RESUMEN
The ability to efficiently modulate autophagy activity is paramount in the study of the field. Conventional broad-range autophagy inhibitors and genetic manipulation using RNA interference (RNAi), although widely used in autophagy research, are often limited in specificity or efficacy. In this chapter, we address the problems of conventional autophagy-modulating tools by exploring the use of three different CRISPR/Cas9 systems to abrogate autophagy in numerous human and mouse cell lines. The first system generates cell lines constitutively deleted of ATG5 or ATG7 whereas the second and third systems express a Tet-On inducible-Cas9 that enables regulated deletion of ATG5 or ATG7. We observed the efficiency of autophagy inhibition using the CRISPR/Cas9 strategy to surpass that of RNAi, and successfully generated cells with complete and sustained autophagy disruption through the CRISPR/Cas9 technology.
Asunto(s)
Autofagia , Sistemas CRISPR-Cas , Edición Génica/métodos , Animales , Proteína 5 Relacionada con la Autofagia/genética , Proteína 7 Relacionada con la Autofagia/genética , Línea Celular , Clonación Molecular/métodos , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Humanos , Ratones , ARN Guía de Kinetoplastida/genéticaRESUMEN
The long-held belief that pituitary hormones act solely on master targets was first questioned when we documented G protein-coupled receptors for thyroid-stimulating hormone, follicle-stimulating hormone, adrenocorticotrophic hormone, oxytocin, and vasopressin on bone cells. These evolutionarily conserved hormones and their receptors are known to have primitive roles, and exist in invertebrate species as far down as coelenterates. It is not surprising therefore that each such hormone has multiple hitherto unrecognized functions in mammalian integrative physiology, and hence, becomes a potential target for therapeutic intervention. Here we discuss the skeletal actions of pituitary hormones.
Asunto(s)
Huesos/efectos de los fármacos , Hormonas Hipofisarias/farmacología , Reproducción/efectos de los fármacos , Animales , Evolución Biológica , Resorción Ósea/patología , Humanos , Transducción de Señal/efectos de los fármacosRESUMEN
Half of lung cancers are diagnosed in former smokers, leading to a significant treatment burden in this population. Chemoprevention in former smokers using the prostacyclin analogue iloprost reduces endobronchial dysplasia, a premalignant lung lesion. Iloprost requires the presence of the WNT receptor Frizzled 9 (Fzd9) for inhibition of transformed growth in vitro. To investigate the relationship between iloprost, cigarette smoke, and Fzd9 expression, we used human samples, mouse models, and in vitro studies. Fzd9 expression was low in human lung tumors and in progressive dysplasias. In mouse models and in vitro studies, tobacco smoke carcinogens reduced expression of Fzd9 while prostacyclin maintained or increased expression. Expression of miR-31 repressed Fzd9 expression, which was abrogated by prostacyclin. We propose a model where cigarette smoke exposure increases miR-31 expression, which leads to decreased Fzd9 expression and prevents response to iloprost. When smoke is removed miR-31 is reduced, prostacyclin can increase Fzd9 expression, and progression of dysplasia is inhibited. Fzd9 and miR-31 are candidate biomarkers for precision application of iloprost and monitoring of treatment progress. As we continue to investigate the mechanisms of prostacyclin chemoprevention and identify biomarkers for its use, we will facilitate clinical trials and speed implementation of this valuable prevention approach.
