MKRN3 mutations represent the most common genetic cause of central precocious puberty (CPP) but associations between genotype and clinical features have not been extensively explored. This systematic review and meta-analysis investigated genotype-phenotype associations and prevalence of MKRN3 mutations in CPP. The search was conducted in seven electronic databases (Cochrane, EMBASE, LILACS, LIVIVO, PubMed, Scopus, and Web of Science) for articles published until 4 September 2018. Studies evaluating MKRN3 mutations in patients with CPP were considered eligible. A total of 22 studies, studying 880 subjects with CPP, fulfilled the inclusion criteria. Eighty-nine subjects (76 girls) were identified as harboring MKRN3 mutations. Girls, compared with boys, exhibited earlier age at pubertal onset (median, 6.0 years; range, 3.0 to 7.0 vs 8.5 years; range, 5.9 to 9.0; P < 0.001), and higher basal FSH levels (median, 4.3 IU/L; range, 0.7 to 13.94 IU/L vs 2.45 IU/L; range, 0.8 to 13.70 IU/L; P = 0.003), and bone age advancement ( Δ BA; median, 2.3 years; range, −0.9 to 5.2 vs 1.2 years; range, 0.0 to 2.3; P = 0.01). Additional dysmorphisms were uncommon. A total of 14 studies evaluating 857 patients were included for quantitative analysis, with a pooled overall mutation prevalence of 9.0% (95% CI, 0.04 to 0.15). Subgroup analysis showed that prevalence estimates were higher in males, familial cases, and in non-Asian countries. In conclusion, MKRN3 mutations are associated with nonsyndromic CPP and manifest in a sex-dimorphic manner, with girls being affected earlier. They represent a common cause of CPP in western countries, especially in boys and familial cases.

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We aimed to evaluate characteristics associated with acute-phase response (APR) following first zoledronic acid infusion in a Brazilian cohort. This retrospective cohort study enrolled all adults with osteoporosis who underwent a first zoledronic acid infusion at our centre between June 2015 and June 2019. Clinical demographics (age, sex, diabetes, smoking, body mass index, and previous oral bisphosphonate use) and laboratory data (calcium, parathyroid hormone, renal function, and serum 25-hydroxyvitamin D and carboxy-terminal crosslinked telopeptide of type 1 collagen [CTX], both before and after infusion) were compared between patients with and without APR. We evaluated association magnitude between the presence of APR and clinical variables through logistic regression. This study enrolled 400 patients (women, 80%). APR was observed in 24.5% (n = 98) of patients. The mean symptom duration in days was 3.5 ± 2.8. Patients with APR were younger (67 ± 12 vs. 71 ± 11 years; p = 0.001 ), used oral bisphosphonates less frequently (34% × 50%; p = 0.005 ), and had greater baseline CTX (0.535 ng/mL [0.375, 0.697] × 0.430 [0.249, 0.681]; p = 0.03 ) and ΔCTX (−69 [−76; −50] × −54 [−72; −23]; p = 0.002 ) than those without APR. The other variables were similar between the groups. Only ΔCTX was associated (OR, 0.62; 95% CI 0.41–0.98) with APR after accounting for age and bisphosphonate use. APR occurred in 24.5% of the cohort. Younger age and absence of prior oral bisphosphonate use were associated with APR following first zoledronic acid infusion. APR was associated with ΔCTX (but no other variables) after adjusting for these factors.

ObjectiveTo describe the frequency of hypophysitis and hypopituitarism in cancer patients who are undergoing antineoplastic treatment with immunotherapy, as well as to describe the clinical, epidemiological, and demographic characteristics of these patients.MethodsA systematic search of the literature in PubMed, Embase, Web of Science, ClinicalTrials.gov and Cochrane Controlled Register of Trials took place on May 8 and 9, 2020. Randomized and nonrandomized clinical trials, cohort studies, case-control studies, case series and case reports were included.ResultsA total of 239 articles were obtained, in which 963 cases of hypophysitis and 128 cases of hypopituitarism were found in a treated population of 30,014 individuals (3.20% and 0.42% of the evaluated population, respectively). In the cohort studies, the incidence of hypophysitis and hypopituitarism ranged from 0% to 27.59% and from 0% to 17.86%, respectively. In the non-randomized clinical trials, the incidence of hypophysitis and hypopituitarism ranged from 0% to 25% and from 0% to 14.67%, and in randomized clinical trials from 0% to 16.2% and from 0% to 33.33%. The most common hormonal changes were in the corticotrophic, thyrotrophic and gonadotrophic axes. The main magnetic resonance imaging (MRI) findings were enlargement of the pituitary gland and enhanced contrast uptake. The main symptoms presented by patients with hypophysitis were fatigue and headache.ConclusionThe present review reported a frequency of hypophysitis and hypopituitarism of 3.20% and 0.42%, respectively, in the evaluated population. The clinical-epidemiological characteristics of patients affected by hypophysitis were also described.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42020175864.

