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BACKGROUND: C-type natriuretic peptide (CNP), its endogenous receptor, natriuretic peptide receptor-B (NPR-B), as well as its downstream mediator, cyclic guanosine monophosphate (cGMP) dependent protein kinase II (cGKII), have been shown to play a pivotal role in chondrogenic differentiation and endochondral bone growth. In humans, biallelic variants in NPR2, encoding NPR-B, cause acromesomelic dysplasia, type Maroteaux, while heterozygous variants in NPR2 (natriuretic peptide receptor 2) and NPPC (natriuretic peptide precursor C), encoding CNP, cause milder phenotypes. In contrast, no variants in cGKII, encoded by the protein kinase cGMP-dependent type II gene (PRKG2), have been reported in humans to date, although its role in longitudinal growth has been clearly demonstrated in several animal models. METHODS: Exome sequencing was performed in two girls with severe short stature due to acromesomelic limb shortening, brachydactyly, mild to moderate platyspondyly and progressively increasing metaphyseal alterations of the long bones. Functional characterisation was undertaken for the identified variants. RESULTS: Two homozygous PRKG2 variants, a nonsense and a frameshift, were identified. The mutant transcripts are exposed to nonsense-mediated decay and the truncated mutant cGKII proteins, partially or completely lacking the kinase domain, alter the downstream mitogen activation protein kinase signalling pathway by failing to phosphorylate c-Raf 1 at Ser43 and subsequently reduce ERK1/2 activation in response to fibroblast growth factor 2. They also downregulate COL10A1 and upregulate COL2A1 expression through SOX9. CONCLUSION: In conclusion, we have clinically and molecularly characterised a new acromesomelic dysplasia, acromesomelic dysplasia, PRKG2 type (AMDP).
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Proteína Quinasa Dependiente de GMP Cíclico Tipo II/genética , Enanismo/genética , Mutación , Osteocondrodisplasias/genética , Braquidactilia , Niño , Enanismo/metabolismo , Femenino , Humanos , Osteocondrodisplasias/metabolismo , Linaje , Secuenciación del ExomaRESUMEN
Variants of NR5A1 are often found in individuals with 46,XY disorders of sex development (DSD) and manifest with a very broad spectrum of clinical characteristics and variable sex hormone levels. Such complex phenotypic expression can be due to the inheritance of additional genetic hits in DSD-associated genes that modify sex determination, differentiation and organ function in patients with heterozygous NR5A1 variants. Here we describe the clinical, biochemical and genetic features of a series of seven patients harboring monoallelic variants in the NR5A1 gene. We tested the transactivation activity of novel NR5A1 variants. We additionally included six of these patients in a targeted diagnostic gene panel for DSD and identified a second genetic hit in known DSD-causing genes STAR, AMH and ZFPM2/FOG2 in three individuals. Our study increases the number of NR5A1 variants related to 46,XY DSD and supports the hypothesis that a digenic mode of inheritance may contribute towards the broad spectrum of phenotypes observed in individuals with a heterozygous NR5A1 variation.
