VINICIUS NAHIME DE BRITO
Projetos de Pesquisa
Unidades Organizacionais
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
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- High Frequency of MKRN3 Mutations in Male Central Precocious Puberty Previously Classified as Idiopathic(2017) BESSA, Danielle S.; MACEDO, Delanie B.; BRITO, Vinicius N.; FRANCA, Monica M.; MONTENEGRO, Luciana R.; CUNHA-SILVA, Marina; SILVEIRA, Leticia G.; HUMMEL, Tiago; BERGADA, Ignacio; BRASLAVSKY, Debora; ABREU, Ana Paula; DAUBER, Andrew; MENDONCA, Berenice B.; KAISER, Ursula B.; LATRONICO, Ana ClaudiaBackground/Aims: Recently, loss-of-function mutations in the MKRN3 gene have been implicated in the etiology of familial central precocious puberty (CPP) in both sexes. We aimed to analyze the frequency of MKRN3 mutations in boys with CPP and to compare the clinical and hormonal features of boys with and without MKRN3 mutations. Methods: This was a retrospective review of clinical, hormonal and genetic features of 20 male patients with idiopathic CPP evaluated at an academic medical center. The entire coding regions of MKRN3, KISS1 and KISS1R genes were sequenced. Results: We studied 20 boys from 17 families with CPP. All of them had normal brain magnetic resonance imaging. Eight boys from 5 families harbored four distinct heterozygous MKRN3 mutations predicted to be deleterious for protein function, p.Ala162Glyfs*14, p.Arg213Glyfs*73, p.Arg328Cys and p. Arg365Ser. One boy carried a previously described KISS1-activating mutation (p.Pro74Ser). The frequency of MKRN3 mutations among these boys with idiopathic CPP was significantly higher than previously reported female data (40 vs. 6.4%, respectively, p < 0.001). Boys with MKRN3 mutations had typical clinical and hormonal features of CPP. Notably, they had later pubertal onset than boys without MKRN3 abnormalities (median age 8.2 vs. 7.0 years, respectively, p = 0.033). Conclusion: We demonstrated a high frequency of MKRN3 mutations in boys with CPP, previously classified as idiopathic, suggesting the importance of genetic analysis in this group. The boys with CPP due to MKRN3 mutations had classical features of CPP, but with puberty initiation at a borderline age. (C) 2016 S. Karger AG, Basel
- Genotype-Phenotype Correlations in Central Precocious Puberty Caused by MKRN3 Mutations(2021) SERAPHIM, Carlos Eduardo; CANTON, Ana Pinheiro Machado; MONTENEGRO, Luciana; PIOVESAN, Maiara Ribeiro; MACEDO, Delanie B.; CUNHA, Marina; GUIMARAES, Aline; RAMOS, Carolina Oliveira; BENEDETTI, Anna Flavia Figueiredo; LEAL, Andrea de Castro; GAGLIARDI, Priscila C.; ANTONINI, Sonir R.; GRYNGARTEN, Mirta; ARCARI, Andrea J.; ABREU, Ana Paula; KAISER, Ursula B.; SORIANO-GUILLEN, Leandro; ESCRIBANO-MUNOZ, Arancha; CORRIPIO, Raquel; I, Jose Labarta; TRAVIESO-SUAREZ, Lourdes; ORTIZ-CABRERA, Nelmar Valentina; ARGENTE, Jesus; MENDONCA, Berenice B.; BRITO, Vinicius N.; LATRONICO, Ana ClaudiaContext: 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.
