CONTEXT:GH deficiency is a rare disorder characterized by severe short stature, which can result from genetic mutations affecting hypothalamic-pituitary development and function. OBJECTIVE:To determine the genetic basis of GH deficiency in a Portuguese cohort. DESIGN, SETTING, PATIENTS:Multicenter cohort of 203 GH-deficient patients (78 with isolated GH deficiency and 125 with combined pituitary hormone deficiency) were analyzed. INTERVENTION:Screening of a panel of 184 GH deficiency-related genes using Sanger sequencing and whole exome sequencing. MAIN OUTCOME MEASURE:Rare sequence variants (population maximum allele frequency <0.01). RESULTS:A genetic cause was identified in 23.2% of patients (9.0% in isolated GH deficiency and 32.0% in combined pituitary hormone deficiency). Mutations were found in the PROP1 (14.8% of patients), GLI2 (2.0%), KMT2D (1.0%), PROK2 (1.0%), PROKR2 (1.0%), CDON (0.5%), COL1A2 (0.5%), COL2A1 (0.5%), GHRHR (0.5%), PTPN11 (0.5%), and SOX3 (0.5%) genes. One patient (0.5%) had a digenic mutation in the BMP4 and NF1 genes. Variants of uncertain significance were identified in 87.8% of patients. CONCLUSION:This study revealed several novel and recurrent mutations that expand the genetic spectrum of GH deficiency and underscore the genetic heterogeneity of this disorder. A significant proportion of patients remained genetically undiagnosed, suggesting the involvement of additional unknown genetic, epigenetic, or environmental factors. These findings contribute to the understanding of the genetic architecture of GH deficiency and highlight the need for further investigations to elucidate underlying mechanisms and identify additional causative factors.

STUDY QUESTION: What is the contribution of genetic defects in Portuguese patients with congenital hypogonadotropic hypogonadism (CHH)? SUMMARY ANSWER: Approximately one-third of patients with CHH were found to have a genetic cause for their disorder, with causal pathogenic and likely pathogenic germline variants distributed among 10 different genes; cases of oligogenic inheritance were also included. WHAT IS KNOWN ALREADY: CHH is a rare and genetically heterogeneous disorder characterized by deficient production, secretion, or action of GnRH, LH, and FSH, resulting in delayed or absent puberty, and infertility. STUDY DESIGN, SIZE, DURATION: Genetic screening was performed on a cohort of 81 Portuguese patients with CHH (36 with Kallmann syndrome and 45 with normosmic hypogonadotropic hypogonadism) and 263 unaffected controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: The genetic analysis was performed by whole-exome sequencing followed by the analysis of a virtual panel of 169 CHH-associated genes. The main outcome measures were non-synonymous rare sequence variants (population allele frequency <0.01) classified as pathogenic, likely pathogenic, and variants of uncertain significance (VUS). MAIN RESULTS AND THE ROLE OF CHANCE: A genetic cause was identified in 29.6% of patients. Causal pathogenic and likely pathogenic variants were distributed among 10 of the analysed genes. The most frequently implicated genes were GNRHR, FGFR1, ANOS1, and CHD7. Oligogenicity for pathogenic and likely pathogenic variants was observed in 6.2% of patients. VUS and oligogenicity for VUS variants were observed in 85.2% and 54.3% of patients, respectively, but were not significantly different from that observed in controls. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: The identification of a large number of VUS presents challenges in interpretation and these may require reclassification as more evidence becomes available. Non-coding and copy number variants were not studied. Functional studies of the variants were not undertaken. WIDER IMPLICATIONS OF THE FINDINGS: This study highlights the genetic heterogeneity of CHH and identified several novel variants that expand the mutational spectrum of the disorder. A significant proportion of patients remained without a genetic diagnosis, suggesting the involvement of additional genetic, epigenetic, or environmental factors. The high frequency of VUS underscores the importance of cautious variant interpretation. These findings contribute to the understanding of the genetic architecture of CHH and emphasize the need for further studies to elucidate the underlying mechanisms and identify additional causes of CHH.

