POU6F2 mutation in humans with pubertal failure alters GnRH transcript expression

Idiopathic hypogonadotropic hypogonadism (IHH) is characterized by the absence of pubertal development and subsequent impaired fertility often due to gonadotropin-releasing hormone (GnRH) deficits. Exome sequencing of two independent cohorts of IHH patients identified 12 rare missense variants in POU6F2 in 15 patients. POU6F2 encodes two distinct isoforms. In the adult mouse, expression of both isoform1 and isoform2 was detected in the brain, pituitary, and gonads. However, only isoform1 was detected in mouse primary GnRH cells and three immortalized GnRH cell lines, two mouse and one human. To date, the function of isoform2 has been verified as a transcription factor, while the function of isoform1 has been unknown. In the present report, bioinformatics and cell assays on a human-derived GnRH cell line reveal a novel function for isoform1, demonstrating it can act as a transcriptional regulator, decreasing GNRH1 expression. In addition, the impact of the two most prevalent POU6F2 variants, identified in five IHH patients, that were located at/or close to the DNA-binding domain was examined. Notably, one of these mutations prevented the repression of GnRH transcripts by isoform1. Normally, GnRH transcription increases as GnRH cells mature as they near migrate into the brain. Augmentation earlier during development can disrupt normal GnRH cell migration, consistent with some POU6F2 variants contributing to the IHH pathogenesis

Effect of maternal and infant vitamin D supplementation on vitamin D levels of breastfed infants

The aim of our study was to investigate the effect of maternal vitamin D-3 (400 U/day) supplementation on breastfed infants at 6 months of age. Mothers (n=96) were enrolled within 1 month after birth and assigned to the 400 IU/day regimen or no vitamin D-3 supplementation for 6 months. All infants received 400 IU/day of vitamin D-3 and were exclusively breastfed until 4 months of age. Of all mothers, 22.2% had vitamin D levels above 20 ng/ml initially. At the end of the study, vitamin D levels of mothers and their infants were similar in both groups. Thirteen percent of the infants in the intervention group and 20.5% in the control group had vitamin D levels below 12 ng/ml. Serum 25-hydroxyvitamin D (25(OH) D) concentrations at 6 months had increased significantly in mothers in the intervention group. Lactating mothers and their children need vitamin D supplementation but further studies are required with higher doses

Management of Systemic Hypersensitivity Reactions to Gonadotropin-Releasing Hormone Analogues during Treatment of Central Precocious Puberty

Background:Besides local reactions, systemic hypersensitivity reactions such as urticaria, anaphylaxis, serum sickness and Henoch-Schonlein purpura (HSP) have been reported during gonadotropin-releasing hormone (GnRH) analogue treatment.Aim:To present the clinical presentation of 9 cases with systemic hypersensitivity reactions to GnRH analogues and discuss the management of such reactions based on our experience.Patients and Methods:Nine of 232 (3.8%) patients with central precocious puberty receiving GnRH analogue treatment had systemic hypersensitivity reactions in 4 years' period. Six patients had a type 1 hypersensitivity reaction (generalized hives, pruritus, and/or edema) to triptorelin acetate (TA), 2 patients to leuprolide acetate (LA), and 1 patient to both medications who also developed anaphylaxis to LA during intradermal test (IDT). Another patient on TA had skin lesions suggestive of HSP. GnRH analogue treatment was discontinued in 2 patients after discussion with the parents. Treatment was changed to another GnRH analogue preparation in 6 patients and was maintained with the same medication with antihistamines and corticosteroid premedication in 1 patient. None of the patients developed new reactions after these precautions.Conclusion:Systemic hypersensitivity reactions should be carefully evaluated and cross-reaction to the other GnRH analogues should be kept in mind. Discontinuation of GnRH analogue is always an option. However, if continuation of GnRH analogue is elected, we recommend switching to an alternative GnRH analogue, which should be considered only after a skin prick test (SPT) and IDT. In the lack of the possibility to perform SPT and IDT, injections may be administered under strict medical supervision in a well-equipped facility to manage anaphylaxis. We discuss additional options in situations where alternative GnRH analogues are unavailable, which enabled us to continue treatment in most cases without further problems

Surgical Practice in Girls with Congenital Adrenal Hyperplasia: An International Registry Study.

