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1.
Arch Endocrinol Metab ; 68: e220395, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38427811

RESUMO

Beckwith-Wiedemann syndrome (BWS) is a common genetic congenital disease characterized by somatic overgrowth and its broad clinical spectrum includes pre- and post-natal macrosomia, macroglossia, visceromegaly, increased risk of neonatal hypoglycemia, and development of embryonic tumors. BWS occurs due to genetic/epigenetic changes involving growth-regulating genes, located on region 11p15, with an important genotype-phenotype correlation. Congenital adrenal hyperplasia (CAH) comprises a spectrum of autosomal recessive diseases presenting a variety of clinical manifestations due to a deficiency in one of the enzymes involved in cortisol secretion. Early diagnosis based on newborn screening prevents the adrenal crisis and early infant death. However, high 17-hydroxyprogesterone (17-OHP) levels can occur in newborns or premature infants without CAH, in situations of stress due to maternal or neonatal factors. Here, we report new cases of false-positive diagnosis of 21-hydroxylase deficiency during newborn screening - two girls and one boy with BWS. Methylation-specific multiplex ligation-dependent probe amplification revealed a gain of methylation in the H19 differentially methylated region. Notably, all three cases showed a complete normalization of biochemical changes, highlighting the transient nature of these hormonal findings that imitate the classical form of CAH. This report sheds light on a new cause of false-positive 21-hydroxylase deficiency diagnosis during newborn screening: Beckwith-Wiedemann syndrome.


Assuntos
Hiperplasia Suprarrenal Congênita , Síndrome de Beckwith-Wiedemann , Masculino , Lactente , Feminino , Humanos , Recém-Nascido , Síndrome de Beckwith-Wiedemann/diagnóstico , Síndrome de Beckwith-Wiedemann/genética , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/genética , Metilação de DNA , Triagem Neonatal
2.
Arch. endocrinol. metab. (Online) ; 68: e220395, 2024. tab, graf
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-1556960

RESUMO

SUMMARY Beckwith-Wiedemann syndrome (BWS) is a common genetic congenital disease characterized by somatic overgrowth and its broad clinical spectrum includes pre- and post-natal macrosomia, macroglossia, visceromegaly, increased risk of neonatal hypoglycemia, and development of embryonic tumors. BWS occurs due to genetic/epigenetic changes involving growth-regulating genes, located on region 11p15, with an important genotype-phenotype correlation. Congenital adrenal hyperplasia (CAH) comprises a spectrum of autosomal recessive diseases presenting a variety of clinical manifestations due to a deficiency in one of the enzymes involved in cortisol secretion. Early diagnosis based on newborn screening prevents the adrenal crisis and early infant death. However, high 17-hydroxyprogesterone (17-OHP) levels can occur in newborns or premature infants without CAH, in situations of stress due to maternal or neonatal factors. Here, we report new cases of false-positive diagnosis of 21-hydroxylase deficiency during newborn screening - two girls and one boy with BWS. Methylation-specific multiplex ligation-dependent probe amplification revealed a gain of methylation in the H19 differentially methylated region. Notably, all three cases showed a complete normalization of biochemical changes, highlighting the transient nature of these hormonal findings that imitate the classical form of CAH. This report sheds light on a new cause of false-positive 21-hydroxylase deficiency diagnosis during newborn screening: Beckwith-Wiedemann syndrome.

