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
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conferenceObject RESPONSE TO RHGH THERAPY IN SHORT CHILDREN BORN AT VERY LOW BIRTH WEIGHT(2023) MALAQUIAS, A. C.; HOMMA, T.; DANTAS, M. C. B.; FREIRE, B. L.; ALBUQUE, E. V. A.; ARNHOLD, I. J. P.; VASQUES, G. A.; JORGE, A. A. L.- Combined pituitary hormone deficiency caused by PROP1 mutations: update 20 years post-discovery(2019) CORREA, Fernanda A.; NAKAGUMA, Marilena; MADEIRA, Joao L. O.; NISHI, Mirian Y.; ABRAO, Milena G.; JORGE, Alexander A. L.; CARVALHO, Luciani R.; ARNHOLD, Ivo J. P.; MENDONCA, Berenice B.The first description of patients with combined pituitary hormone deficiencies (CPHD) caused by PROP1 mutations was made 20 years ago. Here we updated the clinical and genetic characteristics of patients with PROP1 mutations and summarized the phenotypes of 14 patients with 7 different pathogenic PROP1 mutations followed at the Hospital das Clinicas of the University of Sao Paulo. In addition to deficiencies in GH, TSH, PRL and gonadotropins some patients develop late ACTH deficiency. Therefore, patients with PROP1 mutations require permanent surveillance. On magnetic resonance imaging, the pituitary stalk is normal, and the posterior lobe is in the normal position. The anterior lobe in patients with PROP1 mutations is usually hypoplastic but may be normal or even enlarged. Bi-allelic PROP1 mutations are currently the most frequently recognized genetic cause of CPHD worldwide. PROP1 defects occur more frequently among offspring of consanguineous parents and familial cases, but they also occur in sporadic cases, especially in countries in which the prevalence of PROP1 mutations is relatively high. We classified all reported PROP1 variants described to date according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines: 29 were pathogenic, 2 were likely pathogenic, and 2 were of unknown significance. An expansion of the phenotype of patients with PROP1 mutations was observed since the first description 20 years ago: variable anterior pituitary size, different pathogenic mutations, and late development of ACTH deficiency. PROP1 mutations are the most common cause of autosomal recessive CPHD with a topic posterior pituitary lobe.
article 6 Citação(ões) na Scopus Mutations in insulin-like growth factor receptor 1 gene (IGF1R) resulting in intrauterine and postnatal growth retardation(2011) LEAL, Andrea de Castro; CANTON, Ana Pinheiro Machado; MONTENEGRO, Luciana Ribeiro; COUTINHO, Debora Cabral; ARNHOLD, Ivo Jorge Prado; JORGE, Alexander Augusto de LimaApproximately 10% of children born small-for-gestational age (SGA) do not show spontaneous growth catch-up. The causes of this deficit in prenatal growth and its maintenance after birth are not completely known, in most cases. Over the past eight years, several heterozygous inactivating mutations and deletions in IGF1R gene have been reported, indicating the role of defects in the IGFs/IGF1R axis as a cause of growth deficit. It has been hypothesized that at least 2.5% of children born SGA may have IGF1R gene defects. The clinical presentation of these patients is highly variable in the severity of growth retardation and hormonal parameters. In the most evident cases, patients have microcephaly, mild cognitive impairment and high levels of IGF-1, associated with short stature of prenatal onset. This review will describe the clinical, molecular and treatment of short stature with hrGH of children with mutations in the IGF1R gene. Arq Bras Endocrinol Metab. 2011;55(8):541-9- Two rare loss-of-function variants in the STAG3 gene leading to primary ovarian insufficiency(2019) FRANCA, Monica M.; NISHI, Mirian Y.; FUNARI, Mariana F. A.; LERARIO, Antonio M.; BARACAT, Edmund C.; HAYASHIDA, Sylvia A. Y.; MACIEL, Gustavo A. R.; JORGE, Alexander A. L.; MENDONCA, Berenice B.Background/Aim: Primary ovarian insufficiency (POI) is characterized by primary or secondary amenorrhea, infertility, low estradiol levels, and increased gonadotropin levels. Most cases of POI remain unsolved even after exhaustive investigation. Here, we performed a targeted massively parallel sequencing to identify the genetic diagnosis of primary ovarian insufficiency (POI) in a Brazilian patient. Patient and methods: An adopted 21-year-old Brazilian woman with isolated POI was selected. A custom SureSelect(xT) DNA target enrichment panel was designed and sequenced on an Illumina NextSeq 500 sequencer. The variants were confirmed using Sanger sequencing. Results: Two rare heterozygous pathogenic variants in the STAG3 gene were identified in our patient. An unpublished 1-bp duplication c.291dupC (p.Asn98Glnfs*2) and one stop codon variant c.1950C > A (p.Tyr650*) were identified in the STAG3 gene. Both undescribed heterozygous variants were absent in the public databases [1000Genomes, Exome Aggregation Consortium (ExAC), National Heart, Lung, and Blood Institute Exome Variant Server (NHLBI/EVS), database of Single Nucleotide Polymorphisms (dbSNP), Genome Aggregation Database (gnomAD)], and Online Archive of Brazilian Mutations (ABraOM) databases. Moreover, neither heterozygous variants were found in 400 alleles from fertile Brazilian women screened by Sanger sequencing. The parents' DNA was not available to segregate these variants. Conclusion: Our results suggested that POI is caused by pathogenic compound heterozygous variants in the STAG3 gene, supporting the key role of the STAG3 gene in the etiology of primary ovarian insufficiency.