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Os hemangiomas do seio cavernoso são neoplasias vasculares raras que representam cerca de 2% a 3% dos tumores do seio cavernoso. As manifestações clínicas incluem cefaleia, sinais e sintomas decorrentes do efeito de massa, como alterações visuais e paralisia de nervos cranianos e comprometimento da função hipofisária, que mimetizam os achados de outras doenças dessa região, como meningiomas, adenomas hipofisários ou neurinomas. O diagnóstico se baseia nos achados radiológicos e na histologia. O tratamento ideal ainda não está claro, visto que a cirurgia pode se associar a elevada morbidade pelo risco de complicações hemorrágicas, de alterações neurológicas e impossibilidade de ressecção completa da lesão. A radiocirurgia estereotáxica ou a radioterapia fracionada representam opções seguras e eficazes de tratamento e podem propiciar redução significativa do tumor. Os autores descrevem a apresentação clínica, os achados radiológicos, histológicos e a evolução após radioterapia fracionada de uma paciente com hemangioma gigante do seio cavernoso. Palavras-chave. Hemangioma do seio cavernoso; massa selar; radioterapia

Introduction : Central precocious puberty (CPP), defined as the onset of pubertal signs before the age of 8 in girls and 9 in boys, results from the premature reactivation of the hypothalamic-pituitary-gonadal axis. CPP is familial in as many as 27.5% of the cases, which supports a genetic origin of this disorder. Currently, monogenic defects associated with CPP include inactivating mutations in MKRN3 and rare defects in KIS S1, KISS1R and DLK1 . In addition, CPP has been associated with complex genetic syndromes resulting from distinct chromosomal abnormalities as Silver-Russel Syndrome and Temple Syndrome. However in many patients its genetic basis remains unknown. Objective: To investigate pathogenic copy number variations (CNVs) in patients with idiopathic CPP associated with dysmorphic features or congenital malformations. Methods : A cohort of 45 patients with idiopathic CPP was initially evaluated for mutations in the coding region of MKRN3 . Subsequently, 3 patients screened negative for MKRN3 mutations and with additional dysmorphisms or congenital malformations were selected for chromosome microarray analysis (CMA) using the Affymetrix CytoScan 750k according to manufacturer’s protocols. Results: In patient 1 (P1), a boy presenting CPP at the age of 8 associated with autism spectrum disorder and overweight, a pathogenic previously described heterozygous microdeletion at 16p11.2 (761 kbp), and a microduplication at 18p11.22 (363kbp), a variant of unknown significance (VOUS), were detected. His younger brother, who also has ASD and was recently diagnosed with CPP, also carried the same CNVs. Patient 2 (P2) was a monozygotic twin boy with a past history of hypospadia, an angular deformity of the femur, and pubertal onset at age of 6.5years. His monozygotic twin was equally affected and both developed polycythemia in the beginning of the second decade of life. CMA revealed a heterozygous duplication of 155kbp at 7p15.2, classified as VOUS. The third case (P3), a girl with idiopathic CPP associated with congenital heart disease, exhibited no significant chromosomal rearrangements, except for blocks of homozygosity due to parental consanguinity. Conclusion: Our results underscore the relevance of CMA in the investigation of patients with CPP associated with syndromic features. Parental consanguinity can also be identified by CMA and is associated with an increased risk of congenital anomalies, as was the case of P3. The 16p11.2 microdeletion has been previously associated with ASD, however CPP has not been previously reported in these patients. Further studies are needed to address possible associations between CPP and the CNVs and/or genes presented inside these variant regions identified in P1 and P2. Source of research support: C...