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2.
Front Pediatr ; 8: 593315, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33415088

RESUMO

Congenital adrenal hyperplasia includes autosomal recessive conditions that affect the adrenal cortex steroidogenic enzymes (cholesterol side-chain cleavage enzyme; 3ß-hydroxysteroid dehydrogenase; 17α-hydroxylase/17,20 lyase; P450 oxidoreductase; 21-hydroxylase; and 11ß-hydroxylase) and proteins (steroidogenic acute regulatory protein). These are located within the three major pathways of the steroidogenic apparatus involved in the production of mineralocorticoids, glucocorticoids, and androgens. Many countries have introduced newborn screening program (NSP) based on 17-OH-progesterone (17-OHP) immunoassays on dried blood spots, which enable faster diagnosis and treatment of the most severe forms of 21-hydroxylase deficiency (21-OHD). However, in several others, the use of this diagnostic tool has not yet been implemented and clinical diagnosis remains challenging, especially for males. Furthermore, less severe classic forms of 21-OHD and other rarer types of CAHs are not identified by NSP. The aim of this mini review is to highlight both the main clinical characteristics and therapeutic options of these conditions, which may be useful for a differential diagnosis in the neonatal period, while contributing to the biochemical evolution taking place in the steroidogenic field. Currently, chromatographic techniques coupled with tandem mass spectrometry are gaining attention due to an increase in the reliability of the test results of NPS for detecting 21-OHD. Furthermore, the possibility of identifying CAH patients that are not affected by 21-OHD but presenting elevated levels of 17-OHP by NSP and the opportunity to include the recently investigated 11-oxygenated androgens in the steroid profiles are promising tools for a more precise diagnosis and monitoring of some of these conditions.

3.
Int J Mol Sci ; 20(18)2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31533357

RESUMO

The term 'differences of sex development' (DSD) refers to a group of congenital conditions that are associated with atypical development of chromosomal, gonadal, or anatomical sex. Disorders of steroidogenesis comprise autosomal recessive conditions that affect adrenal and gonadal enzymes and are responsible for some conditions of 46,XX DSD where hyperandrogenism interferes with chromosomal and gonadal sex development. Congenital adrenal hyperplasias (CAHs) are disorders of steroidogenesis that mainly involve the adrenals (21-hydroxylase and 11-hydroxylase deficiencies) and sometimes the gonads (3-beta-hydroxysteroidodehydrogenase and P450-oxidoreductase); in contrast, aromatase deficiency mainly involves the steroidogenetic activity of the gonads. This review describes the main genetic, biochemical, and clinical features that apply to the abovementioned conditions. The activities of the steroidogenetic enzymes are modulated by post-translational modifications and cofactors, particularly electron-donating redox partners. The incidences of the rare forms of CAH vary with ethnicity and geography. The elucidation of the precise roles of these enzymes and cofactors has been significantly facilitated by the identification of the genetic bases of rare disorders of steroidogenesis. Understanding steroidogenesis is important to our comprehension of differences in sexual development and other processes that are related to human reproduction and fertility, particularly those that involve androgen excess as consequence of their impairment.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Transtornos 46, XX do Desenvolvimento Sexual/metabolismo , Androgênios/metabolismo , Estudos de Associação Genética , Predisposição Genética para Doença , Transtornos 46, XX do Desenvolvimento Sexual/diagnóstico , Alelos , Biomarcadores , Regulação Enzimológica da Expressão Gênica , Testes Genéticos , Humanos , Padrões de Herança , Redes e Vias Metabólicas , Fenótipo , Esteroides/metabolismo
4.
Clin Biochem ; 73: 50-56, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31344365

