Background/Aims: Increasing numbers of children and adolescents seek medical care because they experience incongruence between their physical sex and their gender identity. Methods: The ESPE working group on gender dysphoria (GD) undertook a survey to investigate the structure and the type of medical care in centers that offer specialist care for transgender adolescents. Results: The personnel of each center varied from country to country, and a nationally organized network or plan for managing GD did not exist in all centers. The majority of young people were transitioning from female to male, and the number of new referrals increased remarkably during the past 3 years. Almost all centers follow the guidelines issued by the Endocrine Society and World Professional Association for Transgender Health. GnRH analogues were used as the initial treatment in the majority of the centers. The age from which adolescents are treated with gender-affirming hormones varied between centers. Several legal restrictions that concern or influence the treatment of children and adolescents with GD were finally addressed. Conclusion: This first international survey examining the variations in availability and provisions of services for children and adolescents with GD serves as a starting block for further dialogue and future studies.

To evaluate the results of the screening program for congenital hypothyroidism (CH) in the Greek Cypriot population. During 1990-2000, 109,532 neonates were screened by TSH determination. Permanent CH was proven with biochemical findings after discontinuation of treatment for scintigraphy at the age of 3 years. Permanent CH was diagnosed in 61 infants, incidence 1/1800, with female/male ratio 2.05/1. The most common clinical findings were omphalocele (61%), large anterior fontanelles (49%) and edema of the eyelids (34%). The more delayed the bone maturation, the lower were initial T4 levels (p = 0.005). Bone maturation tended to be more advanced in thyroid hypoplasia and more delayed in thyroid agenesis (p = 0.049). Scintigraphy of the thyroid with TC99 revealed ectopia in 38%, thyroid agenesis in 36%, thyroid hypoplasia in 24% and dyshormonogenesis in 1.7%. Children with transient CH had significantly lower T4 and higher TSH values initially compared to those with permanent CH after birth; initial TSH level, however, failed to predict the nature of CH. Children with transient CH required less thyroxine dosage to maintain normal thyroid hormone levels and they had a normal thyroid gland on scintigraphy. The TSH level was normalized before the age of 2 months with a starting L-thyroxine dose of 10 microg/kg/daily. The incidence of primary CH in Greek Cypriots is 1/1800 live births. The most common etiology is thyroid dysgenesis. Initial T4 levels correlated with the degree of skeletal maturation and the etiology. Initial TSH level, although lower in children with transient CH, could not predict the nature of CH.

Human sexual and reproductive development is regulated by the hypothalamic-pituitary-gonadal (HPG) axis, which is primarily controlled by the gonadotropin-releasing hormone (GnRH) acting on its receptor (GnRHR). Dysregulation of the axis leads to conditions such as congenital hypogonadotropic hypogonadism (CHH) and delayed puberty. The pathophysiology of GnRHR makes it a potential target for treatments in several reproductive diseases and in congenital adrenal hyperplasia. GnRHR belongs to the G protein-coupled receptor family and its GnRH ligand, when bound, activates several complex and tissue-specific signaling pathways. In the pituitary gonadotrope cells, it triggers the G protein subunit dissociation and initiates a cascade of events that lead to the production and secretion of the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) accompanied with the phospholipase C, inositol phosphate production, and protein kinase C activation. Pharmacologically, GnRHR can be modulated by synthetic analogues. Such analogues include the agonists, antagonists, and the pharmacoperones. The agonists stimulate the gonadotropin release and lead to receptor desensitization with prolonged use while the antagonists directly block the GnRHR and rapidly reduce the sex hormone production. Pharmacoperones include the most recent GnRHR therapeutic approaches that directly correct the misfolded GnRHRs, which are caused by genetic mutations and hold serious promise for CHH treatment. Understanding of the GnRHR’s genomic and protein structure is crucial for the most appropriate assessing of the mutation impact. Such mutations in the GNRHR are linked to normosmic hypogonadotropic hypogonadism and lead to various clinical symptoms, including delayed puberty, infertility, and impaired sexual development. These mutations vary regarding their mode of inheritance and can be found in the homozygous, compound heterozygous, or in the digenic state. GnRHR expression extends beyond the pituitary gland, and is found in reproductive tissues such as ovaries, uterus, and prostate and non-reproductive tissues such as heart, muscles, liver and melanoma cells. This comprehensive review explores GnRHR’s multifaceted role in human reproduction and its clinical implications for reproductive disorders.

Patients with rare diseases face health disparities and are often challenged to find accurate information about their condition. We aimed to use the best available evidence and community partnerships to produce patient education materials for congenital hypogonadotropic hypogonadism (CHH) and the olfacto-genital (Kallmann) syndrome (i.e., CHH and defective sense of smell), and to evaluate end-user acceptability. Expert clinicians, researchers and patients co-created the materials in a multi-step process. Six validated algorithms were used to assess reading level of the final product. Comprehensibility and actionability were measured using the Patient Education Materials Assessment Tool via web-based data collection. Descriptive statistics were employed to summarize data and thematic analysis for analyzing open-ended responses. Subsequently, translation and cultural adaption were conducted by clinicians and patients who are native speakers. Co-created patient education materials reached the target 6th grade reading level according to 2/6 (33%) algorithms (range: grade 5.9–9.7). The online survey received 164 hits in 2 months and 63/159 (40%) of eligible patients completed the evaluation. Patients ranged in age from 18 to 66 years (median 36, mean 39 ± 11) and 52/63 (83%), had adequate health literacy. Patients scored understandability at 94.2% and actionability at 90.5%. The patient education materials were culturally adapted and translated into 20 languages (available in Additional file 1). Partnering with patients enabled us to create patient education materials that met patient- identified needs as evidenced by high end-user acceptability, understandability and actionability. The web-based evaluation was effective for reaching dispersed rare disease patients. Combining dissemination via traditional healthcare professional platforms as well as patient-centric sites can facilitate broad uptake of culturally adapted translations. This process may serve as a roadmap for creating patient education materials for other rare diseases.