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Proteínas de Unión al ADN/genética , Trastorno del Desarrollo Sexual 46,XY/genética , Variación Genética , Heterocigoto , Herencia Multifactorial , Fosfoproteínas/genética , Receptores de Péptidos/genética , Receptores de Factores de Crecimiento Transformadores beta/genética , Factor Esteroidogénico 1/genética , Factores de Transcripción/genética , Adolescente , Niño , Preescolar , Trastorno del Desarrollo Sexual 46,XY/patología , Femenino , Humanos , Lactante , Recién Nacido , MasculinoRESUMEN
Molecular study has become an invaluable tool in the field of RASopathies. Treatment with recombinant human growth hormone is approved in Noonan syndrome but not in the other RASopathies. The aim of this study was to learn about the molecular base of a large cohort of patients with RASopathies, with particular emphasis on patients with pathogenic variants in genes other than PTPN11, and its potential impact on rGH treatment indication. We reviewed the clinical diagnosis and molecular findings in 451 patients with a genetically confirmed RASopathy. HRAS alterations were detected in only 2 out of 19 patients referred with a Costello syndrome suspicion, whereas pathogenic variants in RAF1 and SHOC2 were detected in 3 and 2, respectively. In 22 patients referred with a generic suspicion of RASopathy, including cardiofaciocutaneous syndrome, pathogenic alterations in classic Noonan syndrome genes (PTPN11, SOS1, RAF1, LZTR1, and RIT1) were found in 7 patients and pathogenic variants in genes associated with other RASopathies (HRAS, SHOC2, and PPPCB1) in 4. The correct nosological classification of patients with RASopathies is critical to decide whether they are candidates for treatment with rhGH. Our data illustrate the complexity of differential diagnosis in RASopathies, as well as the importance of genetic testing to guide the diagnostic orientation in these patients.
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INTRODUCTION: Treatment with recombinant human growth hormone (rhGH) has been shown to improve adult height in pediatric patients with GH deficiency (GHD). However, reassessment of patients after they reach their final height shows some of them have permanent GH deficiency (PGHD), while others had a transient deficiency (TGHD). The study objective was to assess, in a cohort of pediatric patients with GHD, potential differences in response to treatment with rhGH depending on whether deficiency is permanent or transient. MATERIALS AND METHODS: A retrospective study of 89 patients with GHD, who were monitored from diagnosis to adult height. Clinical, auxological, radiographic and laboratory variables were collected at diagnosis, after the first year of treatment, and when they had reached their adult height. RESULTS: PGHD was found in 28% of patients. Initial height was -2.46 ± 0.86 SD and -2.24 ± 0.68 SD in subjects with PGHD and TGHD respectively. Peak GH level at diagnosis was 4.26 ± 2.78 and 6.20 ± 2.01 ng/mL (p < 0.01) in the PGHD and TGHD groups respectively. After the first year of treatment, increase in growth velocity was greater in the PGHD group: 4.33 ± 3.53 SD vs. 2.95 ± 2.54 SD in the PGHD group (p = 0.043). Final height was -0.81 ± 0.87 SD in the PGHD and -0.95 ± 0.83 SD in the TGHD group (p = 0.47). CONCLUSIONS: Patients with PGHD had a better short- and long-term response to rhGH. They also showed lower GH levels in stimulation tests at diagnosis, as previously reported.
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Enanismo Hipofisario/tratamiento farmacológico , Trastornos del Crecimiento/tratamiento farmacológico , Hormona de Crecimiento Humana/uso terapéutico , Adolescente , Adulto , Estatura , Niño , Estudios Transversales , Femenino , Estudios de Seguimiento , Humanos , Masculino , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Neonatal diabetes mellitus (NDM) is a rare form of diabetes diagnosed within the first 6 months of life. Genetic studies have allowed the identification of several genes linked to the development of NDM; however, genetic causes for â¼20% of the cases remain to be clarified. Most cases of NDM involve isolated diabetes, but sometimes NDM appears in association with other pathological conditions, including autoimmune diseases. Recent reports have linked activating mutations in STAT3 with early-onset autoimmune disorders that include diabetes of autoimmune origin, but the functional impact of STAT3-activating mutations have not been characterized at the pancreatic ß-cell level. By using whole-exome sequencing, we identified a novel missense mutation in the binding domain of the STAT3 protein in a patient with NDM. The functional analyses showed that the mutation results in an aberrant activation of STAT3, leading to deleterious downstream effects in pancreatic ß-cells. The identified mutation leads to hyperinhibition of the transcription factor Isl-1 and, consequently, to a decrease in insulin expression. These findings represent the first functional indication of a direct link between an NDM-linked activating mutation in STAT3 and pancreatic ß-cell dysfunction.
