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BACKGROUND AND PURPOSE: Patients with LS have an inborn growth hormone resistance, resulting in failure to generate IGF-1. The purpose of this study was to evaluate the size of the eye and orbit in LS. MATERIALS AND METHODS: We retrospectively reviewed the MR imaging of the brain in 9 patients with LS for the following parameters: axial diameter of the globe, interzygomatic distance, perpendicular distance from the interzygomatic line to margins of the globe, medial-to-lateral diameter of the orbit at the anterior orbital rim, distance from the anterior orbital rim to the anterior globe, maximal distance between the medial walls of the orbits, lateral orbital wall angle, lateral orbital wall length, and mediolateral thickness of the intraorbital fat in the most cranial image of the orbit. All measurements were made bilaterally. Twenty patients referred for MR imaging for unrelated reasons served as control subjects. RESULTS: Compared with the control group, the patients with LS had a significantly smaller maximal globe diameter and shallower but wider orbits due to a shorter lateral wall, a smaller medial distance between the orbits, and a larger angle of the orbit. The ratio between the most anterior orbital diameter and the globe was greater than that in controls. The position of the globe was more anterior in relation to the interzygomatic line. CONCLUSIONS: Shallow and wide orbits and small globes relative to orbital size are seen in LS and may be secondary to IGF-1 deficiency.

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UNLABELLED: We have previously reported on the linear growth, growth of the head circumference and foot length in untreated and IGF-I treated patients with Laron syndrome (LS) (primary GH insensitivity). AIM: To assess the size and growth of the hands in patients with LS from early childhood to adult age. PATIENTS: Ten IGF-I treated children with LS (4 M, 6 F) and 24 untreated patients (10 M, 14 F) were studied. METHODS: Measurements of palm length were made on available standardized hand X-rays from infancy to adult age. The measurements were compared to normal references and SD values were calculated for each measurement. The growth of the hand was compared to the concomitant height of the body. RESULTS: Hand SDS in untreated patients with LS decreased with age, from a mean of -2.8 +/- 0.7 (age 1-3 years) to -7.3 +/- 0.8 (age 13-15 years) and to -9.0 +/- 3.9 (age 40-50 years). During 9 years of IGF-I treatment the hand size deficit SDS did not improve in contradistinction to the height SDS which decreased from -6.2 +/- 1.2 to -3.9 +/- 0.5. CONCLUSION: Congenital IGF-I deficiency, as in Laron syndrome, profoundly affects the size and growth of the hand as part of its growth retardation characteristics, resulting in acromicria.

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OBJECTIVE: To establish the prevalence of insulin resistance and impaired glucose tolerance (IGT) and their determinants in a cohort of obese children and adolescents. METHODS: A retrospective design was used. The study group included 234 patients with a body mass index (BMI) greater than the 95th percentile for age and gender and 22 patients with a BMI between the 85th and 95th percentile for age and gender referred for evaluation to a major tertiary-care center in Israel. Ages ranged from 5 to 22 y. Estimates of insulin resistance (homeostatic model assessment (HOMA-IR)); insulin sensitivity (ratio of fasting glucose (GF) to fasting insulin (IF) (GF/IF), the quantitative insulin sensitivity check index (QUICKI)), and pancreatic beta-cell function (HOMA-derived beta-cell function (HOMA %B)) were derived from fasting measurements. An oral glucose tolerance test (OGTT) was performed in 192 patients to determine the presence of IGT. RESULTS: Insulin resistance was detected in 81.2% of the patients, IGT in 13.5%, and silent diabetes in one adolescent girl. Only two patients with IGT also had impaired fasting glucose (IFG). The prevalence of IGT was higher in adolescents than prepubertal children (14.7 vs 8.6%). GF/IF and QUICKI decreased significantly during puberty (P<0.005), whereas HOMA-IR and HOMA %B did not. Insulin resistance and insulin sensitivity indexes were not associated with ethnicity, presence of acanthosis nigricans or family history of type 2 diabetes. Patients with obesity complications had lower insulin sensitivity indexes than those without (P=0.05). Compared with subjects with normal glucose tolerance (NGT), patients with IGT had significantly higher fasting blood glucose (85.9+/-6.5 vs 89.2+/-10.6 mg/dl, P<0.05), higher 2-h post-OGGT insulin levels (101.2+/-74.0 vs 207.6+/-129.7 microU/ml, P<0.001), a lower QUICKI (0.323+/-0.031 vs 0.309+/-0.022, P<0.05), and higher fasting triglyceride levels (117.4+/-53.1 vs 156.9+/-68.9, P=0.002). However, several of the fasting indexes except QUICKI failed to predict IGT. There was no difference between the group with IGT and the group with NGT in fasting insulin, HOMA-IR, HOMA %B or the male-to-female ratio, age, BMI-SDS, presence of acanthosis nigricans, ethnicity, and family history of type 2 diabetes. CONCLUSIONS: Insulin resistance is highly prevalent in obese children and adolescents. The onset of IGT is associated with the development of severe hyperinsulinemia as there are no predictive cutpoint values of insulin resistance or insulin sensitivity indexes for IGT, and neither fasting blood glucose nor insulin levels nor HOMA-IR or HOMA %B are effective screening tools; an OGTT is required in all subjects at high risk. Longitudinal studies are needed to identify the metabolic precursors and the natural history of the development of type 2 diabetes in these patients.