Asunto(s)
Epoprostenol/farmacología , Receptores Frizzled/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , MicroARNs/metabolismo , Humo/efectos adversos , Animales , Bronquios/citología , Células Cultivadas , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Receptores Frizzled/genética , Humanos , Iloprost/farmacología , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones Transgénicos , MicroARNs/genética , Nicotiana/química , Uretano/toxicidadRESUMEN
Global climate models suggest enhanced warming of the tropical mid and upper troposphere, with larger temperature rise rates at higher elevations. Changes in fire activity are amongst the most significant ecological consequences of rising temperatures and changing hydrological properties in mountainous ecosystems, and there is a global evidence of increased fire activity with elevation. Whilst fire research has become popular in the tropical lowlands, much less is known of the tropical high Andean region (>2000 masl, from Colombia to Bolivia). This study examines fire trends in the high Andes for three ecosystems, the Puna, the Paramo and the Yungas, for the period 1982-2006. We pose three questions: (i) is there an increased fire response with elevation? (ii) does the El Niño- Southern Oscillation control fire activity in this region? (iii) are the observed fire trends human driven (e.g., human practices and their effects on fuel build-up) or climate driven? We did not find evidence of increased fire activity with elevation but, instead, a quasicyclic and synchronous fire response in Ecuador, Peru and Bolivia, suggesting the influence of high-frequency climate forcing on fire responses on a subcontinental scale, in the high Andes. ENSO variability did not show a significant relation to fire activity for these three countries, partly because ENSO variability did not significantly relate to precipitation extremes, although it strongly did to temperature extremes. Whilst ENSO did not individually lead the observed regional fire trends, our results suggest a climate influence on fire activity, mainly through a sawtooth pattern of precipitation (increased rainfall before fire-peak seasons (t-1) followed by drought spells and unusual low temperatures (t0), which is particularly common where fire is carried by low fuel loads (e.g., grasslands and fine fuel). This climatic sawtooth appeared as the main driver of fire trends, above local human influences and fuel build-up cyclicity.
Asunto(s)
Cambio Climático , Clima , Ecosistema , Incendios , Altitud , Bosques , Pradera , Humanos , América del Sur , TundraRESUMEN
Histone deacetylase (HDAC) is an emergent anticancer target, and HR23B is a biomarker for response to HDAC inhibitors. We show here that HR23B has impacts on two documented effects of HDAC inhibitors; HDAC inhibitors cause apoptosis in cells expressing high levels of HR23B, whereas in cells with low level expression, HDAC inhibitor treatment is frequently associated with autophagy. The mechanism responsible involves the interaction of HDAC6 with HR23B, which downregulates HR23B and thereby reduces the level of ubiquitinated substrates targeted to the proteasome, ultimately desensitising cells to apoptosis. Significantly, the ability of HDAC6 to downregulate HR23B occurs independently of its deacetylase activity. An analysis of the HDAC6 interactome identified HSP90 as a key effector of HDAC6 on HR23B levels. Our results define a regulatory mechanism that involves the interplay between HR23B and HDAC6 that influences the biological outcome of HDAC inhibitor treatment.
Asunto(s)
Apoptosis/efectos de los fármacos , Enzimas Reparadoras del ADN/metabolismo , Proteínas de Unión al ADN/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Ubiquitina/metabolismo , Autofagia/efectos de los fármacos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Regulación Neoplásica de la Expresión Génica , Histona Desacetilasa 6 , Histona Desacetilasas/genética , Humanos , ARN Interferente Pequeño/genética , TransfecciónRESUMEN
Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder where steroidogenesis in the adrenal cortex is impaired. The most common form is caused by 21-hydroxylase deficiency (21OHD). Classical 21OHD is characterized by glucocorticoid and mineralocorticoid deficiency and by overproduction of adrenal androgens. The diagnosis rests on biochemical and genetic analyses. In families with history of CAH, prenatal genetic diagnosis is offered. We herein present a case of an infant whose parents were identified to carry mutations on the CYP21A2 gene. The fetal DNA analysis demonstrated that the fetus carried a paternal exon 8 (Q318X) mutation and a maternal exon 8 (R356X) mutation. The fetus was presumed to be affected with CAH, yet his clinical presentation at birth was not consistent with the diagnosis. Repeated genetic analysis identified a paternal CYP21A2 gene duplication with Q318X mutation on one copy of CYP21A2. We conclude that a duplication of the CYP21A2 gene should be suspected when clinical and hormonal findings do not support the genetic diagnosis. Furthermore, because individuals with Q318X mutation frequently have a duplication of the CYP21A2 gene, when Q318X is detected, it is important to distinguish the severe point mutation in single gene copy alleles from the non-deficient variant in gene-duplicated alleles.
