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Reports on the association between growth hormone therapy and cardiovascular risk factors in children are limited. This study aimed to evaluate carotid intima-media thickness (cIMT) in children treated with recombinant human growth hormone (rhGH) and assess the effects of rhGH therapy and changes in serum carbohydrate metabolism, lipid profile and adipocytokines on cIMT.Seventy-one isolated idiopathic GH deficiency (GHD) children and 44 age- and sex-matched, healthy controls were enrolled in this study. The study group was divided into two subgroups according to insulin resistance (IR) on oral glucose tolerance tests. Insulin secretion (HOMA B, total insulin) and sensitivity (HOMA-IR, QUICKI, Matsuda) indices were calculated. cIMT was measured and the standard deviation scores (SDS) were calculated. Associations between cIMT-SDS and insulin secretion and sensitivity indices, serum lipid levels, adipocytokines (leptin, resistin, ghrelin), and the other rhGH treatment-related factors were evaluated.The cIMT-SDS was increased in GHD children treated with rhGH compared to controls (0.02 (2.27) vs -1.01 (1.63), p=0.003). cIMT-SDS did not differ between children on rhGH treatment with or without IR. High cIMT-SDS was significantly associated with higher serum ghrelin level and lower serum high density lipoprotein level (ß=0.491, p=0.001 and ß= -0.027, p=0.017), but not with BMI-SDS, blood pressure, insulin secretion and sensitivity indices, or dose and duration of rhGH therapy.Our findings showed that GHD children treated with rhGH have increased cIMT. Alterations in carbohydrate metabolism were not associated with cIMT in children treated with rhGH. GH therapy per se appears to be associated with this increased cIMT but causality should be elucidated in further studies. cIMT also appears to be associated with higher ghrelin and lower HDL levels.

Papillary thyroid cancer (PTC) is extremely rare in children. Herein, we present a case diagnosed with PTC at 15 months of age. We conducted a literature review of the published cases with PTC under five years of age. A 1.25-year-old male patient had initially presented with a complaint of progressively enlarging cervical mass that appeared four months earlier. On physical examination, a mass located in the anterior cervical region with the largest measurements of around 3x3 cm was detected. Cervical and thyroid ultrasonography showed a 50x27 mm solid mass in the right lateral neck. Excisional biopsy revealed a follicular variant of PTC with capsular invasion. Subsequently, he underwent a complementary total thyroidectomy. He was diagnosed with intermediate-risk (T3N0M0) PTC. He developed permanent hypoparathyroidism. In the first year of the operation, he was treated with radioiodine ablation (RAI) since basal and stimulated thyroglobulin (Tg) levels tended to increase. Whole-body scintigraphy was normal in the first year of RAI ablation. On levothyroxine sodium (LT4) treatment, levels of thyroid stimulating hormone (TSH) and Tg were adequately suppressed. He is now 8.5-years-old and disease-free on LT4 replacement therapy for seven years and three months. Pediatric PTC has different biological behavior and an excellent prognosis compared to adults. The optimal treatment strategy for pediatric TC is total thyroidectomy, followed by RAI ablation. Post-operative management should include regular follow-up, TSH suppression by adequate LT4 therapy, serial Tg evaluation, and radioiodine scanning when indicated.

In adolescents and young women, there is limited data on the type of replacement, route of administration, and ideal doses to be used in systemic hormone therapy administered for the treatment of hypogonadism. In particular, management of patients with complicated systemic diseases or at risk of thrombophilia may present significant challenges. We present a case of a 15-year-old adolescent girl with hypogonadism and coexisting medical conditions, who was evaluated for systemic hormone therapy.

Acid-labile subunit (ALS) forms ternary complexes with insulin like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) and is essential for normal circulating IGF-1 levels. The IGFALS gene encodes the ALS and mutations in IGFALS cause ALS deficiency. We describe a patient with ALS deficiency with a novel homozygous frameshift mutation in IGFALS presenting with short stature and delayed puberty but ultimately achieving an adult height (AH) comparable to his target height (TH). A 15.25 year old boy presented with short stature (149.9 cm, -3.04 standard deviation score). The patient had a low circulating IGF-1 concentration, extremely low IGFBP-3 concentration, insulin resistance and osteopenia. The peak growth hormone (GH) response to GH stimulation test was high (31.6 ng/mL). Sequencing of IGFALS revealed a novel, homozygous, frameshift mutation (p.Ser555Thrfs.19). His mother and elder sister were heterozygous carriers. Although he had delayed puberty and short stature at the onset of puberty, he reached his TH and an AH similar to those of his heterozygous mother and sister. The heterozygous carriers had normal or low IGF-1 concentrations and low IGFBP-3 concentrations but not as markedly low as that of the patient. They had normally timed puberty, insulin metabolism and bone mineral density (BMD). The phenotype of ALS deficiency is quite variable. Despite short stature and delayed puberty, patients can achieve normal pubertal growth and AH. ALS deficiency may cause osteopenia and hyperinsulinemia. Heterozygous carriers may have normal prenatal growth, puberty, insulin metabolism and BMD.

In patients with Mayer-Rokitansky-Küster-Hauser syndrome and complete androgen insensitivity syndrome (CAIS), management of vaginal hypoplasia includes non-surgical or surgical vaginal elongation techniques. For these patients, primary vaginal dilation is considered a first-line option to avoid the risks of having surgery and complications that may occur due to these procedures. Non-surgical dilation is a highly successful treatment if treatment is initiated when the patient is emotionally mature and ready. Here, we present a case of CAIS with vaginal hypoplasia managed successfully with non-surgical dilation therapy.

