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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- Diagnosis, Genetics, and Therapy of Short Stature in Children: A Growth Hormone Research Society International Perspective(2019) COLLETT-SOLBERG, Paulo F.; AMBLER, Geoffrey; BACKELJAUW, Philippe F.; BIDLINGMAIER, Martin; BILLER, Beverly M. K.; BOGUSZEWSKI, Margaret C. S.; CHEUNG, Pik To; CHOONG, Catherine Seut Yhoke; COHEN, Laurie E.; COHEN, Pinchas; DAUBER, Andrew; DEAL, Cheri L.; GONG, Chunxiu; HASEGAWA, Yukihiro; HOFFMAN, Andrew R.; HOFMAN, Paul L.; HORIKAWA, Reiko; JORGE, Alexander A. L.; JUUL, Anders; KAMENICKY, Peter; KHADILKAR, Vaman; KOPCHICK, John J.; KRISTROM, Berit; LOPES, Maria de Lurdes A.; LUO, Xiaoping; MILLER, Bradley S.; MISRA, Madhusmita; NETCHINE, Irene; RADOVICK, Sally; RANKE, Michael B.; ROGOL, Alan D.; ROSENFELD, Ron G.; SAENGER, Paul; WIT, Jan M.; WOELFLE, JoachimThe Growth Hormone Research Society (GRS) convened a Workshop in March 2019 to evaluate the diagnosis and therapy of short stature in children. Forty-six international experts participated at the invitation of GRS including clinicians, basic scientists, and representatives from regulatory agencies and the pharmaceutical industry. Following plenary presentations addressing the current diagnosis and therapy of short stature in children, breakout groups discussed questions produced in advance by the planning committee and reconvened to share the group reports. A writing team assembled one document that was subsequently discussed and revised by participants. Participants from regulatory agencies and pharmaceutical companies were not part of the writing process. Short stature is the most common reason for referral to the pediatric endocrinologist. History, physical examination, and auxology remain the most important methods for understanding the reasons for the short stature. While some long-standing topics of controversy continue to generate debate, including in whom, and how, to perform and interpret growth hormone stimulation tests, new research areas are changing the clinical landscape, such as the genetics of short stature, selection of patients for genetic testing, and interpretation of genetic tests in the clinical setting. What dose of growth hormone to start, how to adjust the dose, and how to identify and manage a suboptimal response are still topics to debate. Additional areas that are expected to transform the growth field include the development of long-acting growth hormone preparations and other new therapeutics and diagnostics that may increase adult height or aid in the diagnosis of growth hormone deficiency.
conferenceObject Outcomes in growth hormone-treated Noonan syndrome children: impact of PTPN11 mutation status(2021) JORGE, Alexander A. L.; PIETROPOLI, Alberto; KELEPOURIS, Nicky; HORIKAWA, Reiko- Heterozygous Mutations in Natriuretic Peptide Receptor-B (NPR2) Gene as a Cause of Short Stature in Patients Initially Classified as Idiopathic Short Stature(2013) VASQUES, Gabriela A.; AMANO, Naoko; DOCKO, Ana J.; FUNARI, Mariana F. A.; QUEDAS, Elisangela P. S.; NISHI, Mirian Y.; ARNHOLD, Ivo J. P.; HASEGAWA, Tomonobu; JORGE, Alexander A. L.Context: Based on the stature observed in relatives of patients with acromesomelic dysplasia, type Maroteaux, homozygous for mutations in natriuretic peptide receptor B gene (NPR2), it has been suggested that heterozygous mutations in this gene could be responsible for the growth impairment observed in some children with idiopathic short stature (ISS). Objective: The objective of the study was to investigate the presence of NPR2 mutations in a group of patients with ISS. Patients and Methods: The NPR2 coding region was directly sequenced in 47 independent patients with ISS. The functional consequences of NPR2 nonsynonymous variations were established using in vitro cell-based assays. Results: Three novel heterozygous NPR2 mutations were identified: c.226T>C (p.Ser76Pro), c.788G>C (p.Arg263Pro), and c.2455C>T (p.Arg819Cys). These allelic variants were not found in our controls or in the 1000 Genomes database. In silico analysis suggested that the three missense mutations are probably damaging. All of them were selected for in vitro functional evaluation. Cells transfected with the three mutants failed to produce cyclic GMP after treatment with C-type natriuretic peptide. Cells cotransfected with mutant and wild-type-NPR-B (1:1) showed a significant decrease in cGMP levels after C-type natriuretic peptide stimulation in comparison with cells cotrasnfected with empty vector and wild type, suggesting a dominant-negative effect. These three mutations segregated with short stature phenotype in an autosomal dominant pattern (height SD score ranged from -4.5 to -1.7). One of these patients and two relatives have disproportionate short stature, whereas in another patient a nonspecific skeletal abnormality was observed. All three of these patients were treated with recombinant human GH (33-50 mu g/kg.d) without significant height SD score change during therapy. Conclusions: We identified heterozygous NPR2 mutations in 6% of patients initially classified as ISS. Affected patients have mild and variable degrees of short stature without a distinct phenotype. Heterozygous mutations in NPR2 could be an important cause of nonsyndromic familial short stature.
