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1.
Am J Med Genet A ; 164A(5): 1213-7, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24610892

RESUMEN

Yunis-Varon syndrome is a rare autosomal recessive condition initially characterized by specific skeletal and ectodermal abnormalities, and a poor prognosis, due to neurological and cardiovascular involvement. We describe the cardiovascular and endocrine complications in a 26-year-old man who had been reported previously, adding dilated cardiomyopathy to the clinical features consistent with Yunis-Varon syndrome. Short stature, successfully treated with growth hormone, and hypertension secondary to bilateral renal artery stenosis expand the phenotype.


Asunto(s)
Displasia Cleidocraneal/diagnóstico , Displasia Ectodérmica/diagnóstico , Deformidades Congénitas de las Extremidades/diagnóstico , Micrognatismo/diagnóstico , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Anomalías Cardiovasculares/diagnóstico , Anomalías Cardiovasculares/genética , Niño , Preescolar , Displasia Cleidocraneal/genética , Diagnóstico Diferencial , Displasia Ectodérmica/genética , Electrocardiografía , Enfermedades del Sistema Endocrino/congénito , Enfermedades del Sistema Endocrino/diagnóstico , Gráficos de Crecimiento , Humanos , Deformidades Congénitas de las Extremidades/genética , Masculino , Micrognatismo/genética , Fenotipo , Radiografía Torácica
2.
Exp Clin Endocrinol Diabetes ; 121(8): 509-12, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23765756

RESUMEN

OBJECTIVE: The GH receptor antagonist pegvisomant is increasingly used as therapy in acromegaly. Pituitary surgery might be indicated on pegvisomant treatment, due to side effects, adenoma growth or intention to cure after primary treatment. This study was initiated to clarify if, and when, GH measurement could be useful postoperatively with an assay specific for endogenous GH that does not cross-react with pegvisomant. METHODS: This study was designed as a prospective study in 2006 with the German Pituitary Working Group. Only 2 cases with potentially resectable adenomas from the German Pegvisomant Observational Study (GPOS) had been operated. Now with a post-operative follow-up of more than 5 years in these 2 cases, the usefulness of immediate pre-operative GH measurement shortly after pegvisomant treatment was evaluated. RESULTS: In both patients a steep decline of endogenous GH after transnasal microsurgery could be proven by using the special GH assay after near radical or radical removal, of the GH secreting adenomas respectively. Conventional GH assays showed no effect. GH half-life was more than 20 min in the patient with a small invasive residual adenoma and less than 20 min in the cured patient. Endogenous GH-levels declined to less than 1 ng/ml in the days after surgery in the patient with long-term cure. CONCLUSION: Measurement of endogenous GH in this special subgroup of patients under pegvisomant therapy can be used to decide upon early reoperation. Thus the beneficial effect of pegvisomant on acromegalic symptoms can be kept without interfering with post-operative monitoring of GH levels.


Asunto(s)
Acromegalia/tratamiento farmacológico , Adenoma/cirugía , Adenoma Hipofisario Secretor de Hormona del Crecimiento/cirugía , Hormona de Crecimiento Humana/análogos & derivados , Hormona de Crecimiento Humana/sangre , Microcirugia/métodos , Procedimientos Neuroquirúrgicos/métodos , Acromegalia/sangre , Acromegalia/cirugía , Adenoma/sangre , Adenoma/tratamiento farmacológico , Procedimientos Quirúrgicos Endocrinos/métodos , Femenino , Adenoma Hipofisario Secretor de Hormona del Crecimiento/sangre , Adenoma Hipofisario Secretor de Hormona del Crecimiento/tratamiento farmacológico , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Seno Esfenoidal/cirugía
3.
Scand J Immunol ; 73(2): 147-53, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21198756

RESUMEN

Autoimmune polyendocrine syndrome type 1 (APS1) is a rare monogenic autoimmune disorder caused by mutations in the autoimmune regulator (AIRE) gene. High-titre autoantibodies are a characteristic feature of APS1 and are often associated with particular disease manifestations. Pituitary deficits are reported in approximately 7% of APS1 patients, with immunoreactivity to pituitary tissue frequently described. Using APS1 patient serum to immunoscreen a pituitary cDNA expression library, testis specific, 10 (TSGA10) was isolated. Immunoreactivity against TSGA10 was detected in 5/99 (5.05%) patients with APS1, but also in 5/135 (3.70%) systemic lupus erythematosus (SLE) patients and 1/188 (0.53%) healthy controls. TSGA10 autoantibodies were not detected in the serum from patients with any other autoimmune disease. Autoantibodies against TSGA10 were detectable from a young age in 4/5 positive APS1 patients with autoantibody titres remaining relatively constant over time. Furthermore, real-time PCR confirmed TSGA10 mRNA to be most abundantly expressed in the testis and also showed moderate and low expression levels throughout the entire body. TSGA10 should be considered as an autoantigen in a subset of APS1 patients and also in a minority of SLE patients. No recognizable clinical phenotype could be found to correlate with positive autoantibody reactivity.