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Hipotiroidismo Congénito/genética , Diabetes Mellitus/genética , Células Secretoras de Insulina/metabolismo , Insulina/biosíntesis , Factor de Transcripción STAT3/genética , Animales , Western Blotting , Línea Celular , Inmunoprecipitación de Cromatina , Colitis Colagenosa/complicaciones , Hipotiroidismo Congénito/complicaciones , Femenino , Humanos , Recién Nacido , Proteínas con Homeodominio LIM/metabolismo , Mutación , Mutación Missense , Ratas , Reacción en Cadena en Tiempo Real de la Polimerasa , Análisis de Secuencia de ADN , Factores de Transcripción/metabolismo , TransfecciónRESUMEN
OBJECTIVE: Obesity is associated with insulin-resistance (IR), type 2 diabetes (T2D) and a constellation of cardiovascular risk factors at the early years of life. These features define the so-called metabolic syndrome (MS). AIMS: To assess the frequency of the MS among obese pediatric Spanish population and analyse the individual contribution and the predictive potential of individual components to the development of the syndrome. PATIENTS AND METHODS: A total of 429 patients, 220 boys and 209 girls, aged 4-18 years, with a body mass index of >2 standard deviation scores for Spanish normative charts, were included in the study. Forty-seven percent were prepubertal and ten percent had Hispanic ethnicity. HbA1c, lipids, liver enzymes and uric acid levels were determined from blood and a standard 2-h oral glucose tolerance test was performed. MS was defined by the National Cholesterol Education Program's Adult Treatment Panel III criteria modified by Cook as having at least three features among: obesity, low high-density lipoprotein (HDL), hypertriglyceridemia, hypertension (HTA) or impaired glucose metabolism (IGM). We defined IR as homeostatic model assessment of IR index and/or fasting insulin levels>95th centile of the control population. RESULTS: Almost 18% of the patients had MS, with significantly higher frequency in Hispanic (32%) than in Caucasian (16%) population. There were no differences by sex or pubertal status. Prevalence of low HDL, HTA, hypertriglyceridemia and IGM were 27, 23, 16 and 7% respectively. No silent T2D was identified. According to International Obesity Task Force charts, 22% of the patients were overweight and not obese, but no differences in the frequency of individual features of MS between these two groups were observed. Among IR patients (35% of our population), the frequency of MS reached 28%. IR predicted the presence of MS independently from age and race. CONCLUSION: MS is present in 18% of our obese pediatric population. IR is closely associated with the components of MS and strongly predicts its development.
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Síndrome Metabólico/epidemiología , Obesidad/epidemiología , Adolescente , Peso Corporal , Niño , Preescolar , HDL-Colesterol/sangre , Femenino , Humanos , Hipertensión/epidemiología , Hipertrigliceridemia/epidemiología , Modelos Logísticos , Masculino , Prevalencia , Factores de Riesgo , España/epidemiologíaRESUMEN
OBJECTIVE: To evaluate insulin-secretion kinetics and insulin sensitivity in cystic fibrosis (CF) patients with normal glucose tolerance (CF-NGT), impaired glucose tolerance (CF-IGT) or CF-related diabetes (CFRD), and the potential effects of moderate hyperglycemia on clinical and nutritional status. DESIGN AND METHODS: Cross-sectional study including 50 outpatients with CF. Patients underwent both oral (OGGT) and intravenous (IVGTT) glucose tolerance tests in order to assess insulin secretion and peripheral insulin sensitivity. Homeostasis assessment model and OGGT were used to investigate insulin sensitivity. Forced expiratory volume in the first second (FEV(1)) and forced vital capacity (FVC) were measured to evaluate pulmonary function. Body mass index (BMI) was determined to assess nutritional status. RESULTS: Insulin secretion was significantly decreased (and delayed at OGTT) in the CFRD group (n = 9) versus the CF-IGT group (n = 10) and the CF-IGT versus the CF-NGT group (n = 31). Insulin sensitivity was significantly different in the CF-IGT and CFRD groups versus the CF-NGT group. FEV(1), FVC and BMI presented a significant linear correlation with plasma glucose value at 120 min at OGTT and were significantly lower in both CF-IGT and CFRD versus the CF-NGT group, whereas no differences were found between the CF-IGT and CFRD groups. CONCLUSIONS: CF patients with IGT present diminished insulin secretion and increased peripheral insulin resistance, correlating with a worse clinical status, undernutrition and impaired pulmonary function. These findings open the question of whether early treatment of mild alterations of glucose metabolism with insulin secretagogues or short-action insulin may lead to improvement of clinical status in CF patients.
