Monogenic and polygenic models detected in steroid 21-hydroxylase deficiency-related paediatric hyperandrogenism.

AIMS: Hyperandrogenism, although mostly due to polygenic interactions, is monogenic for some enzymatic adrenal deficiencies. This study evaluates mono- and biallelic 21-hydroxylase deficiency (21OHD)-related hyperandrogenism in pediatric patients. Sensitizing and protective polymorphisms were investigated in carriers and cryptic forms of 21OHD. METHODS: The study involved a monogenic analysis of CYP21A2 in patients (375 nonclassical 21OHD [NC21OHD] children; 306 hyperandrogenic 21OHD carriers, n = 306) and a polygenic association study (CAPN10-UCSNP44, PON1-108, TNFR2-M196R, IGF2-ApaI and IRS1-G972R polymorphisms) of 170 hyperandrogenic carriers plus 277 family members (control groups). The metabolic marker 17OH progesterone defined the degree of deficiency; clinical expressivity was determined by pediatric endocrinologists. RESULTS: The group of 21OHD carriers manifesting hyperandrogenism was enriched in the CAPN-UCSNP44 rare variant in homozygosity (4.9 vs. 0.4%, NCBI data for the general population; p = 0.004). In our patients and controls, contrasting distributions were observed for this and another polymorphism, TNFR2-196R. In a recessive model, their rare variants were more frequently detected among the forms with high (p = 0.048) and low (p = 0.034) expressivity respectively. CONCLUSIONS: 21OHD-related pediatric hyperandrogenism follows monogenic and polygenic models. The opposite behaviors in terms of clinical expressivity detected for CAPN-UCSNP44 and TNFR2-M196R rare variants suggest these variants to be sensitizing and protective factors respectively in adrenal hyperandrogenism.

The majority of cases of neonatal diabetes in Spain can be explained by known genetic abnormalities.

BACKGROUND: Neonatal diabetes is a rare disease characterized by hyperglycaemia within the first 3 months of life and requiring insulin treatment; it can either be transient (TNDM) or permanent (PNDM). Alterations at band 6q24 and heterozygous activating mutations in KCNJ11, the gene encoding the pore-forming subunit of the KATP channel, can cause neonatal diabetes. Aims We screened the 6q24 region, KCNJ11, GCK, FOXP3 and IPF1 genes for mutations in families with PNDM or TNDM to establish a phenotype-genotype correlation. METHODS: Twenty-two patients with neonatal diabetes were recruited. Inclusion criteria were insulin-treated diabetes diagnosed within the first 3 months and insulin treatment for at least 15 days. Clinical data were recorded in a questionnaire. RESULTS: We identified 17 genetic alterations in our patients: six alterations at the 6q24 band associated with TNDM and nine mutations in KCNJ11, five of which were novel. The analysis for a phenotype-genotype correlation showed that patients with 6q24 alterations had a lower birth weight and were diagnosed earlier than patients with KCNJ11 mutations. At follow-up of the TNDM patients with genetic alterations, 43% developed diabetes or impaired glucose tolerance in later life (one with 6q24 duplication and two with N48D and E227K mutations at KCNJ11 gene). Furthermore, half the first-degree relatives who carried a genetic alteration but who had not suffered from neonatal diabetes were diagnosed with diabetes or impaired glucose tolerance before the age of 30 years. CONCLUSIONS: KCNJ11 mutations are common in both TNDM and PNDM and are associated with a higher birth weight compared with patients with 6q24 abnormalities. Patients with TNDM should be screened for abnormalities in glucose metabolism in adult life.

Gene duplications in 21-hydroxylase deficiency: the importance of accurate molecular diagnosis in carrier detection and prenatal diagnosis.