Asunto(s)
Autoanticuerpos/inmunología , Lupus Eritematoso Sistémico/inmunología , Proteínas/inmunología , Proteínas del Citoesqueleto , Femenino , Regulación de la Expresión Génica , Humanos , Lupus Eritematoso Sistémico/genética , Masculino , Poliendocrinopatías Autoinmunes/genética , Poliendocrinopatías Autoinmunes/inmunología , Proteínas/genética , ARN Mensajero/genética
4.
Diabet Med ; 22(6): 711-8, 2005 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15910621

RESUMEN

AIMS: To examine the prevalence of early diabetes complications 6 years after diagnosis of diabetes. The hypothesis that initial contact with a multidisciplinary team would be associated with a reduced risk of microvascular complications was tested in this cohort. METHODS: Participants were recruited from an incident cohort of children aged < 15 years diagnosed between 1990 and 1992 in NSW, Australia. Initial management at a teaching hospital was documented at case notification. At 6 years, health care questionnaires and complications were assessed: retinopathy by 7-field stereoscopic retinal photography and elevated albumin excretion rate (AER) defined as the median of three overnight urine collections > or = 7.5 microg/min. Case attainment was 58% (209/361) with participants younger than non-participants and more likely living in an urban than rural location. RESULTS: Retinopathy was present in 24%, median AER > or = 7.5 microg/min in 18%, and median AER > or = 20 microg/min in 2%. In multivariate analysis, initial management at a teaching hospital or consultation with all three allied health professionals combined with pubertal staging and cholesterol or HbA1c were all determinants of risk for retinopathy. CONCLUSIONS: Early retinopathy and elevated AER are common in children 6 years after diagnosis. Initial allied health contact and management at a teaching hospital were associated with a reduced risk of microvascular complications in this cohort.


Asunto(s)
Diabetes Mellitus Tipo 1/prevención & control , Retinopatía Diabética/prevención & control , Adolescente , Albuminuria/epidemiología , Albuminuria/orina , Niño , Estudios de Cohortes , Diabetes Mellitus Tipo 1/epidemiología , Retinopatía Diabética/epidemiología , Femenino , Conductas Relacionadas con la Salud , Humanos , Modelos Logísticos , Masculino , Prevalencia , Factores de Riesgo , Encuestas y Cuestionarios
5.
Eur J Clin Invest ; 35(2): 126-32, 2005 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-15667584

RESUMEN

BACKGROUND: An autoimmune cause of adrenocorticotropin (ACTH)-deficiency is presented, as it is known to be a characteristic feature of lymphocytic hypophysitis, a disease of the pituitary gland considered to be autoimmune. MATERIALS AND METHODS: The aim of this study was twofold: (1) to evaluate the occurrence of pituitary autoantibodies and (2) to correlate it to clinical and immunological features in a large group of patients with ACTH-deficiency of possible autoimmune aetiology. Sixty-five patients with ACTH-deficiency and 57 healthy subjects participated in the study. Pituitary autoantibodies were measured by an immunoblotting assay with human pituitary cytosol as antigen. RESULTS: Autoantibodies to a novel 36-kDa pituitary autoantigen were seen in sera from 18.5% (12/65) patients and only 3.5% (2/57) of control subjects (P = 0.0214). When taking only those subjects with strong immunoreactivity into account, the significance was lost; P = 0.3642. Immunoreactivity to a 49-kDa pituitary autoantigen was observed in 21.5% (14/65) of ACTH-deficient patients compared with 8.8% (5/57) of control subjects (P = 0.0910). This 49-kDa pituitary autoantigen has recently been identified as neurone-specific enolase and a candidate marker for neuroendocrine autoimmunity. Clinical parameters in patients with positive versus those with negative pituitary immunoreactivity did not differ. However, autoantibodies to thyroglobulin were positively correlated to immunoreactivity against the 36-kDa pituitary autoantigen (P = 0.014). CONCLUSIONS: Our findings of pituitary autoantibodies in patients' sera support the theory that an autoimmune destruction of corticotrophs may be the underlying cause of hormonal deficit in some patients with ACTH-deficiency.