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Fibrosis Quística/complicaciones , Fibrosis Quística/metabolismo , Intolerancia a la Glucosa/complicaciones , Intolerancia a la Glucosa/metabolismo , Insulina/metabolismo , Adolescente , Adulto , Estudios de Cohortes , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Femenino , Genotipo , Intolerancia a la Glucosa/genética , Prueba de Tolerancia a la Glucosa , Humanos , Resistencia a la Insulina , Secreción de Insulina , MasculinoRESUMEN
AIM: To assess lung function in children and adolescents with type 1 diabetes mellitus (T1DM). PATIENTS AND METHODS: We conducted a case-control study of 100 patients with T1DM [median age 13 (10.6-14.7), 44% men, 23% prepubertal, and all nonsmokers] and 77 controls. None had evidence of lung disease or any other comorbidity. We performed pulmonary function tests, including spirometry [forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and FEV1/FVC ratio], plethysmography [total lung capacity (TLC), residual volume (RV), RV/TLC ratio, and airway resistance (Raw)], and diffusing capacity of carbon monoxide in the lung (TLCO), alveolar volume (AV), and TLCO/AV ratio. The duration of diabetes, degree of metabolic control, insulin dose, and presence of diabetic complications were registered. The χ²-test and analysis of variance were used to compare categorical and quantitative variables, respectively. RESULTS: The duration of diabetes was 6.2±3.8 years with a median HbA1c of 7.08±0.4%. FEV1/FVC ratio was found to be significantly higher in patients with TIDM than in controls. Patients with diabetes also had a nonsignificant trend towards lower FVC, FEV1, Raw, and TLCO, and higher RV, TLC, and RV/TLC than controls. There were no differences in pulmonary function based on duration of disease or metabolic control. We found differences in pulmonary evaluation when pubertal stage was analyzed. CONCLUSIONS: The lung is functionally involved in children with T1DM. Pubertal development stage influences the evaluation of lung function.
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Diabetes Mellitus Tipo 1/fisiopatología , Pulmón/fisiopatología , Adolescente , Índice de Masa Corporal , Estudios de Casos y Controles , Niño , Complicaciones de la Diabetes/epidemiología , Complicaciones de la Diabetes/fisiopatología , Diabetes Mellitus Tipo 1/complicaciones , Femenino , Humanos , Enfermedades Pulmonares/epidemiología , Enfermedades Pulmonares/etiología , Enfermedades Pulmonares/fisiopatología , Masculino , Pubertad , Pruebas de Función RespiratoriaRESUMEN
AIM: The "T1D Exchange Clinic Registry" of 13.316 pediatric patients with type 1 diabetes (T1D) in U.S. recently revealed that most children have HbA1c values above target levels established by the American Diabetes Association (ADA) and the International Society for Pediatric and Adolescent Diabetes (ISPAD). The aim of this study is to assess the proportion of youngsters with T1D who meet the internationally accepted targets for good metabolic control of diabetes at a single, referral Pediatric Diabetes Center in Spain. PATIENTS AND METHODS: Cross-sectional study of 236 children and adolescents with T1D controlled at our Pediatric Diabetes Unit. We analyzed the compliance to metabolic goals set by ADA and ISPAD and the differences between patients treated with continuous subcutaneous insulin infusion and multiple daily injections. STATISTICS: SPSS™ version 21.0. RESULTS: Mean age: 12.6 ± 4.6 years old, mean age at diagnosis: 6.1 ± 4.3 years old and mean diabetes duration: 6.4 ± 4.3 years; 47% female. HbA1c average: 6.7 ± 0.7% (49.7 ± 7.6 mmol/mol). The age-specific ADA and ISPAD HbA1c targets were achieved by 93% and 91% of patients, respectively. Among pump users, 97%/97% met ADA/ISPAD HbA1c targets compared to 87%/88% of MDI users (p = 0.04/p = 0.03), without significant differences in the analysis by groups of age. Among participants, 95%, 62%, 95%, 98% and 89% met HDLc, LDLc, triglycerides, BP and BMI targets. CONCLUSIONS: Most patients in our children and adolescent cohort of T1D patients correctly achieve metabolic goals established by ADA and ISPAD with low incidence of hypoglycemia.
