Clinical spectrum of MEN2A in a large family caused by the infrequent RET mutation Cys609Phe.

Mutations in RET proto-oncogene cause multiple endocrine neoplasia 2A (MEN2A). Mutations in codons 609 and 611 are not frequent. We identified two MEN2A families with the Cys609Phe RET mutation, which turned out to be the same family. This mutation has been described a couple of times with no clinical details. We have characterized the clinical phenotype of this large kindred. A 54-year-old woman, with a medullary thyroid carcinoma (MTC), and a 33-year-old woman, who was operated on for an adrenal pheochromocytoma, were the index cases. 35 relatives were studied. Sixteen turned out to be carriers and 12 of them have been operated on. This family showed eight patients with C-cell hyperplasia, six patients affected by MTC and two showing pheochromocytoma. A papillary thyroid carcinoma was also found, together with the MTC, in one of the carriers. The phenotype in this large kindred is clearly of MEN2A. In carriers presenting the Cys609Phe mutation, the timing of the presentation of the syndrome is highly unpredictable. Therefore, a strict follow up of MTC must be carried out because of risk, and pheochromocytoma should not be ignored. These results reinforce the scarce data observed on this particular mutation.

Características de la versión española del cuestionario de calidad de vida QLSM-H en sujetos adultos con deficiencia de hormona de crecimiento tratados con somatotropina. Estudio piloto / Characteristics of the spanish version of the quality of life questionnaire (QLSM-H) in adult subjects with growth hormone deficiency treated with somatotropin: pilot study

El objetivo de este trabajo es describir las características psicométricas de la versión inicial del cuestionario de calidad de vida enfermedad-específico (QLSM-H) en pacientes españoles adultos con deficiencia de hormona de crecimiento (GH).Métodos. A 64 pacientes diagnosticados de deficiencia de GH (36 mujeres y 28 varones), con una edad media (desviación estándar [DE]) de 39,6 años (13,8), se autoadministraron los cuestionarios QLSM-H y SF-36 en las visitas correspondientes a los intervalos -1, 0, 3 y 6 meses de tratamiento sustitutivo con somatotropina. Los resultados se compararon con los datos de referencia españoles del cuestionario QLSM-H obtenidos en 876 sujetos normales, aleatoriamente seleccionados en una muestra poblacional.Resultados. Los pacientes presentaban un panhipopituitarismo con deficiencia de GH grave (factor de crecimiento similar a la insulina 1 [IGF-I] media: 48,4 µg/l). La correlación test-retest fue de 0,88, la consistencia interna evaluada mediante de Cronbach fue de 0,92. Los coeficientes de correlación con las áreas física y mental del SF-36, en condiciones basales, fueron de 0,37 y 0,75, respectivamente (p < 0,005). La puntuación basal del QLSM-H fue de 23,9 y de 45,2 a los 6 meses de tratamiento (p<0,005). La puntuación de la población de referencia para la misma edad y sexo era de 41,2 (p = 0,06 frente a basal y p = 0,626 frente a 6 meses). El tamaño del efecto fue de 0,71.Conclusión. La versión inicial española del módulo enfermedad-específico del cuestionario QLS es una herramienta válida, reproducible y sensible para evaluar la satisfacción de la calidad de vida relacionada con la salud de los pacientes con deficiencia de GH y para monitorizar los efectos del tratamiento sustitutivo con somatotropina sobre la misma (AU)

Estudio de las mutaciones A3243G, C3256T y deleciones mitocondriales en 41 pacientes diabéticos / Analysis of mtDNA point mutations A3243G, C3256T and mtDNA deletions in 41 diabetic patients

FUNDAMENTO: Las mutaciones y/o deleciones del ADN mitocondrial caracterizan un nuevo subtipo de diabetes. PACIENTES Y MÉTODO: Se estudiaron las mutaciones A3243G y C3256T y deleciones mitocondriales en 41 pacientes diabéticos con antecedentes maternos de diabetes y/o sordera neurosensorial. RESULTADOS: La mutación A3243G se detectó en un paciente (2,4 por ciento). En ningún paciente se detectaron la mutación C3256T ni deleciones mitocondriales. CONCLUSIONES: La búsqueda de la mutación A3243G debe considerarse ante la presencia de diabetes con herencia materna y sordera neurosensorial asociada (AU)

[Impact of a selective screening for gestational diabetes in a Spanish population]. / Impacto de un cribado selectivo de la diabetes gestacional en una población española.