Objective 17α-hydroxylase/17,20 lyase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia (CAH), characterized by hypertension and varying degrees of ambiguous genitalia and delayed puberty. The disease is associated with bi-allelic mutations in the CYP17A1 gene located on chromosome 10q24.3. We aimed to present clinical and genetic findings and follow-up and treatment outcomes of 17OHD patients. Methods We evaluated six patients with 17OHD from five families at presentation and at follow up. Standard deviation score of all auxological measurements was calculated according to national data and karyotype status. CYP17A1 gene sequence alterations were investigated in all patients. Results The mean (±standard deviation) age of patients at presentation and follow-up time was 14.6±4.2 and 5.0±2.7 years respectively. Five patients were referred to us because of delayed puberty and primary amenorrhea and four for hypertension. One novel single nucleotide insertion leading to frame shift and another novel variant occurring at an ultra rare position, leading to a missense change, are reported, both of which caused 17OHD deficiency. Steroid replacement was started. The three patients with 46,XY karyotype who were raised as females underwent gonadectomy. Osteoporosis was detected in five patients. Four patients needed antihypertensive treatment. Improvement in osteoporosis was noted with gonadal steroid replacement and supportive therapy. Conclusion 17OHD, a rare cause of CAH, should be kept in mind in patients with pubertal delay and/or hypertension. Patients with 46,XY who are raised as females require gonadectomy. Due to late diagnosis, psychological problems, gender selection, hypertension and osteoporosis are important health problems affecting a high proportion of these patients.

Objective Klinefelter syndrome (KS) is the most common (1/500–1/1000) chromosomal disorder in males, but only 10% of cases are identified in childhood. This study aimed to review the data of children with KS to assess the age and presenting symptoms for diagnosis, clinical and laboratory findings, together with the presence of comorbidities. Methods Twenty-three KS patients were analyzed retrospectively. Age at admission, presenting symptoms, comorbid problems, height, weight, pubertal status, biochemical findings, hormone profiles, bone mineral density and karyotype were evaluated. Molecular analysis was also conducted in patients with ambiguous genitalia. Results The median age of patients at presentation was 3.0 (0.04-16.3) years. Most of the cases were diagnosed prenatally (n=15, 65.2%). Other reasons for admission were scrotal hypospadias (n=3, 14.3%), undescended testis (n=2, 9.5%), short stature (n=1, 4.8%), isolated micropenis (n=1, 4.8%) and a speech disorder (n=1, 4.8%). The most frequent clinical findings were neurocognitive disorders, speech impairment, social and behavioral problems and undescended testes. All except two patients were prepubertal at admission. Most of the patients (n=20, 86.9%) showed the classic 47,XXY karyotype. Steroid 5 alpha-reductase 2 gene and androgen receptor gene mutations were detected in two of the three cases with genital ambiguity. Conclusion Given the large number of underdiagnosed KS patients before adolescence, pediatricians need to be aware of the phenotypic variability of KS in childhood. Genetic analysis in KS patients may reveal mutations associated with other forms of disorders of sex development besides KS.

Objective: Papillary thyroid cancer (PTC) may behave differently in prepubertal children as compared to pubertal children and adults. BRAF gene activating mutations may associate with PTC by creating aberrant activation. We aimed to evaluate the clinicopathological characteristics of PTC patients with emphasis on the pubertal status and also to investigate the association of BRAFV600E mutation with disease characteristics. Methods: The medical records of 75 patients with PTC were reviewed retrospectively. BRAFV600E mutation status was available only in the medical records of 56 patients. Results: Mean age at diagnosis was 12.4±3.8 years. There was no difference in sex, initial signs, tumor histopathology, and pathological evidence of tumor aggressiveness between prepubertal and pubertal children. Although not statistically significant, lateral neck nodal metastasis and lung metastasis at diagnosis were more prevalent in prepubertal children. After excluding patients with microcarcinoma, prepubertal children were found to require lateral neck dissection and further doses of radioactive iodine more frequently than pubertal patients. Recurrence was also more frequent in prepubertal children (p=0.016). Frequency of BRAFV600E mutation was similar in prepubertal and pubertal patients. BRAFV600E mutation was found in 14/56 (25%) patients and was high in the classic variant PTC (p=0.004). Multicentricity was high in BRAFV600E mutation (p=0.01). There was no relation between BRAFV600E mutation and lymph node and pulmonary metastasis at diagnosis, or between BRAFV600E mutation and pathological evidence of tumor aggressiveness. Conclusion: PTC is more disseminated in prepubertal children. BRAFV600E mutation does not correlate with a more extensive or aggressive disease. BRAFV600E mutation is not the cause of the differences in the biological behavior of PTC in prepubertal and pubertal children.

Elhan, Atilla Halil/0000-0003-3324-248X; siklar, zeynep/0000-0003-0921-2694; Turan, Serap/0000-0002-5172-5402; ABALI, SAYGIN/0000-0001-6552-2801; Abaci, Ayhan/0000-0002-1812-0321; Buyukinan, Muammer/0000-0002-2937-823X; GUVEN, AYLA/0000-0002-2026-1326; yilmaz, gulay can/0000-0003-0525-1231; berberoglu, merih/0000-0003-3102-0242; Ozgen, Ilker Tolga/0000-0001-6592-9652 WOS: 000385025700008 PubMed: 27125300 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. Turkish Pediatric Endocrinology and Diabetes Society [042014] This work was supported by the Turkish Pediatric Endocrinology and Diabetes Society (Grant Number: 042014).

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.