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P-57 HEREDITARY ASPECTS OF LARON SYNDROME (PRIMARY GROWTH HORMONE INSENSITIVITY) - A STUDY OF THE ISRAELI COHORT
Poster presentations: Sunday 12 November 2006 patients. In the present study we used IGFBP-2 transgenic mice and their wildtype littermates to specify the role of IGFBP-2 during 1,2 dimethylhydrazine (DMH) induced colon cancer development. Aberrant crypt foci (ACF) served as markers of initial preneoplastic changes of the colon mucosa, whereas adenomas characterized later stages of tumor formation. The number of chemically induced ACF was increased by 34% during the first 10 weeks in IGFBP-2 transgenic mice, as evaluated by methylene blue staining. The effect of IGFBP-2 was restricted to small ACF, comprising 1 to 2 aberrant crypts (AC). Interestingly, in these early lesions IGFBP-2 overexpression led to reduced translocation of b-catenin to the nucleus. The number of small ACF declined significantly over time in IGFBP-2 transgenic mice resulting in similar ACF rates in both genotypes at 38 weeks. Both groups developed adenomas in the large intestine with similar tumor incidences and numbers. However, tumor volumes were two-fold smaller in IGFBP-2 transgenic mice and correlated inversely with serum IGFBP-2 levels. Reduced tumor size in IGFBP-2 transgenic mice was associated with a significantly lower proportion of Ki67positive cells (33.2±3.6% versus 47.9±3.4% in wildtype mice). Immunohistochemical staining for b-catenin showed a distinctly reduced translocation in the nuclei of adenomas from IGFBP-2 overexpressing mice. In conclusion, our studies show that IGFBP-2 supports development of preneoplastic foci in an initial phase of tumor development which is not mediated by enhanced nuclear b-catenin translocation. Moreover, progression of ACF to tumors is not affected by IGFBP-2 as becomes evident from similar tumor incidence in both genotypes. During tumor progression, however, IGFBP-2 is a growth inhibitor, potentially by interfering with b-catenin translocation to the nucleus.
Genetics P-57 HEREDITARY ASPECTS OF LARON SYNDROME (PRIMARY GROWTH HORMONE INSENSITIVITY) – A STUDY OF THE ISRAELI COHORT Zvi Laron ° , Orit Shevah. Endocrinology & Diabetes Research Unit, Schneider Children’s Medical Center of Israel and Tel Aviv University, Israel Background: Laron Syndrome (LS, OMIM #262500) is a rare disorder characterized by high serum levels of GH but very low or undetectable concentrations of IGF-I. The pathology of this syndrome resides in defects of the GH receptor (GH-R) or in post-receptor pathways. The majority of LS patients are of Mediterranean and MiddleEastern origin or their descendents. Early description of patients in our clinic pointed towards inherited autosomal recessive disease. Objective: To present an updated analysis of the hereditary pattern of the disease in the Israeli cohort of patients with LS using the pedigrees and molecular studies of the GH-R. Subjects: Out of the 63 patients with LS followed in our clinic we were able to perform a genetic analysis in 44 patients belonging to 35 families. Thirty were oriental Jews, eight Arabs and six Caucasians from other countries. Of these, a molecular characterization of the mutation in the GH-R was performed in 33 patients and 32 family members (belonging to 21 families). Results: Consanguinity was found in 11/21 families: three JewishIraqi, 2 Jewish-Yemenite, 1 Jewish-Iranian, 1 Jewish-Afghani, 2 Palestinian-Arab, 1 Druze and 1 of Iranian origin. Eleven different mutations of the GH-R were found. Twenty-seven patients were homozygous, one patient was a compound heterozygote and in another patient three different mutations were detected. In addition, three siblings had no mutation in the receptor, and were diagnosed as having a post receptor defect – possibly in STAT5b. One LS patient carried a heterozygous nonsense mutation (R43X) and a heterozygous polymorphism (Gly168Gly). All the 32 family members were heterozygotesfor the molecular defect. .
S35 Conclusions: Analysis of 43 patients with LS belonging to 28 families confirmed the recessive inheritance of LS. Nevertheless, a nonclassical molecular defect in two patients with LS remains to be clarified.
