ANNA FLAVIA FIGUEREDO BENEDETTI
Projetos de Pesquisa
Unidades Organizacionais
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
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conferenceObject Congenital Hypopituitarism: Stem Cell Accumulation in Mutants with Developmental Arrest and Depletion in Mutants with Hyperplasia(2014) CHANG, Claudia Veiga; ARAUJO, Ricardo Viera; CIRQUEIRA, Cinthya Santos; PARFIENIUK, Agata; GUZZO, Mariana F.; BENEDETTI, Anna Flavia F.; SOARES, Ibere C.; MILLAN, Maria Ines Perez; CAMPER, Sally Ann; CARVALHO, Luciani R. S.conferenceObject An Extremely Rare Novel Missense Variant p.M304V in SOX3 Gene is Responsible for an X-Linked GH Deficiency in a Brazilian Patient(2019) BENEDETTI, A. F. F.; SILVA, J. M.; BISCOTTO, I. P.; FERREIRA, N. P.; ARNHOLD, I. J. P.; MENDONCA, B. B.; CARVALHO, L. R. S.conferenceObject Gene Identification in Patients with Hypopituitarism: Next Generation Exome Sequencing Experience(2014) FANG, Qing; ARNHOLD, Ivo J. P.; BENEDETTI, Anna Flavia F.; MENDONAA, Berenice Bilharinho; BRUE, Thierry; CARVALHO, Luciani R. S.; CASTINETTI, Frederic; CORREA, Fernanda de Azevedo; LI, Jun Z.; MA, Qianyi; REYNAUD, Rachel; CAMPER, Sally Ann- 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.
- The phenotypic spectrum associated with OTX2 mutations in humans(2021) GREGORY, Louise C.; GERGICS, Peter; NAKAGUMA, Marilena; BANDO, Hironori; PATTI, Giuseppa; MCCABE, Mark J.; FANG, Qing; MA, Qianyi; OZEL, Ayse Bilge; LI, Jun Z.; POINA, Michele Moreira; JORGE, Alexander A. L.; BENEDETTI, Anna F. Figueredo; LERARIO, Antonio M.; ARNHOLD, Ivo J. P.; MENDONCA, Berenice B.; MAGHNIE, Mohamad; CAMPER, Sally A.; CARVALHO, Luciani R. S.; DATTANI, Mehul T.Objective: The transcription factor OTX2 is implicated in ocular, craniofacial, and pituitary development.& nbsp; Design: We aimed to establish the contribution of OTX2 mutations in congenital hypopituitarism patients with/without eye abnormalities, study functional consequences, and establish OTX2 expression in the human brain, with a view to investigate the mechanism of action.& nbsp; Methods: We screened patients from the UK (n = 103), international centres (n = 24), and Brazil (n = 282); 145 were within the septo-optic dysplasia spectrum, and 264 had no eye phenotype. Transactivation ability of OTX2 variants was analysed in murine hypothalamic GT1-7 neurons. In situ hybridization was performed on human embryonic brain sections. Genetically engineered mice were generated with a series of C-terminal OTX2 variants.& nbsp; Results: Two chromosomal deletions and six haploinsufficient mutations were identified in individuals with eye abnormalities; an affected relative of one patient harboured the same mutation without an ocular phenotype. OTX2 truncations led to significant transactivation reduction. A missense variant was identified in another patient without eye abnormalities; however, studies revealed it was most likely not causative. In the mouse, truncations proximal to aa219 caused anophthalmia, while distal truncations and the missense variant were tolerated. During human embryogenesis, OTX2 was expressed in the posterior pituitary, retina, ear, thalamus, choroid plexus, and partially in the hypothalamus, but not in the anterior pituitary.& nbsp; Conclusions: OTX2 mutations are rarely associated with hypopituitarism in isolation without eye abnormalities, and may be variably penetrant, even within the same pedigree. Our data suggest that the endocrine phenotypes in patients with OTX2 mutations are of hypothalamic origin.
- Allelic Variants in Established Hypopituitarism Genes Expand Our Knowledge of the Phenotypic Spectrum(2021) NAKAGUMA, Marilena; FERREIRA, Nathalia Garcia Bianchi Pereira; BENEDETTI, Anna Flavia Figueredo; MADI, Mariana Cotarelli; SILVA, Juliana Moreira; LI, Jun Z.; MA, Qianyi; OZEL, Ayse Bilge; FANG, Qing; NARCIZO, Amanda de Moraes; CARDOSO, Lais Cavalca; MONTENEGRO, Luciana Ribeiro; FUNARI, Mariana Ferreira de Assis; NISHI, Mirian Yumie; ARNHOLD, Ivo Jorge Prado; JORGE, Alexander Augusto de Lima; MENDONCA, Berenice Bilharinho de; CAMPER, Sally Ann; CARVALHO, Luciani R.We report four allelic variants (three novel) in three genes previously established as causal for hypopituitarism or related disorders. A novel homozygous variant in the growth hormone gene, GH1 c.171delT (p.Phe 57Leufs*43), was found in a male patient with severe isolated growth hormone deficiency (IGHD) born to consanguineous parents. A hemizygous SOX3 allelic variant (p.Met304Ile) was found in a male patient with IGHD and hypoplastic anterior pituitary. YASARA, a tool to evaluate protein stability, suggests that p.Met304Ile destabilizes the SOX3 protein (Delta Delta G = 2.49 kcal/mol). A rare, heterozygous missense variant in the TALE homeobox protein gene, TGIF1 (c.268C>T:p.Arg90Cys) was found in a patient with combined pituitary hormone deficiency (CPHD), diabetes insipidus, and syndromic features of holoprosencephaly (HPE). This variant was previously reported in a patient with severe holoprosencephaly and shown to affect TGIF1 function. A novel heterozygous TGIF1 variant (c.82T>C:p.Ser28Pro) was identified in a patient with CPHD, pituitary aplasia and ectopic posterior lobe. Both TGIF1 variants have an autosomal dominant pattern of inheritance with incomplete penetrance. In conclusion, we have found allelic variants in three genes in hypopituitarism patients. We discuss these variants and associated patient phenotypes in relation to previously reported variants in these genes, expanding our knowledge of the phenotypic spectrum in patient populations.
