RESUMO
CONTEXT: 21-hydroxylase deficiency is the most common cause of Congenital Adrenal Hyperplasia. It presents as severe or classical forms-salt wasting and simple virilizing-and a mild or nonclassical (NC). Several studies have reported the frequency of pathogenic variants in different populations, although few of them included a large number of NC patients. OBJECTIVE: To analyse the CYP21A2 gene defects in a large cohort of Argentine patients. DESIGN: Molecular characterization of 628 patients (168 classical, 460 nonclassical, representing 1203 nonrelated alleles), 398 relatives, 126 partners. METHODS: Genetic variants were assessed by allele-specific PCR, PCR-RFLP or direct sequencing. Deletions, duplications and large gene conversions (LGC) were studied by Southern blot/MLPA or long-range PCR. Biological implications of novel variants were analysed by structure-based in silico studies. RESULTS: The most frequent pathogenic variants were p.V282L (58%) in NC alleles and c.293-13C>G (31.8%) and p.I173N (21.1%) in classical. Deletions and LGC were found at low frequency (6.2%), 57 alleles had rare pathogenic variants, and 3 had novel variants: p.(S166F); p.(P189R), p.(R436L). Genotype-phenotype correlation was observed in 98.6% of the cases, 11 asymptomatic first-degree relatives had pathogenic variants in both alleles, and 21/126 partners were carriers. CONCLUSIONS: We conducted a comprehensive genetic characterization of the largest cohort of 21-hydroxylase patients from the region. In particular, we add to the molecular characterization of a large number of NC patients and to the estimation of the disease carrier's frequency in our population.
Assuntos
Hiperplasia Suprarrenal Congênita , Hiperplasia Suprarrenal Congênita/genética , Alelos , Genótipo , Humanos , Mutação , Fenótipo , Esteroide 21-Hidroxilase/genéticaRESUMO
Los niños con restricción del crecimiento intrauterino (RCIU) presentan en la vida posnatal una serie de alteraciones metabólicas y hormonales, y tienen predisposición al desarrollo de obesidad, hipertensión arterial, enfermedad cardiovascular, resistencia a la insulina y diabetes tipo 2. La exposición a un ambiente intrauterino desfavorable en fases críticas del desarrollo puede tener un efecto deletéreo sobre la gónada en formación. Se realizó una revisión bibliográfica y puesta al día sobre la posible asociación entre RCIU y alteraciones de la función gonadal en niños y adolescentes de ambos sexos. Para facilitar la actualización, se dividió por etapas en: 1, prenatal; 2, posnatal y prepuberal; 3, puberal, y 4, adulta. La mayoría de los niños que nacen muy prematuros o con muy bajo peso al nacer hacen una transición sin obstáculos desde la infancia a la edad adulta con respecto a la salud reproductiva. Sin embargo, en los varones se puede observar criptorquidia, hipospadias, cáncer testicular y menor fertilidad, y en las niñas, pubertad y menarca temprana, hiperandrogenismo y síndrome de ovario poliquístico. Existen datos controvertidos y se necesitan más estudios para aclarar la relación entre el RCIU y la función hipotálamo-hipófiso-gonadal.
Low birth weight due to intrauterine growth restriction (IUGR) is associated with an increased risk of obesity, hypertension, cardiovascular disease, insulin resistance, and type 2 diabetes during postnatal life. Exposure to an unfavourable intrauterine environment in critical phases of development may have a deleterious effect on the forming gonad. The objective was to carry out a bibliographic review and update on the possible association between IUGR and alterations of gonadal function in children and adolescents of both sexes. To facilitate the update, this was divided into stages: 1, prenatal; 2, postnatal and pre-pubertal; 3, puberal, and 4, adult. Most children born preterm or with low birth weight make a normal transition from childhood to adulthood with respect to reproductive health. However, cryptorchidism, hypospadias, testicular cancer and lower fertility could be observed in boys, and early puberty and menarche, hyperandrogenism and polycystic ovarian syndrome in girls. However, the data are controversial, and further studies are needed to clarify the relationship between IUGR and pituitary gonadal function.
