Loss of the Y chromosome PAR2 region and additional rearrangements in two familial cases of satellited Y chromosomes: cytogenetic and molecular analysis.

Two cases of rare structural aberrations of the Y chromosome were detected: a del(Y) (q12) chromosome in a child with mild dysmorphic features, obesity and psychomotor delay, and two identical satellited Y chromosomes (Yqs) in a normal twin, which were originally observed during routine prenatal diagnosis. In both cases a Yqs chromosome was detected in the father which had arisen from a reciprocal translocation involving the short arm of chromosome 15 and the heterochromatin of the long arm of the Y chromosome (Yqh). Cytogenetic and molecular studies demonstrated that in the reciprocal product of chromosomes 15 and Y PAR2 could not be detected, showing that PAR2 had been deleted. It is discussed whether the translocation of the short arm of an acrocentric chromosome to the heterochromatin of the long arm of the Y chromosome causes instability of this region which results either in loss of genetic material or interference with the normal mechanism of disjunction.

Genetic screening for individuals at high risk for type 1 diabetes in the general population using HLA Class II alleles as disease markers. A comparison between three European populations with variable rates of disease incidence.

BACKGROUND: To develop screening strategies for identification of individuals at increased genetic risk for type 1 diabetes in three populations with variable disease incidence rates and distinct ethnic origin. METHODS: A stepwise HLA DQB1-DQA1-DRB1-based screening approach was evaluated. Patients with childhood-onset type 1 diabetes were recruited from Finland (n = 1739), Hungary (n = 149), and Greece (n = 119). Consecutive newborns (2568 from Finland and 1047 from Greece) or healthy schoolchildren (n = 177 from Hungary) served as controls. RESULTS: The DQB1*02/0302 genotype conferred the highest disease risk in all populations. The DQB1*02/y (y not equal DQB1*0301,*0302,*0602,*0603, *0604) genotypes were more common and conferred a higher disease risk in the Greek population (OR 4.9) compared to the Finns (OR 1.2). DQB1*0302/x (x not equal DQB1*02, *0301, *0602, *0603, *0604) genotypes were, in contrast, more prevalent among Finnish cases (32.7%) as compared to Hungarians (18.1%) or Greeks (13.5%). The protective DQB1*0602 or *0603 positive genotypes were most common in the Finns, while DQB1*0301 was more common in Hungarians and Greeks. In all groups, DQA1 and DRB1*04 typing considerably increased the sensitivity of the DQB1-based screening. The different high-risk genotype combinations present in about 10% of the background population had a diagnostic sensitivity of 60% in Finland and 80% in Hungary and Greece. CONCLUSIONS: HLA DR-DQ-based screening is a feasible tool for the identification of individuals at increased genetic risk for type 1 diabetes in populations with diverse genetic background. The risk markers should, however, be individually selected for the target population since the screening efficiency of various markers is highly dependent on the ethnic group studied.

Autonomic neuropathy and gastrointestinal motility disorders in children and adolescents with type 1 diabetes mellitus.

INTRODUCTION: There is little information on the gastrointestinal motility abnormalities and autonomic neuropathy of children with gastrointestinal symptoms and type 1 diabetes mellitus (T1DM). METHODS: The authors studied 33 consecutive patients (mean age, 15.3 years; 13 males) with T1DM (median duration, 7.7 years) attending the outpatient clinic because of chronic dyspepsia (CD; n = 14), or chronic constipation (CC; n = 19), and 48 consecutive non-T1DM patients (mean age, 13.7 years; 18 males), who presented with similar symptoms (18 with CD; 30 with CC). Fasting serum motilin concentrations and cardiovascular autonomic function tests (CAFT) were assessed and compared with those of age- and gender-matched healthy control subjects. Gastric emptying half time (GE t1/2) of a solid meal and mouth-to-anus transit time (MATT) were measured in patients with CD and CC, respectively. RESULTS: CAFT was comparable between patients with T1DM and healthy control subjects. GE t1/2 and MATT were not different between T1DM patients and non-T1DM patients with CD and CC, respectively. However, a marginally significant positive correlation was found in the patients with T1DM between GE t1/2 and blood glucose concentrations (R = 0.54; P = 0.08). In addition, serum motilin concentrations were significantly lower in patients with T1DM compared with healthy control subjects (P < 0.0005), and in patients with T1DM and higher serum glucose concentrations compared with those with lower serum glucose concentrations (P = 0.03). CONCLUSION: Autonomic neuropathy is not an etiological factor of gastrointestinal symptoms in children and adolescents with diabetes. Mild or moderate hyperglycemia does not affect gastrointestinal motility.