Asunto(s)
Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/genética , Errores Diagnósticos , Duplicación de Gen/genética , Diagnóstico Prenatal , Esteroide 21-Hidroxilasa/genética , 17-alfa-Hidroxiprogesterona/sangre , Hiperplasia Suprarrenal Congénita/sangre , Adulto , Muestra de la Vellosidad Coriónica , Análisis Mutacional de ADN , Exones , Femenino , Estudios de Seguimiento , Tamización de Portadores Genéticos , Pruebas Genéticas , Proyecto Mapa de Haplotipos , Humanos , Lactante , Recién Nacido , Intrones , Masculino , Tamizaje Neonatal , Embarazo , Renina/sangre , Adulto JovenRESUMEN
UV-B radiation currently represents c. 1.5% of incoming solar radiation. However, significant changes are known to have occurred in the amount of incoming radiation both on recent and on geological timescales. Until now it has not been possible to reconstruct a detailed measure of UV-B radiation beyond c. 150 yr ago. Here, we studied the suitability of fossil Pinus spp. pollen to record variations in UV-B flux through time. In view of the large size of the grain and its long fossil history, we hypothesized that this grain could provide a good proxy for recording past variations in UV-B flux. Two key objectives were addressed: to determine whether there was, similar to other studied species, a clear relationship between UV-B-absorbing compounds in the sporopollenin of extant pollen and the magnitude of UV-B radiation to which it had been exposed; and to determine whether these compounds could be extracted from a small enough sample size of fossil pollen to make reconstruction of a continuous record through time a realistic prospect. Preliminary results indicate the excellent potential of this species for providing a quantitative record of UV-B through time. Using this technique, we present the first record of UV-B flux during the last 9500 yr from a site near Bergen, Norway.
Asunto(s)
Fósiles , Pinus/química , Polen/química , Rayos Ultravioleta , Absorción , Biopolímeros/química , Carotenoides/química , Ácidos Cumáricos/metabolismo , Europa (Continente) , LuzRESUMEN
OBJECTIVE: Despite earlier detection, treatment, and surgical advances, fertility prognosis in women with classical 21-hydroxylase deficiency (21-OHD) is still low, especially in the salt-wasting (SW) form. PATIENTS AND METHODS: We analysed the course and outcome of four pregnancies in two simple virilizing (SV) and one SW patient. RESULTS: The evaluation of carrier status indicated that all three fathers had two normal CYP21 genes. During the pregnancy, the dose of prednisolone was increased in one of the SV patients and the SW patient. In the SW patient who developed pre-eclampsia, the dose of fludrocortisone was also increased. Three patients gave birth to a total of four healthy girls who were heterozygotes for 21-OHD with normal genitalia (one by vaginal delivery and three by Caesarean section). Family studies revealed that the mother of the SW patient has nonclassical 21-OHD. CONCLUSION: Improving a low birth rate in females with SW 21-OHD remains a problem and new approaches are required. If the mother has 21-OHD (even nonclassical 21-OHD), pre-conception counselling and paternal genotyping are advisable and prenatal dexamethasone therapy should be considered.
Asunto(s)
Hiperplasia Suprarrenal Congénita/genética , Nacimiento Vivo , Complicaciones del Embarazo/genética , Resultado del Embarazo , Esteroide 21-Hidroxilasa/genética , Hiperplasia Suprarrenal Congénita/tratamiento farmacológico , Hiperplasia Suprarrenal Congénita/metabolismo , Adulto , Cesárea , Femenino , Tamización de Portadores Genéticos , Pruebas Genéticas , Genotipo , Edad Gestacional , Glucocorticoides/uso terapéutico , Humanos , Masculino , Mineralocorticoides/uso terapéutico , Mutación , Linaje , Embarazo , Complicaciones del Embarazo/tratamiento farmacológico , Complicaciones del Embarazo/metabolismo , Diagnóstico Prenatal , Esteroide 21-Hidroxilasa/metabolismoRESUMEN
11beta-Hydroxylase deficiency is a common form of congenital adrenal hyperplasia causing virilization of the female fetus and hypertension. DNA analysis of the gene (CYP11B1) encoding 11beta-hydroxylase has been reported previously to be effective in the prenatal diagnosis of one affected female fetus. In that case, prenatal treatment with dexamethasone resulted in normal female genitalia. We now report five new pregnancies that underwent prenatal diagnosis for 11beta-hydroxylase deficiency. In the first family, the proband is homozygous for a T318M mutation and all fetuses from four subsequent pregnancies are carriers. In a second family, the mother is homozygous for a A331V mutation and was started on dexamethasone, but identification of a homozygous normal fetus led to the discontinuation of treatment. In another family, the fetus was a male homozygous for R384Q and treatment was discontinued. Lastly, a novel G444D mutation in exon 8 was identified and proven to reduce 11beta-hydroxylase activity.
