SummaryBackgroundKCNJ11 mutations cause permanent neonatal diabetes through pancreatic ATP-sensitive potassium channel activation. 90% of patients successfully transfer from insulin to oral sulfonylureas with excellent initial glycaemic control; however, whether this control is maintained in the long term is unclear. Sulfonylurea failure is seen in about 44% of people with type 2 diabetes after 5 years of treatment. Therefore, we did a 10-year multicentre follow-up study of a large international cohort of patients with KCNJ11 permanent neonatal diabetes to address the key questions relating to long-term efficacy and safety of sulfonylureas in these patients.MethodsIn this multicentre, international cohort study, all patients diagnosed with KCNJ11 permanent neonatal diabetes at five laboratories in Exeter (UK), Rome (Italy), Bergen (Norway), Paris (France), and Krakow (Poland), who transferred from insulin to oral sulfonylureas before Nov 30, 2006, were eligible for inclusion. Clinicians collected clinical characteristics and annual data relating to glycaemic control, sulfonylurea dose, severe hypoglycaemia, side-effects, diabetes complications, and growth. The main outcomes of interest were sulfonylurea failure, defined as permanent reintroduction of daily insulin, and metabolic control, specifically HbA1c and sulfonylurea dose. Neurological features associated with KCNJ11 permanent neonatal diabetes were also assessed. This study is registered with ClinicalTrials.gov, number NCT02624817.Findings90 patients were identified as being eligible for inclusion and 81 were enrolled in the study and provided long-term (>5·5 years cut-off) outcome data. Median follow-up duration for the whole cohort was 10·2 years (IQR 9·3–10·8). At most recent follow-up (between Dec 1, 2012, and Oct 4, 2016), 75 (93%) of 81 participants remained on sulfonylurea therapy alone. Excellent glycaemic control was maintained for patients for whom we had paired data on HbA1c and sulfonylurea at all time points (ie, pre-transfer [for HbA1c], year 1, and most recent follow-up; n=64)—median HbA1c was 8·1% (IQR 7·2–9·2; 65·0 mmol/mol [55·2–77·1]) before transfer to sulfonylureas, 5·9% (5·4–6·5; 41·0 mmol/mol [35·5–47·5]; p<0·0001 vs pre-transfer) at 1 year, and 6·4% (5·9–7·3; 46·4 mmol/mol [41·0–56·3]; p<0·0001 vs year 1) at most recent follow-up (median 10·3 years [IQR 9·2–10·9]). In the same patients, median sulfonylurea dose at 1 year was 0·30 mg/kg per day (0·14–0·53) and at most recent follow-up visit was 0·23 mg/kg per day (0·12–0·41; p=0·03). No reports of severe hypoglycaemia were recorded in 809 patient-years of follow-up for the whole cohort (n=81). 11 (14%) patients reported mild, transient side-effects, but did not need to stop sulfonylurea therapy. Seven (9%) patients had microvascular complications; these patients had been taking insulin longer than those without complications (median age at transfer to sulfonylureas 20·5 years [IQR 10·5–24·0] vs 4·1 years [1·3–10·2]; p=0·0005). Initial improvement was noted following transfer to sulfo...

ObjectiveHypospadias is a frequent congenital anomaly but in most cases an underlying cause is not found. Steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) is a key regulator of human sex development and an increasing number of SF-1 (NR5A1) mutations are reported in 46,XY disorders of sex development (DSD). We hypothesized that NR5A1 mutations could be identified in boys with hypospadias.Design and methodsMutational analysis of NR5A1 in 60 individuals with varying degrees of hypospadias from the German DSD network.ResultsHeterozygous NR5A1 mutations were found in three out of 60 cases. These three individuals represented the most severe end of the spectrum studied as they presented with penoscrotal hypospadias, variable androgenization of the phallus and undescended testes (three out of 20 cases (15%) with this phenotype). Testosterone was low in all three patients and inhibin B/anti-Müllerian hormone (AMH) were low in two patients. Two patients had a clear male gender assignment. Gender re-assignment to male occurred in the third case. Two patients harbored heterozygous nonsense mutations (p.Q107X/WT, p.E11X/WT). One patient had a heterozygous splice site mutation in intron 2 (c.103-3A/WT) predicted to disrupt the main DNA-binding motif. Functional studies of the nonsense mutants showed impaired transcriptional activation of an SF-1-responsive promoter (Cyp11a). To date, adrenal insufficiency has not occurred in any of the patients.ConclusionsSF-1 (NR5A1) mutations should be considered in 46,XY individuals with severe (penoscrotal) hypospadias, especially if undescended testes, low testosterone, or low inhibin B/AMH levels are present. SF-1 mutations in milder forms of idiopathic hypospadias are unlikely to be common.