M-mode echocardiographic evaluation of systolic function, LV volume and mass in children on growth hormone therapy.

Since abnormal endogenous growth hormone (GH) secretion in adults is associated with cardiac dysfunction, it is important to ensure that GH therapy in children and adolescents does not cause similar effects. Forty-two growth hormone-deficient children (Group 1) (19 girls, 23 boys) were evaluated. Six girls and seven boys were prepubertal with a mean age of 6.65 yr (range 4.37-9.73 yr). Twenty-nine were pubertal (13 girls, 16 boys), mean age 13.57 yr (range 10.08-16.76 yr). The patients had been on long-term GH therapy for 34.97 +/- 18.78 months with an average weekly dose of 17.61 IU/m2/wk. The mean height SDS was -2.85 +/- 1.22 for boys and -2.5 +/- 0.64 for girls at the onset of therapy, and at the time of examination -1.8 +/- 1.32 for the boys and 1.87 +/- 0.94 for the girls. Thirty-four normal control subjects (Group 2) matched for age, sex and body size were also studied. Left ventricular volume (LV), mass and systolic function [shortening fraction (FS)] were evaluated by two-dimensional guided M-mode echocardiography. Blood pressure was also measured. No differences in blood pressure were observed between patients and controls. There was no correlation of GH dose and duration of therapy with LV measurements. No significant differences were found between Group 1 and Group 2. These observations suggest that long term administration of GH does not produce adverse cardiac effects in GH deficient children. Nevertheless, longer follow-up studies are still needed to confirm the safety of long-term rhGH treatment.

Ultrasonography of the pancreas, as a function index, in children with beta-thalassemia.

Increased echogenicity of the pancreas, due to hemosiderosis, is a frequent laboratory finding in children and adolescents with beta-thalassemia. The aim of this study was to investigate whether increased echogenicity of the pancreas is associated with dysfunction. The ultrasonic image of the pancreas was examined in 34 children aged 12+/-3.8 years old and was compared to the endocrine and exocrine functioning of the gland. Oral glucose tolerance test (OGTT) was performed with simultaneous measurement of insulin and serum trypsin. Twenty-six of the 34 patients (76.5%) presented increased echogenicity, while 8 (23.5%) had a normal ultrasonic pancreatic image. 77% of the patients with increased echogenicity had abnormal OGTT, 46%, with subnormal or increased insulin values, and 32.5% manifested low levels of trypsin. Among the patients with normal ultrasound, 25% had abnormal OGTT and 37.5% abnormal insulin values. Statistical analysis with Student's t-test revealed that patients with increased echogenicity had significantly higher glucose values on OGTT at 60: 7.6 +/- 1.8 mmol/l (137.3 +/- 33.7 mg/dl) as compared to the patients with normal ultrasound: 6.1 +/- 1.2 mmol/l (110.75 +/- 21.72 mg/dl) (p<0.05). Insulin values were significantly affected at 30, 60, and 90 min: 570+/-301, 332+/-156, 294+/-158 pmol/l (79.54 +/- 42, 46.4 +/- 21.8, 41.04 +/- 22 mU/l) respectively in patients with increased echogenicity in comparison to those with normal ultrasonographic image of the gland: 301 +/- 170, 192 +/- 52, 135 +/- 63 pmol/l (42 +/- 23.7, 26.85 +/- 7.36, 18.9 +/- 8.8 mU/l) (p<0.05). No statistical significance was observed between the two groups regarding trypsin levels, even though abnormal values were observed in more children with increased echogenicity than in patients with a normal ultrasound. The above findings confirm that increased echogenicity of the pancreas is associated with disturbance of its function. This simple imaging method could be used as a rough early index of detection of an increased risk for developing diabetes mellitus in patients with beta-thalassemia.

The Greek contribution to diabetes research.