3.
Sex Dev ; 16(1): 46-54, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34392242

RESUMO

Wilms' tumor suppressor gene 1 (WT1) plays an essential role in urogenital and kidney development. Heterozygous germline pathogenic allelic variants of WT1 have been classically associated with Denys-Drash syndrome (DDS) and Frasier syndrome (FS). Usually, exonic pathogenic missense variants in the zinc finger region are the cause of DDS, whereas pathogenic variants affecting the canonic donor lysine-threonine-serine splice site in intron 9 cause FS. Phenotypic overlap between WT1 disorders has been frequently observed. New WT1 variant-associated phenotypes, such as 46,XX testicular/ovarian-testicular disorders of sex development (DSD) and primary ovarian insufficiency, have been reported. In this report, we describe the phenotypes and genotypes of 7 Brazilian patients with pathogenic WT1 variants. The molecular study involved Sanger sequencing and massively parallel targeted sequencing using a DSD-associated gene panel. Six patients (5 with a 46,XY karyotype and 1 with a 46,XX karyotype) were initially evaluated for atypical genitalia, and a 46,XY patient with normal female genitalia sought medical attention for primary amenorrhea. Germ cell tumors were identified in 2 patients, both with variants affecting alternative splicing of WT1 between exons 9 and 10. Two pathogenic missense WT1 variants were identified in two 46,XY individuals with Wilms' tumors; both patients were <1 year of age at the time of diagnosis. A novel WT1 variant, c.1453_1456 (p.Arg485Glyfs*14), was identified in a 46,XX patient with testicular DSD. Nephrotic proteinuria was diagnosed in all patients, including 3 who underwent renal transplantation after progressing to end-stage kidney disease. The expanding phenotypic spectrum associated with WT1 variants in XY and XX individuals confirms their pivotal role in gonadal and renal development as well as in tumorigenesis, emphasizing the clinical implications of these variants in genetic diagnosis.


Assuntos
Neoplasias Renais , Desenvolvimento Sexual , Proteínas WT1 , Tumor de Wilms , Feminino , Humanos , Lactente , Masculino , Mutação/genética , Fenótipo , Proteínas WT1/genética , Tumor de Wilms/genética
4.
Clinics ; 77: 100132, 2022. tab, graf
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-1421235

RESUMO

Abstract Objectives To analyze the efficiency of a multigenic targeted massively parallel sequencing panel related to endocrine disorders for molecular diagnosis of patients assisted in a tertiary hospital involved in the training of medical faculty. Material and methods Retrospective analysis of the clinical diagnosis and genotype obtained from 272 patients in the Endocrine unit of a tertiary hospital was performed using a custom panel designed with 653 genes, most of them already associated with the phenotype (OMIM) and some candidate genes that englobes developmental, metabolic and adrenal diseases. The enriched DNA libraries were sequenced in NextSeq 500. Variants found were then classified according to ACMG/AMP criteria, with Varsome and InterVar. Results Three runs were performed; the mean coverage depth of the targeted regions in panel sequencing data was 249×, with at least 96.3% of the sequenced bases being covered more than 20-fold. The authors identified 66 LP/P variants (24%) and 27 VUS (10%). Considering the solved cases, 49 have developmental diseases, 12 have metabolic and 5 have adrenal diseases. Conclusion The application of a multigenic panel aids the training of medical faculty in an academic hospital by showing the picture of the molecular pathways behind each disorder. This may be particularly helpful in developmental disease cases. A precise genetic etiology provides an improvement in understanding the disease, guides decisions about prevention or treatment, and allows genetic counseling.

5.
Arch Endocrinol Metab ; 63(2): 167-174, 2019 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-31090814

RESUMO

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 Clínicas 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. Arch Endocrinol Metab. 2019;63(2):167-74.


Assuntos
Proteínas de Homeodomínio/genética , Hipopituitarismo/genética , Mutação/genética , Feminino , Humanos , Hipopituitarismo/diagnóstico , Masculino , Fenótipo , Displasia Septo-Óptica/genética
6.
Arch. endocrinol. metab. (Online) ; 63(2): 167-174, Mar.-Apr. 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1001214

RESUMO

ABSTRACT 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 Clínicas 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. Arch Endocrinol Metab. 2019;63(2):167-74


Assuntos
Humanos , Masculino , Feminino , Proteínas de Homeodomínio/genética , Mutação/genética , Fenótipo , Displasia Septo-Óptica/genética , Hipopituitarismo/genética
7.
J Clin Endocrinol Metab ; 104(7): 2827-2841, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30830215

