Prevalence of diabetes among children treated with growth hormone in Israel.

AIMS: To determine the long-term risk of diabetes in a cohort of children treated with recombinant human growth hormone in Israel, using data from the Israeli National Diabetes Register. METHODS: Between 1988 and 2009, 2513 children were approved for growth hormone treatment. They were assigned to one of two groups. The first group included children treated for isolated growth hormone deficiency and who were small for gestational age and the second included those treated for multiple pituitary hormone deficiency, chronic renal failure, Turner syndrome or Prader-Willi syndrome. The cohort was cross-linked with the Israeli National Diabetes Register for 2014 (mean follow-up duration 12.1±5.3 years), and prevalent cases of diabetes were identified. Standardized prevalence ratios for diabetes were calculated for people aged 10-29 years. RESULTS: In 2014, a total of 23 individuals were identified with diabetes (four with pre-existing diabetes, seven developed diabetes before age 17 years and 12 developed it at a later age). In the isolated growth hormone deficiency and small-for-gestational-age group there was no difference in the prevalence of diabetes compared with the general population (standardized prevalence ratio 2.05, 95% CI 0.94-3.89). In the group that included people with multiple pituitary hormone deficiency, chronic renal failure, Turner syndrome and Prader-Willi syndrome there was a significantly higher diabetes prevalence (standardized prevalence ratio 11.94, 95% CI 6.53-20.00) compared with the general population. CONCLUSIONS: No difference in diabetes prevalence was found in the isolated growth hormone deficiency and small-for-gestational-age group, compared with the general population. Children treated with growth hormone with pre-existing risk factors had an increased prevalence of diabetes. It is advisable to monitor blood glucose levels closely during and after growth hormone treatment, especially in such children.

Antibodies to islet cell autoantigens, rotaviruses and/or enteroviruses in cord blood and healthy mothers in relation to the 2010-2011 winter viral seasons in Israel: a pilot study.

AIMS: To determine whether antivirus and/or islet cell antibodies can be detected in healthy pregnant mothers without diabetes and/or their offspring at birth in two winter viral seasons. METHODS: Maternal and cord blood sera from 107 healthy pregnant women were tested for islet cell autoantibodies using radioligand binding assays and for anti-rotavirus and anti-CoxB3 antibody using an enzyme-linked immunosorbent assay. RESULTS: Glutamic acid decarboxylase (GAD)65 autoantibodies and rotavirus antibodies, present in both maternal and cord blood sera, correlated with an odds ratio of 6.89 (95% CI: 1.01-46.78). For five, 22 and 17 pregnancies, antibodies to GAD65, rotavirus and CoxB3, respectively, were detected in cord blood only and not in the corresponding maternal serum. In 10 pregnancies, rotavirus antibody titres in the cord blood exceeded those in the corresponding maternal serum by 2.5-5-fold. Increased antibody titres after the 20(th) week of gestation suggested CoxB3 infection in one of the 20 pregnancies and rotavirus in another. CONCLUSION: The concurrent presence of GAD65 antibodies in cord blood and their mothers may indicate autoimmune damage to islet cells during gestation, possibly caused by cross-placental transmission of viral infections and/or antivirus antibodies. Cord blood antibody titres that exceed those of the corresponding maternal sample by >2.5-fold, or antibody-positive cord blood samples with antibody-negative maternal samples, may imply an active in utero immune response by the fetus.

The globe and orbit in Laron syndrome.

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.

Effect of insulin-like growth factor-1 deficiency or administration on the occurrence of acne.