Asunto(s)
Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/genética , Cromosomas Humanos Par 8/genética , Enfermedades Fetales/diagnóstico , Enfermedades Fetales/genética , Esteroide 11-beta-Hidroxilasa/genética , Adolescente , Hiperplasia Suprarrenal Congénita/terapia , Amniocentesis , Niño , Muestra de la Vellosidad Coriónica , Consanguinidad , Análisis Mutacional de ADN , Dexametasona/uso terapéutico , Femenino , Enfermedades Fetales/tratamiento farmacológico , Tamización de Portadores Genéticos/métodos , Glucocorticoides/uso terapéutico , Humanos , Lactante , Recién Nacido , Masculino , Mutación , Linaje , Embarazo , Diagnóstico Prenatal , Virilismo/genética , Virilismo/prevención & controlRESUMEN
The correlation of genotype to phenotype in congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency has been investigated thoroughly since the mapping of the CYP21 gene to the short arm of chromosome 6. In most instances, it is possible to accurately predict the phenotype based on genoytpe; however, in a small number of patients, individuals with identical mutations demonstrate variable phenotypes. We report two HLA-identical brothers who represent a striking case of genotype-phenotype nonconcordance in CAH. Molecular genetic analysis showed both patients had mutations in intron 2 and exon 10 of CYP21. Both brothers underwent salt-deprivation tests at similar ages over three separate hospital admissions. Patient 1 was diagnosed with simple virilizing CAH and was able to maintain sodium balance during salt deprivation tests. Patient 2, 3 years younger, was diagnosed with salt-wasting CAH and was unable to maintain sodium balance but progressively increased his aldosterone secretion with age.
Asunto(s)
Hiperplasia Suprarrenal Congénita/genética , Hiperplasia Suprarrenal Congénita/metabolismo , Genotipo , Fenotipo , Sodio/metabolismo , Esteroide 21-Hidroxilasa/genética , Adolescente , Adulto , Niño , Preescolar , Análisis Mutacional de ADN , Estudios de Seguimiento , Antígenos HLA/genética , Humanos , Masculino , Mutación , Índice de Severidad de la Enfermedad , Hermanos , Equilibrio Hidroelectrolítico/genéticaRESUMEN
The protection of groundwater resources is of great importance in many semi-arid and sub-tropical environments. The Copperbelt of Zambia is one such environment and due to the high proportion of tailings impoundments, residue heaps, high-density informal settlements and extensive sulfidic ore deposits in the region, its groundwater resources are under threat of anthropogenic or geogenic pollution. One such pollutant plume is investigated in this study, to determine its origin, rate of progression and the environmental and health risk it poses. Geological and geochemical investigation strongly suggests an upslope tailings impoundment as the source of contaminants, with the edge of the pollution plume lying 500-700 m downstream of the impoundment. Although cobalt, nickel and zinc concentrations were elevated within the polluted groundwater, the concentrations are low as a result of sulfide precipitation and adsorption within the aquifer, and meets guidelines for drinking water quality. Attenuation of heavy metals is linked to tailings dam and aquifer pH, with the high buffering capacity of each implying that these processes of attenuation are likely to continue removing harmful metals from the aquifer. Thus, it appears unlikely that the contaminated groundwater will present a major environmental risk at this site. However, tailings impoundments are widespread throughout the Copperbelt: sites with low tailings dam buffer capacity and in catchments on crystalline bedrock geology, groundwater pollution through tailings dam leachate may liberate high concentrations of heavy metals into the shallow groundwater, potentially posing a serious human health risk to the communities using the water resources and an environmental risk to the downstream ecosystems.