RESUMO

CONTEXT: Primary ovarian insufficiency (POI) is a cause of female infertility. However, the genetic etiology of this disorder remains unknown in most patients with POI. OBJECTIVE: To investigate the genetic etiology of idiopathic POI. PATIENTS AND METHODS: We performed whole-exome sequencing of 11 families with idiopathic POI. To gain insights into the potential mechanisms associated with this mutation, we generated two mouse lines via clustered regularly interspaced short palindromic repeats/Cas9 technology. RESULTS: A pathogenic homozygous missense mutation (c.149A>G; p.Asp50Gly) in the POLR3H gene in two unrelated families was identified. Pathogenic mutations in this subunit have not been associated with human disorders. Loss-of-function Polr3h mutation in mice caused early embryonic lethality. Mice with homozygous point mutation (Polr3hD50G) were viable but showed delayed pubertal development, characterized by late first estrus or preputial separation. The Polr3hD50G female and male mice showed decreased fertility later in life, associated with small litter size and increased time to pregnancy or to impregnate a female. Polr3hD50G mice displayed decreased expression of ovarian Foxo3a and lower numbers of primary follicles. CONCLUSION: Our manuscript provides a case of POI caused by missense mutation in POLR3H, expanding the knowledge of molecular pathways of the ovarian function and human infertility. Screening of the POLR3H gene may elucidate POI cases without previously identified genetic causes, supporting approaches of genetic counseling.


Assuntos
Insuficiência Ovariana Primária/genética , RNA Polimerase III/genética , Adolescente , Animais , Sistemas CRISPR-Cas , Criança , Feminino , Proteína Forkhead Box O3/metabolismo , Técnicas de Inativação de Genes , Heterozigoto , Homozigoto , Humanos , Infertilidade/genética , Tamanho da Ninhada de Vivíparos , Mutação com Perda de Função , Masculino , Camundongos , Mutação de Sentido Incorreto , Ovário/metabolismo , Maturidade Sexual/genética , Tempo para Engravidar , Sequenciamento do Exoma
8.
Hum Mol Genet ; 28(10): 1620-1628, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30608580

RESUMO

Missense mutations in the gene, MAP3K1, are a common cause of 46,XY gonadal dysgenesis, accounting for 15-20% of cases [Ostrer, 2014, Disorders of sex development (DSDs): an update. J. Clin. Endocrinol. Metab., 99, 1503-1509]. Functional studies demonstrated that all of these mutations cause a protein gain-of-function that alters co-factor binding and increases phosphorylation of the downstream MAP kinase pathway targets, MAPK11, MAP3K and MAPK1. This dysregulation of the MAP kinase pathway results in increased CTNNB1, increased expression of WNT4 and FOXL2 and decreased expression of SRY and SOX9. Unique and recurrent pathogenic mutations cluster in three semi-contiguous domains outside the kinase region of the protein, a newly identified N-terminal domain that shares homology with the Guanine Exchange Factor (residues Met164 to Glu231), a Plant HomeoDomain (residues Met442 to Trp495) and an ARMadillo repeat domain (residues Met566 to Glu862). Despite the presence of the mutation clusters and clinical data, there exists a dearth of mechanistic insights behind the development imbalance. In this paper, we use structural modeling and functional data of these mutations to understand alterations of the MAP3K1 protein and the effects on protein folding, binding and downstream target phosphorylation. We show that these mutations have differential effects on protein binding depending on the domains in which they occur. These mutations increase the binding of the RHOA, MAP3K4 and FRAT1 proteins and generally decrease the binding of RAC1. Thus, pathologies in MAP3K1 disrupt the balance between the pro-kinase activities of the RHOA and MAP3K4 binding partners and the inhibitory activity of RAC1.


Assuntos
Transtornos do Desenvolvimento Sexual/genética , MAP Quinase Quinase Quinase 1/genética , MAP Quinase Quinase Quinase 4/genética , Proteínas rac1 de Ligação ao GTP/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas do Domínio Armadillo/genética , Transtorno 46,XY do Desenvolvimento Sexual , Transtornos do Desenvolvimento Sexual/patologia , Feminino , Proteína Forkhead Box L2/genética , Regulação da Expressão Gênica/genética , Disgenesia Gonadal 46 XY/genética , Disgenesia Gonadal 46 XY/patologia , Humanos , MAP Quinase Quinase Quinase 1/química , MAP Quinase Quinase Quinase 4/química , Sistema de Sinalização das MAP Quinases/genética , Masculino , Mutação de Sentido Incorreto/genética , Ligação Proteica/genética , Proteínas Proto-Oncogênicas/genética , Proteína da Região Y Determinante do Sexo/genética , Proteínas rac1 de Ligação ao GTP/química , Proteína rhoA de Ligação ao GTP/química , Proteína rhoA de Ligação ao GTP/genética
9.
Clin Genet ; 95(1): 172-176, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30294972