BACKGROUND: The role of growth hormone, insulin, and insulin-like growth factor-1 (IGF-1) in the development of acne is incompletely understood. OBJECTIVE: To study the effect of the absence of IGF-1 and its pharmacologic replacement on the occurrence of acne vulgaris. PATIENTS AND METHODS: Laron syndrome (LS) is characterized by congenital IGF-1 deficiency. The study group consisted of 21 patients with classical LS, who underwent puberty: 13 (8 male, 5 female) untreated and under regular follow-up until age 20?48 years; and 8 (2 male, 6 female) treated with IGF-1 (70-200 µg/kg/day), including 6 adults (2 male, treated at age 14.5-29 years and 4 female, treated at age 30-37 years) and 2 adolescents (2 female, treated at age 3.5-16 years). The medical files were reviewed for occurrence of acne and the corresponding sex hormone levels, and the findings were compared between the treated and untreated patients. RESULTS: Puberty was delayed in all untreated patients. Only one patient had slight acne at age 22 years, when he reached full puberty. Among the 2 IGF-1 treated male patients, none acquired acne. Among the 6 treated female patients, 3 had signs of hyperandrogenism (oligo-amenorrhea) and acne during IGF-1 over-dosage. On reduction of the IGF-1 dose (to 50 µg/kg/day) or cessation of treatment, the acne disappeared in all 3 patients. CONCLUSION: This study demonstrates for the first time that serum IGF-1 deficiency prevents the occurrence of acne. The findings suggest that an interaction between IGF-1 and androgens is necessary for the development of acne.

A retrospective study of the incidence of diagnosed Type 1 diabetes among children and adolescents in a large health organization in Israel, 2000-2008.

AIMS: To determine the incidence and examine temporal trends of Type 1 diabetes among children aged < 18 years, in a large Israeli health organization. METHODS: All incident Type 1 diabetes cases diagnosed between 2000 and 2008 were ascertained from an automated diabetes registry based on members' electronic records and validated by comparison with the Israel Juvenile Diabetes Register. RESULTS: During the study period, a total of 648 incident cases of Type 1 diabetes were identified. The average annual age-and-sex-standardized incidence was 11.09 per 100,000 person-years. There was an annual 5.82% (95% CI 1.80-9.98%) rise in incidence, with a greater relative increase in toddlers under 5 years of age. Incidence increased with age and demonstrated seasonal variation. Mean age at onset of diabetes significantly (P = 0.07) decreased from 10.21 years (SD = 4.48) in 2000-2002 to 9.25 years (SD = 4.54) in 2006-2008. Among very young patients (< 5 years), average blood glucose values at diagnosis dropped from 32.4 mmol/l (SD = 9.5) to 19.5 mmol/l (SD = 11.0) over the study period, with little change in average glucose for older children. CONCLUSIONS: Incidence of diagnosed Type 1 diabetes continues to increase in Israel at a rate that is high compared with similar American and European populations. At the same time, the clinical presentation of children is changing.

Long-acting insulin analogues elicit atypical signalling events mediated by the insulin receptor and insulin-like growth factor-I receptor.

AIMS/HYPOTHESIS: Insulin analogues were developed to improve the pharmacological properties of injected insulin and to better mimic endogenous insulin output. However, certain insulin analogues have been suggested to display IGF-I-like biological activities. Furthermore, several recent epidemiological studies have suggested a potential increase in cancer risk for treatment of diabetes patients with long-acting analogue insulin glargine (A21Gly,B31Arg,B32Arg human insulin). Additional studies, however, reported no increased cancer risk. The purpose of the present study was to identify the receptor(s) and signal transduction pathways responsible for the biological actions of insulin glargine and insulin detemir (B29Lys[ε-tetradecanoyl],desB30 human insulin). METHODS: The colon cancer-derived cell line HCT116 was treated with increasing doses of insulin glargine, insulin detemir, regular insulin or IGF-I, and receptor activation was evaluated by immunoprecipitation assays. IGF-I receptor (IGF-IR) internalisation following insulin glargine treatment was assessed by confocal microscopy. Activation of the Akt and extracellular signal-regulated kinase pathways was evaluated by western blots. The anti-apoptotic effect of the analogues was measured by poly-(ADP ribose) polymerase antibody and annexin assays. RESULTS: We found evidence for dual activation of the insulin receptor and IGF-IR by the analogues. Dose-dependency experiments showed that insulin glargine was able to phosphorylate the IGF-IR at fivefold lower doses than those required to activate the insulin receptor. We also showed that insulin glargine can lead to prolonged activation of the receptors and therefore promote abnormal signalling. Confocal imaging experiments showed that insulin glargine, but not regular insulin induced IGF-IR internalisation similarly to IGF-I. Finally, both analogues displayed IGF-I-like anti-apoptotic activities and stimulated cell cycle progression. CONCLUSIONS/INTERPRETATION: Our data indicate that insulin glargine and insulin detemir display atypical signalling activities that differ from those elicited by regular insulin and involve activation of the anti-apoptotic IGF-IR.

