Context Loss-of-function mutations of makorin RING finger protein 3 (MKRN3) are the most common monogenic cause of familial central precocious puberty (CPP). Objective To describe the clinical and hormonal features of a large cohort of patients with CPP due to MKRN3 mutations and compare the characteristics of different types of genetic defects. Methods Multiethnic cohort of 716 patients with familial or idiopathic CPP screened for MKRN3 mutations using Sanger sequencing. A group of 156 Brazilian girls with idiopathic CPP (ICPP) was used as control group. Results Seventy-one patients (45 girls and 26 boys from 36 families) had 18 different loss-of-function MKRN3 mutations. Eight mutations were classified as severe (70% of patients). Among the 71 patients, first pubertal signs occurred at 6.2 ± 1.2 years in girls and 7.1 ± 1.5 years in boys. Girls with MKRN3 mutations had a shorter delay between puberty onset and first evaluation and higher follicle-stimulating hormone levels than ICPP. Patients with severe MKRN3 mutations had a greater bone age advancement than patients with missense mutations (2.3 ± 1.6 vs 1.6 ± 1.4 years, P = .048), and had higher basal luteinizing hormone levels (2.2 ± 1.8 vs 1.1 ± 1.1 UI/L, P = .018) at the time of presentation. Computational protein modeling revealed that 60% of the missense mutations were predicted to cause protein destabilization. Conclusion Inherited premature activation of the reproductive axis caused by loss-of-function mutations of MKRN3 is clinically indistinct from ICPP. However, the type of genetic defect may affect bone age maturation and gonadotropin levels.

No abstract

diseases with improved DA compared to TBFB, but with insufficient evidence in diagnosis and screening of ACR. This study aims to provide data on safety, diagnostic utility and impact on treatment decisions after TBLC in lung transplant recipients (LTRs). Methods: Between December 2019 and June 2020, both TBFB and LBLC were obtained serially in LTRs during the same bronchoscopy session to detect ACR. According to our protocol, after 5 TBFB samples, 2 samples by TBLC were taken from different lung segments. The biopsies were scored according to the recent ISHLT criteria by a dedicated transplant pathologist, assessing TBFB and TBLC samples independently. The severity of bleeding we assessed with the Nashville Bleeding Scale (grade 1 -4), and pneumothoraces were excluded with routine chest radiography. Results: Totally, 25 consecutive procedures in 17 LTRs (13 males, median age 58) were performed either as routine surveillance bronchchoscopy (n = 19) or as clinically indicated (n = 6) using flexible bronchoscopy. Retrospective analysis of 125 TBFB and 50 TBLC samples was performed. ACR (A1 -A3) was detected in 6 cases (24%) by TBLC resulting in a change of immunosuppressive strategy, compared to 0% by TBFB. Nondiagnostic biopsy samples were noted in 3 cases (12%) of TBLC compared to 21 (84%) of TBFB. The biopsy procedure was complicated by moderate (grade 2) bleeding in 6 (24%) cases as a complication of TBCB, since it occurs immediately after this procedure. No pneumothorax was detected. Conclusion: TBLC provided improved DA for diagnosis of ACR with an acceptable safety profile, leading to reclassification and a change of treatment strategy in 24% of the cases. Further prospective studies are needed to confirm these findings and recommend TBLC as gold standard to detect ACR.

Context: Familial central precocious puberty (CPP) is a prevalent form (about 27.5%) of precocious puberty. Loss-of-function mutations in two maternally imprinted genes, MKRN3 and DLK1, were identified in families with CPP showing dominant autosomal inheritance with paternal transmission. Maternally transmitted CPP was previously demonstrated in up to 60% of families using pedigree analysis, however, no definitive genetic abnormality has been identified so far. Objectives To estimate the prevalence of familial cases in a multiethnic cohort with CPP. To characterize the genetic basis and the mode of inheritance of the affected families. To compare clinical and hormonal features of patients with familial CPP due to different modes of transmission. Patients and Methods Clinical and hormonal data were obtained from medical registries of 495 patients with CPP and no brain MRI alterations. Familial CPP was defined as the presence of one or more close relatives with CPP or precocious menarche (≤9 yr). Sanger sequencing of MKRN3 and DLK1 was performed in 427 index cases. Targeted gene panel sequencing was performed in 79 cases, while whole exome sequencing was performed in 101 cases from 36 families Results Among 495 index cases, 159 had familial CPP (31%). The mode of transmission of CPP was identified as paternal in 58 (35%), maternal in 59 (38%), indeterminate in 34 (22%), and both maternal and paternal transmission in 8 (5%). Most families with paternal or maternal transmission had 2 generations known to be affected (51 and 77%, respectively). Notably, 67% of index cases with maternally transmitted CPP had their mother affected. In girls with CPP, the median age of thelarche was 6.5 yr in the paternally transmitted group, 6.9 yr in the maternally transmitted group, and 7.3 yr in the indeterminate group (p= 0.547). Median bone age advancement was 2.1, 2.3 and 1.2 yr, respectively (p= 0.013). Basal LH levels were higher in girls with paternally transmitted CPP (p= 0.047). Among those with paternally transmitted CPP, MKRN3 and DLK1 mutations were identified in, respectively, 63.8% and 10.3% of the families. Conclusions A significant prevalence (31%) of familial CPP was demonstrated in a multiethnic cohort. Maternally transmitted CPP represented the most frequent form of familial CPP (38%). MKRN3 loss-of-function mutations were responsible for most paternally transmitted CPP cases (63.8%), followed by DLK1 loss-of-function mutations (10.3%). Presentation: Monday, June 13, 2022 11:15 a.m. - 11:30 a.m.

Direitos para esta edição cedidos à Atena Editora pelos autores. Todo o conteúdo deste livro está licenciado sob uma Licença de Atribuição Creative Commons. Atribuição-Não-Comercial-NãoDerivativos 4.0 Internacional (CC BY-NC-ND 4.0). O conteúdo dos artigos e seus dados em sua forma, correção e confiabilidade são de responsabilidade exclusiva dos autores, inclusive não representam necessariamente a posição oficial da Atena Editora. Permitido o download da obra e o compartilhamento desde que sejam atribuídos créditos aos autores, mas sem a possibilidade de alterá-la de nenhuma forma ou utilizá-la para fins comerciais. Todos os manuscritos foram previamente submetidos à avaliação cega pelos pares, membros do Conselho Editorial desta Editora, tendo sido aprovados para a publicação com base em critérios de neutralidade e imparcialidade acadêmica. A Atena Editora é comprometida em garantir a integridade editorial em todas as etapas do processo de publicação, evitando plágio, dados ou resultados fraudulentos e impedindo que interesses financeiros comprometam os padrões éticos da publicação. Situações suspeitas de má conduta científica serão investigadas sob o mais alto padrão de rigor acadêmico e ético.