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Logro , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Objetivos , Insulina/administración & dosificación , Insulina/uso terapéutico , Sociedades Médicas/normas , Adolescente , Presión Sanguínea/fisiología , Índice de Masa Corporal , Niño , Estudios Transversales , Diabetes Mellitus Tipo 1/epidemiología , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemia/epidemiología , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/uso terapéutico , Incidencia , Inyecciones , Sistemas de Infusión de Insulina , Metabolismo de los Lípidos/fisiología , Masculino , España/epidemiologíaRESUMEN
La dignidad del paciente puede verse afectada en el transcurso de la hospitalización por conductas observables de los profesionales. A pesar de su importancia, existen pocos instrumentos para evaluarla. Mediante un estudio transversal, descriptivo, analítico y cuantitativo, se evalúa la percepción de dignidad del paciente con el "Cuestionario de percepción de dignidad de paciente hospitalizado (CuPDPH)", en español y validado. La muestra estuvo formada por 148 hombres y 138 mujeres, con una media de edad de 62.82 (DE 4.05). No se detectó diferencias significativas en las puntuaciones y las variables sociodemográficas. Los resultados permiten identificar puntos fuertes y áreas de mejora en el cuidado y respeto a la dignidad de las personas hospitalizadas. Profundizar en el tema resulta una oportunidad en el camino hacia la excelencia profesional, defendiendo las competencias técnica y ética.
Dignity is a fundamental concept that can be modified during hospitalization by the behavior of professionals. Despite its importance, there are few instruments to evaluate it. A transversal, descriptive, analytical and quantitative study evaluates the patient's perception of dignity based on the "Cuestionario de percepción de dignidad de paciente hospitalizado (CuPDPH)" in Spanish and validated. The sample was composed of 148 men and 138 women with an average age of 62.82 (SD 4.05). No significant differences were found in the scores and sociodemographic variables. The results allow us to identify highlights and areas of improvement in the care and respect for the dignity of hospitalized persons. Going deeper into the topic is an opportunity, on the way to professional excellence, defending technical competence and ethical competence.
Resumo A dignidade do paciente pode ser afetada no transcurso da hospitalização por condutas observáveis dos profissionais. Apesar de sua importância, existem poucos instrumentos para avalia-la. Mediante um estudo transversal, descritivo, analítico e quantitativo, avalia-se a percepção da dignidade do paciente com o "Questionário de percepção da dignidade de paciente hospitalizado (CuPDPH, sigla em espanhol)", em espanhol e validado. A amostra foi constituída por 148 homens e 138 mulheres, com uma média de idade de 62,82 (DP 4,05). Não se detectaram diferenças significativas nas pontuações e nas variáveis sócio-demográficas. Os resultados permitem identificar pontos fortes e áreas de melhora no cuidado e respeito à dignidade das pessoas hospitalizadas. Aprofundarse no tema representa uma oportunidade no caminho à excelência profissional, defendendo as competências técnica e ética.