RESUMO

OBJECTIVE: Congenital adrenal hyperplasia (CAH) is an inborn error of metabolism and a common disorder of sex development where >90% of all cases are due to 21-hydroxylase deficiency. Novel and rare pathogenic variants account for 5% of all clinical cases. Here, we sought to investigate the functional and structural effects of four novel (p.Val358Ile, p.Arg369Gln, p.Asp377Tyr, and p.Leu461Pro) and three combinations of CYP21A2 variants (i.e. one allele containing two variants p.[Ile172Asn;Val358Ile], p.[Val281Leu;Arg369Gln], or p.[Asp377Tyr;Leu461Pro]) identified in patients with CAH. METHODS: All variants were reconstructed by in vitro site-directed mutagenesis, the proteins were transiently expressed in COS-1 cells and enzyme activities directed toward the two natural substrates (17-hydroxyprogesterone and progesterone) were determined. In parallel, in silico prediction of the pathogenicity of the variants based on the human CYP21 X-ray structure was performed. RESULTS: The novel variants, p.Val358Ile, p.Arg369Gln, p.Asp377Tyr, and p.Leu461Pro exhibited residual enzymatic activities within the range of non-classic (NC) CAH variants (40-82%). An additive effect on the reduction of enzymatic activity (1-17%) was observed when two variants were expressed together, as identified in several patients, resulting in either NC or more severe phenotypes. In silico predictions were in line with the in vitro data except for p.Leu461Pro. CONCLUSIONS: Altogether, the combination of clinical data, in silico prediction, and data from in vitro studies are important for establishing a correct genotype and phenotype correlation in patients with CAH.


Assuntos
Hiperplasia Suprarrenal Congênita , Alelos , Modelos Moleculares , Mutação de Sentido Incorreto , Esteroide 21-Hidroxilase , Adolescente , Hiperplasia Suprarrenal Congênita/enzimologia , Hiperplasia Suprarrenal Congênita/genética , Adulto , Substituição de Aminoácidos , Animais , Células COS , Criança , Pré-Escolar , Chlorocebus aethiops , Feminino , Humanos , Lactente , Masculino , Domínios Proteicos , Esteroide 21-Hidroxilase/química , Esteroide 21-Hidroxilase/genética
5.
Fertil Steril ; 109(6): 1105-1113, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29935645

RESUMO

OBJECTIVE: To study the functional properties of six novel missense mutations of the NR5A1 gene encoding the steroidogenic factor 1 (SF-1) identified in six patients with 46,XY disorders of sex development (DSD) and to describe their relative phenotype-genotype relationship. DESIGN: Genetic and functional studies. SETTING: University department. PATIENT(S): Six 46,XY DSD patients. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Sanger sequencing and multiplex ligation-dependent probe amplification analysis to identify the mutations or deletions/duplications of the NR5A1 gene. Functional studies by transactivation assays to predict the impact of mutations on molecular function. RESULT(S): NR5A1 exons sequencing identified in six 46,XY DSD patients six novel mutations: p.T40R, p.T47C, p.G328W, p.A351E, p.R427W, and p.Q460R. Five missense variants were heterozygous, and one was homozygous (p.R427W). Functional analysis revealed a significant loss of DNA-binding and transactivation ability for all variants, except for p.Q460R, which showed a modest reduced activity compared with that of the wild-type protein. Phenotypes associated with these mutations varied from males with spontaneous puberty, substantial T production, and possible fertility, to females with and without müllerian structures and primary amenorrhea. CONCLUSION(S): We describe six novel mutations in NR5A1 gene and showed that they might affect protein structure, therefore compromising seriously the SF-1 role in regulating gonadal development. Clinically, we suggest that NR5A1 analysis should be performed whenever atypical sex organs are evidenced or there is an abnormal sexual development, to have proper diagnosis and better management of patients.