Asunto(s)
Hormona Adrenocorticotrópica/deficiencia , Hormona Adrenocorticotrópica/inmunología , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/inmunología , Citosol/inmunología , Enfermedades de la Hipófisis/inmunología , Adulto , Anciano , Femenino , Humanos , Immunoblotting , Masculino , Persona de Mediana Edad
6.
Exp Clin Endocrinol Diabetes ; 112(5): 231-5, 2004 May.
Artículo en Inglés | MEDLINE | ID: mdl-15146367

RESUMEN

OBJECTIVE: The cause of empty sella syndrome (ESS) remains largely unknown. We measured eleven organ-specific autoantibodies in serum in order to evaluate possible autoimmune components in ESS. PATIENTS: Thirty patients with ESS and 50 healthy blood donors participated in the study. MEASUREMENTS: Detection of pituitary autoantibodies was performed by immunoblotting with human pituitary cytosol as antigen. Thyroid peroxidase (TPO) and TSH receptor (TRAK) autoantibodies were analysed by radioimmunoassay. The remaining eight autoantibodies were detected by in vitro transcription and translation of the autoantigens and immunoprecipitation. RESULTS: The majority of the ESS patients (18/30) exhibited no immunoreactivity at all. None of the remaining 12 ESS patients reacted against more than one autoantigen. No immunoreactivity was found more frequently among ESS patients than healthy blood donors. Pituitary autoantibodies were not correlated to the ESS patients' pituitary function or sellar size, although the results indicated a tendency of increased autoimmunity in patients with hypopituitarism and normal sella size respectively. CONCLUSION: Detection of autoantibodies is a valuable tool in the diagnostic work-up of autoimmune diseases. By analysing a large number of organ-specific autoantibodies we found no evidence of ESS being associated with any specific autoimmune disease. The pathogenesis of ESS is believed to be heterogeneous and our findings suggest autoimmune components to be of minor importance. In some selective cases, ESS in combination with hypopituitarism may be the result of an autoimmune disease in the pituitary gland but this needs further investigation.


Asunto(s)
Autoanticuerpos/sangre , Autoinmunidad , Síndrome de Silla Turca Vacía/epidemiología , Adulto , Anciano , Síndrome de Silla Turca Vacía/sangre , Síndrome de Silla Turca Vacía/inmunología , Humanos , Persona de Mediana Edad , Hipófisis/inmunología , Valores de Referencia
7.
Arch Physiol Biochem ; 110(1-2): 94-8, 2002 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-11935405

RESUMEN

The first target autoantigen to have been identified in lymphocytic hypophysitis is a 49 kDa protein, identified as alpha-enolase. Pituitary autoimmunity is strongly associated with pregnancy and we have shown that pituitary autoantibodies from patients with peripartum lymphocytic hypophysitis also recognise enolase in the placenta. Enolase exists in different forms as a number of isoenzymes, which are homo- or heterodimers of three subunits, alpha, beta and gamma. alphaalpha-enolase is ubiquitous, betabeta-enolase is muscle-specific and gammagamma-enolase, which is restricted to neuronal tissue and neuroendocrine cells, is known as neuron-specific enolase (NSE). NSE is expressed in normal human pituitary and pituitary neoplasms. The current study investigated which isoforms of enolase in pituitary and placenta reacted with the sera of patients with lymphocytic hypophysitis. Immunoblotting of two-dimensional gels of human pituitary cytosolic proteins showed that autoantibodies in patient sera react with both an acidic form, and more neutral forms of enolase. Immunoblotting with a monoclonal antibody to NSE confirmed the identity of the acidic enolase isoform as the gammagamma-isoform in both pituitary and placental samples. Gamma-enolase, i.e. NSE, was detected by immunohistochemistry in term placenta in decidua, syncytiotrophoblasts, anchoring villi and terminal villi. Our study is the first to describe the cellular localisation of NSE in normal human placenta, thus establishing a direct link between pituitary and placental autoantigens. This link provides a theoretical basis for the strong prediliction of lymphocytic hypophysitis to occur during or after pregnancy.