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Humanos , Masculino , Femenino , Adolescente , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Adulto Joven , Personeidad , Respeto , Pacientes Internos/psicología , Percepción , Relaciones Profesional-Paciente , Estudios Transversales , Análisis Multivariante , Encuestas y Cuestionarios , Satisfacción del Paciente , Confidencialidad , Vulnerabilidad en Salud , HospitalizaciónRESUMEN
INTRODUCTION AND OBJECTIVES: Molecular characterization of congenital heart diseases now includes the not infrequent dysmorphic Noonan syndrome. A study of 6 genes of the RAS-MAPK pathway in Spanish patients is presented: the impact of heart disease, clinical expressivity, and diagnostic yield are investigated. METHODS: The study included 643 patients (and 182 family members) diagnosed by dysmorphologists, cardiologists, and pediatric endocrinologists from 74 tertiary hospitals. Bidirectional sequencing analysis of PTPN11, SOS1, RAF1, BRAF, KRAS and HRAS focused on exons carrying recurrent mutations accounting for 80% to 95% of previously described mutations. RESULTS: Mutations were detected in 230 patients (91 women and 139 men) in 200 (31%) families (172 PTPN11+, 14 SOS1+, 9 RAF1+, 5 BRAF+). There was specific reference to the heart defect suffered in 156 index cases: 103 patients had shown pulmonary stenosis, 12 pulmonary stenosis with hyperthrophic cardiomyopathy, 18 hypertrophic cardiomiopathy, and 14 other cardiopathies; heart disease was absent in 9 index cases. Heart disease had not been documented in 23 of 30 family members with positive genotype and compatible clinical signs. Diagnostic yield was higher (P=.016) for samples from some centers (53%; 14/32) and even from certain professionals (64%; 9/14; P=.019). Characterization rate was 18% in patients for whom clinical data were not available. Genotyping led to a more precise diagnosis in 26 patients. CONCLUSIONS: Most patients (94%) with a positive genotype had known congenital heart disease, 79% pulmonary stenosis and 12% hyperthrophic cardiomyopathy. Cardiopathy had not been documented in 76% of family members carrying the mutation. Molecular study is a useful tool in these syndromes but a more rigorous clinical diagnosis should be intended as well.
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Cardiomiopatía Hipertrófica/genética , Displasia Ectodérmica/genética , Insuficiencia de Crecimiento/genética , Genes ras/genética , Cardiopatías Congénitas/genética , Proteínas Quinasas Activadas por Mitógenos/genética , Síndrome de Noonan/genética , Estenosis de la Válvula Pulmonar/genética , Adolescente , Niño , Facies , Femenino , Genotipo , Cardiopatías/genética , Humanos , Masculino , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-raf/genética , Proteína SOS1/genéticaAsunto(s)
Dermatomiositis/epidemiología , Dermatomiositis/fisiopatología , Resistencia a la Insulina/fisiología , Lipodistrofia/epidemiología , Lipodistrofia/fisiopatología , Niño , Humanos , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/epidemiología , Hiperglucemia/fisiopatología , Hipoglucemiantes/uso terapéutico , Masculino , Rosiglitazona , Tiazolidinedionas/uso terapéuticoRESUMEN
The aim of this study is to determine the proper initial dose adjustment when switching from multiple daily injections to continuous subcutaneous insulin infusion for type-1 diabetic pediatric patients. Our hypothesis is that the insulin adjustment varies depending on the pubertal status and the previous long-acting insulin used. Charts of 60 patients were reviewed. Data regarding insulin dose, type of insulin administrated, HbA1c, BMI, severe hypoglycemia and DKA events were collected during the previous year and after 6 weeks of pump therapy. In the prepubertal patients the reduction was 19% (26% if the previous insulin used was detemir). Pubertal patients experienced a decrease of 26%, and the detemir group 33%. The ratio long acting-basal/short acting-bolus insulin changed from 1.26 ± 0.84 to 0.93 ± 0.46 (P < 0.05). The total daily insulin dose needs to be decreased. Basal insulin constitutes 40-45% in prepubertal and 45-50% in pubertal patients. The reduction is different depending on the previous long-acting insulin used; being greater if the insulin is detemir.