Assuntos
Humanos , Masculino , Feminino , Recém-Nascido Pequeno para a Idade Gestacional/crescimento & desenvolvimento , Retardo do Crescimento Fetal/fisiopatologia , Transtornos Gonadais/etiologia , Puberdade Precoce/embriologia , Hiperandrogenismo/embriologia , Criptorquidismo/embriologia , Hipospadia/embriologiaRESUMO
The aim of the current study was to search for the presence of genetic variants in the CYP21A2 Z promoter regulatory region in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Screening of the 10 most frequent pseudogene-derived mutations was followed by direct sequencing of the entire coding sequence, the proximal promoter, and a distal regulatory region in DNA samples from patients with at least one non-determined allele. We report three non-classical patients that presented a novel genetic variant-g.15626A>G-within the Z promoter regulatory region. In all the patients, the novel variant was found in cis with the mild, less frequent, p.P482S mutation located in the exon 10 of the CYP21A2 gene. The putative pathogenic implication of the novel variant was assessed by in silico analyses and in vitro assays. Topological analyses showed differences in the curvature and bendability of the DNA region bearing the novel variant. By performing functional studies, a significantly decreased activity of a reporter gene placed downstream from the regulatory region was found by the G transition. Our results may suggest that the activity of an allele bearing the p.P482S mutation may be influenced by the misregulated CYP21A2 transcriptional activity exerted by the Z promoter A>G variation.
Assuntos
Hiperplasia Suprarrenal Congênita/genética , Alelos , Regiões Promotoras Genéticas , Esteroide 21-Hidroxilase/genética , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , MutaçãoRESUMO
Although corticoid replacement is recommended for those late-onset adrenal hyperplasia with clinical manifestations, asymptomatic patients do not need treatment. We describe clinical features at diagnosis, treatment, and growth till adult- height, in 4 boys. At diagnosis, age ranged from 9.2-11.6 years. The initial symptoms/signs were: precocious pubarche (n = 2), accelerated bone age (n = 1) and precocious puberty (n = 1). All of them presented elevated 17 hydroxyprogesterone levels and were compound heterozygotes carrying p.V281L mutation. Since, at diagnosis, bone age was significantly advanced for chronological age (13.1 ± 0.5 vs. 10.2 ± 1.1 p = 0.008), hydrocortisone therapy was initiated. During follow-up, mean height Z score decreased 1.4 ± 0.4 SDS (p = 0.007), though adult mean height was not different from target height (-0.39 ± 0.7 vs. -0.04 ± 0.5 SDS, p = 0.054). In conclusion, in 4 symptomatic patients, accurate treatment of late-onset adrenal hyperplasia led to an adult mean height not different from target height. Advanced bone age at diagnosis and the loss of height during pubertal development suggest the need of therapy.
Assuntos
Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Hiperplasia Suprarrenal Congênita/fisiopatologia , Estatura , Glucocorticoides/uso terapêutico , Idade de Início , Criança , Humanos , MasculinoRESUMO
La hiperplasia suprarrenal congénita no clásica puede ser asintomática o presentar signos de hiperandrogenismo y requerir tratamiento. Se describen las características clínicas en el diagnóstico, tratamiento y seguimiento hasta alcanzar la talla adulta en cuatro varones. La edad en el momento del diagnóstico fue de 9,2 a 11,6 años. Los motivos de consulta fueron pubarca precoz (n= 2), edad ósea acelerada (n= 1) y pubertad precoz (n= 1). Todos los pacientes presentaron 17-hidroxiprogesterona elevada y el estudio molecular confirmó el diagnóstico. La edad ósea adelantada respecto de la edad cronológica (13,1 ± 0,5 contra 10,2 ± 1,1; p = 0,008) motivó el inicio del tratamiento con hidrocortisona. Durante el seguimiento, la media de talla disminuyó 1,4 ± 0,4 desviaciones estándar (DE) con respecto al diagnóstico (p= 0,007). Sin embargo, la media de talla final no difirió de la genética (-0,9 ± 0,7 contra -0,04 ± 0,5 DE; p= 0,054). Conclusión: El tratamiento de los cuatro niños con adelanto de la edad ósea en el momento del diagnóstico permitió lograr una talla adulta que no difirió de la talla genética.