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OBJECTIVE: To assess whether overweight children and adolescents, who often have poor dietary habits, are at increased risk of iron deficiency (ID). METHODS: The study sample included 321 children and adolescents followed in two endocrine centers in Israel between 1999 and 2001. The subjects were divided into three groups on the basis of body mass index (BMI) for age and gender as follows: group 1-BMI below 85th percentile (normal weight); group 2-BMI above 85th, but below 97th percentile (overweight); and group 3-BMI above 97th percentile (obese). ID was defined as iron levels <8 micromol/l (45 mcg/dl), and iron-deficiency anemia (IDA) was defined as ID and hemoglobin level below 2 standard deviation score (SDS) for the mean for age and gender. RESULTS: Iron levels below 8 micromol/l (45 mcg/dl) were noted in 38.8% of the obese children and 12.1% of the overweight children, compared with 4.4% of the normal-weight group (P<0.001). There was a significant negative correlation of low iron levels with BMI SDS (r=-0.44, P<0.001), but not with age or gender. Among the children with ID, 26.6% also had IDA. Groups 1, 2, and 3 accounted for 6.7%, 35%, and 58.3% of the children with IDA, respectively. CONCLUSIONS: ID is common in overweight and obese children. A significantly greater proportion of obese than normal-weight children have IDA. Insufficient dietary intake of iron, whether absolute or relative to body mass, and increased iron needs may be a result of unbalanced nutrition or repeated short-term restrictive diets. Because of potentially harmful effects of ID, obese children should be routinely screened and treated as necessary.