Asunto(s)
Autoanticuerpos/inmunología , Enfermedades Autoinmunes/inmunología , Fosfopiruvato Hidratasa/inmunología , Enfermedades de la Hipófisis/inmunología , Hipófisis/enzimología , Autoanticuerpos/sangre , Electroforesis en Gel Bidimensional , Femenino , Humanos , Immunoblotting , Inmunohistoquímica , Isoenzimas/inmunología , Fosfopiruvato Hidratasa/química , Fosfopiruvato Hidratasa/metabolismo , Hipófisis/inmunología , Placenta/enzimología , Placenta/inmunología , Embarazo
8.
Horm Res ; 55(3): 125-30, 2001.
Artículo en Inglés | MEDLINE | ID: mdl-11549873

RESUMEN

OBJECTIVE: Classical growth hormone insensitivity syndrome (GHIS) comprises a dysmorphic phenotype, extreme short stature (height SDS < 3), normal GH and low IGF-I and IGFBP-3. Wide clinical variation is recognised with classical and atypical forms. We aimed to delineate features of the milder "atypical" GHIS phenotype, and to determine whether this correlates with milder auxological and biochemical features. METHODS: Fifty-nine patients from a European series of 82 patients with GHIS, with strict diagnostic criteria of GHIS, were studied and assigned to classical or atypical GHIS groups according to facial phenotype, i.e. "classical" required 2 of 3 recognized GHIS features (frontal bossing, mid-facial hypoplasia and depressed nasal bridge), "atypical" required 0 or 1 of these facial features. Classical and atypical GHIS groups were compared in terms of (1) phenotypic features, including high-pitched voice, sparse hair, blue sclera, hypoglycaemia, microphallus, (2) birth length, height SDS, and (3) basal IGF-I, IGF-II, IGFBP-1, IGFBP-3, GHBP and increase in IGF-I on IGF-I generation testing. RESULTS: Fifty patients [24 males, 26 females, aged 8.6 +/- 4.6 years (mean +/- SD)] had "classical GHIS", 9 patients (7 males, 2 females, aged 7.8 +/- 4.1 years) had "atypical GHIS", 7 with normal facies. Atypical GHIS patients had lesser height deficit (Ht SDS -4.0 +/- 1.4) compared to classical GHIS (-6.7 +/- 1.4), less reduction in IGFBP-3 SDS (atypical -5.5 +/- 3.3; classical -8.6 +/- 2.4), and more had normal GHBP (>10% binding). Other variables were also less frequent in atypical GHIS patients: high-pitched voice 11% (70% classical), sparse hair 11% (42% classical), blue sclera 0% (38% classical), hypoglycaemia 11% (42% classical), and microphallus 14% (1 of 7 males), compared to 79% of classical (19 of 24 males). CONCLUSIONS: Atypical GHIS patients, with relatively normal facial appearance, demonstrate less height defect and biochemical abnormalities compared to classical patients. GH insensitivity may be present in children with short stature and an otherwise normal appearance.


Asunto(s)
Trastornos del Crecimiento/clasificación , Trastornos del Crecimiento/diagnóstico , Hormona de Crecimiento Humana/metabolismo , Estatura , Niño , Femenino , Trastornos del Crecimiento/genética , Trastornos del Crecimiento/fisiopatología , Hormona de Crecimiento Humana/sangre , Humanos , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Fenotipo , Síndrome
10.
Pediatr Diabetes ; 1(3): 135-41, 2000 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-15016224

RESUMEN

OBJECTIVE: The aim of this study was to compare the clinical efficacy and safety of insulin lispro with regular insulin in 5- to 10-yr-old prepubertal children on twice daily insulin. RESEARCH DESIGN AND METHODS: Thirty-five children (16 M, 19 F) completed an open-label randomised crossover study, with each child receiving insulin lispro for 3 months and regular insulin for 3 months in addition to their intermediate-acting insulin. Families were instructed to give regular insulin 30 min before meals and insulin lispro immediately before meals. Glycaemic control was monitored by eight-point blood glucose profiles and six weekly hemoglobin A1cs (HbA1cs) and the frequency and severity of hypoglycaemia was documented. RESULTS: The endpoint HbA1c after 3 months on insulin lispro (8.33%, SD+/-0.89) was not significantly different to that on regular insulin (8.14%, SD+/-0.77). No significant differences were found in blood glucose levels before or after meals, 2-h postprandial glucose excursions or in blood glucose levels before bed between the treatments. However, blood glucose levels at 3 am were significantly lower on regular insulin than on insulin lispro (mean difference -2.35 mmol/L (95%CI: -3.98, -0.72, p=0.01). There was no significant difference in the frequency of hypoglycaemic episodes between the groups. CONCLUSIONS: The main advantage of insulin lispro in children on twice daily insulin was found to be its greater convenience, this being achieved without a deterioration in glycaemic control. The higher 3 am blood glucose levels in those on insulin lispro could translate to reduced nocturnal hypoglycaemia in some individuals.