Asunto(s)
Monitoreo del Ambiente , Agua Dulce/análisis , Metales Pesados/análisis , Minería , Suelo/análisis , Contaminación del Agua/análisis , Conservación de los Recursos Naturales , Análisis de Componente Principal , Movimientos del Agua , ZambiaRESUMEN
21-Hydroxylase deficiency is a recessively inherited disorder resulting from mutations in the CYP21 gene. The CYP21 gene is located along with the CYP21P pseudogene in the human leukocyte antigen major histocompatibility complex region on chromosome 6. Molecular diagnosis is difficult due to the 98% similarity of CYP21 and CYP21P genes and the fact that almost all frequently reported mutations reside on the pseudogene. Allele-specific PCR for the 8 most frequently reported point mutations was performed in 31 Turkish families with at least a single 21-hydroxylase-deficient individual. The allele frequencies of the point mutations were as follows: P30L, 0%; IVS2 (AS,A/C-G,-13), 22.5%; G110delta8nt, 3.2%; I172N, 11.4%; exon 6 cluster (I236N, V237E, M239K), 3.2%; V281L, 0%; Q318X, 8%; and R356W, 9.6%. Large deletions and gene conversions were detected by Southern blot analysis, and the allele frequencies were 9.6% and 22.5%, respectively. Sequence analysis of the gene, performed on patients with only 1 mutated allele, revealed 2 missense mutations (R339H and P435S). A novel semiquantitative PCR/enzyme digestion-based method for the detection of large scale deletions/conversions of the gene was developed for routine diagnostic purposes, and its accuracy was shown by comparison with the results of Southern blot analysis.
Asunto(s)
Hiperplasia Suprarrenal Congénita/genética , Conversión Génica , Eliminación de Gen , Mutación Puntual , Reacción en Cadena de la Polimerasa , Esteroide 21-Hidroxilasa/genética , Polimerasa Taq , Alelos , Southern Blotting , Frecuencia de los Genes , Humanos , Mutación Missense , Reacción en Cadena de la Polimerasa/métodos , TurquíaRESUMEN
We are reporting a child with congenital panhypopituitarism, in whom deficient fetal steroidogenesis was suspected prenatally because of undetectable estriol levels measured in the maternal triple-marker screen. No fetal abnormalities were detected by ultrasonography. Amniocentesis demonstrated a normal 46,XX karyotype. Measurement of maternal urinary steroids failed to show elevation in the excretion of the major precursor for estriol, 16 alpha-hydroxydehydroepiandrosterone, indicating that the fetus did not have steroid sulfatase deficiency (placental sulfatase deficiency), the most common genetic cause of extremely low estriol. The steroid analysis excluded other rare single gene defects, including aromatase deficiency and 17 alpha-hydroxylase deficiency. We therefore suspected that the cause of low estriol in this fetus was adrenal insufficiency. Postnatal evaluation was consistent with panhypopituitarism, characterized by deficiency of all anterior pituitary hormones. Because this screen is now offered to more than half the pregnant women in the United States, reports of low estriol levels have become increasingly common. Therefore, it is essential that physicians be familiar with the various etiologies, perform the appropriate antenatal evaluation to determine the specific cause, and closely monitor both mother and child ante- and postnatally.
