Publications by authors named "Ana Pinheiro Machado Canton"

6 Publications

  • Page 1 of 1

Brain MRI in girls with central precocious puberty: a time for new approaches.

J Clin Endocrinol Metab 2021 May 4. Epub 2021 May 4.

Developmental Endocrinology Unit, Laboratory of Hormones and Molecular Genetics, LIM42, Department of Endocrinology and Metabolism, Clinicas Hospital, Faculty of Medicine of the University of São Paulo, São Paulo, Brazil.

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http://dx.doi.org/10.1210/clinem/dgab293DOI Listing
May 2021

Genotype-Phenotype Correlations in Central Precocious Puberty Caused by MKRN3 Mutations.

J Clin Endocrinol Metab 2021 Mar;106(4):1041-1050

Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.

Context: 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.
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http://dx.doi.org/10.1210/clinem/dgaa955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993586PMC
March 2021

Insights from the genetic characterization of central precocious puberty associated with multiple anomalies.

Hum Reprod 2021 01;36(2):506-518

Developmental Endocrinology Unit, Laboratory of Hormones and Molecular Genetics, LIM42, Department of Endocrinology and Metabolism, Clinicas Hospital, Faculty of Medicine, University of São Paulo, São Paulo, Brazil.

Study Question: Is there an (epi)genetic basis in patients with central precocious puberty (CPP) associated with multiple anomalies that unmasks underlying mechanisms or reveals novel genetic findings related to human pubertal control?

Summary Answer: In a group of 36 patients with CPP associated with multiple phenotypes, pathogenic or likely pathogenic (epi)genetic defects were identified in 12 (33%) patients, providing insights into the genetics of human pubertal control.

What Is Known Already: A few studies have described patients with CPP associated with multiple anomalies, but without making inferences on causalities of CPP. Genetic-molecular studies of syndromic cases may reveal disease genes or mechanisms, as the presentation of such patients likely indicates a genetic disorder.

Study Design, Size, Duration: This translational study was based on a genetic-molecular analysis, including genome-wide high throughput methodologies, for searching structural or sequence variants implicated in CPP and DNA methylation analysis of candidate regions.

Participants/materials, Setting, Methods: A cohort of 197 patients (188 girls) with CPP without structural brain lesions was submitted to a detailed clinical evaluation, allowing the selection of 36 unrelated patients (32 girls) with CPP associated with multiple anomalies. Pathogenic allelic variants of genes known to cause monogenic CPP (KISS1R, KISS1, MKRN3 and DLK1) had been excluded in the entire cohort (197 patients). All selected patients with CPP associated with multiple anomalies (n = 36) underwent methylation analysis of candidate regions and chromosomal microarray analysis. A subset (n = 9) underwent whole-exome sequencing, due to presenting familial CPP and/or severe congenital malformations and neurocognitive abnormalities.

Main Results And The Role Of Chance: Among the 36 selected patients with CPP, the more prevalent associated anomalies were metabolic, growth and neurocognitive conditions. In 12 (33%) of them, rare genetic abnormalities were identified: six patients presented genetic defects in loci known to be involved with CPP (14q32.2 and 7q11.23), whereas the other six presented defects in candidate genes or regions. In detail, three patients presented hypomethylation of DLK1/MEG3:IG-DMR (14q32.2 disruption or Temple syndrome), resulting from epimutation (n = 1) or maternal uniparental disomy of chromosome 14 (n = 2). Seven patients presented pathogenic copy number variants: three with de novo 7q11.23 deletions (Williams-Beuren syndrome), three with inherited Xp22.33 deletions, and one with de novo 1p31.3 duplication. Exome sequencing revealed potential pathogenic variants in two patients: a sporadic female case with frameshift variants in TNRC6B and AREL1 and a familial male case with a missense substitution in UGT2B4 and a frameshift deletion in MKKS.

Limitations, Reasons For Caution: The selection of patients was based on a retrospective clinical characterization, lacking a longitudinal inclusion of consecutive patients. In addition, future studies are needed, showing the long-term (mainly reproductive) outcomes in the included patients, as most of them are not in adult life yet.

Wider Implications Of The Findings: The results highlighted the relevance of an integrative clinical-genetic approach in the elucidation of mechanisms and factors involved in pubertal control. Chromosome 14q32.2 disruption indicated the loss of imprinting of DLK1 as a probable mechanism of CPP. Two other chromosomal regions (7q11.23 and Xp22.33) represented new candidate loci potentially involved in this disorder of pubertal timing.