11.
J Clin Endocrinol Metab ; 84(3): 844-52, 1999 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-10084559

RESUMEN

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder for which the gene (AIRE) has recently been identified on chromosome 21q22.3. We present the mutational analyses of a French-Canadian family with APECED, in which there are two affected siblings, as well as the response to cyclosporine A(CyA) therapy in the index patient, the eldest sibling. Haplotype analysis suggested compound heterozygozity at the AIRE locus. Direct sequencing of exon 8 revealed a previously described mutation, a 13-bp deletion (1085-1097) of maternal origin, found in the index patient, her affected sister, and her unaffected sister. A novel missense mutation characterized by a T-->G transversion at nucleotide position 398, resulting in a leu-->arg amino acid substitution (L93R), was found in exon 2. The mutation was present in the father, the brother, the index patient, and the affected sister. The presence of the mutation in the propositus was verified by cloning of PCR products from genomic DNA. The mutation destroys a PstI restriction enzyme site, as confirmed in the aforementioned patients. Screening of 50 French-Canadian controls with PstI digestion did not show destruction of the restriction-enzyme site. The index patient's phenotype was severe, manifested by classic features of the illness (adrenal insufficiency, hypoparathyroidism, candidiasis, and keratoconjunctivitis with alopecia universalis), as well as by severe exocrine pancreatic insufficiency, diabetes mellitus, hepatic inflammation, growth hormone (GH) deficiency due to lymphocytic hypophysitis, and primary ovarian failure. Oral CyA (5 mg/kg/day) was initiated at 13 yr of age. After 8 months of therapy, stimulated pancreatic lipase increased 24-fold with normalization of stool fat (from 31.5 g/day to 2.5 g/day, normal(N) < 5). There was complete resolution of her photophobia, and considerable hair regrowth was diffusely apparent. Minimal side effects were noted. Our experience supports the use of oral CyA for the treatment of severe APECED-associated exocrine pancreatic failure and keratoconjunctivitis.


Asunto(s)
Ciclosporina/uso terapéutico , Inmunosupresores/uso terapéutico , Mutación/genética , Poliendocrinopatías Autoinmunes/tratamiento farmacológico , Poliendocrinopatías Autoinmunes/genética , Factores de Transcripción/genética , Adolescente , Ciclosporina/efectos adversos , Análisis Mutacional de ADN , Femenino , Humanos , Inmunosupresores/efectos adversos , Magnesio/sangre , Masculino , Linaje , Resultado del Tratamiento , Ácido Úrico/sangre , Proteína AIRE
12.
Nat Genet ; 20(2): 143-8, 1998 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-9771706

RESUMEN

Wolfram syndrome (WFS; OMIM 222300) is an autosomal recessive neurodegenerative disorder defined by young-onset non-immune insulin-dependent diabetes mellitus and progressive optic atrophy. Linkage to markers on chromosome 4p was confirmed in five families. On the basis of meiotic recombinants and disease-associated haplotypes, the WFS gene was localized to a BAC/P1 contig of less than 250 kb. Mutations in a novel gene (WFS1) encoding a putative transmembrane protein were found in all affected individuals in six WFS families, and these mutations were associated with the disease phenotype. WFS1 appears to function in survival of islet beta-cells and neurons.


Asunto(s)
Cromosomas Humanos Par 4 , Proteínas de la Membrana/genética , Mutación , Síndrome de Wolfram/genética , Adulto , Secuencia de Bases , Niño , Clonación Molecular , Femenino , Ligamiento Genético , Haplotipos , Humanos , Masculino , Repeticiones de Microsatélite , Datos de Secuencia Molecular , Linaje , Polimorfismo Genético
13.
J Endocrinol ; 157(3): 475-80, 1998 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-9691980

RESUMEN

Autoantibodies to human pituitary cytosol proteins were determined by immunoblotting in sera from patients with hypopituitarism and their relatives. Reactivity to an M(r) 49,000 protein was significantly more frequent in patients (6/21 (28%) P < 0.05) as well as in relatives (10/35 (28%) P < 0.02) compared with controls (3/44 (6.8%)). Autoantibodies to this particular protein have previously been detected in sera from 70% of patients with biopsy-proven lymphocytic hypophysitis. Unlike patients with biopsy-proven lymphocytic hypophysitis, none of the patients in this study presented with a suspected pituitary adenoma or showed an enlarged sella turcica. Cisternal herniation was seen in 6/21 patients and this may very well represent the end stage of lymphocytic hypophysitis. Since organ specific autoantibodies are frequent in patients with autoimmune endocrine disease as well as in their unaffected relatives, autoantibodies to this M(r) 49,000 pituitary cytosolic protein may represent markers for an immunological process affecting the pituitary gland.