- Novel SUZ12 mutations in Weaver-like syndrome(2018) IMAGAWA, Eri; ALBUQUERQUE, Edoarda V. A.; ISIDOR, Bertrand; MITSUHASHI, Satomi; MIZUGUCHI, Takeshi; MIYATAKE, Satoko; TAKATA, Atsushi; MIYAKE, Noriko; BOGUSZEWSKI, Margaret C. S.; BOGUSZEWSKI, Cesar L.; LERARIO, Antonio M.; FUNARI, Mariana A.; JORGE, Alexander A. L.; MATSUMOTO, NaomichiSUZ12 is a core component of polycomb repressive complex 2 (PRC2) along with EZH2 and EED. Recently, germline mutations in the SUZ12, EZH2 and EED genes have been reported in Weaver syndrome (WS) or Weaver-like syndrome, suggesting a functional link between PRC2 deficits and WS. However, only one case of a SUZ12 mutation presenting with Weaver-like syndrome has been reported. Here, we report a missense and a frameshift mutation in SUZ12 (c.1797A>C; p.Gln599His and c.844_845del; p.Ala282Glnfs*7), both of which are novel, in two individuals. Their clinical features included postnatal overgrowth, increased bifrontal diameter, large ears, round face, horizontal chin crease and skeletal anomalies, but did not fulfill the WS diagnostic criteria. These data provide strong evidence that SUZ12 mutations cause Weaver-like syndrome.
conferenceObject A systematic review of core outcomes reported in clinical trials of growth hormone therapy in children with growth hormone deficiency(2023) TSERETOPOULOU, Xanthippi; LUCAS-HERALD, Angela; CHEN, Jiajia; BACHEGA, Tania; CHARMANDARI, Evangelia; CHOI, Jin-Ho; DOU, Xinyu; GONG, Chunxiu; HAMZA, Rasha; HARVEY, Jamie; HOFFMAN, Andrew R.; HORIKAWA, Reiko; JOHANNSSON, Gudmundur; JORGE, Alexander; MILLER, Bradley S.; ROEHRICH, Sebastian; SAVENDAHL, Lars; VITALI, Diana; WAJNRAJCH, Michael; CHEN, Suet Ching; AHMED, Syed Faisal- GH-Releasing Hormone Receptor Gene: A Novel Splice-Disrupting Mutation and Study of Founder Effects(2012) MARUI, Suemi; TRARBACH, Ericka B.; BOGUSZEWSKI, Margaret C. S.; FRANCA, Marcela M.; JORGE, Alexander A. L.; INOUE, Hiroshi; NISHI, Mirian Y.; LACERDA FILHO, Luiz de; AGUIAR-OLIVEIRA, Manuel H.; MENDONCA, Berenice B.; ARNHOLD, Ivo J. P.Background: Mutations in GH-releasing hormone receptor gene (GHRHR) are emerging as the most common cause of autosomal recessive isolated GH deficiency (IGHD). Objective: To search for GHRHR mutations in patients with familial or sporadic IGHD and to investigate founder effects in recurring mutations. Methods: The coding region of GHRHR was entirely amplified and sequenced from DNA of 18 patients with IGHD (16 unrelated) with topic posterior pituitary lobe on MRI. Haplotypes containing promoter SNPs and microsatellites flanking GHRHR were analyzed in patients with c.57+1G>A (IVS1+1G>A) mutation of our previously published kindred and also a Brazilian patient and 2 previously reported Japanese sisters with c. 1146G>A (p.E382E) mutation. Results: A novel homozygous intronic GHRHR c.752-1G>A (IVS7-1G>A) mutation, predicting loss of the constitutive splice acceptor site, was identified in two siblings with IGHD. A compound heterozygous c.