Interest in diabetes mellitus research has escalated in Greece during the last decade. This may be attributed to the realization that diabetes is becoming a major problem for the Greek population, the effect of the St Vincent Declaration in passing specific government legislation, and the founding of the National Hellenic Center for the Prevention and Treatment of Diabetes and its Complications. Research areas include epidemiology, etiopathogenesis, glucose metabolism, complications, prevention and treatment of the disease.

Serum angiogenin levels in the female from birth to postmenopause.

This study investigated serum angiogenin levels of the potent angiogenic factor angiogenin, during fetal and neonatal life, childhood, adulthood, pregnancy and postmenopause and compared them with respective levels in age-matched males. Serum angiogenin levels were measured by an enzyme immunoassay in 139 healthy male and female subjects, allocated in the above six groups. Multiple linear regression applied (a) for both genders and (b) only for females showed serum angiogenin levels in adults to differ statistically highly significantly from levels in cord blood (P = 0.0001), neonates (P = 0.0001), children (P = 0.0001), and pregnant women (P = 0.01), but not from "elderly" subjects (P = 0.80). A significant difference existed between levels in the proliferative and secretory phase of the menstrual cycle (P = 0.006). Furthermore, a significant trend for serum angiogenin levels with advancing age groups was noted (P = 0.0001). In conclusion, serum angiogenin levels increase significantly from fetal life to adulthood, possibly implying additional biological functions to that of angiogenesis.

Education and certification of genetic counselors.

Genetic counseling is defined by the American Society of Human Genetics as a communication process which deals with the human problems associated with the occurrence, or risk of occurrence, of a genetic disorder in a family. The first graduate program (Master's degree) in genetic counseling started in 1969 at Sarah Lawrence College, NY, USA, while in 1979 the National Society of Genetic Counseling (NSGC) was established. Today, there are 29 programs in U.S.A. offering a Master's degree in Genetic Counseling, five programs in Canada, one in Mexico, one in England and one in S. Africa. Most of these graduate programs offer two year training, consisting of graduate courses, seminars, research and practical training. Emphasis is given in human physiology, biochemistry, clinical genetics, cytogenetics, molecular and biochemical genetics, population genetics and statistics, prenatal diagnosis, teratology and genetic counseling in relation to psychosocial and ethical issues. Certification for eligible candidates is available through the American Board of Medical Genetics (ABMG). Requirements for certification include a master's degree in human genetics, training at sites accredited by the ABMG, documentation of genetic counseling experience, evidence of continuing education and successful completion of a comprehensive ABMG certification examination. As professionals, genetic counselors should maintain expertise, should insure mechanisms for professional advancement and should always maintain the ability to approach their patients.

Serum levels of basic fibroblast growth factor and vascular endothelial growth factor in children and adolescents with type 1 diabetes mellitus.

Diabetes mellitus is characterized by microangiopathy and increased angiogenic response in various organs. Basic fibroblast growth factor (bFGF) as well as vascular endothelial growth factor (VEGF) are both angiogenic and are involved in vascular endothelial cell growth. The purpose of this study was to determine serum levels of bFGF and VEGF, in children and adolescents (youngsters) with type 1 diabetes mellitus, and correlate them with parameters reflecting the severity of the disease. Forty diabetic youngsters without clinical evidence of complications were compared with 30 healthy control subjects (mean age +/- SD, 14.3 +/- 3.6 and 13.8 +/- 3.6 y, respectively). Diabetes duration and metabolic control (expressed by glycosylated Hb) were (mean +/- SD) 6.2 +/- 3.8 y and 9.6 +/- 1.8%, respectively. bFGF and VEGF (pg/mL) were measured in serum samples by enzyme immunoassays, and both were not significantly different between the type 1 diabetes mellitus and the control group (p = 0.952 and p = 0.559, respectively). Restricting the analysis to the type 1 diabetes mellitus group, neither the duration nor the metabolic control of the disease showed any correlation with bFGF and VEGF serum levels, whereas a significantly positive correlation was found between the two examined angiogenic factors both in the diabetic (r = 0.3464, p = 0.025) and the control group (r = 0.4619, p = 0.0013). In conclusion, serum levels of bFGF and VEGF were not found to vary significantly in diabetic youngsters in relation to controls and had no correlation with the duration and metabolic control of the disease. Nevertheless, a positive correlation was found between these two angiogenic factors both in the type 1 diabetes mellitus and the control group.