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OBJECTIVE: To evaluate whether genotype differences can explain the clinical variability of non-classical steroid 21-hydroxylase deficiency (NC21-OHD) and to determine if genotype is related to ethnic origin. DESIGN: Genotyping for mutations in the steroid 21-hydroxylase (CYP21) gene was performed in 45 unrelated Israeli Jewish patients (nine males) with NC21-OHD (60min 17-hydroxyprogesterone (17-OHP), 45-386nmol/l) who were referred for evaluation of postnatal virilization or true precocious/early puberty. Eleven siblings diagnosed through family screening were genotyped as well. METHODS: Patients were divided by genotype into three groups: (A) homozygous or compound heterozygous for the mild mutations (V281L or P30L) (n=29; eight males); (B) compound heterozygous for one mild and one severe mutation (Q318X, I2 splice, I172N) (n=12; no males); (C) mild mutation detected on one allele only (n=4; one male; peak 17-OHP 58-151nmol/l). We then related the genotype to the ethnic origin, clinical phenotype and hormone level. Since group C was very small, comparisons were made between groups A and B only. RESULTS: At diagnosis, group B tended to be younger (5. 8+/-3.0 vs 8.1+/-4.3 years, P=0.09), had greater height SDS adjusted for mid-parental height SDS (1.6+/-1.1 vs 0.7+/-1.4, P=0.034), tended to have more advanced bone age SDS (2.9+/-1.5 vs 1.7+/-2.1, P=0.10) and had a higher peak 17-OHP level in response to ACTH stimulation (226+/-92 vs 126+/-62nmol/l, P<0.01). Group B also had pubarche and gonadarche at an earlier age (5.1+/-2.4 vs 7.4+/-2.2 years, P<0.01 and 7.4+/-1.8 vs 9.9+/-1.4 years, P<0.001, respectively) and a higher rate of precocious puberty (50 vs 17%, P=0.04). Stepwise logistic regression analysis (excluding males) yielded age at gonadarche as the most significant variable differentiating the two groups, with a positive predictive value of 86% for a cut-off of 7.5 years. CONCLUSIONS: The findings suggest that genotype might explain some of the variability in the phenotypic expression of NC21-OHD. Compound heterozygotes for one mild and one severe mutation have a higher peak 17-OHP associated with pubarche and gonadarche at an earlier age and more frequent precocious puberty. Hence, the severity of the enzymatic defect might determine the timing and pattern of puberty.

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Fifteen patients with primary GH resistance (Laron syndrome, LS) were studied before and during 6 months of daily replacement treatment with IGF-I. The main findings were that patients with LS and normal or high serum GH binding protein (GHBP) were less obese than those with a negative GHBP, and that serum leptin levels varied with body mass as in other types of obesity.

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Forty-six prepubertal children with idiopathic short stature (ISS), 39 boys and 7 girls, with a mean age of 7.4 +/- 1.8 (SD) years, and mean bone age of 4.5 +/- 1.5 years were treated by human growth hormone (GH) 0.1 U/kg/day s.c. for 30.5 +/- 16.2 months (M +/- SD) (2-5 years range) and were followed for 1-2 years after stopping GH. The mean net gain in height at the end of treatment was 1.03 +/- 0.6 SDS and the bone age SDS was accelerated by 0.95 +/- 1.05. Despite a transitory "catch-down" in growth velocity after stopping GH administration, there was a mean height gain at the end of 2 years follow-up of 0.87 SDS. Children who started treatment before age 6.5 benefited more than older ones. In conclusion, the gain in height observed in children with ISS by GH treatment was maintained during 2 years of follow-up after interruption of treatment. Even if this benefit is transitory and not permanent, it may help short children to achieve self-confidence and raise their physical performance at the critical period of school entry.

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Diabetic nephropathy in Jewish insulin-dependent diabetes mellitus (IDDM) patients has been found to correlate to their ethnic origin. It has also been found that increased sodium-lithium countertransport (SLC) in erythrocytes, as a genetic marker for essential hypertension, may identify those patients at risk for diabetic nephropathy. The purpose of this study was to investigate a possible correlation between this genetic marker and the ethnic origin of Jewish IDDM patients and their parents and the risk for developing diabetic nephropathy. Although SLC was slightly increased in IDDM patients with microalbuminuria, SLC was not correlated with the existence of diabetic nephropathy nor with the ethnic origin and blood pressure of these Jewish IDDM patients. Thus, other genetic factors may play a role in the different prevalence of diabetic nephropathy in Jewish IDDM patients of different ethnic origin.

