype distribution, congenital anomaly and comorbidity profile closely parallel that from other countries and support the need for close medical surveillance of these complex patients throughout their lifespan.

Cleidocranial dysplasia: Clinical, endocrinologic and molecular findings in 15 patients from 11 families

Cleidocranial dysplasia (CCD) is an autosomal dominant disorder characterized by skeletal anomalies such as delayed closure of the cranial sutures, underdeveloped or absent clavicles, multiple dental abnormalities, short stature and osteoporosis. RUNX2, encoding Runt DNA-binding domain protein important in osteoblast differentiation, is the only known gene related to the disease and identified as responsible in 70% of the cases. Our clinical evaluations revealed that short stature present at a rate of 28.6%, osteoporosis at a rate of 57.1% and osteopenia at 21.4%. In this study, RUNX2 sequencing revealed nine different variations in 11 families, eight being pathogenic of which one was novel gross insertion (c.1271_1272ins20) and one other being predicted benign in frame gross deletion (c.241_258del).

Two novel mutations in XYLT2 cause spondyloocular syndrome

We report on two new patients with spondyloocular syndrome. Both patients harbor novel homozygous mutations in the XYLT2 gene. The patients present severe generalized osteoporosis, multiple fractures, short stature, cataract, and mild hearing impairment. XYLT2 mutations have been identified in spondyloocular syndrome, however only five mutations have been reported previously. These two patients with novel mutations extend the phenotypic and genotypic spectrum of spondyloocular syndrome.

Severe short stature: an unusual finding in lipoid proteinosis.

Lipoid proteinosis (LP) is a rare disorder and it can affect every organ in the body. The clinical manifestations of LP may vary considerably between affected individuals. Short stature is reported in patients with LP however the underlying etiology is not clear. Short stature may be due to endocrine dysfunction caused by deposition of hyaline−like material in endocrine glands. We investigated a 13 year old patient with LP (507 delT mutation) who had severe short stature. He had hoarseness since the age of one year, followed by characteristic skin lesions for LP and short stature. There was no pathology with respect to endocrinological investigations in our patient including growth hormone−IGF axis. Our results show that short stature in LP can not be explained by endocrinological abnormalities. Short stature may be an intrinsic component of the syndrome. Conflict of interest:None declared.

Prevalence, clinical characteristics and long-term outcomes of classical 11 β-hydroxylase deficiency (11BOHD) in Turkish population and novel mutations in CYP11B1 gene

Congenital adrenal hyperplasia (CAH) due to 11β-hydroxylase deficiency (11BOHD) is a rare autosomal recessive disorder and the second most common form of CAH. AIM To investigate genotype-phenotype correlation and to evaluate clinical characteristics and long-term outcomes of patients with 11BOHD. METHODS A total of 28 patients (n = 14, 46,XX; n = 14, 46,XY) with classical 11BOHD from 25 unrelated families were included in this study. Screening of CYP11B1 is performed by Sanger sequencing. Pathogenic features of novel variants are investigated by the use of multiple in silico prediction tools and with family based co-segregation studies. Protein simulations were investigated for two novel coding region alterations. RESULTS The age at diagnosis ranged from 6 days to 12.5 years. Male patients received diagnose at older ages than female patients. The rate of consanguinity was high (71.4%). Five out of nine 46,XX patients were diagnosed late (age 2-8.7 years) and were assigned as male due to severe masculinization. Twenty one patients have reached adult height and sixteen were ultimately short due to delayed diagnosis. Two male patients had testicular microlithiasis and 5 (35.7%) patients had testicular adrenal rest tumor during follow up. Four patients (28.6%) had gynecomastia. Mutation analyses in 25 index patients revealed thirteen different mutations in CYP11B1 gene, 4 of which were novel (c.393 + 3A > G, c.428G > C, c.1398 + 2T > A, c.1449_1451delGGT). The most frequent mutations were c.896T > C with 32%, c.954G > A with 16% and c.1179_1180dupGA with 12% in frequency. There was not a good correlation between genotype and phenotype; phenotypic variability was observed among the patients with same mutation. CONCLUSION This study presents the high allelic heterogeneity of CYP11B1 mutations in CAH patients from Turkey. Three dimensional protein simulations may provide additional support for the pathogenicity of the genetic alterations. Our results provide reliable information for genetic counseling, preventive and therapeutic strategies for the families.

The Growth Characteristics of Patients with Noonan Syndrome: Results of Three Years of Growth Hormone Treatment: A Nationwide Multicenter Study.

Objective: Noonan syndrome (NS) is a multisystem disorder, and short stature is its most striking manifestation. Optimal growth hormone (GH) treatment for NS is still controversial. In this study, using a nationwide registration system, we aimed to evaluate the growth characteristics and the clinical features of NS patients in Turkey and their growth response to GH treatment. Methods: Children and adolescents with a diagnosis of NS were included inthe study. Laboratory assessment including standard GH stimulation test results were evaluated. Height increment of patients with or without GH treatment were analyzed after three years of therapy. Results: A total of 124 NS patients from different centers were entered in the web-based system. Short stature and typical face appearance were the most frequently encountered diagnostic features of our patients. Of the 84 patients who were followed long-term, 47 hadreceived recombinant human GH (rhGH). In this group of 47 patients, height standard deviation score (HSDS) increased from -3.62±1.14 to -2.85±0.96 after three years of therapy, indicating significant differences from the patients who did not receive GH treatment. PTPN11 gene was analyzed in 61 patients, and 64% of these patients were found to have a mutation. HSDS at admission was similar in patients with or without PTPN11 gene mutation. Conclusion: A diagnosis of NS should be kept in mind in all patients with short stature showing systemic clinical findings. GH therapy is effective for improvement of short stature especially in the first two years of treatment. Further studies are needed for optimisation of GH therapy and evaluation of final height data in NS patients.