Serum angiogenin levels in children and adolescents with insulin-dependent diabetes mellitus.

Microangiopathy, one of the most important complications of diabetes mellitus in humans, is associated with increased angiogenic response and proliferative lesions in various organs. Angiogenin, a polypeptide with a molecular size of 14 kD, is a potent inducer of vascular growth. This study aimed at investigating whether serum angiogenin levels are elevated in children and adolescents (youngsters) with insulin-dependent diabetes mellitus and whether angiogenin levels are affected by duration and metabolic control of the disease. It is assumed that angiogenin levels reflect the increased angiogenesis associated with microangiopathy, whether clinically evident or not. Forty diabetic youngsters were compared with 30 healthy control subjects (mean age +/- SD, 14.3 +/- 3.6 y and 13.8 +/- 3.6 y, respectively). The patients' disease duration and glycosylated Hb were (mean +/- SD) 6.2 +/- 3.8 y and 9.6 +/- 1.8%, respectively. Angiogenin (ng/mL) was measured in serum samples by an enzyme immunoassay and was found to be significantly higher (mean +/- SE) in patients (353.3 +/- 20.0) than in control subjects (244.7 +/- 9.6) (p = 0.0002). Levels did not vary with age, but were significantly higher in females compared with male subjects (p = 0.01). In the diabetic youngsters no significant differences were noticed with respect to duration or metabolic control of the disease. In conclusion, serum angiogenin levels were found to be increased among diabetic youngsters, irrespective of the duration and metabolic control of the disease, as well as in female subjects, with or without diabetes.

Growth and growth hormone therapy in children with achondroplasia: a two-year experience.

The efficacy and safety of recombinant human growth hormone (hGH) administration was studied in children with achondroplasia. Fifteen children with achondroplasia, seven boys (4.8-12.2 years of age) and 12 girls (5.7-2.2 years of age), were treated daily with hGH at a dosage of 1 IU/kg/week. Auxological assessments were performed 6 months before, at initiation of, and at 6, 12, and 24 months following initiation of growth hormone (GH) therapy. Before initiating GH therapy, hypothalamic-pituitary and thyroid functions were evaluated. Levels of serum insulin-like growth factor (IGF)-I and IGF binding protein (BP)-3 (IGFBP-3) were assessed, as was GH response to provocative stimuli. GH responses in two stimulation tests were normal for all but three children. During the first semester of GH treatment, a significant increase in height velocity (HV), from 3.2 to 8.3 cm/year, was observed in all children. However, during the second semester, a relative decrease in growth rate was observed. By the end of the first year, HV had increased from 3.2 to 6.9 cm/year (mean, 3.7 cm/year; range, 1.1-8 cm/year) in 13 children and remained unchanged in two children. HV declined progressively during the next 12 months and, by the end of the second year of treatment, had increased in seven of the nine children who had completed 2 years of therapy (mean increase, 3.1 cm/year); two children did not respond to GH therapy, as shown by the lack of increase in HV. Sitting-height (SH) to standing-height ratio % (SH%) remained unchanged throughout GH therapy, and no significant change in skeletal maturation was observed. In conclusion, hGH treatment resulted in an increased growth rate in some children with achondroplasia; however, this increase waned during the second year of treatment. Children with the lowest pretreatment HVs seemed to benefit most from GH therapy. Nonetheless, the usefulness of GH treatment in achondroplasia will be known only when a study of final height is completed.

Effect of growth hormone therapy on bone metabolism of growth hormone deficient children.

UNLABELLED: The effects of human growth hormone (hGH) therapy on biochemical markers of bone metabolism were studied in 17 children (10 boys and 7 girls, aged 3.7-13.1 years old) with idiopathic GH deficiency, before and 1 and 6 months after GH therapy (0.5 0.7 IU/kg weekly SC). Serum levels of calcium, phosphate, alkaline phosphatase osteocalcin, parathyroid hormone, 1,25 dihydroxyvitamin D, insulin-like growth factor I (IGF-I) and renal phosphate per 100 ml glomerular filtrate (TPO4/GFR) were assessed. During therapy with hGH a significant decrease of serum calcium levels and increases of phosphate, osteocalcin, parathyroid hormone 1,25 dihydroxyvitamin D and IGF-I were observed. TPO4/GFR was also significantly increased. Growth response (increment in HV) was positively related with changes in alkaline phosphatase and IGF-I levels after 6 months of hGH therapy. There was also a significant positive correlation between increment in HV and increment in TPO4/GFR after 1 month of GH therapy, whereas no correlation between HV and changes in osteocalcin levels was found. CONCLUSION: GH treatment significantly influences mineral metabolism and the measurement of TPO4/ GFR after 1 month of GH therapy may serve as a useful predictor of growth response to hGH therapy in GH-deficient children.