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In the framework of an epidemiologic study we collected data on all the 162 patients with achalasia in central Israel. The mean (+/- SD) follow-up was 9.9 +/- 8.7 years (range 1-52). At the last, as compared to the initial examination, the clinical condition of the patients had improved: 38% were without dysphagia as compared to 0% initially, 67% did not vomit and 92% did not complain of aspiration as compared to 17% and 68% initially, and 67% did not complain of chest pain as against 36% initially. In contrast, X-ray examinations, endoscopy as well as manometry did not show major changes. Esophageal retention of a semisolid radiolabeled meal 10 min after ingestion was 46 +/- 25% initially and 34 +/- 26% at last examination (NS). Medical therapy was given to 99 patients and a beneficial response was initially noted in 65% of them. About 88.7% had a beneficial response to surgery and 82.7% to pneumatic dilatations which were associated with a 7.3% perforation rate. Overall the clinical course of this unselected, regional group of patients was better than expected.

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The epidemiology of achalasia was studied in a predominantly urban, Jewish population of approximately 1.3 million, in central Israel, during the years 1973-1983. One hundred sixty-two proven cases were collected, representing all known patients with achalasia in the study area. There were no gender differences. The majority of cases were diagnosed within two years of onset of symptoms, although the median delay in diagnosis was 4.4 +/- 5.3 years. The disease was rare in the first two decades of life. The prevalence (in 1983) in the first two decades was 0.7/10(5) rising to 36.2/10(5) above age 70. The mean annual incidence in the years 1973-1978 was 0.8/10(5). It rose slightly to a mean annual incidence of 1.1/10(5) in the years 1979-1983. The prevalence of the disease in 1973 and 1983 was 7.9/10(5) and 12.6/10(5), respectively. The age-adjusted prevalence in 1973 was higher in Asian and African born Jews as compared to those born in Europe, America, or Israel. This difference disappeared by the year 1983. No case of cancer of the esophagus was found among our patients. This may be due to the nonselected, regional nature of our series or to the effects of earlier therapy of achalasia in recent decades.

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Growth curves for children with Laron syndrome were constructed on the basis of repeated measurements made throughout infancy, childhood, and puberty in 24 (10 boys, 14 girls) of the 41 patients with this syndrome investigated in our clinic. Growth retardation was already noted at birth, the birth length ranging from 42 to 46 cm in the 12/20 available measurements. The postnatal growth curves deviated sharply from the normal from infancy on. Both sexes showed no clear pubertal spurt. Girls completed their growth between the age of 16-19 years to a final mean (SD) height of 119 (8.5) cm whereas the boys continued growing beyond the age of 20 years, achieving a final height of 124 (8.5) cm. At all ages the upper to lower body segment ratio was more than 2 SD above the normal mean. These growth curves constitute a model not only for primary, hereditary insulin-like growth factor-I (IGF-I) deficiency (Laron syndrome) but also for untreated secondary IGF-I deficiencies such as growth hormone gene deletion and idiopathic congenital isolated growth hormone deficiency. They should also be useful in the follow up of children with Laron syndrome treated with biosynthetic recombinant IGF-I.

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To evaluate the prevalence of hepatitis B virus (HBV) and hepatitis D virus (HDV) infection among intravenous drug addicts (IVDA) in Israel, serum samples were collected from 400 asymptomatic individuals attending a methadone clinic in Tel Aviv. Overall 5.5% were HBsAg positive, 2.4% HBeAg positive, 52% anti-HBc positive and 6.6% were positive for anti-HD. Anti-HD was identified in 18% of addicts who were HBsAg positive and in 3% who were HBsAg negative and anti-HBc positive. Strong correlation was found between positivity to HBV antibodies and age and duration of drug use. History of jaundice correlated more strongly with anti-HD positivity than with presence of antibodies to HBV. We conclude that Israeli IVDA are less exposed to HBV and HDV infection than their North American and European counterparts.