BACKGROUND: Recently, the American Diabetes Association (ADA) concluded that pregnant women with low risk factors for gestational diabetes need not to be tested. The aims of this study was to determine the prevalence of gestational diabetes in a Spanish low risk pregnant women population, to analyze the criteria that define low risk pregnancies for gestational diabetes, and to compare the differences in morbidity between pregnant women with and without gestational diabetes. DESIGN AND METHODS: Cohort study of 2,262 gestations (2,085 Caucasians) during a period of 7 years in a reference hospital. RESULTS: The gestational diabetes prevalence was 15%. Two-hundred and seventy-four (12.1%) women were considered as a low risk group for gestational diabetes. Among these, 13 (4.7%) presented gestational diabetes in comparison with 16.6% in the remaining women (p = 0.0001). Gestational diabetes in the low risk pregnant women constituted the 3.8% of all gestational diabetes. We did not find differences in gestational outcomes or fetal antropometry between the groups. The relative risk of macrosomia in the low risk pregnant was 0.9% (95% confidence interval for the mean: 0.86-0.94). CONCLUSIONS: In spite of their capacity of identifying current complications, 4% of gestational diabetes would not have been diagnosed with the new ADA criteria. The misdiagnosis will prevent in this small group of women the adoption of preventive measures for subsequent pregnancies and for diabetes in later life.

[Insulin resistance and metabolic syndrome in first-degree relatives of patients with NIDDM]. / Resistencia a la insulina y síndrome metabólico en familiares de primer grado de pacientes con diabetes mellitus tipo 2.

BACKGROUND: Relatives of type 2 diabetes mellitus (DM2) patients present or can develop the plurimetabolic syndrome (MS). Insulin sensitivity determination could be useful to detect relatives with higher risk. PATIENTS AND METHODS: Insulin sensitivity (IS) and MS in 106 first degree relatives of DM2 and 52 control subjects, matched for age, sex and body mass index (BMI). Insulin sensitivity was evaluated by the HOMA method. Insulin sensitivity was classified as high, middle or low according to the percentiles 33 and 66 observed in the control group. MS was diagnosed if hyperglycemia, hypertension, hypertriglyceridemia and overweight (two or more) were present. RESULTS: Insulin sensitivity was lower in relatives (36.3 vs 51.8%; p = 0.0001). Relatives with lower insulin sensitivity (n = 56) have higher BMI (29.2 vs 25.6 kg/m2), higher systolic (128 vs 116 mmHg) and diastolic (80 vs 74) blood pressure, hyperglycemia (5.7 vs 5.1 mmol/l), hyperinsulinemia (116 vs 59 pmol/l) and hypertriglyceridemia (1.4 vs 1.0 mmol/l) when compared with the remainder relatives (n = 50). Age, sex, waist/hip ratio and cholesterol level were similar in both groups. 23 relatives have MS (20 of them with low insulin sensitivity, relative risk = 8.7; 95% confidence interval 2.4-31.6). In multiple logistic regression analysis, only age and IS have a significant value to predict the presence of MS. CONCLUSIONS: Relatives of DM2 are insulin-resistant and present a high prevalence of MS. Both insulin sensitivity and MS are highly correlated. Insulin sensitivity evaluation using a simple methodology like HOMA can be useful in the selection of relatives at higher risk of MS.

[Diabetes mellitus associated with the A3243G mutation of mitochondrial DNA. Apropos a case]. / Diabetes mellitus asociada a la mutación A3243G de ADN mitocondrial. A proposito de un caso.

The mitochondrial A3243G mutation of the tRNA(Leu) has been described in pedigrees with maternally inherited diabetes mellitus and deafness. Ten diabetic patients with sensorineural deafness were studied. Polymerase chain reaction and enzyme restriction analysis with Apa I were performed. The mutation was found in heteroplasmy in only one patient (1/10). She was a 43-years-old woman with maternally inherited diabetes and deafness since she was 29. The association of sensorineural deafness and maternal inherited diabetes are the clues to suspect this subtype of diabetes.

High prevalence of the C634Y mutation in the RET proto-oncogene in MEN 2A families in Spain.

The RET proto-oncogene encodes a receptor tyrosine kinase expressed in neural crest derived tissues. Germline mutations in the RET proto-oncogene are responsible for three different dominantly inherited cancer syndromes: multiple endocrine neoplasia type 2A (MEN 2A), type 2B (MEN 2B), and familial medullary thyroid carcinoma (FMTC). MTC can also occur sporadically. Molecular characterisation of the RET proto-oncogene has been performed by PCR-SSCP analysis, direct DNA sequencing, and restriction enzyme analysis in 49 unrelated, Spanish, MEN 2 families: 30 MEN 2A families, six FMTC families, and 13 families classified as "other". Germline missense mutations in one of six cysteine codons (609, 611, 618, and 620 in exon 10, and codons 630 and 634 in exon 11), which encode part of the extracellular cysteine rich domain of RET, have been detected in the majority of these families: 100% of MEN 2A families, 67% of FMTC families, and 54% of families classified as "other". No RET mutations in exons 10, 11, 13, 14, 15, or 16 were detected in the remaining families. The most frequent RET mutation in MEN 2A Spanish families is C634Y, occurring in 73% of cases. Haplotype analysis does not exclude the possibility of founder effects in Spanish MEN 2A families with the C634Y mutation.

Neuromas and prominent corneal nerves without MEN 2B.