Background: Steroidogenic factor 1 (SF-1, NR5A1) is a key transcriptional regulator of many genes involved in the hypothalamic-pituitary-gonadal axis and mutations in NR5A1 can result in 46,XY disorders of sex development (DSD). Patients with this condition typically present with ambiguous genitalia, partial gonadal dysgenesis, and absent/rudimentary Mü llerian structures. In these cases, testosterone is usually low in early infancy, indicating significantly impaired androgen synthesis. Further, Sertoli cell dysfunction is seen (low inhibin B, anti-Mü llerian hormone). However, gonadal function at puberty in patients with NR5A1 mutations is unknown. Subjects and methods: Clinical assessment, endocrine evaluation, and genetic analysis were performed in one female and one male with 46,XY DSD who showed spontaneous virilization during puberty. The female patient presented at adolescence with clitoral hypertrophy, whereas the male patient presented at birth with severe hypospadias and entered puberty spontaneously. Molecular analysis of NR5A1 was performed followed by in vitro functional analysis of the two novel mutations detected. Results: Testosterone levels were normal during puberty in both patients. Analysis of NR5A1 revealed two novel heterozygous missense mutations in the ligand-binding domain of SF-1 (patient 1: p.L376F; patient 2: p.G328V). The mutant proteins showed reduced transactivation of the CYP11A promoter in vitro. Conclusion: Patients with 46,XY DSD and NR5A1 mutations can produce sufficient testosterone for spontaneous virilization during puberty. Phenotypic females (46,XY) with NR5A1 mutations can present with clitoromegaly at puberty, a phenotype similar to other partial defects of androgen synthesis or action. Testosterone production in 46,XY males with NR5A1 mutations can be sufficient for virilization at puberty. As progressive gonadal dysgenesis is likely, gonadal function should be monitored in adolescence and adulthood, and early sperm cryopreservation considered in male patients if possible.

Objective:The aim of our study is to assess the risk factors for medical treatment failure and to predict the patients who will require the surgical therapy as well as to predict the factors affecting treatment success. Material and Methods:This was a cross-sectional study including 76 women with tubo-ovarian abscesses (TOA) who were either conservatively or surgically treated and were admitted to two gynecology units over a 4-year period. The demographic characteristics of the patients, gynecologic and obstetric histories, size and localization of abscesses were recorded. Gentamicin plus clindamycin treatment protocol was implemented for all patients. Ampicillin treatment was added in three patients with the positive culture of Actinomyces. Response to treatment was evaluated after 48-72 h. Patients who fail to respond to medical treatment required surgery or percutaneous drainage. We compared clinical and laboratory factors between the groups. Results:In surgery group, patients were significantly older than the others (44.9±5.4 versus 39.1±7.6 years). Fifty-six patients (74%) responded to antibiotics and 20 of the patients required surgical intervention. Patients treated with antibiotics were hospitalized for an average of 6.32±2.8 days versus 12.75±5.6 days for those who required surgery (p=0.021). Patients who were surgically treated had a mean size of TOA of 67.9±11.2 mm versus 53.6±9.4 mm for those treated with antibiotics alone (p=0.036). There were no significant differences between groups in laboratory parameters, except for initial white blood cell (WBC) counts. The complications of surgery included in descending order of frequency blood transfusions, surgical wound infections, bowel injury, and bladder injury. Conclusion:An increased size of pelvic mass, higher initial WBC counts, advanced age, and smoking were all associated with failed response to conservative treatment. It is important to identify the risk factors to distinguish patients who will respond to antibiotic therapy and those who will need a surgical treatment. Thus, the required early intervention can result in a reduction in the morbidity associated with TOA. (J Turk Ger Gynecol Assoc 2015; 16: 226-30) Keywords: Antibiotic therapy, pelvic abscess, surgery, tubo-ovarian abscesses Received: 01 July, 2015 Accepted: 06 August, 2015 Available Online Date: 02 November, 2015 The evaluation of risk factors for failed response to conservative treatment in tubo-ovarian abscesses Material and MethodsThis was a cross-sectional study including 76 women with TOA who were either treated conservatively (group 1) and surgically (group 2) and were admitted to two gynecology units over a 4-year period. The study was subject to local ethics committee's approval, and written informed consent was obtained from patients who participated in this study. All authors and the study protocol have complied with the World Medical Association Declaration of Helsinki regarding the ethical conduct of research involving human subjects. In this study, some of t...