Anthropometric indices at age 17 years of full-term neonates born short.

BACKGROUND: Measurements at the end of puberty of neonates short for gestational age (SGA-L) are scant. OBJECTIVE: To determine the correlation between birth length and weight in neonates, with height and weight at age 17 years. SUBJECTS AND METHODS: 385 full-term neonates, measuring less than 48 cm (SGA-L) and 585 full-term neonates, measuring 48 cm or greater (adequate birth length for gestational age; AGA-L) were included. 234 SGA-L and 359 AGA-L were identified at age 17 years. RESULTS: Comparison of the two groups revealed that both sexes born SGA-L were also shorter at age 17 years than those born AGA-L (girls 158.9 cm (SD 7.6) vs 164.2 cm (SD 64) (p<0.001) and boys 167.3 cm (SD 8.7) vs 173.8 cm (SD 7.1) (p<0.001)). The subjects born SGA-L also weighed significantly less than those born AGA-L (p<0.001) both at birth and at age 17 years. CONCLUSIONS: Children born SGA-L become short adults and weigh less at age 17 years than children with a normal birth length.

Hand size and growth in untreated and IGF-I treated patients with Laron syndrome.

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.

Abnormalities of the axial and proximal appendicular skeleton in adults with Laron syndrome (growth hormone insensitivity).

OBJECTIVE: To investigate abnormalities in the skeleton (with the exclusion of the skull, cervical spine, hands and feet) in patients with Laron syndrome, who have an inborn growth hormone resistance and congenital insulin-like growth factor-1 (IGF-1) deficiency. DESIGN AND PATIENTS: The study group was composed of 15 untreated patients with Laron syndrome (seven male and eight female) aged 21-68 years. Plain films of the axial and appendicular skeleton were evaluated retrospectively for abnormalities in structure and shape. The cortical width of the long bones was evaluated qualitatively and quantitatively (in the upper humerus and mid-femur), and the cortical index was calculated and compared with published references. Measurements were taken of the mid-anteroposterior and cranio-caudal diameters of the vertebral body and spinous process at L3, the interpedicular distance at L1 and L5, and the sacral slope. Thoracic and lumbar osteophytes were graded on a 5-point scale. Values were compared with a control group of 20 healthy persons matched for age. RESULTS: The skeleton appeared small in all patients. No signs of osteopenia were visible. The cortex of the long bones appeared thick in the upper limbs in 11 patients and in the lower limbs in four. Compared with the reference values, the cortical width was thicker than average in the humerus and thinner in the femur. The vertebral diameters at L3 and the interpedicular distances at L1 and L5 were significantly smaller in the patients than in the control subjects (P<0.001); however, at L5 the canal was wider, relative to the vertebral body. The study group had a higher rate of anterior osteophytes in the lumbar spine than the controls had, and their osteophytes were also significantly larger. In the six patients for whom radiographs of the upper extremity in its entirety were available on one film, the ulna appeared to be rotated. In one 22-year-old man, multiple epiphyses were still open. CONCLUSION: Congenital IGF-1 deficiency leads to skeletal abnormalities characterized by small bones, narrow spinal canal, and delayed bone age. The limitation in elbow distensibility common to patients with Laron syndrome may be related to a marked retroversion of the humeral head.

Obese adults with primary growth hormone resistance (Laron Syndrome) have normal endothelial function.