In this article international trends in surgical practice in girls with congenital adrenal hyperplasia (CAH) are evaluated. All cases that had been classified in the I-CAH/I-DSD registry as 46,XX CAH and who were born prior to 2017 were identified. Centers were approached to obtain information on surgical decision making. Of the 330 included participants, 208 (63.0%) presented within the first month of life, and 326 (98.8%) cases were assigned female. Genital surgery had been performed in 250 (75.8%). A total of 64.3, 89.2, and 96.8% of cases residing in Europe, South America and Asia, respectively, had at least one surgery. In a logistic regression model for the probability of surgery before the second birthday (early surgery) over time an increase of probability for early vaginal surgery could be identified, but not for clitoral surgery or both surgeries combined. Genitoplasty in girls with CAH remains controversial. This large international study provides a snapshot of current practice and reveals geographical and temporal differences. Fewer surgeries were reported for Europe, and there seems to be a significant trend towards aiming for vaginal surgery within the first 2 years of life

Characteristics of Turkish children with Type 2 diabetes at onset: a multicentre, cross-sectional study

Aims To describe the baseline clinical and laboratory findings and treatment modalities of 367 children and adolescents diagnosed with Type 2 diabetes in various paediatric endocrinology centres in Turkey. Methods A standard questionnaire regarding clinical and laboratory characteristics at onset was uploaded to an online national database system. Data for 367 children (aged 6-18 years) newly diagnosed with Type 2 diabetes at 37 different paediatric endocrinology centres were analysed. Results After exclusion of the children with a BMI Z-score 50% of the children were asymptomatic at diagnosis. The other important result of our study was the high rate of exclusion from the initial registration (38%), suggesting that accurate diagnosis of Type 2 diabetes in youth is still problematic, even for paediatric endocrinologists

Characteristics of Turkish children with Type 2 diabetes at onset: a multicentre, cross-sectional study

Aims To describe the baseline clinical and laboratory findings and treatment modalities of 367 children and adolescents diagnosed with Type 2 diabetes in various paediatric endocrinology centres in Turkey. Methods A standard questionnaire regarding clinical and laboratory characteristics at onset was uploaded to an online national database system. Data for 367 children (aged 6-18 years) newly diagnosed with Type 2 diabetes at 37 different paediatric endocrinology centres were analysed. Results After exclusion of the children with a BMI Z-score < 1 SD, those with genetic syndromes associated with Type 2 diabetes, and those whose C-peptide and/or insulin levels were not available, 227 cases were included in the study. Mean age was 13.8 +/- 2.2 (range 6.5-17.8) years, with female preponderance (68\%). Family history of Type 2 diabetes was positive in 86\% of the children. The mean BMI was 31.3 +/- 6.5 kg/m(2) (range 18.7-61) and BMI Z-score was 2.4 +/- 0.8 (range 1-5). More than half (57\%) of the children were identified by an opportunistic diabetes screening due to existing risk markers without typical symptoms of diabetes. Only 13\% (n = 29) were treated solely by lifestyle modification, while 40.5\% (n = 92) were treated with metformin, 13\% (n = 30) were treated with insulin, and 33.5\% (n = 76) were treated with a combination of insulin and metformin initially. Mean HbA(1C) levels of the insulin and combination of insulin and metformin groups were 98 (11.1\%) and 102 mmol/mol (11.5\%), respectively, and also were significantly higher than the lifestyle modification only and metformin groups mean HbA(1C) levels (70(8.6\%) and 67 mmol/mol (8.3\%), respectively). Conclusions An opportunistic screening of children who are at high risk of Type 2 diabetes is essential, as our data showed that > 50\% of the children were asymptomatic at diagnosis. The other important result of our study was the high rate of exclusion from the initial registration (38\%), suggesting that accurate diagnosis of Type 2 diabetes in youth is still problematic, even for paediatric endocrinologists