Asunto(s)
Estriol/sangre , Hipopituitarismo/congénito , Hipopituitarismo/complicaciones , Enfermedades de las Glándulas Suprarrenales/sangre , Enfermedades de las Glándulas Suprarrenales/diagnóstico , Hormona Adrenocorticotrópica/uso terapéutico , Adulto , Biomarcadores , Diagnóstico Diferencial , Estriol/deficiencia , Estriol/orina , Femenino , Feto/metabolismo , Humanos , Hipopituitarismo/tratamiento farmacológico , Recién Nacido , Tamizaje Neonatal , Fosfoproteínas/deficiencia , Embarazo , Esteroide 17-alfa-Hidroxilasa/metabolismo , Esteroides/sangre , Esteroides/orinaRESUMEN
Congenital adrenal hyperplasia (CAH) refers to a family of monogenic inherited disorders of adrenal steroidogenesis most often caused by enzyme 21-hydroxylase deficiency (21-OHD). In the classic forms of CAH (simple virilizing and salt wasting), androgen excess causes external genital ambiguity in newborn females and progressive postnatal virilization in males and females. Prenatal treatment of CAH with dexamethasone has been successfully used for over a decade. This article serves as an update on 532 pregnancies prenatally diagnosed using amniocentesis or chorionic villus sampling between 1978 and 2001 at New York Presbyterian Hospital-Weill Medical College of Cornell University. Of the 532 pregnancies, 281 were prenatally treated for CAH due to the risk of 21-hydroxylase deficiency. Follow-up telephone interviews with mothers, genetic counselors, endocrinologists, pediatricians, and obstetricians were performed in all cases. Of the pregnancies evaluated, 116 babies were affected with classic 21-OHD. Of these, 61 were female, 49 of whom were treated prenatally with dexamethasone. Dexamethasone administered at or before 9 wk gestation (in proper doses) was effective in reducing virilization. There were no statistical differences in the symptoms during pregnancy between mothers treated with dexamethasone and those not treated with dexamethasone, except for weight gain, edema, and striae, which were greater in the treated group. No significant or enduring side-effects were noted in the fetuses, indicating that dexamethasone treatment is safe. Prenatally treated newborns did not differ in weight from untreated, unaffected newborns. Based on our experience, prenatal diagnosis and proper prenatal treatment of 21-OHD are effective in significantly reducing or eliminating virilization in the newborn female. This spares the affected female the consequences of genital ambiguity, genital surgery, and possible sex misassignment.
Asunto(s)
Hiperplasia Suprarrenal Congénita/diagnóstico , Diagnóstico Prenatal , Hiperplasia Suprarrenal Congénita/tratamiento farmacológico , Hiperplasia Suprarrenal Congénita/enzimología , Hiperplasia Suprarrenal Congénita/genética , Amniocentesis , Muestra de la Vellosidad Coriónica , Dexametasona/uso terapéutico , Femenino , Frecuencia de los Genes , Glucocorticoides/uso terapéutico , Heterocigoto , Homocigoto , Humanos , Masculino , Embarazo , Atención Prenatal , Virilismo/prevención & controlRESUMEN
Congenital adrenal hyperplasia (CAH) is a family of adrenal disorders whereby cortisol biosynthesis is impaired or abolished. In most cases, CAH is caused by a deficiency of the enzyme 21-hydroxylase causing a massive build up of adrenal precursors. In addition to prenatal virilisation of genetic females and postnatal virilisation of both males and females, short adult stature is characteristic of the disorder. The inadequate final height in CAH patients is often attributed to overtreatment with glucocorticoid replacement and poor control of adrenal androgen levels. In a recent study, the use of growth hormone alone and in combination with gonadotropin releasing hormone analogue in children with CAH and poor predicted final height was found to decrease height deficit after one and two years of treatment.
Asunto(s)
Hiperplasia Suprarrenal Congénita/fisiopatología , Estatura/fisiología , Hiperplasia Suprarrenal Congénita/tratamiento farmacológico , Hiperplasia Suprarrenal Congénita/genética , Estatura/efectos de los fármacos , Estatura/genética , Femenino , Humanos , Recién Nacido , MasculinoRESUMEN
Whereas it is now more than 150 yr since T. Addison first described the clinical and pathological features of adrenal failure (1 ), the disease remains underdiagnosed, leading to unnecessary morbidity and mortality. Over the past decade, there have been important advances in elucidating the pathogeneses and underlying genetics of the individual forms of the disease. This review emphasizes the multiple etiologies and the diagnostic steps to be taken with consideration to age at onset and gender and summarizes new genetic insights in the disease.