OBJECTIVE: Classic Laron Syndrome (LS) is a recessive disease of insulin-like growth factor I (IGF-I) deficiency and primary growth hormone insensitivity, clinically characterized by dwarfism and marked obesity. The aim of the current study was to investigate the impact of long-term IGF-I deficiency on flow-mediated dilation (FMD) in 11 non-IGF-I-treated LS adults with long-term IGF-I deficiency who on stress echocardiography were found to have reduced cardiac dimensions and output, but normal left ventricular (LV) ejection fraction at rest and LV contractile reserve following stress. DESIGN: Following an overnight fast we assessed percent improvement in endothelium-dependent FMD (%FMD) and endothelium-independent nitroglycerin (%NTG)-mediated vasodilation non-invasively in the brachial artery, using high resolution ultrasound in 11 non-treated adult patients with LS without known coronary artery disease, and compared them to 11 age- and sex-matched healthy controls. All subjects underwent symptom-limited exercise testing (Bruce protocol). RESULTS: LS patients had a significantly higher body mass index (29+/-6 vs. 25+/-2 kg/m(2), p=0.04), lower low-density lipoprotein cholesterol (142+/-28 vs. 176+/-12 mg/dl, p=0.03) and a smaller mean brachial artery diameter (4.63+/-0.72 vs. 5.70+/-1.06 mm, p=0.01) compared to controls. However, brachial artery %FMD and %NTG were not significantly different between the LS patients and controls (13.1+/-6.2% vs. 15.4+/-5.2%, p=0.28 and 22.3+/-6.0% vs. 18.9+/-6.2%, p=0.30; respectively). Cardiac performance, assessed by exercise duration time and metabolic equivalents (METs), was significantly greater in control subjects than in LS patients (10.3+/-2.0 vs. 6.0+/-1.4 min, p<0.01 and 10.2+/-2.0 vs. 7.2+/-1.4 METs, p<0.01; respectively). CONCLUSIONS: FMD was found to be within normal limits in non-IGF-I-treated adult patients with LS, despite congenital absence of IGF-I and obesity.

Patients with congenital deficiency of IGF-I seem protected from the development of malignancies: a preliminary report.

OBJECTIVE: Overexpression of IGF-I occurs in tumors diagnosed in childhood (osteosarcoma, Wilms tumor, neuroblastoma, etc.) and in adults (breast, ovaries, colon and prostate cancer). The aim of our study was to establish the prevalence of malignancies in states of congenital IGF-I deficiency. SUBJECTS: We surveyed 222 patients with congenital IGF-I deficiency (Laron syndrome, GH gene deletion, GHRH receptor defects and IGF-I resistance) and 338 first and second-degree relatives. RESULTS: None of the IGF-I deficient patients had cancer, whereas 9-24% of the family members had a history of malignancy. CONCLUSIONS: Congenital IGF-I deficiency acts as a protecting factor for the development of cancer.

The intellectual capacity of patients with Laron syndrome (LS) differs with various molecular defects of the growth hormone receptor gene. Correlation with CNS abnormalities.

The correlation between the molecular defects of the GH receptor (R), psychosocial development and brain abnormalities were evaluated in 10 patients with Laron syndrome (LS), in whom all data were available. The findings revealed that the intelligence quotient (IQ) and abnormalities in the brain of the patients with LS differ with various molecular defects of the GH-receptor. The most severe mental deficits and brain pathology occurred in patients with 3, 5, 6 exon deletion. Patients with point mutations in exons 2, 4 and 7 presented various degrees of medium to mild CNS abnormalities that correlated with the IQ. Notably, the patient with the E180 splice mutation in exon 6 had a normal IQ, which fits the report on normal IQ in a large Ecuadorian cohort with the same mutation. This is the first report to support a correlation between IQ, brain abnormalities and localization of the molecular defects in the GH-R gene. As all patients with LS are IGF-I-deficient, it must be assumed that other as yet unknown factors related to the molecular defects in the GH-R are the major cause of the differences in intellect and brain abnormalities.

Relationship between the incidence of type 1 diabetes and maternal enterovirus antibodies: time trends and geographical variation.

AIMS/HYPOTHESIS: We have previously observed an inverse correlation between the incidence of type 1 diabetes and enterovirus infections in the background population. The aim of this study was to analyse whether maternal enterovirus antibody status, which reflects both the frequency of enterovirus infections and the protection conferred by the mother on the offspring, also correlates with the incidence of type 1 diabetes. METHODS: Maternal enterovirus antibodies were analysed from serum samples taken from pregnant women between 1983 and 2001 in Finland and Sweden using enzyme immunoassay and neutralisation assays. Comparable samples were also taken between 1999 and 2001 in countries with a lower incidence of diabetes (Estonia, Germany, Hungary, Israel, Lithuania, Russia). RESULTS: A clear decrease was observed in maternal enterovirus antibody levels over the past 20 years (p<0.0001). The frequency of enterovirus antibodies was higher in countries with a low or intermediate incidence of type 1 diabetes compared with high-incidence countries (p<0.0001). CONCLUSIONS/INTERPRETATION: These findings are in line with our previous observations supporting the hypothesis that a low frequency of enterovirus infection in the background population increases the susceptibility of young children to the diabetogenic effect of enteroviruses.