bookPart Aplicações clínicas dos testes genéticos em endocrinologia(2017) SOUZA, Bruno Ferraz de; SILVA, Magnus Régios Dias da; ALMEIDA, Madson Queiroz de; JORGE, Alexander Augusto de Lima- STAT5B mutations in heterozygous state have negative impact on height: another clue in human stature heritability(2015) SCALCO, Renata C.; HWA, Vivian; DOMENE, Horacio M.; JASPER, Hector G.; BELGOROSKY, Alicia; MARINO, Roxana; PEREIRA, Alberto M.; TONELLI, Carlos A.; WIT, Jan M.; ROSENFELD, Ron G.; JORGE, Alexander A. L.Context and objective: GH insensitivity with immune dysfunction caused by STAT5B mutations is an autosomal recessive condition. Heterozygous mutations in other genes involved in growth regulation were previously associated with a mild height reduction. Our objective was to assess for the first time the phenotype of heterozygous STAT5B mutations. Methods: We genotyped and performed clinical and laboratory evaluations in 52 relatives of two previously described Brazilian brothers with homozygous STAT5B c.424_427del mutation (21 heterozygous). Additionally, we obtained height data and genotype from 1104 adult control individuals from the same region in Brazil and identified five additional families harboring the same mutation (18 individuals, 11 heterozygous). Furthermore, we gathered the available height data from first-degree relatives of patients with homozygous STAT5B mutations (17 individuals from seven families). Data from heterozygous individuals and non-carriers were compared. Results: Individuals carrying heterozygous STAT5B c.424_427del mutation were 0.6 SDS shorter than their non-carrier relatives (P=0.009). Heterozygous subjects also had significantly lower SDS for serum concentrations of IGF1 (P=0.028) and IGFBP3 (P=0.02) than their non-carrier relatives. The 17 heterozygous first-degree relatives of patients carrying homozygous STAT5B mutations had an average height SDS of -1.4 +/- 0.8 when compared with population-matched controls (P<0.001). Conclusions: STAT5B mutations in the heterozygous state have a significant negative impact on height (similar to 3.9 cm). This effect is milder than the effect seen in the homozygous state, with height usually within the normal range. Our results support the hypothesis that heterozygosity of rare pathogenic variants contributes to normal height heritability.
- Genetic Predictors of Long-Term Response to Growth Hormone (GH) Therapy in Children With GH Deficiency and Turner Syndrome: The Influence of a SOCS2 Polymorphism(2014) BRAZ, Adriana F.; COSTALONGA, Everlayny F.; TRARBACH, Ericka B.; SCALCO, Renata C.; MALAQUIAS, Alexsandra C.; GUERRA-JUNIOR, Gil; ANTONINI, Sonir R. R.; MENDONCA, Berenice B.; ARNHOLD, Ivo J. P.; JORGE, Alexander A. L.Background: There is great interindividual variability in the response to GH therapy. Ascertaining genetic factors can improve the accuracy of growth response predictions. Suppressor of cytokine signaling (SOCS)-2 is an intracellular negative regulator of GH receptor (GHR) signaling. Objective: The objective of the study was to assess the influence of a SOCS2 polymorphism (rs3782415) and its interactive effect with GHR exon 3 and -202 A/C IGFBP3 (rs2854744) polymorphisms on adult height of patients treated with recombinant human GH (rhGH). Design and Patients: Genotypes were correlated with adult height data of 65 Turner syndrome (TS) and 47 GH deficiency (GHD) patients treated with rhGH, by multiple linear regressions. Generalized multifactor dimensionality reduction was used to evaluate gene-gene interactions. Results: Baseline clinical data were indistinguishable among patients with different genotypes. Adult height SD scores of patients with at least one SOCS2 single-nucleotide polymorphism rs3782415-C were 0.7 higher than those homozygous for the T allele (P < .001). SOCS2 (P < .003), GHR-exon 3 (P = .016) and -202 A/C IGFBP3 (P = .013) polymorphisms, together with clinical factors accounted for 58% of the variability in adult height and 82% of the total height SD score gain. Patients harboring any two negative genotypes in these three different loci (homozygosity for SOCS2 T allele; the GHR exon 3 full-length allele and/or the -202C-IGFBP3 allele) were more likely to achieve an adult height at the lower quartile (odds ratio of 13.3; 95% confidence interval of 3.2-54.2, P = .0001). Conclusion: The SOCS2 polymorphism (rs3782415) has an influence on the adult height of children with TS and GHD after long-term rhGH therapy. Polymorphisms located in GHR, IGFBP3, and SOCS2 loci have an influence on the growth outcomes of TS and GHD patients treated with rhGH. The use of these genetic markers could identify among rhGH-treated patients those who are genetically predisposed to have less favorable outcomes.