Assuntos
Transtorno 46,XY do Desenvolvimento Sexual/genética , Mutação com Perda de Função , Fator Esteroidogênico 1/genética , Criança , Desenvolvimento Infantil , Pré-Escolar , Análise Mutacional de DNA , Transtorno 46,XY do Desenvolvimento Sexual/terapia , Feminino , Estudos de Associação Genética , Células HEK293 , Humanos , Lactente , Recém-Nascido , Masculino , Mutação de Sentido Incorreto/fisiologia
6.
Sex Dev ; 11(2): 82-85, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28190008

RESUMO

We report the case of 2 sisters (46,XX) born from consanguineous Moroccan parents. Both sisters had normal female genitalia, but within 2 weeks after birth, they presented with a severe salt-wasting crisis. Hormonal investigations suggested the diagnosis of congenital adrenal hyperplasia, which was confirmed by subsequent molecular analysis to be caused by 3ß-hydroxysteroid dehydrogenase type 2 deficiency. Here, we discuss the main features like onset, possible complications, genetics, and replacement therapy of this rare disease.


Assuntos
Hiperplasia Suprarrenal Congênita/patologia , Genitália Feminina/patologia , Irmãos , Glândulas Suprarrenais/diagnóstico por imagem , Glândulas Suprarrenais/patologia , Hiperplasia Suprarrenal Congênita/diagnóstico por imagem , Feminino , Humanos , Recém-Nascido , Masculino , Marrocos , Linhagem
7.
Eur J Hum Genet ; 22(5): 610-6, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24022297

RESUMO

Congenital adrenal hyperplasia (CAH) is one of the most common autosomal recessive inherited endocrine disease. Steroid 11ß-hydroxylase deficiency (11ß-OHD) is the second most common form of CAH. The aim of the study was to study the functional consequences of three novel and one previously described CYP11B1 gene mutations (p.(Arg143Trp), p.(Ala306Val), p.(Glu310Lys) and p.(Arg332Gln)) detected in patients suffering from classical and non-classical 11ß-OHD. Functional analyses were performed by using a HEK293 cell in vitro expression system comparing wild type (WT) with mutant 11ß-hydroxylase activity. Mutant proteins were examined in silico to study their effect on the three-dimensional structure of the protein. Two mutations (p.(Ala306Val) and p.(Glu310Lys)) detected in patients with classical 11ß-OHD showed a nearly complete loss of 11ß-hydroxylase activity. The mutations p.(Arg143Trp) and p.(Arg332Gln) detected in patients with non-classical 11ß-OHD showed a partial functional impairment with approximately 8% and 6% of WT activity, respectively. Functional mutation analysis allows the classification of novel CYP11B1 mutations as causes of classical and non-classical 11ß-OHD. The detection of patients with non-classical phenotypes underscores the importance to screen patients with a phenotype comparable to non-classical 21-hydroxylase deficiency for mutations in the CYP11B1 gene in case of a negative analysis of the CYP21A2 gene. As CYP11B1 mutations are most often individual for a family, the in vitro analysis of novel mutations is essential for clinical and genetic counselling.


Assuntos
Hiperplasia Suprarrenal Congênita/genética , Mutação , Esteroide 11-beta-Hidroxilase/genética , Adolescente , Corticosteroides/sangue , Corticosteroides/metabolismo , Hiperplasia Suprarrenal Congênita/metabolismo , Sequência de Aminoácidos , Linhagem Celular , Criança , Análise Mutacional de DNA , Ativação Enzimática , Feminino , Estudos de Associação Genética , Humanos , Cinética , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Conformação Proteica , Alinhamento de Sequência , Esteroide 11-beta-Hidroxilase/química , Esteroide 11-beta-Hidroxilase/metabolismo , Adulto Jovem
8.
J Clin Res Pediatr Endocrinol ; 5 Suppl 1: 29-39, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23154162