GH clinical/therapy P-59 THE GROWTH RESPONSE TO GH TREATMENT IN CHILDREN WITH GH DEFICIENCY (GHD) IS NOT DIFFERENT BETWEEN THOSE WHO DO OR DO NOT NORMALIZE THEIR IGF-I LEVELS Werner F Blum1 ° , Elena P Shavrikova2 , Brenda J Crowe3 . 1 Eli Lilly and Company; 2 Pharma Support Inc., St. Petersburg, Russia, 3 Lilly Research Laboratories, Indianapolis, USA It has been suggested to adjust the GH dose in patients with GHD by titrating IGF-I levels into the normal range. This study aimed to investigate whether such an approach is clinically meaningful by comparing the 1st-y height velocity (HV) in patients who did or did not normalize their IGF-I levels. Patients were selected from a post-marketing study (GeNeSIS) according to the following criteria: diagnosis GHD with peak stimulated GH < 10mcg/L, prepubertal at baseline and at 1y of GH treatment, IGF-I standard deviation score (SDS) at baseline <−2. Patients were divided into 2 groups: A (n = 26): those whose IGF-I SDS remained <−2 at 1y; B (n = 129): those whose IGF-I normalized to >−2 SDS. Significantly lower baseline values in group A vs. B were observed for the following variables: bone age SDS (−4.3 vs. −3.1, p < 0.001), height (Ht) SDS (−3.8 vs. −3.0, p = 0.002), Ht SDS minus target Ht SDS (−3.4 vs. −2.5, p = 0.003), maximum GH peak (2.3 vs. 5.1 mcg/L, p < 0.001), baseline IGF-I SDS (−5.2 vs. −2.7, p < 0.001) and IGFBP-3 SDS (−3.8 vs. −2.0, p < 0.001), suggesting more severe GHD in group A. No significant differences were observed for baseline age (7.3 vs. 6.4y) and GH dose (0.21 vs. 0.20 mg/Kg/wk), and change in 1st-y IGF-I SDS (2.3 vs. 2.8) or 1st-y HV (11.2 vs. 10.2 cm/y). To test the hypothesis that the 1st-y HV was not smaller in group A, a non-inferiority analysis was performed using ANCOVA with baseline values for age, Ht SDS, Ht SDS minus target Ht SDS and IGF-I SDS as covariates. The betweengroup difference in HV LS means was 0.01 cm/y with no inferiority of group A. Conclusions: Patients with severe GHD often do not normalize their serum IGF-I with GH treatment; however, their growth response is not different from those who do normalize IGF-I. Therefore, titrating IGF-I into the normal range in children with severe GHD may be unnecessary and unhelpful. Instead, clinical endpoints such as HV should be the primary consideration for individualization of GH dose. P-61 KOREAN ADULT GROWTH HORMONE DEFICIENCY TREATMENT REGISTRY Yoon-Sok Chung1,2 ° , Sung-Woon Kim2 , Seong-Yeon Kim2 , Ahn Sang-Mi1,2 , Eun-Gyoung Hong2 , In-Kyung Jeong2 , Jong-Ryeal Hahm2 , Minho Shong2 , Dong-Sun Kim2 , SeongKeun Lee2 , Sungdae Moon2 , Hyun-Koo Yoon2 , Dooman Kim2 , Hye-Kyung Park2 , Hyun Kwak2 , Jung-Hyun Noh2 , Seong-Kyu Lee2 , Yun-Kyung Kim1,2 , Ui-Hyun Kim2 , Sang-Woo Kim2 , SunHye Jung1,2 . 1 Dept. Endocrinology and Metabolism, Ajou University School of Medicine; 2 The Korean Adult Growth Hormone Study Group of the Korean Endocrine Society, South Korea Adult growth hormone (GH) deficiency is related with decreased lean body mass, increased body fat, and poor quality of life. In western countries, adult growth hormone deficiency treatment registry provided database of effects and safety of GH. The Korean Adult Growth Hormone Study Group of the Korean Endocrine Society has begun to register patients with adult growth hormone deficiency since
