Genetic architecture of congenital hypogonadotropic hypogonadism: insights from analysis of a Portuguese cohort.

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. STUDY FUNDING/COMPETING INTERESTS: This research was funded by the Portuguese Foundation for Science and Technology (grant numbers PTDC/SAU-GMG/098419/2008, UIDB/00709/2020, CEECINST/00016/2021/CP2828/CT0002, and 2020.04924.BD) and by Sidra Medicine-a member of the Qatar Foundation (grant number SDR400038). The authors declare no competing interests.

Turner syndrome and neurofibromatosis type 1: the unusual combination of two common genetic disorders.

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.

Non-immune-mediated versus immune-mediated type 1 diabetes: diagnosis and long-term differences-retrospective analysis.

BACKGROUND: The American Diabetes Association proposed two subcategories for type 1 diabetes mellitus: type 1A or immune-mediated diabetes (IDM) and type 1B or idiopathic diabetes. The absence of ß-cell autoimmune markers, permanent insulinopenia and prone to ketoacidosis define the second category, whose pathogenesis remains unclear. Only a minority of patients fall into this category, also designated non-immune-mediated (NIDM), which is considered by several authors similar to type 2 diabetes. The aim of this study is to evaluate differences at the diagnosis and 10 years later of two categories. METHODS: Retrospective cohort study of patients with ß-cell autoimmune markers performed at diagnosis and undetectable c-peptide. Were excluded patients with suspicion of another specific type of diabetes. We obtained two groups: IDM (≥ 1 positive antibody) and NIDM (negative antibodies). Age, family history, anthropometry, duration of symptoms, clinical presentation, blood glucose at admission, A1C, lipid profile, arterial hypertension, total diary insulin dose (TDID), microvascular and macrovascular complications were evaluated. Results were considered statistically significant with p < 0.05. RESULTS: 37 patients, 29 with IDM and 8 patients with NIDM. The age of diagnosis of IDM group (23 years) was significantly different (p = 0.004) from the NIDM group (38.1). The body mass index (BMI) at the diagnosis did not differ significantly (p = 0.435). The duration of symptoms was longer in the NIDM (p = 0.003). The disease presentation (p = 0.744), blood glucose (p = 0.482) and HbA1c (p = 0.794) at admission and TDID at discharge (p = 0.301) did not differ significantly. Total and LDL cholesterol levels were higher in NIDM group but did not differ significantly (p = 0.585 and p = 0.579, respectively). After 10 years BMI did not differ between groups (p = 0.079). Patients with IDM showed a significantly higher HbA1c (p = 0.008) and TDID (p = 0.017). Relative to the lipid profile, there was no significant difference, however the LDL cholesterol and triglycerides were higher on the NIDM group, as the percentage of hypertension. Microvascular complications were higher in the IDM group, but no significant difference was found. CONCLUSION: Patients with IDM had a poor metabolic control and higher insulin requirement. Patients with NIDM were older and showed higher cardiovascular risk, resembling a clinical phenotype of type 2 diabetes.

Metformin in gestational diabetes mellitus: predictors of poor response.

OBJECTIVE: Metformin can be regarded as a first-line treatment in gestational diabetes mellitus (GDM) due to its safety and effectiveness. However, a proportion of women do not achieve adequate glycemic control with metformin alone. We aim to identify predictors of this poor response to metformin. DESIGN AND METHODS: Retrospective multicentre cohort study of women with GDM who started metformin as first-line treatment. The assessed cohort was divided into a metformin group and metformin plus insulin group. Biometric and demographic characteristics, glycemic control data, obstetric, neonatal and postpartum outcomes were compared between groups and analysed in order to identify predictors of poor response to metformin. Data were analysed using STATA, version 13.1. RESULTS: Of the 388 women enrolled in the study, 135 (34.8%) required additional insulin therapy to achieve the glycemic targets. Higher age (aOR: 1.08 (1.03-1.13), P = 0.003), higher pre-pregnancy body mass index (BMI) (1.06 (1.02-1.10), P = 0.003) and earlier introduction of metformin (0.89 (0.85-0.94), P < 0.001) were independent predictors for insulin supplementation. Regarding all the analysed outcomes, only cesarean delivery rates and postpartum glucose levels were higher in women requiring insulin supplementation. CONCLUSIONS: Although almost 35% of women did not achieve adequate glycemic control with metformin, insulin supplementation was not associated with poor neonatal outcomes. Higher age, higher pre-pregnancy BMI and earlier introduction of metformin could be used as predictors of poor response to metformin.

Giant macroprolactinoma and pregnancy.