Study Funding/competing Interest(s): This work was supported by grant number 2018/03198-0 (to A.P.M.C.) and grant number 2013/08028-1 (to A.C.V.K) from the São Paulo Research Foundation (FAPESP), and grant number 403525/2016-0 (to A.C.L.) and grant number 302849/2015-7 (to A.C.L.) and grant number 141625/2016-3 (to A.C.V.K) from the National Council for Scientific and Technological Development (CNPq). The authors have nothing to disclose.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/deaa306DOI Listing
January 2021

Pioneering studies on monogenic central precocious puberty.

Arch Endocrinol Metab 2019 Aug 22;63(4):438-444. Epub 2019 Aug 22.

Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42 do Hospital das Clínicas, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil.

Pubertal timing in humans is determined by complex interactions including hormonal, metabolic, environmental, ethnic, and genetic factors. Central precocious puberty (CPP) is defined as the premature reactivation of the hypothalamic-pituitary-gonadal axis, starting before the ages of 8 and 9 years in girls and boys, respectively; familial CPP is defined by the occurrence of CPP in two or more family members. Pioneering studies have evidenced the participation of genetic factors in pubertal timing, mainly identifying genetic causes of CPP in sporadic and familial cases. In this context, rare activating mutations were identified in genes of the kisspeptin excitatory pathway (KISS1R and KISS1 mutations). More recently, loss-of-function mutations in two imprinted genes (MKRN3 and DLK1) have been identified as important causes of familial CPP, describing novel players in the modulation of the hypothalamic-pituitary-gonadal axis in physiological and pathological conditions. MKRN3 mutations are the most common cause of familial CPP, and patients with MKRN3 mutations present clinical features indistinguishable from idiopathic CPP. Meanwhile, adult patients with DLK1 mutations present high frequency of metabolic alterations (overweight/obesity, early onset type 2 diabetes and hyperlipidemia), indicating that DLK1 may be a novel link between reproduction and metabolism. Arch Endocrinol Metab. 2019;63(4):438-44.
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http://dx.doi.org/10.20945/2359-3997000000164DOI Listing
August 2019

Good response to long-term therapy with growth hormone in a patient with 9p trisomy syndrome: A case report and review of the literature.

Am J Med Genet A 2016 Apr 22;170A(4):1046-9. Epub 2015 Dec 22.

Unidade de Endocrinologia Genética, Laboratório de Endocrinologia Celular e Molecular LIM/25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.

The 9p trisomy syndrome is a rare condition, clinically characterized by a wide range of dysmorphic features, intellectual disability, and, in most patients, by short stature. Recombinant human growth hormone (rhGH) therapy is still controversial in syndromic disorders, the reason for which it is not currently indicated. Here we report a 7-year-old boy with 9p trisomy syndrome and marked short stature. Results of routine laboratory assessments were normal. IGF1 and IGFBP3 levels were both in the normal range (-1.6 and -0.7 SDS, respectively). GH peak in response to oral clonidine stimulation test was 3.5 μg/L, which is considered a normal response. Chromosomal analysis revealed the karyotype 47,XY, + del(9)(pter-q11:) dn. SNP array data indicated absence of mosaicism [arr 9p24.3-p13.1 (203,861-38,787,480) x3]. By the age of 8.3 years, the patient had persistent short stature (-2.9 SDS) with normal growth velocity (4.9 cm/y; -0.7 SDS), not showing spontaneous catch-up. After 5.6 years of rhGH therapy (50 μg/kg/d), height SDS improved from -2.9 to -1.0. This result suggests that rhGH therapy could be considered for patients with 9p trisomy syndrome who present with short stature. The degree of intellectual disability and the potential for social inclusion should be taken into account when recommending this treatment. Additional studies are needed to establish the benefits of height gain in these patients.
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http://dx.doi.org/10.1002/ajmg.a.37521DOI Listing
April 2016

[Mutations in insulin-like growth factor receptor 1 gene (IGF1R) resulting in intrauterine and postnatal growth retardation].

Arq Bras Endocrinol Metabol 2011 Nov;55(8):541-9

Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, São Paulo, Brasil.

Approximately 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.
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http://dx.doi.org/10.1590/s0004-27302011000800007DOI Listing
November 2011