Although corticoid replacement is recommended for those lateonset adrenal hyperplasia with clinical manifestations, asymptomatic patients do not need treatment. We describe clinical features at diagnosis, treatment, and growth till adult- height, in 4 boys. At diagnosis, age ranged from 9.2-11.6 years. The initial symptoms/signs were: precocious pubarche (n= 2), accelerated bone age (n= 1) and precocious puberty (n= 1). All of them presented elevated 17 hydroxyprogesterone levels and were compound heterozygotes carrying p.V281L mutation. Since, at diagnosis, bone age was significantly advanced for chronological age (13.1 ± 0.5 vs. 10.2 ± 1.1 p= 0.008), hydrocortisone therapy was initiated. During follow-up, mean height Z score decreased 1.4 ± 0.4 SDS (p= 0.007), though adult mean height was not different from target height (-0.39 ± 0.7 vs. -0.04 ± 0.5 SDS, p= 0.054). In conclusion, in 4 symptomatic patients, accurate treatment of late-onset adrenal hyperplasia led to an adult mean height not different from target height. Advanced bone age at diagnosis and the loss of height during pubertal development suggest the need of therapy.
Assuntos
Criança , Humanos , Masculino , Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Hiperplasia Suprarrenal Congênita/fisiopatologia , Estatura , Glucocorticoides/uso terapêutico , Idade de InícioRESUMO
La hiperplasia suprarrenal congénita no clásica puede ser asintomática o presentar signos de hiperandrogenismo y requerir tratamiento. Se describen las características clínicas en el diagnóstico, tratamiento y seguimiento hasta alcanzar la talla adulta en cuatro varones. La edad en el momento del diagnóstico fue de 9,2 a 11,6 años. Los motivos de consulta fueron pubarca precoz (n= 2), edad ósea acelerada (n= 1) y pubertad precoz (n= 1). Todos los pacientes presentaron 17-hidroxiprogesterona elevada y el estudio molecular confirmó el diagnóstico. La edad ósea adelantada respecto de la edad cronológica (13,1 ± 0,5 contra 10,2 ± 1,1; p = 0,008) motivó el inicio del tratamiento con hidrocortisona. Durante el seguimiento, la media de talla disminuyó 1,4 ± 0,4 desviaciones estándar (DE) con respecto al diagnóstico (p= 0,007). Sin embargo, la media de talla final no difirió de la genética (-0,9 ± 0,7 contra -0,04 ± 0,5 DE; p= 0,054). Conclusión: El tratamiento de los cuatro niños con adelanto de la edad ósea en el momento del diagnóstico permitió lograr una talla adulta que no difirió de la talla genética.(AU)
Although corticoid replacement is recommended for those lateonset adrenal hyperplasia with clinical manifestations, asymptomatic patients do not need treatment. We describe clinical features at diagnosis, treatment, and growth till adult- height, in 4 boys. At diagnosis, age ranged from 9.2-11.6 years. The initial symptoms/signs were: precocious pubarche (n= 2), accelerated bone age (n= 1) and precocious puberty (n= 1). All of them presented elevated 17 hydroxyprogesterone levels and were compound heterozygotes carrying p.V281L mutation. Since, at diagnosis, bone age was significantly advanced for chronological age (13.1 ± 0.5 vs. 10.2 ± 1.1 p= 0.008), hydrocortisone therapy was initiated. During follow-up, mean height Z score decreased 1.4 ± 0.4 SDS (p= 0.007), though adult mean height was not different from target height (-0.39 ± 0.7 vs. -0.04 ± 0.5 SDS, p= 0.054). In conclusion, in 4 symptomatic patients, accurate treatment of late-onset adrenal hyperplasia led to an adult mean height not different from target height. Advanced bone age at diagnosis and the loss of height during pubertal development suggest the need of therapy.(AU)
Assuntos
Criança , Humanos , Masculino , Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Hiperplasia Suprarrenal Congênita/fisiopatologia , Estatura , Glucocorticoides/uso terapêutico , Idade de InícioRESUMO
Although corticoid replacement is recommended for those late-onset adrenal hyperplasia with clinical manifestations, asymptomatic patients do not need treatment. We describe clinical features at diagnosis, treatment, and growth till adult- height, in 4 boys. At diagnosis, age ranged from 9.2-11.6 years. The initial symptoms/signs were: precocious pubarche (n = 2), accelerated bone age (n = 1) and precocious puberty (n = 1). All of them presented elevated 17 hydroxyprogesterone levels and were compound heterozygotes carrying p.V281L mutation. Since, at diagnosis, bone age was significantly advanced for chronological age (13.1 ± 0.5 vs. 10.2 ± 1.1 p = 0.008), hydrocortisone therapy was initiated. During follow-up, mean height Z score decreased 1.4 ± 0.4 SDS (p = 0.007), though adult mean height was not different from target height (-0.39 ± 0.7 vs. -0.04 ± 0.5 SDS, p = 0.054). In conclusion, in 4 symptomatic patients, accurate treatment of late-onset adrenal hyperplasia led to an adult mean height not different from target height. Advanced bone age at diagnosis and the loss of height during pubertal development suggest the need of therapy.