- Genetic Disorders in Prenatal Onset Syndromic Short Stature Identified by Exome Sequencing(2019) HOMMA, Thais Kataoka; FREIRE, Bruna Lucheze; KAWAHIRA, Rachel Sayuri Honjo; DAUBER, Andrew; FUNARI, Mariana Ferreira de Assis; LERARIO, Antonio Marcondes; NISHI, Mirian Yumie; ALBUQUERQUE, Edoarda Vasco de; VASQUES, Gabriela de Andrade; COLLETT-SOLBERG, Paulo Ferrez; SUGAYAMA, Sofia Mizuho Miura; BERTOLA, Debora Romeo; KIM, Chong Ae; ARNHOLD, Ivo Jorge Prado; MALAQUIAS, Alexsandra Christianne; JORGE, Alexander Augusto de LimaObjective To perform a prospective genetic investigation using whole exome sequencing of a group of patients with syndromic short stature born small for gestational age of unknown cause. Study design For whole exome sequencing analysis, we selected 44 children born small for gestational age with persistent short stature, and additional features, such as dysmorphic face, major malformation, developmental delay, and/or intellectual disability. Seven patients had negative candidate gene testing based on clinical suspicion and 37 patients had syndromic conditions of unknown etiology. Results Of the 44 patients, 15 (34%) had pathogenic/likely pathogenic variants in genes already associated with growth disturbance: COL2A1 (n = 2), SRCAP (n = 2), AFF4, ACTG1, ANKRD11, BCL11B, BRCA1, CDKN1C, GINS1, INPP5K, KIF11, KMT2A, and POC1A (n = 1 each). Most of the genes found to be deleterious participate in fundamental cellular processes, such as cell replication and DNA repair. Conclusions The rarity and heterogeneity of syndromic short stature make the clinical diagnosis difficult. Whole exome sequencing allows the diagnosis of previously undiagnosed patients with syndromic short stature.
- Influence of growth hormone receptor (GHR) exon 3 and-202A/C IGFBP-3 genetic polymorphisms on clinical and biochemical features and therapeutic outcome of patients with acromegaly(2015) JALLAD, Raquel S.; TRARBACH, Ericka B.; DUARTE, Felipe H.; JORGE, Alexander A. L.; BRONSTEIN, Marcello D.The association of GHR-exon 3 and -202 A/C IGFBP3 polymorphisms with clinical presentation, biochemical measurements and response to therapies in acromegaly have been suggested. To evaluate the presence of these polymorphisms in acromegaly and their influence on clinical and laboratorial characteristics of patients at diagnosis and after treatment in a large cohort of acromegalic patients. This is a cross-sectional study developed in a single tertiary reference center. Clinical data were obtained from the medical records of 186 acromegalic patients (116 women, age range 21-88 years). GH and IGF1 levels and GHR-exon 3 and -202 A/C IGFBP3 polymorphisms were evaluated in the same hospital. At diagnosis, serum GH concentrations were lower in patients with GHR-d3 genotype than those with GHR-fl, whereas an association of lower IGFBP3 levels with d3 allele was observed only after neurosurgical or medical treatments. However, these associations were not confirmed in posterior statistical analysis. Our results suggest that GHR-exon 3 and -202 A/C IGFBP3 polymorphisms did not show any consistent association on clinical and laboratorial features of acromegalic patients even after treatment.
conferenceObject Copy Number Variants in Patients with Congenital Hypopituitarism Associated with Complex Phenotypes(2015) CORREA, F.; FRANCA, M.; CANTON, A.; OTTO, A.; COSTALONGA, E.; BRITO, V; CARVALHO, L.; COSTA, S.; ARNHOLD, I; JORGE, A.; ROSENBERG, C.; MENDONCA, B.