[57+1G>A];[1146G>A] and a heterozygous c.527C>T (p.A176V) were found in two sporadic cases. Haplotype analysis provided evidence for a founder effect for the c.57+1G>A mutation and independent recurrence for the c.1146G>A mutation. Conclusion: We report a novel splice-disrupting mutation in GHRHR in 2 siblings and provide evidence that all c.57+1G>A (IVS1+1G>A) mutant chromosomes have the same haplotype ancestor, indicating the occurrence of a founder effect in Brazilian patients with IGHD.
- Diagnosis and management of Silver-Russell syndrome: first international consensus statement(2017) WAKELING, Emma L.; BRIOUDE, Frederic; LOKULO-SODIPE, Oluwakemi; O'CONNELL, Susan M.; SALEM, Jennifer; BLIEK, Jet; CANTON, Ana P. M.; CHRZANOWSKA, Krystyna H.; DAVIES, Justin H.; DIAS, Renuka P.; DUBERN, Beatrice; ELBRACHT, Miriam; GIABICANI, Eloise; GRIMBERG, Adda; GRONSKOV, Karen; HOKKEN-KOELEGA, Anita C. S.; JORGE, Alexander A.; KAGAMI, Masayo; LINGLART, Agnes; MAGHNIE, Mohamad; MOHNIKE, Klaus; MONK, David; MOORE, Gudrun E.; MURRAY, Philip G.; OGATA, Tsutomu; PETIT, Isabelle Oliver; RUSSO, Silvia; SAID, Edith; TOUMBA, Meropi; TUMER, Zeynep; BINDER, Gerhard; EGGERMANN, Thomas; HARBISON, Madeleine D.; TEMPLE, I. Karen; MACKAY, Deborah J. G.; NETCHINE, IreneThis Consensus Statement summarizes recommendations for clinical diagnosis, investigation and management of patients with Silver-Russell syndrome (SRS), an imprinting disorder that causes prenatal and postnatal growth retardation. Considerable overlap exists between the care of individuals born small for gestational age and those with SRS. However, many specific management issues exist and evidence from controlled trials remains limited. SRS is primarily a clinical diagnosis; however, molecular testing enables confirmation of the clinical diagnosis and defines the subtype. A 'normal' result from a molecular test does not exclude the diagnosis of SRS. The management of children with SRS requires an experienced, multidisciplinary approach. Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges. An early emphasis on adequate nutritional status is important, with awareness that rapid postnatal weight gain might lead to subsequent increased risk of metabolic disorders. The benefits of treating patients with SRS with growth hormone include improved body composition, motor development and appetite, reduced risk of hypoglycaemia and increased height. Clinicians should be aware of possible premature adrenarche, fairly early and rapid central puberty and insulin resistance. Treatment with gonadotropin-releasing hormone analogues can delay progression of central puberty and preserve adult height potential. Long-term follow up is essential to determine the natural history and optimal management in adulthood.