RESUMO

Molecular diagnosis is rarely established in 46,XX testicular (T) disorder of sex development (DSD) individuals with atypical genitalia. The Wilms' tumour factor-1 (WT1) gene is involved in early gonadal development in both sexes. Classically, WT1 deleterious variants are associated with 46,XY disorders of sex development (DSD) because of gonadal dysgenesis. We report a novel frameshift WT1 variant identified in an SRY-negative 46,XX testicular DSD girl born with atypical genitalia. Target massively parallel sequencing involving DSD-related genes identified a novel heterozygous WT1 c.1453_1456del; p.Arg485Glyfs*14 variant located in the fourth zinc finger of the protein which is absent in the population databases. Segregation analysis and microsatellite analysis confirmed the de novo status of the variant that is predicted to be deleterious by in silico tools and to increase WT1 target activation in crystallographic model. This novel and predicted activating frameshift WT1 variant leading to the 46,XX testicular DSD phenotype includes the fourth zinc-finger DNA-binding domain defects in the genetic aetiology of 46,XX DSD.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/diagnóstico , Patologia Molecular , Doenças Testiculares/diagnóstico , Proteínas WT1/genética , Transtornos 46, XX do Desenvolvimento Sexual/genética , Transtornos 46, XX do Desenvolvimento Sexual/patologia , Criança , Proteínas de Ligação a DNA/genética , Feminino , Heterozigoto , Humanos , Lactente , Masculino , Mutação , Fenótipo , Desenvolvimento Sexual/genética , Doenças Testiculares/genética , Doenças Testiculares/patologia , Testículo/patologia
10.
Clin Endocrinol (Oxf) ; 89(2): 164-177, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29668062

RESUMO

BACKGROUND: Follow-up data on patients with 46,XY partial gonadal dysgenesis (PGD) until adulthood are scarce, making information on prognosis difficult. OBJECTIVE: To analyse the long-term outcomes of patients with 46,XY PGD regarding testosterone production, germ cell tumour risk, genotype and psychosexual adaptation. METHODS: A retrospective longitudinal study of 33 patients (20 assigned male and 13 patients assigned female at birth). Molecular diagnosis was performed by Sanger sequencing or by targeted massively parallel sequencing of 63 genes related to disorders of sex development (DSDs). RESULTS: Age at first and last visit ranged from 0.1 to 43 and from 17 to 53 years, respectively. Spontaneous puberty was observed in 57% of the patients. During follow-up, six of them had a gonadectomy (four due to female gender, and two because of a gonadal tumour). At last evaluation, five of six patients had adult male testosterone levels (median 16.7 nmol/L, range 15.3-21.7 nmol/L) and elevated LH and FSH levels. Germ cell tumours were found in two postpubertal patients (one with an abdominal gonad and one patient with Frasier syndrome). Molecular diagnosis was possible in 11 patients (33%). NR5A1 variants were the most prevalent molecular defects (n = 6), and four of five patients harbouring them developed spontaneous puberty. Gender change was observed in four patients, two from each sex assignment group; all patients reported satisfaction with their gender at final evaluation. Sexual intercourse was reported by 81% of both gender and 82% of them reported satisfaction with their sexual lives. CONCLUSION: Spontaneous puberty was observed in 57% of the patients with 46,XY PGD, being NR5A1 defects the most prevalent ones among all the patients and in those with spontaneous puberty. Gender change due to gender dysphoria was reported by 12% of the patients. All the patients reported satisfaction with their final gender, and most of them with their sexual life.

11.
Arch. endocrinol. metab. (Online) ; 62(2): 227-235, Mar.-Apr. 2018. tab, graf
Artigo em Inglês | LILACS | ID: biblio-887640

RESUMO

ABSTRACT Androgenic insensitivity syndrome is the most common cause of disorders of sexual differentiation in 46,XY individuals. It results from alterations in the androgen receptor gene, leading to a frame of hormonal resistance, which may present clinically under 3 phenotypes: complete (CAIS), partial (PAIS) or mild (MAIS). The androgen receptor gene has 8 exons and 3 domains, and allelic variants in this gene occur in all domains and exons, regardless of phenotype, providing a poor genotype - phenotype correlation in this syndrome. Typically, laboratory diagnosis is made through elevated levels of LH and testosterone, with little or no virilization. Treatment depends on the phenotype and social sex of the individual. Open issues in the management of androgen insensitivity syndromes includes decisions on sex assignment, timing of gonadectomy, fertility, physcological outcomes and genetic counseling.