Hashimoto's thyroiditis is a common autoimmune disorder of the thyroid gland. It has been linked to infections with hepatitis C, EBV, HTLV-1, and Yersinia enterocolitica. As parvovirus B19 has been associated with a wide spectrum of autoimmune diseases, we investigated the potential role of B19 infection in inducing Hashimoto's thyroiditis. Serum samples derived from 73 children and adolescents with Hashimoto's thyroiditis and from 73 age-matched controls were included in the study. The mean age of disease manifestation was 10 y 7 mo. All samples were analyzed for the presence of viral DNA and for antibodies against VP1, VP2, and NS1 proteins. VP1- and VP2-specific antibodies were present in 38 patients (52%) and 43 controls (59%; N.S.). NS1-specific antibodies were detectable in 23 patients (32%) and 19 controls (26%; N.S.). Parvovirus B19 DNA was detectable in 9 patients (12%) and 2 controls (3%; p < 0.03), indicating recent B19-infection. A negative correlation between disease duration and the detection of viral DNA was seen. The mean disease duration in B19-DNA-positive patients was 6 mo, compared to 29 mo in the remainder (p < 0.01). There is strong evidence that acute parvovirus B19 infections are involved in the pathogenesis of some cases of Hashimoto's thyroiditis.

The recurrence of myoma was relatively low following CM. Subsequent pregnancy is protective for recurrence of myoma without increased adhesion formation and obstetric complications.

Aside from clinical endpoints like height gain, health-related quality of life has also become an important outcome indicator in the medical field. However, the data on short stature and health-related quality of life is inconsistent. Therefore, we examined changes in health-related quality of life in German children with idiopathic growth hormone deficiency or children born small for gestational age before and after 12 months of human growth hormone treatment. Children with idiopathic short stature without treatment served as a comparison group. At baseline, health-related quality of life data of 154 patients with idiopathic growth hormone deficiency ( n = 65), born small for gestational age ( n = 58), and idiopathic short stature ( n = 31) and one parent each was collected. Of these, 130 completed health-related quality of life assessments after 1-year of human growth hormone treatment. Outcome measures included the Quality of Life in Short Stature Youth questionnaire, as well as clinical and sociodemographic data. Our results showed that the physical, social, and emotional health-related quality of life of children treated with human growth hormone significantly increased, while untreated patients with idiopathic short stature reported a decrease in these domains. Along with this, a statistically significant increase in height in the treated group can be observed, while the slight increase in the untreated group was not significant. In conclusion, the results showed that human growth hormone treatment may have a positive effect not only on height but also in improving patient-reported health-related quality of life of children with idiopathic growth hormone deficiency and children born small for gestational age.

Background: Congenital adrenal hyperplasia (CAH) is one of the most common autosomal recessive inherited endocrine diseases. Steroid 11b-hydroxylase (P450c11) deficiency (11OHD) is the second most common form of CAH. Aim: The aim of the study was to study the functional consequences of three novel CYP11B1 gene mutations (p.His125Thrfs*8, p.Leu463_Leu464dup and p.Ser150Leu) detected in patients suffering from 11OHD and to correlate this data with the clinical phenotype. Methods: Functional analyses were done by using a HEK293 cell in vitro expression system comparing WT with mutant P450c11 activity. Mutant proteins were examined in silico to study their effect on the three-dimensional structure of the protein.Results: Two mutations (p.His125Thrfs*8 and p.Leu463_Leu464dup) detected in patients with classic 11OHD showed a complete loss of P450c11 activity. The mutation (p.Ser150Leu) detected in a patient with non-classic 11OHD showed partial functional impairment with 19% of WT activity. Conclusion: Functional mutation analysis enables the correlation of novel CYP11B1 mutations to the classic and non-classic 11OHD phenotype respectively. Mutations causing a non-classic phenotype show typically partial impairment due to reduced maximum reaction velocity comparable with non-classic mutations in 21-hydroxylase deficiency. The increasing number of mutations associated with non-classic 11OHD illustrate that this disease should be considered as diagnosis in patients with otherwise unexplained hyperandrogenism.