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Diabetes Mellitus Tipo 1/tratamiento farmacológico , Cálculo de Dosificación de Drogas , Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Niño , Preescolar , Diabetes Mellitus Tipo 1/metabolismo , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Lactante , Inyecciones Subcutáneas , Sistemas de Infusión de Insulina , Insulina de Acción Prolongada/administración & dosificación , Masculino , Estudios RetrospectivosRESUMEN
OBJECTIVE: To report a case of a 46,XX male with an intratubular undifferentiated germ cell neoplasia within an extra-abdominal gonad. DESIGN: Case report. SETTING: Molecular, cytogenetic, pathologic, and clinical units of three tertiary hospitals. PATIENT(S): A male with ambiguous genitalia at birth and descended testes observed in a pediatric endocrinology setting. INTERVENTION(S): Physical examination, hormonal assays, cytogenetic investigation, molecular analysis, surgical intervention for biopsies and bilateral orchiectomy, and pathologic evaluation. MAIN OUTCOME MEASURE(S): Pathologic evaluation with immunostaining for placental alkaline phosphatase and C-kit. RESULT(S): Conventional chromosome analysis revealed a 46,XXq- karyotype, and fluorescence in situ hybridization experiments with the SRY probe found a signal at the short arm of the deleted X chromosome. Molecular analysis indicated the presence of a portion of the short arm of the Y chromosome including the proto-oncogene TSPY. Pathologic evaluation of the gonads revealed an intratubular undifferentiated germ cell neoplasia. CONCLUSION(S): This is the first case of a 46,XX male with descended testes in whom an intratubular undifferentiated germ cell neoplasia developed. When proposals of management in this subgroup of disorders of sexual differentiation are formulated, the risk of germ cell malignancy must be taken into account.
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Diferenciación Celular , Disgenesia Gonadal 46 XX/genética , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias Testiculares/patología , Testículo/patología , Adolescente , Fosfatasa Alcalina , Proteínas de Ciclo Celular/genética , Proteínas Ligadas a GPI , Humanos , Isoenzimas/análisis , Masculino , Neoplasias de Células Germinales y Embrionarias/química , Neoplasias de Células Germinales y Embrionarias/genética , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas c-kit/análisis , Proteína de la Región Y Determinante del Sexo/genética , Neoplasias Testiculares/química , Neoplasias Testiculares/genética , Testículo/químicaRESUMEN
OBJECTIVE: To describe and discuss our experience of patients with congenital adrenal hyperplasia (CAH) conceived via assisted reproduction techniques (ART). DESIGN: Case reports. SETTING: Tertiary hospitals and a CAH molecular diagnosis reference laboratory belonging to one of these. PATIENT(S): Five patients with CAH (with 21-hydroxylase deficiency [21OHD]) conceived via homo/heterologous ART with egg or sperm donations. INTERVENTION(S): Molecular diagnosis following DNA analysis of patients, parents, and siblings, including direct analysis of the gene (polymerase chain reaction/allele-specific hybridization), Southern analysis (for gene deletions and duplications), semiquantitative primer extension (to confirm duplications), complementary sequencing, and microsatellite analysis to confirm allele segregation. MAIN OUTCOME MEASURE(S): Genotype identification and segregation analysis of alleles. Clinical evaluation of patients. RESULT(S): Three children (two girls, one boy) with classic neonatal forms of CAH (salt wasting and severe virilization) and two with nonclassic forms (two girls, one compound heterozygous with a severe mutation who showed clinical signs at 3.5 years of age) were born to parents who used ART. All showed segregated 21OH gene mutations. The respective genotypes were: 655G/655G, Q318X/Q318X,R356W, gene deletion hybrid with break point at exons 3-4/8 bp deletion at exon 3, 655G/V281L, and V281L/V281L. The severe mutations in the donated gametes were 655G and Q318X-R356W. CONCLUSION(S): As a common, infertility-related and prenatal treatment-susceptible recessive genetic disease, 21OHD genotyping should be considered in ART.