BACKGROUND: The detection of 21-OH deficiency (21OHD) carriers in the general population requires that misinterpretations of apparently severe mutations in alleles carrying duplicated genes be avoided. Prenatal treatment prevents virilization in female fetuses and genetic counseling may be offered to couples in which one partner is either a patient or a carrier. This paper proposes a semiquantitative PCR method involving primer extension that distinguishes the severe point mutation Q318X in single gene copy alleles from the normal/nondeficient variant in gene-duplicated alleles. SAMPLES AND METHODS: DNA from 65 individuals carrying Q318X variants, that of 85 partners of 21OHD carriers or patients, and one fetal sample (as well as the DNA of his family) were analyzed. 21OHD alleles were studied by gene-specific PCR/allele-specific oligonucleotides hybridization for common mutations, Southern analysis, complementary direct sequencing and microsatellite typing. Primer extension analysis of the Q318X variants using fluorescent dideoxynucleotides was performed on CYP21A2 gene-specific PCR-amplified DNA samples from controls, patients, potential carriers and prenatal samples. RESULTS: Different fluorescence patterns were seen for the severe mutation (single gene copy) and the nondeficient (gene-duplicated) alleles carrying Q318X. The normal/mutant fluorescence peak (N/M) ratio was < 1 in all heterozygous carriers (mean 0.83; min. 0.70; max. 0.95). In all normal individuals carrying the gene-duplicated Q318X normal variant, the N/M ratio was > 1 (mean 1.69; min. 1.44; max. 2.02). CONCLUSION: The proposed method discriminated between the severe Q318X mutation and the normal Q318X variant in gene duplication, and could be a useful complementary tool in prenatal diagnosis and carrier detection.

Aspectos epidemiológicos de la diabetes mellitus tipo 1 / Epidemiological features of type1 diabetes mellitus

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[Low sensitivity of IGF-I, IGFBP-3 and urinary GH in the diagnosis of growth hormone insufficiency in slowly-growing short-statured boys. Grupo Español de Estudio de la Talla Baja]. / Baja sensibilidad del IGF-I, la IGFBP-3 y la GH urinaria en el diagnóstico de la insuficiencia de la hormona del crecimiento en niños y adolescentes varones con talla baja y velocidad de crecimiento disminuida.

BACKGROUND: The usefulness of IGF-I, IGFBP-3, and the urinary GH excretion in the diagnostic evaluation of growth retardation in boys with short stature was studied. SUBJECTS AND METHOD: Serum samples from two GH-stimulation tests and two 24-h urine samples were sent to a Central Laboratory to measure serum and urinary GH, serum IGF-I, IGFBP-3 and GHBP, both in absolute and standardized values (Z-score). Short children were classified as growth hormone deficient (GHD) (n = 25), and idiopathic short statured (ISS) (n = 54), on the basis of the peak stimulated GH concentration of < 7.5 microg/l or > or = 7.5 microg/l respectively. A group of 15 normally growing children and adolescents was also included. RESULTS: Height-velocity standard deviation score (HV)-SDS was lower and body mass index higher in GHD than ISS. Standardized IGF-I differed significantly by ANOVA among the three groups (p = 0.001). Multiple stepwise linear regression analysis with HV-SDS as dependent variable showed IGF-I SDS as the best predictor followed by peak GH clonidine response and uGH excretion. ROC curves showed optimum cut-off level for IGF-I SDS as 2.05 (sensitivity: 32%, specificity: 90%) and 1.14 for IGFBP-3 SDS sensitivity: 28%, specificity: 94%). CONCLUSIONS: Standardized IGF-I and IGFBP-3 measurements were highly efficient only in diagnosis of severe GHD, but they show low sensitivity for the diagnosis of isolated idiopathic GHD as defined according to the low GH response to stimulation tests.

Diabetes tipo 1 en el niño menor de 5 años

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HLA class II immunogenetics and incidence of insulin-dependent diabetes mellitus in the population of Cantabria (Northern Spain).

HLA class II genes were analyzed to study IDDM susceptibility in Cantabria (Northern Spain). Patients showed highly significant increases in DRB1*0301 (RR = 4.581, p < 0.00005), DRB1*0401 (RR = 2.6, p < 0.05), DRB1*0402 (RR = 8.78, p < 0.05) and DRB1*0405 (RR = 14.73, p < 0.005). Highly significant diferences were in the DQA1*0301 (RR = 3.62, p < 0.000005) and DQA1*0501 (RR = 2.13, p < 0.05) alleles. DQB*0201 (RR = 4.1, p < 0.00005) and DQB1*0302 (RR = 5.42, p < 0.000005) alleles were also significantly increased. A significant increase in DRB1*0402-DQA1*0301-DQB1*0302 (RR = 16.18, p < 0.05), DRB1*0405-DQA1*0301-DQB1*0302 (RR = 16.12, p < 0.05), DRB1*0301-DQA1*0501-DQB1*0201 (RR = 4.58, p < 0.00005) and DRB1*0401-DQA1*0301-DQB1*0302 (RR = 4.36, p < 0.005) was apparent in the diabetic group, while the DRB1*1501-DQA1*0102-DQB1*0602 and DRB1*1401-DQA *0104-DQB1*05031 protective haplotypes (RR = 0.17 and 0.09, p < 0.0005 and 0.05, respectively) were significantly lower in patients. The absence of Asp57 and the presence of Arg52 were associated with disease in a dose-dependent manner. Several genotypes encoding the identical DQalpha52/DQbeta57 phenotype carried very different RRs. Finally, the Cantabrian population has the highest incidence of IDDM reported for Spain (15.2 of 100.000 in the 0-14 age group, Poisson's 95% CI: 10.6-19.3).