Asunto(s)
Autoanticuerpos/sangre , Hipopituitarismo/inmunología , Hipófisis/inmunología , Anciano , Enfermedades Autoinmunes/diagnóstico , Biomarcadores/sangre , Citosol/inmunología , Femenino , Humanos , Immunoblotting , Masculino , Enfermedades de la Hipófisis/diagnóstico
14.
J Clin Endocrinol Metab ; 83(7): 2554-61, 1998 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-9661642

RESUMEN

A Vietnamese girl with Laron syndrome has been treated with recombinant human insulin-like growth factor-I for 4 yr from age 11.28 yr. Her height SD score increased from -6.3 to -4.7 without acceleration of bone age. Isolated breast development progressed despite pubertal suppression with luteinizing hormone-releasing hormone analogue, which was stopped after 3 yr because of growth deceleration. Facial coarsening was documented with serial photographs. Sequencing and in vitro analysis identified a homozygous base pair substitution in exon 6 of the proband's GH receptor (GHR), which changed amino acid 131 from proline to glutamine (P131Q) and disrupted GH binding. Both the P131Q-mutated human GHR and wildtype (wt) hGHR were transiently expressed in COS-1 cells, as demonstrated by Western blotting, but the P131Q-transfected cells did not bind 125I-hGH. Similarly, FDC-P1 cells transfected with wthGHR bound 125I-hGH with high affinity and proliferated in response to GH, whereas the P131Q hGHR cells did neither. In CHO-K1 cells cotransfected with wthGHR and the Egr-1 promotor linked to a luciferase reporter gene, GH evoked a 2.14 +/- 0.21-fold increase in luciferase activity, but there was no response in the cells carrying the P131Q hGHR mutation. From examination of the crystal structure of the GHR, we suggest that the P131Q mutation disrupts the interdomain link between the extracellular domains of the GHR, causing a conformational change that results in disruption of the GH binding site.


Asunto(s)
Enanismo/tratamiento farmacológico , Hormona Liberadora de Gonadotropina/análogos & derivados , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Estructura Terciaria de Proteína , Pubertad Precoz/tratamiento farmacológico , Receptores de Somatotropina/genética , Animales , Células CHO , Células COS , Niño , Cricetinae , Enanismo/genética , Femenino , Hormona Liberadora de Gonadotropina/uso terapéutico , Homocigoto , Humanos , Mutación , Pubertad Precoz/genética , Proteínas Recombinantes/uso terapéutico , Síndrome , Resultado del Tratamiento , Vietnam/etnología
15.
Acta Paediatr ; 87(4): 381-6, 1998 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-9628291

RESUMEN

Benign intracranial hypertension (BIH) is reported in three children from Australia and one from New Zealand, who were being treated with recombinant human growth hormone (rhGH). Three males and one female, aged between 10.5 and 14.2 y, developed intracranial hypertension within 2 weeks to 3 months of starting treatment. A national database, OZGROW, has been prospectively collecting data on all 3332 children treated with rhGH in Australia and New Zealand from January 1986 to 1996. The incidence of BIH in children treated with growth hormone (GH) is small, 1.2 per 1000 cases overall, but appears to be greater with biochemical GHD (<10 IU ml(-1)), i.e. 6.5/1000 (3 in 465 cases), relative risk 18.4, 95% confidence interval 1.9-176.1, than in all other children on the database. The incidence in patients with Turner's syndrome was 2.3/1000 (1 in 428 cases). No cases in patients with partial GHD (10-20 IU ml(-1)) or chronic renal failure were identified. Possible causative mechanisms are discussed. The authors' practice is now to start GH replacement at less than the usual recommended dose of 14 IU m(-2) week(-1) in those children considered to be at high risk of developing BIH. Ophthalmological evaluation is recommended for children before and during the first few months following commencement of rhGH therapy and is mandatory in the event of peripheral or facial oedema, persistent headaches, vomiting or visual symptoms. The absence of papilloedema does not exclude the diagnosis.