Assuntos
Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Hiperplasia Suprarrenal Congênita/fisiopatologia , Estatura , Glucocorticoides/uso terapêutico , Idade de Início , Criança , Humanos , MasculinoRESUMO
The aim of the study was to establish the characteristics of presentation of 94 patients with Kinelfelter's syndrome (KS) referred to the endocrinologist at different ages. The diagnosis of KS was more frequent in the age group between 11 and 20 years (46.8%). Most of the patients (83.7%) showed the classic 47,XXY karyotype and 7.1% showed a 47,XXY/46,XY mosaicism. Half of the patients younger than 18 years presented mild neurodevelopmental disorders. The most frequent clinical findings were cryptorchidism in prepubertal patients, and small testes, cryptorchidism, and gynecomastia in pubertal patients. FSH, LH, AMH, and inhibin B levels were normal in prepubertal patients and became abnormal from midpuberty. Most adults were referred for small testes, infertility, and gynecomastia; 43.6% had sexual dysfunction. Testosterone levels were low in 45%. Mean stature was above the 50th percentile, and 62.5% had BMI ≥25.0 kg/m(2). In conclusion, the diagnosis of Klinefelter syndrome seems to be made earlier nowadays probably because pediatricians are more aware that boys and adolescents with neuro-developmental disorders and cryptorchidism are at increased risk. The increasing use of prenatal diagnosis has also decreased the mean age at diagnosis and allowed to get insight into the evolution of previously undiagnosed cases, which probably represent the mildest forms. In adults average height and weight are slightly higher than those in the normal population. Bone mineral density is mildly affected, more at the spine than at the femoral neck level, in less than half of cases.
RESUMO
UNLABELLED: Male hypogonadism implies decreased function of one or more testicular cell population, i.e. germ, Leydig and/or Sertoli cells. In the normal prepubertal boy, Sertoli cells are very active, as indicated by high anti-Müllerian hormone (AMH) and inhibin B secretion, whereas the functional activity of Leydig cells is minimal, as evidenced by low testosterone production, and germ cells do not undergo the full spermatogenic process. Klinefelter syndrome is the most frequent cause of hypogonadism in the adult male. In this review, we discuss whether the gonadal failure is already established during infancy and childhood. In Klinefelter syndrome, there is increased germ cells degeneration from mid-foetal life - resulting in a decreased number at birth - which persists during infancy and childhood and becomes dramatic during puberty. Controversial results exist in the literature regarding Leydig cell function in Klinefelter boys: while some authors have found normal to low testosterone levels in infancy and childhood, others have reported normal to high values. Sertoli cell products AMH and inhibin B are normal in prepubertal boys and only decline during mid- to late puberty. CONCLUSION: Klinefelter syndrome is a primary hypogonadism affecting all testicular cell populations. Germ cells are affected from foetal life, and a severe depletion occurs at puberty. Leydig cell function may be normal or mildly affected in foetal and early postnatal life. Sertoli cell function is not impaired until mid- to late puberty, as reflected by normal AMH and inhibin B in Klinefelter boys.
Assuntos
Hipogonadismo/diagnóstico , Síndrome de Klinefelter/fisiopatologia , Criança , Células Germinativas/fisiologia , Humanos , Lactente , Síndrome de Klinefelter/embriologia , Células Intersticiais do Testículo/fisiologia , Masculino , Puberdade/fisiologia , Células de Sertoli/fisiologia , Testículo/embriologia , Testículo/metabolismoRESUMO
The high prevalence of menstrual disorders during the first years after menarche is well recognized. This is usually a cause of concern for parents and patients, and a common reason for visiting the pediatrician. The immaturity of the hypothalamic-pituitary-ovarian axis is the major cause of these disorders, but there are also some general organic or emotional conditions that may alter the menstrual cycle, which is a sensitive indicator of health. Physiology of the menstrual cycle, its alterations, etiology, assessment, diagnosis and treatment are reviewed in this article.