Asunto(s)
Enfermedad de Addison , Enfermedad de Addison/diagnóstico , Enfermedad de Addison/etiología , Enfermedad de Addison/genética , Enfermedad de Addison/terapia , Femenino , Humanos , MasculinoRESUMEN
The effects of classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency on final height and fertility were evaluated in 30 affected males, aged 17-43 yr. The mean adult height of these patients was 165.64 +/- 8.4 cm (mean +/- SD), with a mean SD score of -1.65 +/- 1.2 cm. The difference between the mean final height SD score and mean target height SD score was -1.67 +/- 1.0 cm. All patients had short stature and did not reach their estimated target heights. There was no difference in height SD score between the salt-wasting and simple virilizing CAH patients. No correlation between the final height and degree of hormonal control or bone age advancement was observed. Of the 30 subjects, 18 had testicular sonograms. Abnormal sonogram findings of testicular adrenal rests were present in 9 patients (group 1), whereas sonogram without adrenal rests comprised the remaining 9 patients (group 2). In group 1, 8 of 9 patients and in group 2, 4 of 9 patients were salt-wasters; the remainder were simple virilizers. In group 1, 7 of 9 patients had semen analysis, and all were judged infertile. Of the 6 patients in group 2 who had semen analysis, 1 was azoospermic, and the remainder were normal. During optimal adrenal hormone suppression, gonadotropins at baseline and after GnRH stimulation were significantly higher in group 1 than in group 2, reflecting the loss of Leydig cell function to secrete testosterone. In conclusion, adult males affected with CAH due to 21-hydroxylase deficiency do not achieve the height predicted from parental heights. The presence of adrenal rests within the testes of adult males with classic CAH are more frequent in the salt-wasting form and are associated with a higher risk for infertility.
Asunto(s)
Hiperplasia Suprarrenal Congénita/fisiopatología , Adolescente , Hiperplasia Suprarrenal Congénita/complicaciones , Hiperplasia Suprarrenal Congénita/genética , Adulto , Estatura , Hormona Folículo Estimulante/sangre , Hormona Liberadora de Gonadotropina , Humanos , Infertilidad Masculina/etiología , Células Intersticiales del Testículo/fisiología , Hormona Luteinizante/sangre , Masculino , Mutación , Oligospermia/etiología , Pronóstico , Semen/fisiología , Testículo/diagnóstico por imagen , Testosterona/metabolismo , UltrasonografíaRESUMEN
A 14-year-old Native American girl from the Iroquois Nation was referred as a potential patient with the syndrome of Apparent Mineralocorticoid Excess. Instead, her evaluation revealed resistance to glucocorticoids, mineralocorticoids, and androgens. She lacked Cushingoid features in spite of significantly high cortisol levels. Menstruation was regular and there was no clinical evidence of masculinization despite high serum androgen levels in the male range. The patient's sister had similar clinical features. Partial resistance to exogenous glucocorticoid and mineralocorticoid administration was well demonstrated in both patients. It is proposed that these patients represent the first cases of partial resistance to multiple steroids, possibly owing to a coactivator defect.
Asunto(s)
Andrógenos/sangre , Glucocorticoides/sangre , Mineralocorticoides/sangre , Adolescente , Glándulas Suprarrenales/diagnóstico por imagen , Glándulas Suprarrenales/patología , Niño , Femenino , Humanos , Hidrocortisona/sangre , Sistema Hipotálamo-Hipofisario/fisiopatología , Masculino , Linaje , RadiografíaRESUMEN
Based on the author's experience, prenatal diagnosis and treatment of 21-hydroxylase deficiency is safe and effective in significantly reducing or eliminating virilization in the affected female, and the same outcome seems to be true in the treatment of 11 beta-hydroxylase deficiency. Prenatal treatment spares the newborn female the consequences of genital ambiguity, genital surgery, sex misassignment, and gender confusion. Of the monogenic disorders, steroid 21- and 11 beta-hydroxylase deficiency are two of the few in which prenatal treatment is effective and influences postnatal life.
