ALEXANDER AUGUSTO DE LIMA JORGE
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Clínica Médica, Faculdade de Medicina - Docente
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
LIM/25 - Laboratório de Endocrinologia Celular e Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
LIM/25 - Laboratório de Endocrinologia Celular e Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
22 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 22
- Diagnostic yield of a multigene sequencing approach in children classified as idiopathic short stature(2022) ANDRADE, Nathalia Liberatoscioli Menezes; FUNARI, Mariana Ferreira de Assis; MALAQUIAS, Alexsandra Christianne; COLLETT-SOLBERG, Paulo Ferrez; GOMES, Nathalia L. R. A.; SCALCO, Renata; DANTAS, Naiara Castelo Branco; REZENDE, Raissa C.; TIBURCIO, Angelica M. F. P.; SOUZA, Micheline A. R.; FREIRE, Bruna L.; V, Ana C. Krepischi; LONGUI, Carlos Alberto; LERARIO, Antonio Marcondes; ARNHOLD, Ivo J. P.; JORGE, Alexander A. L.; VASQUES, Gabriela AndradeObjectiveMost children with short stature remain without an etiologic diagnosis after extensive clinical and laboratory evaluation and are classified as idiopathic short stature (ISS). This study aimed to determine the diagnostic yield of a multigene analysis in children classified as ISS. Design and methodsWe selected 102 children with ISS and performed the genetic analysis as part of the initial investigation. We developed customized targeted panel sequencing, including all genes already implicated in the isolated short-stature phenotype. Rare and deleterious single nucleotide or copy number variants were assessed by bioinformatic tools. ResultsWe identified 20 heterozygous pathogenic (P) or likely pathogenic (LP) genetic variants in 17 of 102 patients (diagnostic yield = 16.7%). Three patients had more than one P/LP genetic alteration. Most of the findings were in genes associated with the growth plate differentiation: IHH (n = 4), SHOX (n = 3), FGFR3 (n = 2), NPR2 (n = 2), ACAN (n = 2), and COL2A1 (n = 1) or involved in the RAS/MAPK pathway: NF1 (n = 2), PTPN11 (n = 1), CBL (n = 1), and BRAF (n = 1). None of these patients had clinical findings to guide a candidate gene approach. The diagnostic yield was higher among children with severe short stature (35% vs 12.2% for height SDS <= or > -3; P = 0.034). The genetic diagnosis had an impact on clinical management for four children. ConclusionA multigene sequencing approach can determine the genetic etiology of short stature in up to one in six children with ISS, removing the term idiopathic from their clinical classification.
conferenceObject X-Linked Central Precocious Puberty Associated with MECP2 defects(2022) CANTON, Ana; TINANO, Flavia; GUASTI, Leonardo; MONTENEGRO, Luciana; RYAN, Fiona; SHEARS, Deborah; MELO, Maria Edna; GOMES, Larissa; PIANA, Mariana; BRAUNER, Raja; ESPINO, Rafael; ESCRIBANO-MUNOZ, Arancha; PAGANONI, Alyssa; KORBONITS, Marta; SERAPHIM, Carlos Eduardo; FARIA, Aline; COSTA, Silvia; KREPISCHI, Ana Cristina; JORGE, Alexander; DAVID, Alessia; ARGENTE, Jesus; MENDONCA, Berenice; BRITO, Vinicius; HOWARD, Sasha; LATRONICO, Ana Claudia- Adult Height of Patients with SHOX Haploinsufficiency with or without GH Therapy: A Real-World Single-Center Study(2022) DANTAS, Naiara C. B.; FUNARI, Mariana F. A.; VASQUES, Gabriela A.; ANDRADE, Nathalia L. M.; REZENDE, Raissa C.; BRITO, Vinicius; SCALCO, Renata C.; ARNHOLD, Ivo J. P.; MENDONCA, Berenice B.; JORGE, Alexander A. L.Introduction: Isolated SHOX haploinsufficiency is a common monogenic cause of short stature. Few studies compare untreated and rhGH-treated patients up to adult height (AH). Our study highlights a growth pattern from childhood to AH in patients with SHOX haploinsufficiency and analyzes the real-world effectiveness of rhGH alone or plus GnRH analog (GnRHa). Methods: Forty-seven patients (18 untreated and 29 rhGH-treated) with SHOX haploinsufficiency were included in a longitudinal retrospective study. Adult height was attained in 13 untreated and 18 rhGH-treated (rhGH alone [n = 8] or plus GnRHa [n = 10]) patients. Results: The untreated group decreased height SDS from baseline to AH (-0.8 [-1.1; -0.4]), with an increase in the prevalence of short stature from 31% to 77%. Conversely, the rhGH-treated group had an improvement in height SDS from baseline to AH (0.6 [0.2; 0.6]; p < 0.001), with a reduction in the prevalence of short stature (from 61% to 28%). AH in the rhGH-treated patients was 1 SD (6.3 cm) taller than in untreated ones. Regarding the use of GnRHa, the subgroups (rhGH alone or plus GnRHa) attained similar AH, despite the higher prevalence of pubertal patients and worse AH prediction at the start of rhGH treatment in patients who used combined therapy. Conclusion: The use of rhGH treatment improves AH in patients with SHOX haploinsufficiency, preventing the loss of height potential during puberty. In peripubertal patients, the addition of GnRHa to rhGH allows AH attainment similar to the AH of patients who start rhGH alone in the prepubertal age. (C) 2022 S. Karger AG, Basel
- Novel OTX2 loss of function variant associated with congenital hypopituitarism without eye abnormalities(2022) GRIFFERO, Mariana; BENEDETTI, Anna Flavia Figueredo; PEREZ, Marcela; CARVALHO, Luciani; JORGE, Alexander; LATRONICO, Ana Claudia; MENDONCA, Berenice; ARNHOLD, Ivo; MERICQ, VeronicaObjectives The normal development of the pituitary gland requires multiple induction signals and transcription factors encoded by more than 30 genes, including OTX2. OTX2 mutations have been described with eye abnormalities and variable congenital hypopituitarism, but rarely with hypopituitarism without ocular manifestations. Case presentation We report a girl with hypopituitarism associated with pituitary hypoplasia and pituitary stalk atrophy, without ocular manifestations. NGS revealed a novel heterozygous mutation in OTX2 c.426dupC:p.(Ser143Leufs*2). Conclusions Mutations in the transcription factor OTX2 have been associated with ocular, craniofacial, and pituitary development anomalies. Here we describe a novel mutation in OTX2 associated with hypopituitarism without an ocular phenotype.
- High-throughput Sequencing to Identify Monogenic Etiologies in a Preselected Polycystic Ovary Syndrome Cohort(2022) CRESPO, Raiane P.; ROCHA, Thais P.; MONTENEGRO, Luciana R.; NISHI, Mirian Y.; JORGE, Alexander A. L.; MACIEL, Gustavo A. R.; BARACAT, Edmund; LATRONICO, Ana Claudia; MENDONCA, Berenice B.; GOMES, Larissa G.Context: Polycystic ovary syndrome (PCOS) etiology remains to be elucidated, but familial clustering and twin studies have shown a strong heritable component. Objective: The purpose of this study was to identify rare genetic variants that are associated with the etiology of PCOS in a preselected cohort. Methods: This prospective study was conducted among a selected group of women with PCOS. The study's inclusion criteria were patients with PCOS diagnosed by the Rotterdam criteria with the following phenotypes: severe insulin resistance (IR), normoandrogenic-normometabolic phenotype, adrenal hyperandrogenism, primary amenorrhea, and familial PCOS. Forty-five patients were studied by target sequencing, while 8 familial cases were studied by whole exome sequencing. Results: Patients were grouped according to the inclusion criteria with the following distribution: 22 (41.5%) with severe IR, 13 (24.5%) with adrenal hyperandrogenism, 7 (13.2%) with normoandrogenic phenotype, 3 (5.7%) with primary amenorrhea, and 8 (15.1%) familial cases. DNA sequencing analysis identified 1 pathogenic variant in LMNA, 3 likely pathogenic variants in INSR, PIK3R1, and DLK1, and 6 variants of uncertain significance level with interesting biologic rationale in 5 genes (LMNA, GATA4, NR5A1, BMP15, and FSHR). LMNA was the most prevalent affected gene in this cohort (3 variants). Conclusion: Several rare variants in genes related to IR were identified in women with PCOS. Although IR is a common feature of PCOS, patients with extreme or atypical phenotype should be carefully evaluated to rule out monogenic conditions.