RESUMO

Thyroid-stimulating hormone receptor (TSHR) loss-of-function (LOF) mutations lead to a wide spectrum of phenotypes, ranging from severe congenital hypothyroidism (CH) to mild euthyroid hyperthyrotropinemia. The degree of TSH resistance depends on the severity of the impairment of the receptor function caused by the mutation and on the number of mutated alleles In this review data about genotype-phenotype correlation and criteria for clinical work-up will be presented and discussed. Complete TSH resistance due to biallelic LOF TSHR mutations must be suspected in all patients with severe not syndromic CH and severe thyroid hypoplasia diagnosed at birth by neonatal screening. Partial forms of TSH resistance show a more heterogeneous hormonal and clinical pattern . In these cases TSH serum levels are above the upper limit of normal range for the age but with a very variable pattern, free thyroxine (T4) concentrations are within the normal range and thyroid size can be normal or hypoplastic at ultrasound scan. An early substitutive treatment with L-T4 must be mandatory in all patients with severe CH due to complete uncompensated TSH resistance diagnosed at birth by neonatal screening. The usefulness of substitutive treatment appears much more controversial inpatients with subclinical hypothyroidism due to partial TSH resistance in whom the increased TSH concentration should be able to compensate the mild functional impairment of the mutant receptor. Together with standard criteria we recommend also an accurate clinical work-up to select patients who are candidates for a LOF TSHR mutation.


Assuntos
Hipotireoidismo Congênito/genética , Mutação/genética , Receptores da Tireotropina/genética , Receptores da Tireotropina/metabolismo , Hipotireoidismo Congênito/diagnóstico , Hipotireoidismo Congênito/terapia , Humanos
9.
J Clin Endocrinol Metab ; 94(11): 4187-94, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19820021

RESUMO

CONTEXT: Mutations in TSH receptor (TSHR) are notoriously associated with congenital hypothyroidism as well as with non-autoimmune subclinical hypothyroidism, a mild form of TSH resistance that is not as well characterized by diagnostic procedures. OBJECTIVE: The genetic analysis of the TSHR gene was performed to determine the prevalence of TSHR gene mutations in non-autoimmune subclinical hypothyroidism during the pediatric age. The new mutations were studied for genotypic-phenotypic correlation. PATIENTS: Thirty-eight children (ages 0.5-18.0 yr) affected by non-autoimmune subclinical hypothyroidism diagnosed in our center (follow-up from 1 to 11.5 yr) and normal at neonatal screening were enrolled in the genetic study. In 11 cases, the relatives were included in the genetic analysis. RESULTS: Eleven different mutations of the TSHR gene were identified in 11 of the 38 patients. Two are new: the nonsense mutation C31X and the missense mutation P68S, which shows a decrease in TSH binding capacity but not in biological activity. In all cases the carrier parent was identified. CONCLUSIONS: To date, this study demonstrates the highest prevalence (29%) of TSHR gene mutations in children and adolescents with non-autoimmune subclinical hypothyroidism not selected by neonatal screening. Functional studies show that some mutations cause a slight inactivation of the TSHR. This reveals a possible limit of the in vitro study or of the knowledge of mechanisms involving TSHR, or that other candidate genes must be considered.


Assuntos
Hipotireoidismo/genética , Mutação , Receptores da Tireotropina/genética , Adolescente , Substituição de Aminoácidos , Animais , Células COS/metabolismo , Criança , Pré-Escolar , Chlorocebus aethiops , Família , Humanos , Lactente , Tireotropina/sangue , Tireotropina/metabolismo , Transfecção
10.
Horm Res ; 70(2): 124-8, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18547961

RESUMO

BACKGROUND: Persistentmullerian duct syndrome (PMDS) is characterized by the presence of uterus, fallopian tubes and the upper part of the vagina in 46,XY patients with perfectly virilized external genitalia. It is mostly caused by mutations of the AMH or AMH type 2 receptor (AMHR2) gene. The AMH serum level is very often low or undetectable in the AMH gene defect and normal in the AMHR2 gene defect. AIM: We investigate an Italian patient, genotypically and phenotypically male, observed at 1 month of age for a right inguinal hernia that at surgery showed the presence of both testes in the same hernial sac and uterus and fallopian tubes in the abdomen. RESULTS: Genetic tests first showed the absence of the common 27-bp deletion in the AMHR2 gene, then the presence of three new sequence variations in the AMH geneleading to the following variants: the p.A405P carried by the paternal allele; the p.G326V plus the p.V508A carried by the maternal allele. CONCLUSIONS: The determination of serum AMH, performed after the genetic analysis, showed a normal level for age, suggesting that these mutations may affect the function and the bioactivity of the hormone and not the secretion rate.