- Outcomes in growth hormone-treated Noonan syndrome children: Impact of PTPN11 variant status(2022) JORGE, Alexander; PIETROPOLI, Alberto; KELEPOURIS, Nicky; HORIKAWA, Reiko
- High-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficiency(2021) GERGICS, Peter; SMITH, Cathy; BANDO, Hironori; JORGE, Alexander A. L.; ROCKSTROH-LIPPOLD, Denise; VISHNOPOLSKA, Sebastian A.; CASTINETTI, Frederic; MAKSUTOVA, Mariam; CARVALHO, Luciani Renata Silveira; HOPPMANN, Julia; MAYER, Julian Martinez; ALBAREL, Frederique; BRASLAVSKY, Debora; KESELMAN, Ana; BERGADA, Ignacio; MARTI, Marcelo A.; SAVEANU, Alexandru; BARLIER, Anne; JAMRA, Rami Abou; GUO, Michael H.; DAUBER, Andrew; NAKAGUMA, Marilena; MENDONCA, Berenice B.; JAYAKODY, Sajini N.; OZEL, A. Bilge; FANG, Qing; MA, Qianyi; LI, Jun Z.; BRUE, Thierry; MILLAN, Maria Ines Perez; ARNHOLD, Ivo J. P.; PFAEFFLE, Roland; KITZMAN, Jacob O.; CAMPER, Sally A.Pituitary hormone deficiency occurs in similar to 1:4,000 live births. Approximately 3% of the cases are due to mutations in the alpha isoform of POU1F1, a pituitary-specific transcriptional activator. We found four separate heterozygous missense variants in unrelated individuals with hypopituitarism that were predicted to affect a minor isoform, POU1F1 beta, which can act as a transcriptional repressor. These variants retain repressor activity, but they shift splicing to favor the expression of the beta isoform, resulting in dominant-negative loss of function. Using a high-throughput splicing reporter assay, we tested 1,070 single-nucleotide variants in POU1F1. We identified 96 splice-disruptive variants, including 14 synonymous variants. In separate cohorts, we found two additional synonymous variants nominated by this screen that co-segregate with hypopituitarism. This study underlines the importance of evaluating the impact of variants on splicing and provides a catalog for interpretation of variants of unknown significance in POU1F1.
- Outcomes in growth hormone-treated Noonan syndrome children: impact of PTPN11 mutation status(2022) JORGE, Alexander A. L.; EDOUARD, Thomas; MAGHNIE, Mohamad; PIETROPOLI, Alberto; KELEPOURIS, Nicky; ROMANO, Alicia; ZENKER, Martin; HORIKAWA, ReikoIntroductionMutations in PTPN11 are associated with Noonan syndrome (NS). Although the effectiveness of growth hormone therapy (GHT) in treating short stature due to NS has been previously demonstrated, the effect of PTPN11 mutation status on the long-term outcomes of GHT remains to be elucidated. MethodsThis analysis included pooled data from the observational American Norditropin Studies: Web-Enabled Research Program (NCT01009905) and the randomized, double-blinded GHLIQUID-4020 clinical trial (NCT01927861). Pediatric patients with clinically diagnosed NS and confirmed PTPN11mutation status were eligible for inclusion. The effectiveness analysis included patients who were GHT-naive and pre-pubertal at GHT start. Growth outcomes and safety were assessed over 4 years of GHT (Norditropin (R), Novo Nordisk A/S). ResultsA total of 69 patients were included in the effectiveness analysis (71% PTPN11 positive). The proportion of females was 32.7 and 30.0% in PTPN11-positive and negative patients, respectively, and mean age at GHT start was 6.4 years in both groups. Using general population reference data, after 4 years of GHT, the mean (s.d.) height SD score (HSDS) was -1.9 (1.1) and -1.7 (0.8) for PTPN11-positive and PTPN11-negative patients, respectively, with no statistical difference observed between groups. The mean (s.d.) change in HSDS at 4 years was +1.3 (0.8) in PTPN11-positive patients and +1.5 (0.7) in PTPN11-negative patients (no significant differences between groups). Safety findings were consistent with previous analyses. ConclusionsGHT resulted in improved growth outcomes over 4 years in GHT-naive, pre-pubertal NS patients, irrespective of PTPN11 mutation status.