Asunto(s)
Hiperplasia Suprarrenal Congénita/tratamiento farmacológico , Enfermedades Fetales/tratamiento farmacológico , Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/enzimología , Femenino , Glucocorticoides/administración & dosificación , Glucocorticoides/efectos adversos , Glucocorticoides/uso terapéutico , Humanos , Masculino , Mutación , Embarazo , Diagnóstico Prenatal , Esteroide 11-beta-Hidroxilasa/genética , Esteroide 21-Hidroxilasa/genética , Estados UnidosRESUMEN
OBJECTIVES: 1) To determine the extent of short stature in patients with Fanconi anemia (FA); 2) to determine the extent and nature of endocrinopathy in FA; 3) to assess the impact on height of any endocrinopathies in these patients; and 4) to study the correlation, if any, between height, endocrinopathy, and FA complementation group. STUDY DESIGN: Fifty-four patients with FA, 30 males and 24 females from 47 unrelated families, were prospectively evaluated in a Pediatric Clinical Research Center. The patients ranged in age from 0.1-31.9 years, with the mean age at assessment 8.6 years. RESULTS: Endocrine abnormalities were found in 44 of the 54 FA patients tested (81%), including short stature, growth hormone (GH) insufficiency, hypothyroidism, glucose intolerance, hyperinsulinism, and/or overt diabetes mellitus. Twenty-one of 48 (44%) participants had a subnormal response to GH stimulation; 19 of 53 (36%) had overt or compensated hypothyroidism, while 8 of 40 participants had reduced thyroid-hormone binding. Two patients were diabetic at the time of study; impaired glucose tolerance was found in 8 of 40 patients (25%), but most surprisingly, hyperinsulinemia was present in 28 of 39 (72%) participants tested. Significantly, spontaneous overnight GH secretion was abnormal in all patients tested (n = 13). In addition, participants demonstrated a tendency toward primary hypothyroidism with serum tetraiodothyronine levels at the lower range of normal, while also having thyrotropin (thyroid-stimulating hormone) levels at the high end of normal. Sixteen patients were assigned to FA complementation group A, (FA-A), 12 to FA-C, and 5 to FA-G; 10 of the 12 participants in FA-C were homozygous for a mutation in the intron-4 donor splice site of the FANCC gene. Patients in groups FA-A and FA-G were relatively taller than the group as a whole (but still below the mean for the general population), whereas those in FA-C had a significantly reduced height for age. GH response to stimulation testing was most consistently normal in participants from FA-G, but this did not reach statistical significance. The tendency toward hypothyroidism was more pronounced in participants belonging to complementation groups FA-C and FA-G, whereas insulin resistance was most evident in patients in FA-G, and least evident in those in FA-C. Short stature was a very common finding among the patients with a mean height >2 standard deviations below the reference mean (standard deviation score: -2.35 +/- 0.28). Patients with subnormal GH response and those with overt or compensated hypothyroidism were shorter than the group with no endocrinopathies. The heights of those participants with glucose or insulin abnormalities were less severely affected than those of normoglycemic, normoinsulinemic participants, although all were significantly below the normal mean. The mean height standard deviation score of patients with entirely normal endocrine function was also >2 standard deviations below the normal mean, demonstrating that short stature is an inherent feature of FA. CONCLUSION: Endocrinopathies are a common feature of FA, primarily manifesting as glucose/insulin abnormalities, GH insufficiency, and hypothyroidism. Although short stature is a well-recognized feature of FA, 23 patients (43%) were within 2 standard deviations, and 5 of these (9% of the total) were actually above the mean for height for the general population. Those patients with endocrine dysfunction are more likely to have short stature. These data indicate that short stature is an integral feature of FA, but that superimposed endocrinopathies further impact on growth. The demonstration of abnormal endogenous GH secretion may demonstrate an underlying hypothalamic-pituitary dysfunction that results in poor growth.