Assuntos
Humanos , Masculino , Feminino , Síndrome de Resistência a Andrógenos/genética , Síndrome de Resistência a Andrógenos/terapia , Fenótipo , Síndrome de Resistência a Andrógenos/fisiopatologia , Terapia de Reposição Hormonal
12.
Clin Endocrinol (Oxf) ; 87(6): 725-732, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28734020

RESUMO

BACKGROUND: Mutations in PROP1, HESX1 and LHX3 are associated with combined pituitary hormone deficiency (CPHD) and orthotopic posterior pituitary lobe (OPP). OBJECTIVE: To identify mutations in PROP1, HESX1 and LHX3 in a large cohort of patients with CPHD and OPP (35 Brazilian, two Argentinian). DESIGN AND METHODS: We studied 23 index patients with CPHD and OPP (six familial and 17 sporadic) as well as 14 relatives. PROP1 was sequenced by the Sanger method in all except one sporadic case studied using a candidate gene panel. Multiplex ligation-dependent probe amplification (MLPA) was applied to one familial case in whom PROP1 failed to amplify by PCR. In the 13 patients without PROP1 mutations, HESX1 and LHX3 were sequenced by the Sanger method. RESULTS: We identified PROP1 mutations in 10 index cases. Three mutations were novel: one affecting the initiation codon (c.1A>G) and two affecting splicing sites, c.109+1G>A and c.342+1G>C. The known mutations, c.150delA (p.Arg53Aspfs*112), c.218G>A (p.Arg73His), c.263T>C (p.Phe88Ser) and c.301_302delAG (p.Leu102Cysfs*8), were also detected. MLPA confirmed complete PROP1 deletion in one family. We did not identify HESX1 and LHX3 mutations by Sanger. CONCLUSION: PROP1 mutations are a prevalent cause of congenital CPHD with OPP, and therefore, PROP1 sequencing must be the first step of molecular investigation in patients with CPHD and OPP, especially in populations with a high frequency of PROP1 mutations. In the absence of mutations, massively parallel sequencing is a promising approach. The high prevalence and diversity of PROP1 mutations is associated with the ethnic background of this cohort.


Assuntos
Proteínas de Homeodomínio/genética , Hipopituitarismo/genética , Proteínas com Homeodomínio LIM/genética , Mutação/genética , Neuro-Hipófise/metabolismo , Fatores de Transcrição/genética , Adolescente , Adulto , Brasil , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
13.
Sex Dev ; 11(2): 70-77, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28376482

RESUMO

17α-hydroxylase/17,20-lyase deficiency is a rare form of congenital adrenal hyperplasia caused by mutations in CYP17A1. Two phenotypic female sisters, aged 17 and 15 years and with 46,XY and 46,XX karyotypes, respectively, presented with primary amenorrhea and absent secondary sexual characteristics. The elder sib also presented with high blood pressure. Both patients had elevated levels of ACTH, gonadotropins, progesterone, corticosterone, and deoxycorticosterone, and reduced levels of estradiol, testosterone, androstenedione, 17-OH-P, DHEA-S, cortisol, aldosterone, and renin activity. The CYP17A1 gene was sequenced, and polymorphic haplotypes were further analyzed in the Spanish family and in Brazilian patients. The 2 sisters were compound heterozygous for p.Arg362Cys and p.Trp406Arg mutations, previously described as the most prevalent mutations in Brazilian families of Spanish (p.Trp406Arg) or Portuguese (p.Arg362Cys) origin. Analysis of polymorphisms in CYP17A1 suggested that the paternal allele with p.Arg362Cys may share a common origin with the Brazilian carriers, while the maternal allele with p.Trp406Arg did not. Hydrocortisone and sex hormone replacement therapy was initiated in both patients. In conclusion, one CYP17A1 mutation (p.Arg362Cys) may share a common ancestry in Brazilian and our present Spanish patients, while p.Trp406Arg may have arisen separately. The elder patient (46,XY) developed a more severe phenotype and a poorer response to estradiol replacement therapy.