Seasonality in clinical onset of type 1 diabetes in belgian patients above the age of 10 is restricted to HLA-DQ2/DQ8-negative males, which explains the male to female excess in incidence.

AIMS/HYPOTHESIS: Type 1 diabetes arises from an interplay between environmental and genetic factors. The reported seasonality at diagnosis supports the hypothesis that currently unknown external triggers play a role in the onset of the disease. We investigated whether a seasonal pattern is observed at diagnosis in Belgian Type 1 diabetic patients, and if so whether seasonality varies according to age, sex and genetic risk, all known to affect the incidence of Type 1 diabetes. METHODS: The seasonal pattern at clinical diagnosis was assessed in 2176 islet antibody-positive diabetic patients aged 0 to 39 years diagnosed between 1989 and 2000. Additional stratification was performed for age, sex and HLA-DQ genotype. RESULTS: Overall, a significant seasonal pattern at clinical diagnosis of diabetes was observed (p<0.001). More subjects were diagnosed in the period of November to February (n=829) than during the period of June to September (n=619) characterised by higher averages of maximal daily temperature and daily hours of sunshine. However, the seasonal pattern was restricted to patients diagnosed above the age of 10 (0-9 years: p=0.398; 10-19 years: p<0.001; 20-29 years: p=0.003; 30-39 years: p=0.015). Since older age at diagnosis is associated with a male to female excess and a lower prevalence of the genetic accelerator HLA-DQ2/DQ8, we further stratified the patients aged 10 to 39 years (n=1675) according to HLA-DQ genotype and sex, and we found that the seasonal pattern was largely restricted to male subjects lacking DQ2/DQ8 (n=748; p<0.00 vs all others: n=927; p=0.031). CONCLUSIONS/INTERPRETATION: In a subgroup of male patients diagnosed over the age of 10, the later stages of the subclinical disease process may be more driven by sex- and season-dependent external factors than in younger, female and genetically more susceptible subjects. These factors may explain the male to female excess in diabetes diagnosed in early adulthood.

Laron syndrome (primary growth hormone insensitivity): a unique model to explore the effect of insulin-like growth factor 1 deficiency on human hair.

BACKGROUND: Classical Laron syndrome is a recessive disease of primary insulin-like growth factor 1 (IGF-1) deficiency and primary growth hormone insensitivity. Affected children have, among other defects, sparse hair growth and frontal recessions. The hair is thin and easy to pluck. Young adults have various degrees of alopecia, more pronounced in males. OBJECTIVE: The aim of the present study was to investigate the effect of primary IGF-1 deficiency on hair structure. The study sample included 11 patients with Laron syndrome--5 children (2 untreated) and 6 adults (5 untreated). Hairs were examined by light and electron microscopy. RESULTS: The most significant structured defect, pili torti et canaliculi, was found in 2 young, untreated patients. Grooving, tapered hair and trichorrhexis nodosa were found in the remainder. IGF-1-treated patients had either none or significantly fewer pathological changes compared to the untreated patients. CONCLUSION: This is the first documentation of the role of primary IGF-1 deficiency on hair structure in human beings.

Identification of two novel mutations in the human growth hormone receptor gene.

Deletions and mutations in the growth hormone receptor gene are the underlying etiology of Laron syndrome (LS). Most of the patients are distributed in and originating from the Mediterranean and Middle-Eastern countries. Thirty-nine mutations have been described so far. We hereby report 2 novel nonsense mutations, one in exon 2 found in three Jewish-Iraqi patients from Israel; and another in exon 6 found in an Italian girl. DNA sequencing of exon 2 revealed a G to A transition at nucleotide 83 in the fourth codon of the signal peptide (W-15X). In exon 6, a T to A transversion was found in amino acid 141 (L141X). Both mutations introduced a premature termination codon that led to a truncated non-functioning receptor. In addition we found in the Jewish-Iraqi patients, a mutation in exon 7 (R211H, previously described) and in the Italian family the polymorphism Gly168, in exon 6.