Assuntos
Distúrbios Menstruais , Adolescente , Feminino , Humanos , Ciclo Menstrual/fisiologia , Distúrbios Menstruais/diagnóstico , Distúrbios Menstruais/etiologia , Distúrbios Menstruais/terapiaRESUMO
Adrenal insufficiency is defined by impaired secretion of adrenocortical hormones. It is classified upon the etiology in primary and secondary. Rapid recognition and therapy of adrenocortical crisis are critical to survival. Patients often have nonspecific symptoms: anorexia, vomiting, weakness, fatigue and lethargy. They are followed by hypotension, shock, hypoglicemia, hyponatremia and hyperkalemia. All patients with adrenal insufficiency require urgent fluid reposition, correction of hypoglycemia and glucocorticoid replacement, in order to avoid serious consequences of adrenal crisis. After initial crisis treatment, maintenance dose of corticoids should be indicated. Mineralocorticoids replacement, if necessary, should also be initiated.
Assuntos
Insuficiência Adrenal , Insuficiência Adrenal/terapia , Criança , Emergências , Humanos , Índice de Gravidade de DoençaRESUMO
La insuficiencia suprarrenal aguda es un cuadro originado por deficiencia mineralocorticoidea o glucocorticoidea, cuyo no diagnóstico y adecuado tratamiento lleva a una emergenciagrave con riesgo para la vida del paciente. Se clasifica en insuficiencia suprarrenal primaria, que presenta en general compromiso glucocorticoideo y mineralocorticoideo, y secundaria,sin deficiencia mineralocorticoidea. Los pacientes pueden no presentar síntomas que alerten precozmente, comoanorexia, náuseas, astenia, vómitos y dolor abdominal. De no corregirse, aparecen hipotensión, hipoglucemia, hiponatremia con hipercaliemia, deshidratación y shock. Es indispensable,aun en caso de duda, corregir la hipovolemia, el desequilibrioelectrolítico y la hipoglucemia, y administrar glucocorticoidesa dosis de estrés. Superada la fase aguda, administrar la dosis de corticoides de mantenimiento y, en caso necesario, añadir mineralocorticoides.
Assuntos
Humanos , Masculino , Criança , Corticosteroides/uso terapêutico , Emergências , Insuficiência Adrenal/classificação , Insuficiência Adrenal/complicações , Insuficiência Adrenal/prevenção & controle , Insuficiência Adrenal/terapiaRESUMO
La insuficiencia suprarrenal aguda es un cuadro originado por deficiencia mineralocorticoidea o glucocorticoidea, cuyo no diagnóstico y adecuado tratamiento lleva a una emergenciagrave con riesgo para la vida del paciente. Se clasifica en insuficiencia suprarrenal primaria, que presenta en general compromiso glucocorticoideo y mineralocorticoideo, y secundaria,sin deficiencia mineralocorticoidea. Los pacientes pueden no presentar síntomas que alerten precozmente, comoanorexia, náuseas, astenia, vómitos y dolor abdominal. De no corregirse, aparecen hipotensión, hipoglucemia, hiponatremia con hipercaliemia, deshidratación y shock. Es indispensable,aun en caso de duda, corregir la hipovolemia, el desequilibrioelectrolítico y la hipoglucemia, y administrar glucocorticoidesa dosis de estrés. Superada la fase aguda, administrar la dosis de corticoides de mantenimiento y, en caso necesario, añadir mineralocorticoides.(AU)
Assuntos
Humanos , Masculino , Criança , Emergências , Insuficiência Adrenal/classificação , Insuficiência Adrenal/complicações , Insuficiência Adrenal/prevenção & controle , Insuficiência Adrenal/terapia , Corticosteroides/uso terapêuticoRESUMO
Allograft function and metabolic effects of four treatment regimens, namely, methylprednisone (MP) standard dose (MP-STD), deflazacort (DFZ), MP-late steroid withdrawal (MP-LSW), and MP-very low dose (MP-VLD), were evaluated in prepubertal patients. MP was decreased by month 4 post-transplantation to 0.2 mg/kg/day in MP-STD and DFZ patients and to <0.1 mg/kg/day in MP-LSW and MP-VLD patients. Starting in month 16 post-transplant, MP was switched to DFZ in the DFZ group and totally withdrawn in the MP-LSW group. Creatinine clearance diminished in the MP-STD and MP-LSW groups from 77 +/- 6 to 63 +/- 6 ml/min/1.73 m(2)and from 103 +/- 5 to 78 +/- 3 ml/min/1.73 m(2), respectively (p < 0.01 and p < 0.001, respectively). Height increased >0.5 SDS only in the MP-LSW and MP-VLD groups. The body mass index and fat body mass for height-age increased only in the MP-STD patients (p < 0.05 and p < 0.01, respectively). Fat body mass decreased in the DFZ group (p < 0.05), total cholesterol and LDL-cholesterol increased in the MP-STD group, while LDL-cholesterol and total cholesterol/HDL-cholesterol ratio decreased in the DFZ group (p < 0.01). Lumbar spine bone mineral density (BMD) for height-age showed an increase in the MP-LSW and MP-VLD groups (p < 0.01). Our data suggest that MP-LSW and MP-VLD strategies improve linear growth, BMD, the peripheral distribution of fat, and preservation of the bone-muscle unit and maintain the normal lipid profile. The MP-LSW patients had a concerning rate of acute rejections and graft function deterioration in prepubertal patients.