Assuntos
Hormônio Antimülleriano/sangue , Hormônio Antimülleriano/genética , Ductos Paramesonéfricos/patologia , Sequência de Aminoácidos , Pré-Escolar , Criptorquidismo/genética , Hérnia Inguinal/genética , Humanos , Lactente , Recém-Nascido , Masculino , Dados de Sequência Molecular , Linhagem , Receptores de Peptídeos/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Alinhamento de Sequência , Síndrome
11.
Eur J Endocrinol ; 155(2): 201-5, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16868131

RESUMO

OBJECTIVE: Mutations in the gonadotropin-releasing hormone receptor (GnRHR) gene are the cause of isolated hypogonadotropic hypogonadism (HH). We describe the molecular investigations of the GnRHR gene in two siblings affected by HH and their clinical course. DESIGN: The female was referred at age 14 for pubertal delay with no secondary sexual signs, whereas the male had been followed since prepuberty. Hormonal evaluation showed very low levels of gonadotropins, luteinizing hormone-releasing hormone test (LHRH test) and sexual steroids in both patients, suggesting a possible defect in the mechanism of action of the GnRH gene on its receptor. METHODS: The GnRHR gene of the two siblings and their parents were analyzed by PCR followed by direct sequencing. RESULTS: Two new single nucleotide substitutions resulting in the T104I and the Y108C substitutions in the first extracellular loop (ECL1) were identified in both siblings. The molecular analysis confirmed the carrier status of the parents. CONCLUSIONS: We identified two new missense mutations in the GnRHR gene in two siblings with HH. The nature of the substitutions lying in the ECL1 involved in the ligand-receptor interaction, as well as the high conservation of the two residues in all mammalian GnRHR, are suggestive of some implications in the phenotype observed.


Assuntos
Hipogonadismo/genética , Mutação de Sentido Incorreto , Receptores LHRH/genética , Adolescente , Adulto , Feminino , Gonadotropinas/sangue , Humanos , Ligantes , Masculino , Gravidez , Receptores LHRH/metabolismo , Irmãos
12.
Clin Endocrinol (Oxf) ; 63(4): 375-80, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16181229

RESUMO

OBJECTIVE: The differential diagnosis of male under-masculinization, including a wide spectrum of phenotypes and a heterogeneous genetic basis, is crucial for the correct management of the patients. To characterize an Italian population of under-masculinized males, we performed the molecular analysis of the SRD5A2 gene (2p23), encoding the 5alpha-reductase-2 enzyme that converts testosterone (T) to dihydrotestosterone (DHT), and is required for full masculinization of the male foetus. DESIGN AND PATIENTS: Twenty-six Italian patients with 46,XY kariotype and various degrees of ambiguous genitalia were retrospectively selected for this study. Twelve of these patients, 10 of whom were referred for partial androgen insensitivity syndrome (PAIS), were raised as females; 15 were raised as males and all had a severe hypospadias. For most of the patients, the case histories and hormonal findings were incomplete but all could be included in the clinical characteristics of under-masculinization. MEASUREMENT: For hormonal evaluation, T and DHT were measured by means of radioimmunoassay (RIA) and high-performance liquid chromatography (HPLC)-RIA methods, respectively. Genomic DNA of all patients and relatives was extracted from peripheral blood, the five exons of the SRD5A2 gene were amplified by polymerase chain reaction (PCR) and submitted to automatic sequencing. RESULTS: Five known mutations affecting the NADPH binding function and one new mutation affecting the enzyme C-terminus were identified in a total of eight patients (two of whom were sisters). Five families were characterized, and in two patients only one affected allele was observed. The extension of the analysis to the regions flanking exons allowed the identification of a new polymorphism in intron 2, whose frequency was determined. CONCLUSION: This first report of an Italian population underlines the importance of differential diagnoses in patients with under-masculinization. The lack of precise genotype-phenotype correlation in some of the mutations highlights the necessity to improve knowledge about the biochemical aspects of steroid 5alpha-reductase action and about the interactions of genetic and environmental factors.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Transtornos do Desenvolvimento Sexual/genética , Mutação Puntual , Polimorfismo Genético , Estudos de Casos e Controles , Criança , Pré-Escolar , Transtornos do Desenvolvimento Sexual/cirurgia , Heterozigoto , Humanos , Lactente , Itália , Cariotipagem , Masculino , Orquiectomia
13.
Am J Med Genet A ; 135(3): 292-6, 2005 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-15884018