Asunto(s)
Hormona de Crecimiento Humana/efectos adversos , Hipertensión Intracraneal/inducido químicamente , Adolescente , Sistemas de Registro de Reacción Adversa a Medicamentos , Australia/epidemiología , Niño , Femenino , Humanos , Hipertensión Intracraneal/epidemiología , Masculino , Nueva Zelanda/epidemiología
16.
J Clin Endocrinol Metab ; 83(2): 609-18, 1998 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-9467582

RESUMEN

Lymphocytic hypophysitis was first recognized postmortem, then by biopsy, but detection of antipituitary autoantibodies by immunofluorescence has proved unsatisfactory. Immunoblotting has the dual advantages of increased specificity and identification of the mol wt of autoantigens. Sera from 115 patients and 52 normal subjects were immunoblotted against human autopsy pituitary cytosolic proteins. Among the neurosurgical cohort (30), 10 patients had biopsy-proven lymphocytic hypophysitis, and 20 had hypopituitarism secondary to tumor. There were 22 cases with suspected hypophysitis; 47 with either Hashimoto's, Graves', or Addison's diseases; and 15 with rheumatoid arthritis. Antipituitary autoantibodies reactive to a 49-kDa pituitary cytosolic protein were found in 70% of biopsy-proven lymphocytic hypophysitis, 55% of suspected hypophysitis, 42% of Addison's disease, 20% of pituitary tumors, 15% of patients with thyroid autoimmunity, 13% of rheumatoid arthritis patients, and 9.8% of normal subjects. Reactivity to a 40-kDa cytosolic protein was also found in 50% of patients with biopsy-proven disease. These 49- and 40-kDa autoantigens are conserved across species and are not exclusive to pituitary tissue. Immunoblotting has demonstrated antipituitary autoantibodies to 49- and 40-kDa cytosolic proteins in biopsy-proven cases of lymphocytic hypophysitis.


Asunto(s)
Autoantígenos/inmunología , Citosol/inmunología , Hipopituitarismo/inmunología , Linfocitos/inmunología , Adulto , Anciano , Animales , Autoanticuerpos/sangre , Femenino , Humanos , Immunoblotting , Macaca fascicularis , Masculino , Persona de Mediana Edad , Especificidad de Órganos , Adenohipófisis/inmunología , Adenohipófisis/ultraestructura , Ratas , Ovinos , Especificidad de la Especie
17.
J Pediatr Hematol Oncol ; 19(5): 477-81, 1997.
Artículo en Inglés | MEDLINE | ID: mdl-9329475

RESUMEN

PURPOSE: We describe a patient with a late recurrence of rhabdomyosarcoma and review the relevant literature. PATIENT AND METHODS: Recurrent rhabdomyosarcoma occurred in a young woman 25 years after initial presentation, with the onset of symptoms 3 months after commencing hormonal replacement therapy with estrogen and progestogen. The primary and recurrent tumors were immunocytochemically identical. The primary tumor was steroid receptor negative but the recurrent tumor was estrogen and progesterone receptor positive. DISCUSSION: Estrogen priming can stimulate synthesis of progesterone receptors which may modulate mitotic activity, which suggests a functional role for receptor positive cells in modulating cell growth when sex hormone primed, with a possible tumor induction role of sex hormone replacement therapy. CONCLUSION: The late tumor recurrence may have been induced by estrogen and progestogen treatment.


Asunto(s)
Neoplasias Cerebelosas/patología , Terapia de Reemplazo de Estrógeno , Neoplasias Nasofaríngeas/patología , Neoplasias Primarias Secundarias/patología , Progestinas/uso terapéutico , Rabdomiosarcoma/patología , Adulto , Edad de Inicio , Amenorrea , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Cerebelosas/tratamiento farmacológico , Neoplasias Cerebelosas/etiología , Resultado Fatal , Femenino , Humanos , Imagen por Resonancia Magnética , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/etiología , Neoplasias Primarias Secundarias/tratamiento farmacológico , Neoplasias Primarias Secundarias/etiología , Oligomenorrea , Receptores de Estrógenos/análisis , Receptores de Progesterona/análisis , Rabdomiosarcoma/tratamiento farmacológico , Rabdomiosarcoma/etiología , Factores de Tiempo , Vimentina/análisis
18.
J Immunol Methods ; 162(1): 31-40, 1993 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-8509651

RESUMEN

A new approach to the detection of anti-pituitary autoantibodies by immunoblotting is presented. This method distinguishes pituitary membrane fraction from cytosolic fraction autoantigens and characterizes them by their molecular weight. A 45 kDa pituitary specific membrane protein was identified as an autoantigen in one of 19 patients with idiopathic growth hormone deficiency and the empty sella syndrome. A 43 kDa membrane protein in pituitary and brain was identified as an autoantigen in one other patient with idiopathic growth hormone deficiency and in one of 14 patients with secondary growth hormone deficiency. These autoantibodies were not seen in any of 27 control subjects. Anti-pituitary autoantibodies can be demonstrated by immunoblotting at titres of up to 1/1000. We conclude that immunoblotting is a useful method for the detection of anti-pituitary autoantibodies.