- HESX1 mutations in patients with congenital hypopituitarism: variable phenotypes with the same genotype(2016) FANG, Qing; BENEDETTI, Anna Flavia Figueredo; MA, Qianyi; GREGORY, Louise; LI, Jun Z.; DATTANI, Mehul; SADEGHI-NEJAD, Abdollah; ARNHOLD, Ivo J. P.; MENDONCA, Berenice Bilharinho; CAMPER, Sally A.; CARVALHO, Luciani R.IntroductionMutations in the transcription factor HESX1 can cause isolated growth hormone deficiency (IGHD) or combined pituitary hormone deficiency (CPHD) with or without septo-optic dysplasia (SOD). So far there is no clear genotype-phenotype correlation. Patients and ResultsWe report four different recessive loss-of-function mutations in three unrelated families with CPHD and no midline defects or SOD. A homozygous p.R160C mutation was found by Sanger sequencing in two siblings from a consanguineous family. These patients presented with ACTH, TSH and GH deficiencies, severe anterior pituitary hypoplasia (APH) or pituitary aplasia (PA) and normal posterior pituitary. The p.R160C mutation was previously reported in a case with SOD, CPHD and ectopic posterior pituitary (EPP). Using exome sequencing, a homozygous p.I26T mutation was found in a Brazilian patient born to consanguineous parents. This patient had evolving CPHD, normal ACTH, APH and normal posterior pituitary (NPP). A previously reported patient homozygous for p.I26T had evolving CPHD and EPP. Finally, we identified compound heterozygous mutations in HESX1, p.[R159W];[R160H], in a patient with PA and CPHD. We showed that both of these mutations abrogate the ability of HESX1 to repress PROP1-mediated transcriptional activation. A patient homozygous for p.R160H was previously reported in a patient with CPHD, EPP, APH. ConclusionThese three examples demonstrate that HESX1 mutations cause variable clinical features in patients, which suggests an influence of modifier genes or environmental factors on the phenotype.
- Genetic diagnosis of congenital hypopituitarism by a target gene panel: novel pathogenic variants in GLI2, OTX2 and GHRHR(2019) NAKAGUMA, Marilena; CORREA, Fernanda A.; SANTANA, Lucas S.; BENEDETTI, Anna F. F.; V, Ricardo Perez; HUAYLLAS, Martha K. P.; MIRAS, Mirta B.; FUNARI, Mariana F. A.; LERARIO, Antonio M.; MENDONCA, Berenice B.; CARVALHO, Luciani R. S.; JORGE, Alexander A. L.; ARNHOLD, Ivo J. P.Aim: Congenital hypopituitarism has an incidence of 1:3500-10,000 births and is defined by the impaired production of pituitary hormones. Early diagnosis has an impact on management and genetic counselling. The clinical and genetic heterogeneity of hypopituitarism poses difficulties to select the order of genes to analyse. The objective of our study is to screen hypopituitarism genes (candidate and previously related genes) simultaneously using a target gene panel in patients with congenital hypopituitarism. Methods: Screening of 117 subjects with congenital hypopituitarism for pathogenic variants in 26 genes associated with congenital hypopituitarism by massively parallel sequencing using a customized target gene panel. Results: We found three novel pathogenic variants in OTX2 c.295C>T:p.Gln99*, GLI2 c.1681G>T:p.Glu561* and GHRHR c.820_821insC:p.Asp274Alafs*113, and the previously reported variants in GHRHR c.57+1G>A and PROP1 [c.301_302delAG];(c.109+1G>A]. Conclusions: Our results indicate that a custom-designed panel is an efficient method to screen simultaneously variants of biological and clinical relevance for congenital GH deficiency. A genetic diagnosis was possible in 5 out of 117 (4%) patients of our cohort. We identified three novel pathogenic variants in GHRHR, OTX2 and GLI2 expanding the spectrum of variants associated with congenital hypopituitarism.
conferenceObject MOLECULAR ANALYSIS OF BRAZILIAN PATIENTS WITH COMBINED PITUITARY HORMONE DEFICIENCY (CPHD) AND ORTHOTOPIC POSTERIOR PITUITARY LOBE (OPP) REVEALS 8 DIFFERENT PROP1 ALTERATIONS WITH THREE NOVEL MUTATIONS(2017) MADEIRA, Joao L. O.; NISHI, Mirian Y.; NAKAGUMA, Marilena; BENNEDETTI, Anna F.; BISCOTTO, Isabela P.; FERNANDES, Thamiris; PEQUENO, Thiago; FIGUEIREDO, Thalita; FRANCA, Marcela M.; CORREA, Fernanda A.; OTTO, Aline P.; ABRAO, Milena; MIRAS, Mirta; SANTOS, Silvana; JORGE, Alexander A. L.; COSTALONGA, Everlayny F.; MENDONCA, Berenice B.; ARNHOLD, Ivo J. P.; CARVALHO, Luciani R.conferenceObject HESX1 Mutations Cause Hypopituitarism with Different Clinical Features(2015) BENEDETTI, A. Figueredo; FANG, Q.; GREGORY, L.; MENDONCA, B. Bilharinho de; ARNHOLD, I; DATTANI, M.; CAMPER, S.; LI, J.; MA, Q.; SADEGHI-NEJAD, A.; CARVALHO, L.