RESUMO

We report on a DAX1 gene investigation in a patient with X-linked adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HH) in order to identify mutations causing this disorder and to confirm the clinical diagnosis. The description of the clinical course of the condition with a detailed documentation of longitudinal data is also reported. A male newborn was referred at 45 days of life because of vomiting, dehydration, and weight loss. The diagnosis was primary adrenal insufficiency. The appropriateness of glucocorticoid therapy during the prepubertal period was difficult to judge because of elevated ACTH levels on one hand and progressive retardation of bone age on the other hand. Basal and GnRH stimulated gonadotropin levels remained low during the entire period of examination and exogenous gonadotropin treatment was begun. This had to be interrupted at age 14.6 years because of the occurrence of a 3rd degree anaplastic ependimoma of the left posterior-parietal region, without apparent lepto-meningeal involvement. The molecular analysis of DAX1 gene of the propositus showed deletion of nucleotides AAT in exon 2, resulting in the loss of the Asn430. No alterations were found in the mother and grandmother. This deleted residue lies in one of the helices forming the hydrophobic core of the ligand-binding domain (LBD); thus this mutation may be the cause of the observed phenotype. Further investigations are needed to verify its causal role in AHC associated with HH.


Assuntos
Doenças das Glândulas Suprarrenais/genética , Proteínas de Ligação a DNA/genética , Hipogonadismo/genética , Mutação , Receptores do Ácido Retinoico/genética , Proteínas Repressoras/genética , Adolescente , Doenças das Glândulas Suprarrenais/patologia , Sequência de Aminoácidos , Sequência de Bases , Estatura/efeitos dos fármacos , Criança , Pré-Escolar , Receptor Nuclear Órfão DAX-1 , DNA/química , DNA/genética , Análise Mutacional de DNA , Feminino , Seguimentos , Gonadotropinas/deficiência , Gonadotropinas/uso terapêutico , Humanos , Hipogonadismo/patologia , Lactente , Recém-Nascido , Masculino , Linhagem , Deleção de Sequência
14.
Am J Med Genet A ; 135(2): 150-4, 2005 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-15880570