Vitamin D status in children with Down's syndrome.

The serum levels of the active Vitamin D metabolites 25-hydroxyvitamin D[25(OH)D], 1,25-dihydroxyvitamin D[1,25(OH)2D] and 24,25 dihydroxyvitamin D [24,25(OH)2D], were studied in 21 children with Down's syndrome (DS) in Cantabria, a northern region of Spain, located at 44 degrees N latitude. Serum calcium, magnesium, phosphate, alkaline phosphatase, parathormone and osteocalcine were also determined. In the DS group, the average values of the three Vitamin D metabolites were comparable to those of an age-matched group both in winter and summer times. No child with DS showed values below the normal range, either in Vitamin D metabolites, or in the other parameters of calcium metabolism. The normal increment of 25(OH)D and 24,25(OH)2 values from March to October was not observed in five children. This anomaly was corrected in three, after adequate rules of sun exposure during summer time were followed. In the other two, the 25(OH)D levels were high throughout the study. This investigation shows that children with DS do not require Vitamin D prescription when appropriate periods of sunlight exposure are provided.

[Neurological symptoms precipitated by loperamide (author's transl)]. / Síntomas neurológicos secundarios al tratamiento con loperamida en la infancia.

Three children with neurological symptoms precipitated by loperamide are presented, one of them with irreversible sequelae. The use of this drug in infancy is discouraged in view of these secondary effects.

[Diabetic ketoacidosis: results with two different patterns of insulin administration (author's transl)]. / Cetoacidosis diabética: resultados con dos pautas distintas de terapéutica insulinica.

The response to insulin treatment in 15 children with diabetic ketoacidosis is studied. Insulin continous infusion was administered to nine patients. The other six patients received insulin subcutaneously except one half of the first dose injected by vein as a bolus. Both patterns of insulin administration proved to be equally effective. Anyway the insulin continuous infusion appears as a simple and easier method for a good general control and to prevent hypoglycemic episodes. To prevent a hyperglycemic rebound it is suggested that a dose of subcutaneous insulin must be injected immediately after the insulin infusion is discontinued. A discordance between hyperglycemia correction and the degree of acidosis has been noticed in some patients; this can be corrected decreasing insulin infusion rate.

[Stimulation of growth hormone (HGH) secretion by physical exercise (author's transl)]. / Estimulación de la secreción de hormona de crecimiento (HGH) por medio del ejercicio físico.

Authors study forty eight children with severe lineal growth retardation. The more frequent causes of a stunted growth were ruled out previously (systemic and chronic diseases, metabolic disorders, genetic alterations, etc.). As a screening test, physical exercise was used to detect growth hormone (HGH) deficiency. A normal response was considered when HGH levels rose more than 7,0 ng./ml. after 20 minutes of continuous exercise. In those cases in which this level was not attained. insulin-hypoglycemia alone and followed by insulin plus an arginine infusion were used as stimuli, to confirm the lack of HGH response. A correct response to the exercise was found in 81% of the cases. It is concluded that the physical exercise as HGH stimulus is a good screening test. It presents a high degree of confidence with some other qualities, mainly: little disturbances to the patients, a rapid performance, lack of unpleasant colateral effects, and the possibility that it can be carried out by sanitary non-medical personnel.

[Infantile cushing's disease with paradoxical response to dexamethasona due to a probable periodic hormogenesis (author's transl)]. / Enfermedad de Cushing infantil con respuesta paradójica a la dexametasona por probable hormogénesis periódica.

A case of Cushing's disease in a ten year old girl with bilateral diffuse hyperplasia of the adrenal cortex and postoperative enlargment of the sella turcica is presented. The administration of dexamethasone elicited a paradoxical response with a clear elevation of the already high excretion of 17-hydroxycorticoids. The possible mechanisms for this previously described, but infrequent, response to dexamethasone are discussed. It is concluded that: 1) Interpretation of the classical dexamethasone suppression test can occasionally be misleading; and 2) Periodic hormonogenesis may account for this type of paradoxical response.