Assuntos
Alelos , Mutação/genética , Irmãos , Esteroide 17-alfa-Hidroxilase/genética , Adolescente , Sequência de Bases , Brasil , Feminino , Genótipo , Heterozigoto , Hormônios/sangue , Humanos , Masculino , Fenótipo , Espanha , Testículo/patologia
14.
J Steroid Biochem Mol Biol ; 165(Pt A): 79-85, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27163392

RESUMO

17ß-hydroxysteroid dehydrogenase 3 deficiency consists of a defect in the last phase of steroidogenesis, in which androstenedione is converted into testosterone and estrone into estradiol. External genitalia range from female-like to atypical genitalia and most affected males are raised as females. Virilization in subjects with 17ß-HSD3 deficiency occurs at the time of puberty and several of them change to male social sex. In male social sex patients, testes can be safely maintained, as long as they are positioned inside the scrotum The phenotype of 46,XY DSD due to 17ß-HSD3 deficiency is extremely variable and clinically indistinguishable from other causes of 46,XY DSD such as partial androgen insensitivity syndrome and 5α-reductase 2 deficiency. Laboratory diagnosis is based on a low testosterone/androstenedione ratio due to high serum levels of androstenedione and low levels of testosterone. The disorder is caused by a homozygous or compound heterozygous mutations in the HSD17B3 gene that encodes the 17ß-HSD3 isoenzyme leading to an impairment of the conversion of 17-keto into 17-hydroxysteroids. Molecular genetic testing confirms the diagnosis and provides the orientation for genetic counseling. Our proposal in this article is to review the previously reported cases of 17ß-HSD3 deficiency adding our own cases.


Assuntos
17-Hidroxiesteroide Desidrogenases/deficiência , Cromossomos Humanos X/genética , Cromossomos Humanos Y/genética , Transtornos do Desenvolvimento Sexual/genética , 17-Hidroxiesteroide Desidrogenases/genética , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/deficiência , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Adolescente , Adulto , Síndrome de Resistência a Andrógenos/genética , Criança , Pré-Escolar , Transtorno 46,XY do Desenvolvimento Sexual/genética , Éxons , Feminino , Testes Genéticos , Genótipo , Homozigoto , Humanos , Hipospadia/genética , Masculino , Mutação , Fenótipo , Estudos Retrospectivos , Erros Inatos do Metabolismo de Esteroides/genética , Virilismo/genética , Adulto Jovem
15.
J Clin Endocrinol Metab ; 98(10): E1636-44, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24001744

RESUMO

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 µg/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.


Assuntos
Estatura/genética , Nanismo/genética , Receptores do Fator Natriurético Atrial/genética , Criança , Feminino , Heterozigoto , Humanos , Masculino , Mutação
16.
Pediatr Endocrinol Rev ; 8(2): 79-85, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21150837

RESUMO

Heterozygous SHOX defects are observed in about 50 to 90% of patients with Leri-Weill dyschondrosteosis (LWD), a common dominant inherited skeletal dysplasia; and in 2 to 15% of children with idiopathic short stature (ISS), indicating that SHOX defects are the most important monogenetic cause of short stature. In addition, children selected by disproportionate idiopathic short stature had a higher frequency of SHOX mutations (22%). A careful clinical evaluation of family members with short stature is recommended since it usually revealed LWD patients in families first classified as having ISS or familial short stature. SHOX-molecular analysis is indicated in families with LWD and ISS children with disproportionate short stature. Treatment with recombinant human growth hormone is considered an accepted approach to treat short stature associated with isolated SHOX defect. Here we review clinical, molecular and therapeutic aspects of SHOX haploinsufficiency.