RESUMO

The identification of Y-chromosome material is important in females with Ullrich-Turner syndrome (UTS) due to the risk of developing gonadoblastoma or other gonadal tumors. There is controversy regarding the frequency of the Y-chromosome-derived material and the occurrence of gonadoblastoma in these patients. The aim of our study was to evaluate a large number of patients with UTS, followed before and during the pubertal age for the prevalence of Y-chromosome derived material, the occurrence of gonadoblastoma, and the incidence of possible neoplastic degeneration. An unselected series of 171 patients with UTS (1-34 years old), diagnosed cytogenetically, was studied for Y-chromosome markers (SRY and Y-centromeric DYZ3 repeats). The follow-up was of 2-22 years; 101 of these patients were followed during pubertal age. Y-chromosome material was found in 14 patients (8%): 12 of these were gonadectomized (2.8-25.9 years). A gonadoblastoma was detected in four patients under 16 years of age: in two, Y-material was detected only at molecular analysis (at conventional cytogenetic analysis, one was included in the 45,X group and one in the X + mar group) and one had also an immature teratoma and an endodermal sinus carcinoma. The prevalence of gonadoblastoma in our series of gonadectomized UTS patients with Y-positive material was of 33.3% (4/12). Our data suggest that the age of appearance and the possibility of malignant degeneration of gonadoblastoma can occur early in life. These patients, in particular those with 45,X or a marker chromosome may benefit from molecular screening to detect the presence of Y-chromosome material; PCR is a rapid and inexpensive technique. At the moment, laparoscopy and preventive gonadectomy performed as soon as possible remain the procedures of choice for patients with UTS, when Y-chromosome has been identified, as we are still unable to predict a future malignant evolution of gonadoblastoma.


Assuntos
Cromossomos Humanos Y/genética , Gonadoblastoma/diagnóstico , Neoplasias Ovarianas/diagnóstico , Síndrome de Turner/genética , Adolescente , Adulto , Análise de Variância , Centrômero/genética , Distribuição de Qui-Quadrado , Criança , Pré-Escolar , Feminino , Genes sry/genética , Marcadores Genéticos/genética , Gonadoblastoma/complicações , Gonadoblastoma/cirurgia , Humanos , Hibridização in Situ Fluorescente , Lactente , Cariotipagem , Modelos Lineares , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/cirurgia , Sequências Repetitivas de Ácido Nucleico/genética , Síndrome de Turner/complicações
15.
J Clin Endocrinol Metab ; 88(12): 5680-8, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14671153

RESUMO

In a retrospective study we evaluated long-term growth, pubertal developmental patterns to final height (FH), and medication in 55 patients (35 females) affected by 21-hydroxylase deficiency. The patients were classified into 3 groups according to predicted mutation severity: group A (11 women and 9 men), homozygous or compound heterozygous for null or In2 splice mutations [residual enzymatic activity (RA), <1%]; group B (11 women and 4 men), homozygous for I172N or R341P or R426H mutations (RA, approximately 2-3%) or compound heterozygous with any of the group A or B mutations; and group C (13 women and 7 men), homozygous for P30L or V281L or P453S mutations (RA, >30%) or compound heterozygous with any of the group A, B, or C mutations. Three patients showed unclassifiable genotypes. FH was similar in the female groups, whereas male patients in group B were shorter than males in groups A and C. Fifty-five percent of patients in group A, 33% in group B, and 40% in group C reached an FH within 0.5 SD of target height. Four of the 7 patients diagnosed via neonatal screening achieved an FH equal to or above the target height. In the entire group, early diagnosis (<1 yr) improved height outcome. Early diagnosed CAH patients who received lower cortisol equivalent doses during the first year of life reached a better FH. Our results underline the importance of mineralocorticoid therapy, as CAH subjects in groups A and B who did not receive this treatment showed reduced FH. Early diagnosis, the use of more physiological cortisol equivalent dosages during the first year of life, and the extension of mineralocorticoid therapy to all classical patients are shown to improve the auxological outcome. Genotypic analysis helped to interpret the height results of our cases and prospectively may represent a useful tool for improving the therapeutic choice and the height outcome.


Assuntos
Hiperplasia Suprarrenal Congênita/genética , Hiperplasia Suprarrenal Congênita/patologia , Estatura , Mineralocorticoides/uso terapêutico , Puberdade , Esteroide 21-Hidroxilase/genética , Hiperplasia Suprarrenal Congênita/fisiopatologia , Envelhecimento , Criança , Pré-Escolar , Feminino , Fertilidade , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Estudos Retrospectivos
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