PURPOSE: We studied a family composed of 2 members with the characteristic phenotype of the MEN 2B and without RET protooncogene mutations in order to determine whether they had multiple endocrine neoplasia associated with MEN 2B in the 5-year follow-up. SUBJECTS AND METHODS: The family consisted of a 15 year old female complaining of burning eyes, examined ophthalmologically in 1992 and her mother and sister, who were examined later on in 1992. The proband and the mother were affected with multiple mucosal neuromas and visible corneal nerves. Pentagastrin-stimulated serum calcitonin levels, catecholamines, serum calcium and phosphate levels were measured. Molecular genetic studies were performed on the 2 affected members to look for the specific RET mutation seen in MEN 2B. RESULTS: Endocrine neoplasia of the syndrome MEN 2B, medullary thyroid carcinoma, pheochromocytoma and hyperparathyroidism, were ruled out in the first examination and after 5-year follow-up. In the 2 cases no mutation at codon 918 for the RET proto-oncogene was found. CONCLUSIONS: We consider that familial multiple mucosal neuromas are a highly distinctive entity of MEN 2B.

Beta-cell dysfunction in first-degree relatives of patients with non-insulin-dependent diabetes mellitus.

To analyse the relationship between age, glucose tolerance, beta-cell function, and insulin sensitivity in preclinical states of non-insulin-dependent (Type 2) diabetes mellitus (NIDDM), we have done a cross-sectional, age-stratified analysis of 86 non-diabetic first-degree relatives of NIDDM patients and 49 controls with similar age, sex, and BMI. A 5 mg kg ideal body weight-1 min-1 for 60 min of continuous infusion of glucose with model assessment (CIGMA) of serum glucose and C-peptide values at the end of the infusion was used to determine glucose tolerance and beta-cell function. Insulin sensitivity was estimated by modelling basal serum glucose and insulin values. Relatives and controls were divided into tertiles on the basis of age. Relatives had higher basal (5.3 vs 5 mmol l-1, p = 0.02) and achieved serum glucose (9.1 vs 8.4 mmol l-1, p = 0.01), lower beta-cell function (128 vs 145%, p = 0.007), and lower insulin sensitivity (37 vs 43%, p = 0.002). Beta-cell function declined with age in relatives (from 139% in young subjects to 134% in intermediate subjects and to 111% in older subjects, p = 0.002) and this decline was associated with an increase in basal serum glucose (from 5.1 to 5.3 and to 5.7 mmol l-1, p = 0.000) and achieved glucose (from 8.3 to 9.1 and to 9.3 mmol l-1, p = 0.038), without significant changes in insulin sensitivity. These trends were observed even after the exclusion of subjects with mild glucose intolerance. We conclude that both beta-cell dysfunction and insulin resistance are present in first-degree relatives of NIDDM. The progression of beta-cell dysfunction and glucose intolerance with age suggests that beta-cell dysfunction is the key factor in the apparition and progression of the disease.

Ketoacidosis at diagnosis is predictive of lower residual beta-cell function and poor metabolic control in type 1 diabetes.

To determine the factors at diagnosis predictive of changes in residual beta-cell function and metabolic control in Type 1 diabetes, 125 patients older than 7 years of age consecutively diagnosed between March 1986 and June 1991 were followed prospectively for two years. The effect of age, gender and the presence of ketoacidosis (DKA) and islet-cell antibodies (ICA) on beta-cell function, metabolic control and insulin requirements were studied by multivariate analysis of variance (repeated measurements over time) in 90 patients who completed follow-up. DKA had an independent negative effect on residual beta-cell function over time (p = 0.001). ICA-positive patients had lower residual beta-cell function at the end of follow-up (p < 0.05), but overall differences were not significant. DKA and younger age had an independent negative influence on metabolic control (p < 0.05) and insulin requirements (p < 0.001) over time. It is concluded that residual beta-cell function in Type 1 diabetic patients two years after diagnosis was independently influenced by DKA and ICA at diagnosis. Moreover, DKA and age influenced metabolic control and could thus be used to predict those patients with rapidly deteriorating metabolic control who might benefit from a more intensive therapeutic approach.

[The molecular pathology of RET protooncogene in families with multiple endocrine neoplasia type 2A]. / Alteraciones moleculares del protooncogén RET en familias con neoplasia endocrina múltiple tipo 2A.

BACKGROUND: Multiple endocrine neoplasm type 2A (MEN 2A) is an autosomal dominantly inherited disease characterized by medullary thyroid carcinoma, pheochromocytoma and hyperparathyroidism. Mutations have been identified in the extracellular domain of the RET proto-oncogen product (10q11.2) in MEN 2A patients. In each case a single base pair substitution results in replacement of cysteine with another amino acid. Most MEN 2A patients have mutations of codon 634. PATIENTS AND METHODS: Sixty-five unrelated MEN 2A patients from seven families were studied. Polymerase chain reaction, segregation, sequence analysis and restriction enzyme digestion were performed. RESULTS: Of seven families, four had the TGC to TAC transition, two families the TGC to TGG transversion and one family the TGC to CGC transition in codon 634 of RET. CONCLUSIONS: We found all the mutations in codon 634. The characterization of MEN 2A mutations allows early and presymptomatic diagnosis in this syndrome.