Arterial blood pressure changes in children and adolescents with insulin-dependent diabetes mellitus.

Diabetic nephropathy may develop in childhood and is often related to hypertension. The 24-hour ambulatory blood pressures were measured in 63 children with insulin-dependent diabetes mellitus and were compared with those of 54 healthy siblings. The patients were without clinical complications. The 24-hour recording of their blood pressures revealed higher 24-hour systolic blood pressure (SBP) (115.8 +/- 8.2), 24-hour diastolic blood pressure (DBP) (67.5 +/- 4.6), 24-hour mean arterial pressure (MAP) (81.8 +/- 5.2) compared with control subjects: 24-hour SBP (112.7 +/- 6.7), 24-hour DBP (64.7 +/- 4.1), 24-hour MAP (78.9 +/- 4.5) (p = 0.03, p = 0.001, p = 0.002, respectively). Of the daytime blood pressures, SBP, DBP, MAP were also higher (117.7 +/- 8.7, 69.7 +/- 5.2, 83.8 +/- 5.8) compared with those of siblings (114.9 +/- 6.9, 67.3 +/- 4.3, 81.1 +/- 4.9) (p = 0.05, p = 0.009, p = 0.008, respectively). Of the nighttime blood pressures, SBP, DBP, MAP were higher in patients (108.7 +/- 8.9, 59.5 +/- 6.9, 74.6 +/- 6.9) compared with control subjects (104.8 +/- 7.0, 55.1 +/- 5.0, 70.5 +/- 5.1) (p = 0.01, p = 0.0002, p = 0.0006, respectively). Furthermore, the blood pressure burden was evaluated. Blood pressure burden was defined as the percentage of the increased blood pressure readings greater than the 95th percentile divided by the total number of recorded blood pressures during a corresponding period. Patients had a 43% higher 24-hour SBP burden (19.6 +/- 16.5) and a 50% higher 24-hour DBP burden (12.3 +/- 9.6) in relation to that of control subjects (13.7 +/- 12.8, 8.3 +/- 12.3) (p = 0.03, p = 0.009, respectively). The SBP burden (17.9 +/- 14.6) and DBP burden (11.5 +/- 9.2) of the day was approximately 50% higher in the patients in the relation to control subjects (11.9 +/- 11.1, 7.8 +/- 6.7) (p = 0.01, p = 0.01, respectively). Therefore it seems that hemodynamic changes may appear early in children with diabetes.

Endothelin 1-21 plasma concentrations in children and adolescents with insulin-dependent diabetes mellitus.

This study is based on the hypothesis that endothelins (ETs), which are 21-amino acid peptides with vasoactive and proliferative properties, could be implicated in the development of complications of insulin dependent diabetes mellitus (IDDM) in children and adolescents. We determined plasma ET 1-21 concentrations by radioimmunoassay in 59 patients with IDDM (32 male, 27 female) and in 41 healthy siblings (20 male, 21 female) and investigated the association of ET 1-21 concentrations with age, sex, control of diabetes (expressed as % of glycosylated hemoglobin), duration of disease and presence of complications. Plasma ET 1-21 concentrations (mean +/- SEM) were 14.12 +/- 0.30 pg/ml in IDDM and 15.34 +/- 0.47 pg/ml in healthy siblings. The difference was statistically significant (p = 0.01) after controlling for age and sex by multiple logistic regression. In the group with IDDM, analysis of covariance showed duration of disease to be the only variable associated with ET 1-21 values (b = 0.2179 pg/ml/yr, p = 0.04). It is concluded that in youngsters with IDDM ET plasma concentrations are lower than in healthy controls, negatively associated with duration of the disease and not directly implicated in diabetic angiopathy.