Asunto(s)
Autoanticuerpos/análisis , Hipófisis/inmunología , Adolescente , Adulto , Autoantígenos/análisis , Autoantígenos/química , Niño , Preescolar , Femenino , Hormona del Crecimiento/deficiencia , Humanos , Immunoblotting , Lactante , Masculino , Peso Molecular
19.
Clin Invest Med ; 14(4): 331-7, 1991 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-1782731

RESUMEN

Growth hormone (GH) response to standardized exercise, L-DOPA/propranolol and a 6-h diurnal GH profile (GHP) were evaluated in twenty-three children with very short stature and abnormal growth velocities. Standardized exercise (Jones Stage I) was performed on a cycle ergometer at 53% of the maximum oxygen consumption (VO2max) for 20 min. VO2max was determined by an incremental progressive workload until exhaustion. The mean +/- SEM peak GH concentration (ng/ml) for each test was: exercise, 8.7 +/- 1.3; L-DOPA/P: 12.8 +/- 1.9 and GHP: 3 +/- 0.7. There was no statistical difference between exercise and L-DOPA/P peaks but both peaks were significantly higher than the peak observed during the profile. During exercise 14 of 23 patients had a GH response greater than 8 ng/ml. Two patients were found to be GH deficient. Therefore 16 of 23 patients (86%) had a result concordant with their final diagnosis. During the L-DOPA/P test 17 of 23 patients had a GH response greater than 8 ng/ml. By contrast only 6 of 23 patients had a positive response during GHP. Standardized exercise is as effective as L-DOPA/P as a stimulation test for growth hormone response in very short children with abnormal growth velocities. Exercise has the advantages of being physiological, having minimal side effects, and requiring fewer blood samples. In this population of children, exercise and L-DOPA/propranolol are significantly better than the 6-h growth hormone profile for assessing GH secretion.


Asunto(s)
Enanismo Hipofisario/diagnóstico , Hormona del Crecimiento/metabolismo , Adolescente , Niño , Ritmo Circadiano , Diagnóstico Diferencial , Enanismo Hipofisario/sangre , Enanismo Hipofisario/fisiopatología , Prueba de Esfuerzo , Femenino , Trastornos del Crecimiento/diagnóstico , Hormona del Crecimiento/sangre , Humanos , Levodopa , Masculino , Valor Predictivo de las Pruebas , Propranolol , Pubertad , Estimulación Química
20.
J Paediatr Child Health ; 26(4): 221-4, 1990 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-2257185

RESUMEN

In order to examine whether the anabolic steroid oxandrolone has any long-term effect on height in Turner syndrome, the short- and long-term effects were studied in a group of 35 individuals with the syndrome. At commencement of treatment, age range was 8.2-16 years (mean 12.9); oxandrolone dosage was 0.07-0.26 mg/kg per day (mean 0.14 mg/kg per day) and continued for 12 months-6 years (mean 33 months), ending at 12-18.5 years (mean 15.6 years). Height velocity increased significantly on therapy from 3.3 +/- 0.1 to 5.8 +/- 0.3 cm/year at 6 and 12 months, and maintained at 4.8 +/- 0.3 cm/year by two years (all P less than 0.001). Girls who were younger and whose bone age was delayed grew faster (P less than 0.001). Oxandrolone dose correlated with height velocity at 12 (r = 0.39, P less than 0.05) and 18 months (r = 0.31, P less than 0.05). Both height standard deviation score (SDS) and estimated mature height (EMH) increased significantly by the end of treatment (-0.31 +/- 0.2 to 0.45 +/- 0.2, and 140.4 +/- 1.1 cm to 144.4 +/- 1.1 cm respectively (both P less than 0.0001). In 23 patients who had completed growth at a mean age of 20.6 +/- 0.83 years, final height was 145.5 +/- 1.3 cm. This was not significantly different from EMH of 144.9 +/- 1.3 cm at the end of therapy, and based on a pre-treatment EMH of 140.5 +/- 1.3 cm, represented a mean height gain of 5 cm.(ABSTRACT TRUNCATED AT 250 WORDS)


Asunto(s)
Estatura/efectos de los fármacos , Oxandrolona/uso terapéutico , Síndrome de Turner/tratamiento farmacológico , Adolescente , Factores de Edad , Niño , Evaluación de Medicamentos , Etinilestradiol/uso terapéutico , Femenino , Humanos , Oxandrolona/efectos adversos , Oxandrolona/farmacología , Estudios Prospectivos , Síndrome de Turner/fisiopatología
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