Assuntos
Estatura/genética , Transtornos do Crescimento , Proteínas de Homeodomínio/genética , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/genética , Transtornos do Crescimento/terapia , Haplótipos , Humanos , Proteína de Homoeobox de Baixa Estatura
17.
Eur J Med Genet ; 53(5): 234-8, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20538086

RESUMO

SHOX haploinsufficiency causes a wide spectrum of short stature phenotypes, such as Leri-Weill dyschondrosteosis (LWD) and disproportionate short stature (DSS). SHOX deletions are responsible for approximately two thirds of isolated haploinsufficiency; therefore, it is important to determine the most appropriate methodology for detection of gene deletion. In this study, three methodologies for the detection of SHOX deletions were compared: the fluorescence in situ hybridization (FISH), microsatellite analysis and multiplex ligation-dependent probe amplification (MLPA). Forty-four patients (8 LWD and 36 DSS) were analyzed. The cosmid LLNOYCO3'M'34F5 was used as a probe for the FISH analysis and microsatellite analysis were performed using three intragenic microsatellite markers. MLPA was performed using commercial kits. Twelve patients (8 LWD and 4 DSS) had deletions in SHOX area detected by MLPA and 2 patients generated discordant results with the other methodologies. In the first case, the deletion was not detected by FISH. In the second case, both FISH and microsatellite analyses were unable to identify the intragenic deletion. In conclusion, MLPA was more sensitive, less expensive and less laborious; therefore, it should be used as the initial molecular method for the detection of SHOX gene deletion.


Assuntos
Deleção de Genes , Proteínas de Homeodomínio/genética , Técnicas de Amplificação de Ácido Nucleico , Osteocondrodisplasias/genética , Transtornos do Crescimento/genética , Haploinsuficiência , Humanos , Hibridização in Situ Fluorescente , Repetições de Microssatélites , Fenótipo , Proteína de Homoeobox de Baixa Estatura
18.
J Clin Endocrinol Metab ; 95(3): 1458-62, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20080844

RESUMO

BACKGROUND: Steroidogenic factor 1 (SF-1) is a key determinant of endocrine development and function of adrenal cortex. SF-1 overexpression and gene amplification were previously demonstrated in a small group of pediatric adrenocortical tumors. OBJECTIVE: Our objective was to determine the frequency of SF-1 protein expression and gene amplification in a large cohort of pediatric and adult adrenocortical tumors. PATIENTS: SF-1 protein expression was assessed in a cohort of 103 adrenocortical tumors from 36 children and 67 adults, whereas gene amplification was studied in 38 adrenocortical tumors (17 from children). METHODS: Tissue microarray, multiplex ligation-dependent probe amplification, and quantitative real-time PCR were used. RESULTS: A strong nuclear SF-1 expression was detected by tissue microarray in 56% (20 of 36) and 19% (13 of 67) of the pediatric and adult adrenocortical tumors, respectively (P = 0.0004). Increased SF-1 copy number was identified in 47% (eight of 17) and 10% (two of 21) of the pediatric and adult adrenocortical tumors, respectively (P = 0.02). All adrenocortical tumors with SF-1 gene amplification showed a strong SF-1 staining, whereas most of the tumors (61%) without SF-1 amplification displayed a weak or negative staining (P = 0.0008). Interestingly, a strong SF-1 staining was identified in five (29%) pediatric adrenocortical tumors without SF-1 amplification. The frequency of SF-1 overexpression and gene amplification was similar in adrenocortical adenomas and carcinomas. CONCLUSION: We demonstrated a higher frequency of SF-1 overexpression and gene amplification in pediatric than in adult adrenocortical tumors, suggesting an important role of SF-1 in pediatric adrenocortical tumorigenesis.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Adenoma Adrenocortical/genética , Carcinoma Adrenocortical/genética , Amplificação de Genes/genética , Fator Esteroidogênico 1/genética , Adulto , Fatores Etários , Distribuição de Qui-Quadrado , Criança , Pré-Escolar , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise Serial de Tecidos
19.
J Clin Endocrinol Metab ; 95(1): 328-32, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19926713