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Hiperplasia Suprarrenal Congénita/genética , Técnicas Reproductivas Asistidas , Esteroide 21-Hidroxilasa/genética , Hiperplasia Suprarrenal Congénita/diagnóstico , Preescolar , Femenino , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas/métodos , Genotipo , Humanos , Masculino , LinajeRESUMEN
INTRODUCTION: Worldwide poliomyelitis eradication was proposed in 1988 by the World Health Organization (WHO), based on reaching and maintaining high vaccination coverage and on implementing effective poliovirus infection surveillance systems. METHODS: In Spain the surveillance system focuses on active searching for acute flaccid paralysis cases through a nine-laboratory network, coordinated by the National Poliovirus Laboratory (NPL) in the National Center of Microbiology, and supported by Autonomous Community epidemiologists. Additionally, the Network sends enterovirus isolation data from other syndromes. The Laboratory Network is responsible for the primary virological study, while the NPL characterizes all polioviruses and the most epidemiologically relevant non-polio enteroviruses. RESULTS: A total of 54,533 samples were studied during the six-year period, and enteroviruses were detected in 9%. All the polioviruses isolated (n = 196), were characterized as Sabin-like (poliovirus vaccine), and among the non-polio enteroviruses, the most frequent was Echovirus 30. A total of 3% of the samples studied corresponded to the 268 acute flaccid paralysis cases or their contacts. DISCUSSION: According to the results and the WHO virological classification, Spain can be considered polio-free. However, the geographic situation of our country may facilitate the introduction of wild polioviruses that can give rise to imported poliomyelitis. Hence, the laboratory network should actively continue to participate in all the proposed WHO strategies, particularly maintenance of the poliomyelitis eradication infrastructures, and continuing monitoring and vaccination.
Asunto(s)
Poliomielitis/epidemiología , Poliomielitis/prevención & control , Humanos , Laboratorios/organización & administración , Parálisis/virología , Poliovirus/aislamiento & purificación , Vigilancia de la Población , España/epidemiologíaRESUMEN
BACKGROUND: Optimal treatment of Graves' disease in paediatric patients is still a matter of controversy. Antithyroid drugs, radioiodine and thyroidectomy are the three therapeutic options available. AIM: To report our experience of long-term medical treatment and outcome of paediatric Graves' disease. METHODS: A 5-y-long medical protocol was implemented in 20 children and adolescents with Graves' disease. All patients received antithyroid drugs as the first therapeutic option; patients who did not enter long-term remission received I(131) and/or surgery as the definitive treatment. RESULTS: The mean age at diagnosis was 12.1+/-4 y. Only two patients were males, both presenting concomitant type 1 diabetes. Mean follow-up was 13.8+/-5.5 y. Forty per cent of patients achieved long-term remission with low antithyroid drugs doses (mean treatment time: 5.4+/-1.4 y). Six patients received I(131) as definitive treatment and another six underwent surgery after completing medical treatment for 6.8+/-4.1 and 5.1+/-2 y, respectively. No patients requiring high antithyroid drugs doses to maintain euthyroidism reached long-term remission and needed I(131) and/or surgery. CONCLUSION: Implementation of a long-term antithyroid drug protocol achieved 40% long-term remissions in paediatric patients with Graves' disease. Need for maintained high doses of antithyroid drugs could be considered a predictive factor for no remission. When permanent remission was not obtained by medical treatment, I(131)and/or surgery allowed healing in all cases.