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Seventy-one ventilated very-low-birth-weight infants (birth weight, 500 to 1250 g) with (n = 30) and without (n = 41) bronchopulmonary dysplasia were studied to compare their growth achievements and to determine the association between neurodevelopmental outcome, growth, and nutrition. Growth delay was observed in both groups. No association was found between head circumference and percent weight loss, age to full gavage feeds, age to regain birth weight and energy intake at 2 and 4 weeks of life. Fifty percent of infants with bronchopulmonary dysplasia and 37% of the control group had minor and major handicap. Mean duration of assisted ventilation was significantly longer in handicapped infants (21.5 vs 12.5 days; F = 6.49; df = 1,53). No association was found between abnormal neurodevelopmental outcome and weight, length, and head circumference at 12 and 21 months after term. Although mean energy intake per kilogram per day at 2 weeks of life was significantly lower in handicapped infants (344.82 vs 412.86 kJ; F = 7.6; df = 1,53), age to regain birth weight, age to full feeds, percent weight loss, and energy intake at 4, 6, and 8 weeks of life did not differ significantly between normal and handicapped infants. Aggressive nutritional support to promote growth in ventilated very-low-birth-weight infants may not influence the neurodevelopmental outcome.

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The epidemiology of ulcerative colitis (UC) was studied in the Jewish population of central Israel in a densely populated urban area of more than 1,400,000 inhabitants. The mean annual incidence for the years 1970-80 was 3.86/100,000, 3.94 in males, and 3.79 in females. The incidence rose from 2.67 in 1970 to 5.09 in 1979, the rise being similar in both sexes. This rise in incidence was found in 3 separate localities in the study area inhabited by communities of different extraction and age composition. The disease started most frequently between the ages of 25 and 29. The crude prevalence of UC in 1980 was 55.2/100,000. The age-adjusted prevalence in Israel-born Jews was 45.8, in Asia-Africa-born 48.5 and in Europe-America-born 52.7/100,000. Compared with our previous study in 1960-70 in the city of Tel Aviv-Yafo, the prevalence of UC was increased and the differences between the community groups have narrowed. This suggests an effect of environmental factors in the causation of ulcerative colitis.

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A population study of Crohn's disease (CD) during the years 1970-1980 was performed in a defined area in central Israel with 1,400,000 inhabitants. Three hundred and sixty-five patients with definite CD were identified, and a complete follow-up was obtained with particular attention to intestinal cancer. The mean follow-up time was 9.95 years (range, 1-49 years). Forty-four per cent of the patients were operated on, but only a few had total colectomy or bypass operations. Only one patient developed colorectal cancer after 7 years of disease. The observed to expected ratio for this cancer was 1.14 at 10 years of disease and 0.73 at 20 years of disease. The incidence of colorectal cancer was not significantly different from the expected in the population. None of the patients developed small-bowel cancer. At least five patients had extraintestinal malignancies. A review of the literature showed conflicting results with regard to cancer risk in CD. The risk was not significantly increased in the two existing population studies, including the present one.

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The epidemiology of Crohn's disease (CD) during the years 1970-80 was studied in the Jewish population in a defined area of central Israel with 1.4 million inhabitants. Three hundred sixty-five patients with definite CD were identified, and a complete follow-up was obtained. The incidence of CD rose from 0.33 (per 10(5)) in 1970 to 3.10 in 1979. This rise was noted in both sexes, in all age groups, in all major Jewish community groups, and was demonstrated in three different regions of the study area. It is thought to represent a true (10-fold) increase in incidence. The mean annual incidence was 1.55/10(5). The prevalence in 1970 was 7.08/10(5), and in 1980 it was 19.47/10(5). In 1970, the age-adjusted prevalence in immigrants from Europe-America was 13.27 and in immigrants from Asia-Africa it was 1.69. In 1980, the difference between the two groups narrowed and the prevalences were 26.05 and 12.37, respectively. This decrease in differences between original migrant groups, as well as the rapid changes in incidence, point to the effect of environmental factors in the pathogenesis of CD. Population studies worldwide have demonstrated an increased incidence of CD in Jews, with marked differences among Jews in different geographic areas. This suggests the coexistence of genetic and environmental factors in the pathogenesis of the disease.