Prolactinomas are a common cause of gonadal dysfunction and infertility. We present the case of a 38-year-old woman with history of amenorrhea and infertility. At seven weeks of pregnancy she presented neuro-ophthalmologic complaints of headaches, diplopia, and right ptosis. The work-up study revealed an invasive pituitary macroadenoma with a maximum diameter of 9 cm and serum prolactin of 25,800 ng/mL (3-20). At 12 weeks, she was referred to the Endocrinology Department of the Coimbra University Hospital and started therapy with bromocriptine, initially 5 mg/day and then at crescent doses. Hyperprolactinemia was rapidly and drastically reduced to 254 ng/mL three weeks after taking bromocriptine 15 mg/day. Tumoral volume was reduced and there was improvement of III pair paresis. At 38 weeks, a male healthy baby was born. This is a relevant clinical case that illustrates the efficacy and safety of bromocriptine therapy during pregnancy, even in severe cases like this one.

Giant macroprolactinoma and pregnancy / Macroprolactinoma gigante e gravidez

Prolactinomas are a common cause of gonadal dysfunction and infertility. We present the case of a 38-year-old woman with history of amenorrhea and infertility. At seven weeks of pregnancy she presented neuro-ophthalmologic complaints of headaches, diplopia, and right ptosis. The work-up study revealed an invasive pituitary macroadenoma with a maximum diameter of 9 cm and serum prolactin of 25,800 ng/mL (3-20). At 12 weeks, she was referred to the Endocrinology Department of the Coimbra University Hospital and started therapy with bromocriptine, initially 5 mg/day and then at crescent doses. Hyperprolactinemia was rapidly and drastically reduced to 254 ng/mL three weeks after taking bromocriptine 15 mg/day. Tumoral volume was reduced and there was improvement of III pair paresis. At 38 weeks, a male healthy baby was born. This is a relevant clinical case that illustrates the efficacy and safety of bromocriptine therapy during pregnancy, even in severe cases like this one.

Os prolactinomas são uma causa comum de anovulação e infertilidade. Apresenta-se o caso de uma mulher de 38 anos com antecedentes de amenorreia e infertilidade. Por volta das sete semanas de gestação, iniciaram-se clínica neuro-oftalmológica de cefaleias hemicranianas, ptose palpebral direita e diplopia. O estudo complementar revela a presença de macroadenoma hipofisário com cerca de 9 cm de maior diâmetro, de crescimento invasivo e destrutivo associado à hiperprolactinemia de 25.800 ng/mL (3-20). Às 12 semanas, foi referenciada à consulta de Endocrinologia e iniciou terapêutica com bromocriptina 5 mg/dia em doses crescentes. A prolactina diminuiu drasticamente para 254 ng/mL três semanas após, sob 15 mg/dia de bromocriptina. O volume tumoral também foi significativamente reduzido nas suas diferentes extensões. Clinicamente, houve regressão da ptose palpebral e da restante sintomatologia neuro-oftalmológica. O parto ocorreu por via vaginal às 38 semanas, com recém-nascido saudável. Este caso clínico é relevante, ilustrando bem a eficácia e a inocuidade da terapêutica com bromocriptina durante toda a gravidez, mesmo em casos graves como este.

[Late onset congenital adrenal hyperplasia due to 21-hydroxylase deficiency: revision of literature and preconception genetic study of five couples]. / Hiperplasia congénita da suprarenal de expressão tardia por deficiência de 21-hidroxilase: revisão da literatura e estudo genético preconcepção de cinco casais.

The deficiency of the enzyme 21-hydroxylase (21-HO) is responsible for about 90% to 95% of all cases of congenital adrenal hyperplasia (HCSR). This disorder is one of the most frequent hereditary illnesses of autosomal recessive trait. The illness can be presented in two clinical forms: 1 - classic, subdivided in saltwasting form and simple virilizing form; 2 - nonclassic or late-onset. The severity of the illness is correlated with the degree of enzymatic activity of 21-HO, which depends on the type of mutation that occurs in gene CYP21A2. The late onset congenital adrenal hyperplasia is that one where the enzymatic blockade is less intense. The clinical is variable: precocious pubarche, polycystic ovaries, hirsutism, oligoamenorrhea, acne and infertility. Gold standard for the diagnosis of late onset congenital adrenal hyperplasia consists on the test of the tetracosactide, considering itself diagnostic positive when 17-hidroxiprogesterona (17-OHP) is higher of 10-15 ng per mL. Many patients don't need treatment; however, if necessary, such a treatment essentially consists on the Administration of glucocorticoids and antiandrogens. Considering that affected individuals and the carriers may have a severe mutation in CYP21A2, they can have descendents with the classic form (if their partner is also a carrier of a severe mutation), it is mandatory the genetic study of the couple. The authors illustrate the importance of this genetic study through five clinical cases, whose common link is the desire to have children, as well as the presence on the feminine element of late onset congenital adrenal hyperplasia. The genetic study of the couple allows adequate pre-conception counseling and also prevents the use of corticoids throughout the pregnancy (if there's no risk of descendents being affected with the classic form). This aspect must be had in account in programming the pregnancy, in order to prevent therapeutics and unnecessary distrusts.