Assuntos
Composição Corporal/fisiologia , Transtornos do Crescimento/prevenção & controle , Crescimento/fisiologia , Transplante de Rim/efeitos adversos , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/fisiologia , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Rejeição de Enxerto/induzido quimicamente , Transtornos do Crescimento/fisiopatologia , Transtornos do Crescimento/reabilitação , Humanos , Imunossupressores/uso terapêutico , Transplante de Rim/reabilitação , Vértebras Lombares/efeitos dos fármacos , Vértebras Lombares/metabolismo , Masculino , Metilprednisolona/uso terapêutico , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/reabilitação , Pregnenodionas/uso terapêuticoRESUMO
Definición: El niño con restricción del crecimiento intrauterino/pequeño para edad gestacional (RCIU/PEG) se define como aquel que nace con un peso (PN) y/o longitud corporal (LC) igual o menor a 2 desvíos standard (DS) debajo de la media de acuerdo a la edad gestacional. En algunas situaciones se define como aquellos que nacen con un peso menor de percentilo 10, corregido para edad gestacional. Crecimiento postnatal: Aunque el 87% de los niños nacidos con RCIU/PEG recuperan su peso/estatura antes de los dos años de edad; el 13% no desarrolla este crecimiento compensador. Algunos pueden recuperar estatura normal, pero a los 18 años alrededor del 7% queda definitivamente con una estura por debajo de -2 DS. Alteraciones metabólicas: La reprogramación fetal propone que la desnutrición intrauterina materno-fetal programa la actividad metabólica y hormonal del recien nacido. Estudios epidemiológicos mostraron que el tamaño al nacer puede asociarse con rápida ganancia de peso, mayor masa grasa con distribución visceral y obesidad a largo plazo. La conexión entre un medio ambiente perinatal adverso y las consecuencias observadas en la vida adulta podría ser una permanente reducción en la sensibilidad a la insulina. Se ha detectado tempranamente una resistencia a la insulina, preferentemente en aquellos que recuperaron muy rápidamente el peso o lo excedieron. El RCIU se ha asociado a mayor riesgo de síndrome metabólico con mayor tendencia a diabetes tipo II, dislipidemia, hipertensión, enfermedad cardiaca isquémica y accidentes cerebro vasculares. Existe también reprogramación del eje hipotálamo-hipófiso-adrenal y gonadal con aparición de pubarca precoz, hiperandrogenismo ovárico (PCO). Se observa además de rápido progreso de la pubertad y menarca temprana, hipersecreción de FSH y ovarios pequeños. En los varones existe mayor tendencia a hipospadias, criptorquidismo, hipersecreción de FSH en la prepubertad, testículos chicos y subfertilidad. Existe cierta evidencia para sugerir que algunas consecuencias metabólicas del RCIU pueden ser mitigadas asegurando un buen crecimiento compensador y evitando una excesiva ganancia de peso.