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Insulin-like growth factor I levels were measured in a parallel fashion in 77 extracted sera using the INCSTAR RIA (radioimmunoassay) and in the EDTA plasma of the same subjects by the NICHOLS RIA. The subjects suffered from untreated hGH deficiency, short stature, delayed and precocious puberty and acromegaly. Significant differences (P less than 0.05) were found between the mean IGF-I levels of all groups using both RIA systems. However, using the INCSTAR RIA, 85% of IGF-I values in untreated hGH deficiency were below normal, and a rise in IGF-I detected in the sera of all 5 patients who were treated with hGH. Using NICHOLS RIA, 55% of basal IGF-I values were below normal and a hGH-stimulated rise in IGF-I was found in only two of the treated patients. The INCSTAR RIA seems more precise and reproducible than the NICHOLS RIA and enables better discrimination of hGH-deficient patients from age-matched controls.

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The incidence of colorectal cancer was studied in an unselected group of 1035 patients (total group) with ulcerative colitis and in a subgroup of 822 who resided, at the time of diagnosis, within a defined area in central Israel (regional group). The operation rate was 5.2% and the follow-up period (mean +/- SD) was 11.5 +/- 8.3 yr, range 1-52 yr. The cumulative incidence of colorectal cancer in all patients was 0.2% at 10 yr, 2.8% at 15 yr, 5.5% at 20 yr, and 13.5% at 30 yr. The ratio of observed to expected cancer was 0.9 at 10 yr, 5.0 at 20 yr, and 6.4 at 30 yr. The cancer incidence was 1 case per 3895 patient-years in the first decade of disease, 1 case per 198 patient-years in the second decade, and 1 case per 100 patient-years in the third decade. All these figures were higher in patients with total colonic involvement. There were no significant differences between the total and regional patient groups. Onset of ulcerative colitis in the first and second decade of life was not associated with a higher cancer incidence when standardized for extent and duration of disease. The risk of colorectal cancer in patients with ulcerative colitis was more strongly expressed in population groups with a lower incidence of this cancer. The cumulative incidence of colorectal cancer in ulcerative colitis is much lower in population-based studies than that reported from major medical centers. Worldwide this incidence may also vary among different populations.

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This international case control study was conducted in 14 centers in 9 countries to investigate factors in childhood which may have a bearing on the etiology or pathogenesis of ulcerative colitis (UC) and Crohn's disease (CD). 197 patients with UC and 302 with CD (499 with inflammatory bowel disease (IBD] whose disease started before age 20 years and whose age at time of study was less than 25 years were investigated, with two age- and sex-matched controls for each patient. All subjects were studied with uniform questionnaires. Eczema was found significantly more frequently in patients with CD (p less than 0.005) and in their fathers (p less than 0.025), mothers (p less than 0.002), and siblings (p less than 0.01) as compared with their respective controls. IBD was significantly more frequent in parents, siblings, cousins, grandparents, and uncles of patients than in their respective controls. The fathers of patients with UC had significantly more major gastrointestinal and cardiovascular diseases at the time of the patient's birth than the fathers of controls. In North America mothers of patients with UC and CD took vitamin, mineral, and iron preparations during pregnancy significantly less frequently than mothers of controls. Patients with CD and UC consumed a lower residue diet than controls. Recurrent respiratory infections were more frequent in patients with UC and CD (p less than 0.001); it is uncertain whether this preceded disease. Hospitalization for respiratory diseases was more frequent in patients than controls, and the use of antibiotics more frequent in patients with CD. Smallpox vaccination was less frequent (p less than 0.05) in patients with CD, and chickenpox infection was less common in patients with UC (p less than 0.01). No significant differences were found between patients and controls in relation to various human and non-human contacts during childhood. Number of siblings, being an only child, and birth order did not differ markedly between patients and controls, and we could not confirm the 'sheltered child' hypothesis in IBD. The parents of controls were slightly better educated and their social class tended to be higher than those of parents of patients. There were significant associations between some of the main factors investigated in this study. No significant differences were found between patients and controls in the frequency of breast feeding, cereal consumption, sugar added to milk in infancy, gastroenteritis in childhood, major stressful life events, and many other factors.(ABSTRACT TRUNCATED AT 400 WORDS)

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