- High frequency of genetic/epigenetic disorders in short stature children born with very low birth weight(2022) FREIRE, Bruna Lucheze; HOMMA, Thais Kataoka; LERARIO, Antonio Marcondes; SEO, Go Hun; HAN, Heonjong; FUNARI, Mariana Ferreira de Assis; GOMES, Nathalia Lisboa; ROSEMBERG, Carla; KREPISCHI, Ana Cristina Victorino; VASQUES, Gabriela de Andrade; MALAQUIAS, Alexsandra Christianne; JORGE, Alexander Augusto de LimaMost infants born with very low birth weight (VLBW, birth weight < 1500 g) show spontaneous catch-up growth in postnatal life. The reasons for the absence of catch-up growth are not entirely understood. We performed a comprehensive investigation of 52 children born with VLBW. Ten children had a history of an external cause that explained the VLBW and five refused genetic evaluation. Twenty-three cases were initially evaluated by a candidate gene approach. Patients with a negative result in the candidate gene approach (n = 14) or without clinical suspicion (n = 14) were assessed by chromosome microarray analysis (CMA) and/or whole-exome sequencing (WES). A genetic condition was identified in 19 of 37 (51.4%) patients without an external cause, nine by candidate gene approach, and 10 by a genomic approach (CMA/WES). Silver-Russell syndrome was the most frequent diagnosis (n = 5) and the remaining patients were diagnosed with other rare monogenic conditions. Almost all patients with a positive genetic diagnosis exhibited syndromic features (94.4%). However, microcephaly, neurodevelopmental disorders, major malformation, or facial dysmorphism were also frequently observed in children with an external cause. In conclusion, a significant proportion of children born with VLBW with persistent short stature have a genetic/epigenetic condition.
- Variants in 46,XY DSD-Related Genes in Syndromic and Non-Syndromic Small for Gestational Age Children with Hypospadias(2022) BRAGA, B. L.; GOMES, N. L.; NISHI, M. Y.; FREIRE, B. L.; BATISTA, R. L.; FARIA JUNIOR, J. A. D.; FUNARI, M. F. A.; BENEDETTI, A. F. F.; NARCIZO, A. De Moraes; CARDOSO, L. Cavalca; LERARIO, A. M.; GUERRA-JUNIOR, G.; COSTA, E. M. F.; DOMENICE, S.; JORGE, A. A. L.; MENDONCA, B. B.Hypospadias is a common congenital disorder of male genital formation. Children born small for gestational age (SGA) present a high frequency of hypospadias of undetermined etiology. No previous study investigated the molecular etiology of hypospadias in boys born SGA using massively parallel sequencing. Our objective is to report the genetic findings of a cohort of patients born SGA with medium or proximal hypospadias. We identified 46 individuals with this phenotype from a large cohort of 46,XY DSD patients, including 5 individuals with syndromic features. DNA samples from subjects were studied by either whole exome sequencing or target gene panel approach. Three of the syndromic patients have 5 main clinical features of Silver-Russell syndrome (SRS) and were first studied by MLPA. Among the syndromic patients, loss of DNA methylation at the imprinting control region H19/IGF2 was identified in 2 individuals with SRS clinical diagnosis. Two novel pathogenic variants in compound heterozygous state were identified in the CUL7 gene establishing the diagnosis of 3M syndrome in one patient, and a novel homozygous variant in TRIM37 was identified in another boy with Mulibrey nanism phenotype. Among the non-syndromic subjects, 7 rare heterozygous variants were identified in 6 DSD-related genes. However, none of the variants found can explain the phenotype by themselves. In conclusion, a genetic defect that clarifies the etiology of hypospadias was not found in most of the non-syndromic SGA children, supporting the hypothesis that multifactorial causes, new genes, and/or unidentified epigenetic defects may have an influence in this condition.
bookPart Crescimento(2022) VASQUES, Gabriela de Andrade; JORGE, Alexander Augusto de Lima; ARNHOLD, Ivo Jorge PradobookPart Investigação genética(2022) JORGE, Alexander Augusto de Lima; SOUZA, Bruno Ferraz de; MENDONçA, Berenice Bilharinho de- Outcomes in growth hormone-treated Noonan syndrome children: Impact of PTPN11 variant status(2022) JORGE, Alexander; PIETROPOLI, Alberto; KELEPOURIS, Nicky; HORIKAWA, Reiko
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