Definition: The term small for gestational age (SGA) has been used to describe a neonate whose weight and / or crown-heel length at birth is 2 SD below the mean for the infant's gestational age. Some publications define SGA as a birth weight or length below the 10th percentile for gestational age. Postnatal growth: Although the vast majority of SGA children show catch-up growth by 2 years of age, 13% do not and most of these children continue to experience poor growth throughout childhood. Metabolic alterations: Fetal reprogramming proposes that maternal-fetal undernutrition programs metabolic and hormonal activity of the new born. It is a theory that highlights the role of the fetal environment in the etiology of disease in adult life. Epidemiologic studies showed that low birth weight is associated with rapid catch-up growth, more abdominal adiposity and obesity in adulthood. One of the potential mechanisms suggested stated that undernutrition during critical periods of fetal development could program permanent lower insulin sensitivity. Early insulin resistance has been described in SGA who achieved rapid catch-up growth. Being born SGA carries an increased risk of type II diabetes, dyslipidemia, hypertension, cardiovascular disease including coronary heart disease and stroke. In addition, developmental sequelae affecting the GH-IGF axis and adrenal and gonadal function are seen and so premature adrenarche, hyperandrogenism and polycystic ovarian syndrome are frequent, particularly in individuals with abnormal weight gain in infancy and childhood. The rise in FSH levels is greater during infancy in both boys and girls and when studied in young adulthood, females also had FSH hypersecretion and evidence of reduced growth of the uterus and ovaries as assessed by ultrasound examination with reduced ovulation rate. In boys reduced testicular volume, decreased serum inhibin B and testosterone concentrations and increased LH and FSH values were described. Low birth weight is a common risk factor for abnormal spermatogenesis, testicular cancer, hypospadias and cryptorchidism. There is evidence to suggest that some of the metabolic consequences of intrauterine growth retardation can be mitigated by ensuring early appropriate catch-up growth, while avoiding excessive weight gain.
Assuntos
Humanos , Recém-Nascido , Hormônio do Crescimento Humano/uso terapêutico , Recém-Nascido Prematuro/crescimento & desenvolvimento , Recém-Nascido/crescimento & desenvolvimento , Doenças Metabólicas/epidemiologia , Insulina/efeitos adversosRESUMO
Definición: El niño con restricción del crecimiento intrauterino/pequeño para edad gestacional (RCIU/PEG) se define como aquel que nace con un peso (PN) y/o longitud corporal (LC) igual o menor a 2 desvíos standard (DS) debajo de la media de acuerdo a la edad gestacional. En algunas situaciones se define como aquellos que nacen con un peso menor de percentilo 10, corregido para edad gestacional. Crecimiento postnatal: Aunque el 87% de los niños nacidos con RCIU/PEG recuperan su peso/estatura antes de los dos años de edad; el 13% no desarrolla este crecimiento compensador. Algunos pueden recuperar estatura normal, pero a los 18 años alrededor del 7% queda definitivamente con una estura por debajo de -2 DS. Alteraciones metabólicas: La reprogramación fetal propone que la desnutrición intrauterina materno-fetal programa la actividad metabólica y hormonal del recien nacido. Estudios epidemiológicos mostraron que el tamaño al nacer puede asociarse con rápida ganancia de peso, mayor masa grasa con distribución visceral y obesidad a largo plazo. La conexión entre un medio ambiente perinatal adverso y las consecuencias observadas en la vida adulta podría ser una permanente reducción en la sensibilidad a la insulina. Se ha detectado tempranamente una resistencia a la insulina, preferentemente en aquellos que recuperaron muy rápidamente el peso o lo excedieron. El RCIU se ha asociado a mayor riesgo de síndrome metabólico con mayor tendencia a diabetes tipo II, dislipidemia, hipertensión, enfermedad cardiaca isquémica y accidentes cerebro vasculares. Existe también reprogramación del eje hipotálamo-hipófiso-adrenal y gonadal con aparición de pubarca precoz, hiperandrogenismo ovárico (PCO). (AU)
Assuntos
Humanos , Recém-Nascido , Recém-Nascido Prematuro/crescimento & desenvolvimento , Recém-Nascido/crescimento & desenvolvimento , Hormônio do Crescimento Humano/uso terapêutico , Insulina/efeitos adversos , Doenças Metabólicas/epidemiologiaRESUMO
Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is a disorder which can adopt three clinical expressions: two classical forms -salt-wasting (SW), with residual enzymatic activity (EA) < or = 1% and simple virilizing (SV), with EA 1-2%- and a mild late onset or nonclassical (NC) form, with EA 10-60%. Our objective is to describe clinical characteristics, growth, and bone mass in a group of patients affected by 21-hydroxylase deficiency. Besides, molecular genetics studies were performed in patients, and also when available in their parents and siblings. Nine patients with neonatal diagnosis and 8 with pre or postpubertal diagnosis were studied. Analyses of 10-point mutations in the CYP21A2 gene were performed. We found that all the patients with the classical expression, except one with a de novo mutation R356W in one allele, were fully genotyped with predictive < 2% EA mutations. Signs of hyperandrogenism were present in 5/6 NC patients; one was diagnosed by searching for mutations in asymptomatic siblings. All the NC patients were compound heterozygotes carrying V281L mutation in one allele and a predictive low EA in the other, except for one not yet determined. In patients with neonatal diagnosis, mean height was low at one year of age, though it showed a significant increase before the onset of puberty. We conclude that neonatal diagnosis of classical CAH allows an adequate follow up enhancing growth. Molecular analyses of all members of an affected family may disclose asymptomatic patients. The presence of de novo mutations, as well as, the presence of mutations with low predicted EA in NC patients reinforces the importance of genotyping for appropriate genetic counseling. In fully genotyped NC patients, the lowest value of ACTH-stimulated 17OHP was 14 ng/ml. Lower cut-off values might overestimate the diagnosis of the NC form.
Assuntos
Hiperplasia Suprarrenal Congênita/genética , Mutação/genética , Adolescente , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/enzimologia , Alelos , Criança , Pré-Escolar , Feminino , Seguimentos , Conversão Gênica , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Mutação Puntual/genética , Esteroide 21-Hidroxilase/metabolismoRESUMO
INTRODUCTION: Around 50% of Noonan syndrome (NS) patients present heterozygous mutations in the PTPN11 gene. AIM: To evaluate the frequency of mutations in the PTPN11 in patients with NS, and perform phenotype-genotype correlation. PATIENTS: 33 NS patients (23 males). METHODS: DNA was extracted from peripheral blood leukocytes, and all 15 PTPN11 exons were directly sequenced. RESULTS: Nine different missense mutations, including the novel P491H, were found in 16 of 33 NS patients. The most frequently observed features in NS patients were posteriorly rotated ears with thick helix (85%), short stature (79%), webbed neck (77%) and cryptorchidism (60%) in boys. The mean height SDS was -2.7 +/- 1.2 and BMI SDS was -1 +/- 1.4. Patients with PTPN11 mutations presented a higher incidence of pulmonary stenosis than patients without mutations (38% vs. 6%, p< 0.05). Patients with and without mutations did not present differences regarding height SDS, BMI SDS, frequency of thorax deformity, facial characteristics, cryptorchidism, mental retardation, learning disabilities, GH peak at stimulation test and IGF-1 or IGFBP-3 SDS. CONCLUSION: We identified missense mutations in 48.5% of the NS patients. There was a positive correlation between the presence of PTPN11 mutations and pulmonary stenosis frequency in NS patients.
Assuntos
Estatura , Transtornos do Crescimento/etiologia , Mutação de Sentido Incorreto/genética , Síndrome de Noonan/genética , Fenótipo , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Adolescente , Estatura/efeitos dos fármacos , Criança , Feminino , Genótipo , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Masculino , Síndrome de Noonan/complicações , Síndrome de Noonan/tratamento farmacológicoRESUMO
True hermaphroditism usually appears with ambiguous genitalia requiring extensive evaluation during the neonatal period. There have been occasional cases with better differentiation of external genitalia, leading to delays in diagnosis. We report the case of an adolescent boy with true hermaphroditism who presented with normal external genitalia and no sexual ambiguity. He was referred due to progressive gynecomastia and arrest of puberty. He presented at the age of 16 years for gynecomastia of rapid progression with normal penile development and both gonads in scrotum and normal testosterone and increased gonadotropin levels. Gonadal ultrasound scan was compatible with testicular and ovarian tissues in scrotum, and the karyotype showed two cellular lines (46,XX/46,XY). Gonadal histology revealed bilateral ovotestes. A genotype polymerase chain reaction mediated analysis using seven microsatellite markers did not confirm chimerism. Clinical findings and mechanism of generation are discussed.