- Early onset of primary hypogonadism revealed by serum anti-Mullerian hormone determination during infancy and childhood in trisomy 21(2011) GRINSPON, R. P.; BEDECARRAS, P.; BALLERINI, M. G.; INIGUEZ, G.; ROCHA, A.; RESENDE, E. A. Mantovani Rodrigues; BRITO, V. N.; MILANI, C.; GACITUA, V. Figueroa; CHIESA, A.; KESELMAN, A.; GOTTLIEB, S.; BORGES, M. F.; ROPELATO, M. G.; PICARD, J. -Y.; CODNER, E.; REY, R. A.Male patients with an extra sex chromosome or autosome are expected to present primary hypogonadism at puberty owing to meiotic germ-cell failure. Scarce information is available on trisomy 21, a frequent autosomal aneuploidy. Our objective was to assess whether trisomy 21 presents with pubertal-onset, germ-cell specific, primary hypogonadism in males, or whether the hypogonadism is established earlier and affects other testicular cell populations. We assessed the functional status of the pituitary-testicular axis, especially Sertoli cell function, in 117 boys with trisomy 21 (ages: 2 months-20 year). To compare with an adequate control population, we established reference levels for serum anti-Mullerian hormone (AMH) in 421 normal males, from birth to adulthood, using a recently developed ultrasensitive assay. In trisomy 21, AMH was lower than normal, indicating Sertoli cell dysfunction, from early infancy, independently of the existence of cryptorchidism. The overall prevalence rate of AMH below the 3rd percentile was 64.3% in infants with trisomy 21. Follicle-stimulating hormone was elevated in patients <6 months and after pubertal onset. Testosterone was within the normal range, but luteinizing hormone was elevated in most patients <6 months and after pubertal onset, indicating a mild Leydig cell dysfunction. We conclude that in trisomy 21, primary hypogonadism involves a combined dysfunction of Sertoli and Leydig cells, which can be observed independently of cryptorchidism soon after birth, thus prompting the search for new hypotheses to explain the pathophysiology of gonadal dysfunction in autosomal trisomy.
- Clinical, hormonal, ovarian, and genetic aspects of 46,XX patients with congenital adrenal hyperplasia due to CYP17A1 defects(2016) CARVALHO, Luciane Carneiro de; BRITO, Vinicius Nahime; MARTIN, Regina Matsunaga; ZAMBONI, Aline Machado; GOMES, Larissa Garcia; INACIO, Marlene; MERMEJO, Livia Mara; COELI-LACCHINI, Fernanda; TEIXEIRA, Virginia Ribeiro; GONCALVES, Fabricia Torres; CARRILHO, Alexandre Jose Faria; CAMARGO, Kenny Yelena Del Toro; FINKIELSTAIN, Gabriela Paula; TABOADA, Giselle Fernandes; COSTA, Elaine Maria Frade; DOMENICE, Sorahia; MENDONCA, Berenice BilharinhoObjective: To perform a clinical, biochemical, and molecular evaluation of patients with CYP17A1 defects, including ovarian imaging. Design: Retrospective study. Setting: Tertiary care center. Patient(s): Sixteen patients with congenital adrenal hyperplasia due to CYP17A1 defects with a median chronological age of 20 years and belonging to 10 unrelated families. Intervention(s): None. Main Outcome Measure(s): Clinical and biochemical parameters, molecular diagnosis, ovarian imaging, and therapeutic management. Result(s): Seventy-one percent of patients presented with primary amenorrhea, 500/0 had no breast development, and pubic hair was absent or sparse in all patients; 880/o had high blood pressure at diagnosis. Basal LH and P levels were high, and androgen levels were low in all patients. Ultrasound revealed ovarian enlargement in 68.70/0 and ovarian macrocysts in 62.50/0 of patients before treatment; three patients had a previous surgical correction of ovarian torsion or rupture. Molecular analysis revealed inactivating CYP17A1 mutations in all patients. The most prevalent mutation was p.W406R, and one patient bore a novel p.G478S/ p.1223Nfs*10 compound heterozygous mutation. Treatment with dexamethasone, estrogen, and P resulted in reduction of ovarian volume. Conclusion (s): Amenorrhea, absent/sparse pubic hair, hypertension, and ovarian macrocysts, whichincrease the risk of ovarian torsion, are important elements in the diagnosis of 46,XX patients with CYP17A1 defects. High basal P levels in patients with hypergonadotropic hypogoriadisiri point to the diagnosis of CYP17A1 defects. Fertility can be achieved in these patients with novel reproductive techniques. (Fertil Steil(R) 2016;105:1612-9. (C) 2016 by American Society for Reproductive Medicine.)