The 17-beta-hydroxysteroid dehydrogenase type 3 (17-β-HSD3) enzyme converts androstenedione to testosterone and is encoded by the HSD17B3 gene. Homozygous or compound heterozygous HSD17B3 mutations block the synthesis of testosterone in the fetal testis, resulting in a Disorder of Sex Development (DSD). We describe a child raised as a female in whom the discovery of testes in the inguinal canals led to a genetic study by whole exome sequencing (WES) and to the identification of a compound heterozygous mutation of the HSD17B3 gene (c.608C>T, p.Ala203Val, and c.645A>T, p.Glu215Asp). Furthermore, we review all HSD17B3 mutations published so far in cases of 17-β-HSD3 deficiency. A total of 70 different HSD17B3 mutations have so far been reported in 239 patients from 187 families. A total of 118 families had homozygous mutations, 63 had compound heterozygous mutations and six had undetermined genotypes. Mutations occurred in all 11 exons and were missense (55%), splice-site (29%), small deletions and insertions (7%), nonsense (5%), and multiple exon deletions and duplications (2%). Several mutations were recurrent and missense mutations at codon 80 and the splice-site mutation c.277+4A>T each represented 17% of all mutated alleles. These findings may be useful to those involved in the clinical management and genetic diagnosis of this disorder.

Summary The coexistence of neurofibromatosis type 1 (NFT1) and Turner syndrome (TS) has only been reported in a few patients and may represent a diagnostic challenge. We describe the case of a 16-year-old girl, with a prior clinical diagnosis of NFT1, who was referred to Endocrinology appointments for the etiological study of primary amenorrhea. Evaluation of the anterior pituitary function was requested and hypergonadotropic hypogonadism was detected. During the etiological study, a 45X karyotype was found and TS was diagnosed. The fact that NFT1 can also be associated with short stature, short broad neck and hypertelorism was likely responsible for TS being diagnosed in late adolescence. As both TS and NFT1 are relatively common genetic disorders, it is important to be alert to the possibility that the presence of one disease does not invalidate the other. Learning points The concomitant presence of two syndromes in the same patient is unlikely and represents a diagnostic challenge. Some phenotypic characteristics and clinical manifestations may be shared by several syndromes. Some syndromes, such as neurofibromatosis type 1 may have very heterogeneous presentations. It is important to be alert to the characteristics that are not explained by the initial diagnosis. If such features are present, diagnostic work-up must be performed regardless of the initial syndromic diagnosis.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

To analyze the association between scan frequency and glycemic measures in continuous subcutaneous insulin infusion (CSII) treated type 1 diabetes (T1DM) adults. This retrospective study included 140 patients (> 18 years) with T1DM who used flash glucose monitoring (FGM). For each patient, we analyzed the Ambulatory Glucose Profile data over a period of 90 days. Data regarding glucose management indicator (GMI), time above, below and within range (TIR) and coefficient of variation (CV) were correlated with the number of daily scans. The effect of each additional test on glucose parameters was also evaluated. Users performed a mean of 8.6 ± 4.4 scans per day. There was an inverse correlation between scanning frequency and GMI (r = − 0.431, p < 0.001), CV (r = − 0.440, p < 0.001), time above and below range (r = − 0.446, p < 0.001 and r = − 0.200, p = 0.018, respectively). The number of daily scans correlated positively with TIR (r = 0.554, p < 0.001). For each additional scan per day, the mean GMI decreased 0.09% and TIR increased 1.60%. In patients with T1DM and CSII, higher rates of scanning correlated with improved glycemic markers, including reduced GMI and CV and increased TIR. For each test performed, there was a significant effect on the improvement of all glucose parameters.

(SS) amenorrhea, karyotype ,i(Xq), and XXX [10]/46, [2], T2DM after oral tolerance test, the of respectively, in the first cases, fasting glucose levels in the metformin, metabolic The with at of 2 to SS, karyotype ,i(Xq). At was with T1DM, with autoimmune thy- roiditis and This has an unsatisfactory control, was diagnosed with diabetic retinopathy at the of T2DM cases easily controlled and were diagnosed at as previously described. it’s that mortality, especially cardiovascular, is augmented in this syndrome. It’s that autoimmunity is increased in TS, contributes to the development of T1DM. It was demons-trated association between certain cytogenetic alterations and DM. The recognition of this risk and the establishment of an adequate follow-up in a specialized and multidisciplinary team are essential.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Turner syndrome is the most common chromosomal abnormalities in women, due to total or partial loss of the X chromosome. It is characterized by short stature, gonadal dysgenesis and systemic involvement, that leads to an increase in morbidity and mortality and a decrease in quality of life. Therefore, a multidisciplinary approach to these women in adulthood is mandatory. This article aims to describe the main implications of Turner syndrome and provide recommendations for its management in adult life.