RESUMO

CONTEXT: Isolated heterozygous SHOX defects are the most frequent monogenic cause of short stature, and combined therapy with recombinant human GH (rhGH) and GnRH analog (GnRHa) in pubertal patients has been suggested, but there are no data on final height. OBJECTIVE: The aim of the study was to analyze adult height after rhGH and GnRHa therapy in patients with SHOX haploinsufficiency. PATIENTS: Ten peripubertal patients with isolated SHOX defects participated in the study. INTERVENTION: Five patients were followed without treatment, and five were treated with rhGH (50 mug/kg/d) and depot leuprolide acetate (3.75 mg/month). MAIN OUTCOME MEASURES: Adult height sd score (SDS) was measured. RESULTS: All patients followed without treatment had marked downward growth shift during puberty (height SDS, -1.2 +/- 0.7 at 11.4 +/- 1.4 yr; adult height SDS, -2.5 +/- 0.5). Conversely, four of five patients treated with rhGH for 2 to 4.9 yr associated to GnRHa for 1.4 to 5.8 yr improved their height SDS from -2.3 +/- 1.3 at 11.8 +/- 2.1 yr to a final height SDS of -1.7 +/- 1.6. The difference between the mean height SDS at the first evaluation and final height SDS was statistically significant in nontreated vs. treated patients (mean height SDS change, -1.2 +/- 0.4 vs. 0.6 +/- 0.4, respectively; P <0.001). CONCLUSION: A gain in adult height of patients with isolated SHOX defects treated with combined rhGH and GnRHa therapy was demonstrated for the first time, supporting this treatment for children with SHOX defects who have just started puberty to avoid the loss of growth potential observed in these patients during puberty.


Assuntos
Hormônio Liberador de Gonadotropina/análogos & derivados , Transtornos do Crescimento/tratamento farmacológico , Proteínas de Homeodomínio/genética , Hormônio do Crescimento Humano/administração & dosagem , Leuprolida/administração & dosagem , Puberdade/efeitos dos fármacos , Adolescente , Estatura/efeitos dos fármacos , Estatura/genética , Criança , Códon sem Sentido , Esquema de Medicação , Combinação de Medicamentos , Feminino , Hormônio Liberador de Gonadotropina/administração & dosagem , Transtornos do Crescimento/genética , Humanos , Masculino , Proteínas Recombinantes/administração & dosagem , Proteína de Homoeobox de Baixa Estatura , Resultado do Tratamento
20.
Arq. bras. endocrinol. metab ; 52(8): 1382-1387, Nov. 2008. ilus
Artigo em Inglês | LILACS | ID: lil-503309

RESUMO

LWD is associated to SHOX haploinsufficiency, in most cases, due to gene deletion. Generally FISH and microsatellite analysis are used to identify SHOX deletion. MLPA is a new method of detecting gene copy variation, allowing simultaneous analysis of several regions. Here we describe the presence of a SHOX intragenic deletion in a family with LWD, analyzed through different methodologies. Genomic DNA of 11 subjects from one family were studied by microsatellite analysis, direct sequencing and MLPA. FISH was performed in two affected individuals. Microsatellite analysis showed that all affected members shared the same haplotype suggesting the involvement of SHOX. MLPA detected an intragenic deletion involving exons IV-VIa, which was not detected by FISH and microsatellite analysis. In conclusion, the MLPA technique was proved to be the best solution on detecting this small deletion, it has the advantage of being less laborious also allowing the analysis of several regions simultaneously.


Discondrosteose de Léri-Weill (DLW) está associada à haploinsuficiência do gene SHOX resultante, principalmente, de deleções. Geralmente, o FISH e a análise de microssatélites são os métodos utilizados para a identificação destas deleções. MLPA é um novo método para detectar variações do número de cópias gênicas, permitindo uma análise simultânea de várias regiões. Aqui, descrevemos uma pequena deleção intragênica no SHOX em uma família com DLW analisada por diferentes metodologias. DNA genômico de 11 membros de uma família foram estudados por microssatélites, seqüenciamento direto e MLPA. FISH foi realizado em dois indivíduos afetados. Os microssatélites demonstraram que todos os membros afetados apresentavam o mesmo haplotipo, sugerindo o envolvimento do SHOX. MLPA identificou uma deleção intragênica envolvendo os éxons IV-VIa, que não foi detectada pelo FISH e pelos microssatélites. Conclui-se que o MLPA demonstrou melhor resolução para detectar esta pequena deleção, com a vantagem de ser menos trabalhoso e permitir a análise de várias regiões simultaneamente.


Assuntos
Criança , Feminino , Humanos , Masculino , Sondas de DNA/genética , Deleção de Genes , Proteínas de Homeodomínio/genética , Técnicas de Amplificação de Ácido Nucleico/métodos , Osteocondrodisplasias/genética , Estudos de Casos e Controles , Repetições de Microssatélites , Linhagem , Análise de Sequência de DNA/métodos
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