Summary Familial hypomagnesemia with secondary hypocalcemia (FHSH) is a rare autosomal recessive disorder (OMIM# 602014) characterized by profound hypomagnesemia associated with hypocalcemia. It is caused by mutations in the gene encoding transient receptor potential cation channel member 6 (TRPM6). It usually presents with neurological symptoms in the first months of life. We report a case of a neonate presenting with recurrent seizures and severe hypomagnesemia. The genetic testing revealed a novel variant in the TRPM6 gene. The patient has been treated with high-dose magnesium supplementation, remaining asymptomatic and without neurological sequelae until adulthood. Early diagnosis and treatment are important to prevent irreversible neurological damage. Learning points: Loss-of-function mutations of TRPM6 are associated with FHSH. FHSH should be considered in any child with refractory hypocalcemic seizures, especially in cases with serum magnesium levels as low as 0.2 mM. Normocalcemia and relief of clinical symptoms can be assured by administration of high doses of magnesium. Untreated, the disorder may be fatal or may result in irreversible neurological damage.

Maturity-onset diabetes of the young (MODY) is a frequently misdiagnosed type of diabetes, which is characterized by early onset, autosomal dominant inheritance, and absence of insulin dependence. The most frequent subtypes are due to mutations of the GCK (MODY 2), HNF1A (MODY 3), and HNF4A (MODY 1) genes. We undertook the first multicenter genetic study of MODY in the Portuguese population. The GCK, HNF1A, and HNF4A genes were sequenced in 46 unrelated patients that had at least two of the three classical clinical criteria for MODY (age at diagnosis, family history, and clinical presentation). The functional consequences of the mutations were predicted by bioinformatics analysis. Mutations were identified in 23 (50%) families. Twelve families had mutations in the GCK gene, eight in the HNF1A gene, and three in the HNF4A gene. These included seven novel mutations (GCK c.494T>C, GCK c.563C>G, HNF1A c.1623G>A, HNF1A c.1729C>G, HNF4A c.68delG, HNF4A c.422G>C, HNF4A c.602A>C). Mutation-positive patients were younger at the time of diagnosis when compared to mutation-negative patients (14.3 vs. 23.0 years, p = 0.011). This study further expands the spectrum of known mutations associated with MODY, and may contribute to a better understanding of this type of diabetes and a more personalized clinical management of affected individuals.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Introdudion: The advent of glucocorticoid therapy for autoimmune diseases in the 1940s led to the discovery of its adverse metabolic effects. These mimic the effect of endogenous glucocorticoids, with effects at the pancreatic beta cell level, leading to their dysfunction, and peripheral tissues, with development of insulin resistance. Overweight elderly patients with long-term and high-dose corticosteroids are at increased risk of developing steroid induced diabetes mellitus. It is responsible for the increase in hospital admissions, risk of infection and graft dysfunction in patients who underwent solid organ transplantation. This article aims to review the pathophysiology, risk factors, diagnosis and treatment of steroid induced diabetes mellitus. Methods: A systematic search of articles published on this topic until April 2017 was carried out in the PubMed database. The research terms used were "diabetes", "glucocorticoid", "steroid" "treatment", "management" and "effect". Conclusion: The challenges associated with this entity relate to postprandial glycemic fluctuation and the absence of clearly defined consensus and treatment protocols. The main therapeutic option is insulin, adapted to the type of glucocorticoid and its dosage.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Introduction: Gender dysphoria (GD) is characterized by a marked discordance between the psychological perception of individual sex and the biological phenotype. In the present article, the authors aimed to analyze the clinical data of a cohort of subjects diagnosed with GD, referred to a national unit, specialized in the endocrine, psychiatric and surgical treatment of this entity. Methods: Data about demographics and response to treatment, were retrospectively analysed in 85 subjects diagnosed with GD, who were observed in the Endocrinology Consultation, during a 12-year period. Results: It was verified that among 85 patients included in the study, 38 (44.7%) were transgender females and 47 (55.3%) were transgender males. The number of patients seeking treatment substantially increased in the last 5 years, with an inferior age of referral in transgender males. Sixty-three patients (74.1%) started cross-sex hormone therapy, deprived of significant adverse events, and gender affirming surgery was performed in 25 patients (29.4%). Conclusion: Our study revealed a progressively growing number of patients seeking sexual reassignment, being predominantly transgender males. The majority of subjects started hormone therapy without substantial related adverse events, corroborating that it may be considered as a relatively safe treatment. Gender affirming surgery was performed in a reasonable number of patients, which was comparable with the experience of other centers.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)