Genetics P-57 HEREDITARY ASPECTS OF LARON SYNDROME (PRIMARY GROWTH HORMONE INSENSITIVITY) – A STUDY OF THE ISRAELI COHORT Zvi Laron ° , Orit Shevah. Endocrinology & Diabetes Research Unit, Schneider Children’s Medical Center of Israel and Tel Aviv University, Israel Background: Laron Syndrome (LS, OMIM #262500) is a rare disorder characterized by high serum levels of GH but very low or undetectable concentrations of IGF-I. The pathology of this syndrome resides in defects of the GH receptor (GH-R) or in post-receptor pathways. The majority of LS patients are of Mediterranean and MiddleEastern origin or their descendents. Early description of patients in our clinic pointed towards inherited autosomal recessive disease. Objective: To present an updated analysis of the hereditary pattern of the disease in the Israeli cohort of patients with LS using the pedigrees and molecular studies of the GH-R. Subjects: Out of the 63 patients with LS followed in our clinic we were able to perform a genetic analysis in 44 patients belonging to 35 families. Thirty were oriental Jews, eight Arabs and six Caucasians from other countries. Of these, a molecular characterization of the mutation in the GH-R was performed in 33 patients and 32 family members (belonging to 21 families). Results: Consanguinity was found in 11/21 families: three JewishIraqi, 2 Jewish-Yemenite, 1 Jewish-Iranian, 1 Jewish-Afghani, 2 Palestinian-Arab, 1 Druze and 1 of Iranian origin. Eleven different mutations of the GH-R were found. Twenty-seven patients were homozygous, one patient was a compound heterozygote and in another patient three different mutations were detected. In addition, three siblings had no mutation in the receptor, and were diagnosed as having a post receptor defect – possibly in STAT5b. One LS patient carried a heterozygous nonsense mutation (R43X) and a heterozygous polymorphism (Gly168Gly). All the 32 family members were heterozygotesfor the molecular defect. .
S35 Conclusions: Analysis of 43 patients with LS belonging to 28 families confirmed the recessive inheritance of LS. Nevertheless, a nonclassical molecular defect in two patients with LS remains to be clarified.
GH clinical/therapy P-59 THE GROWTH RESPONSE TO GH TREATMENT IN CHILDREN WITH GH DEFICIENCY (GHD) IS NOT DIFFERENT BETWEEN THOSE WHO DO OR DO NOT NORMALIZE THEIR IGF-I LEVELS Werner F Blum1 ° , Elena P Shavrikova2 , Brenda J Crowe3 . 1 Eli Lilly and Company; 2 Pharma Support Inc., St. Petersburg, Russia, 3 Lilly Research Laboratories, Indianapolis, USA It has been suggested to adjust the GH dose in patients with GHD by titrating IGF-I levels into the normal range. This study aimed to investigate whether such an approach is clinically meaningful by comparing the 1st-y height velocity (HV) in patients who did or did not normalize their IGF-I levels. Patients were selected from a post-marketing study (GeNeSIS) according to the following criteria: diagnosis GHD with peak stimulated GH < 10mcg/L, prepubertal at baseline and at 1y of GH treatment, IGF-I standard deviation score (SDS) at baseline <−2. Patients were divided into 2 groups: A (n = 26): those whose IGF-I SDS remained <−2 at 1y; B (n = 129): those whose IGF-I normalized to >−2 SDS. Significantly lower baseline values in group A vs. B were observed for the following variables: bone age SDS (−4.3 vs. −3.1, p < 0.001), height (Ht) SDS (−3.8 vs. −3.0, p = 0.002), Ht SDS minus target Ht SDS (−3.4 vs. −2.5, p = 0.003), maximum GH peak (2.3 vs. 5.1 mcg/L, p < 0.001), baseline IGF-I SDS (−5.2 vs. −2.7, p < 0.001) and IGFBP-3 SDS (−3.8 vs. −2.0, p < 0.001), suggesting more severe GHD in group A. No significant differences were observed for baseline age (7.3 vs. 6.4y) and GH dose (0.21 vs. 0.20 mg/Kg/wk), and change in 1st-y IGF-I SDS (2.3 vs. 2.8) or 1st-y HV (11.2 vs. 10.2 cm/y). To test the hypothesis that the 1st-y HV was not smaller in group A, a non-inferiority analysis was performed using ANCOVA with baseline values for age, Ht SDS, Ht SDS minus target Ht SDS and IGF-I SDS as covariates. The betweengroup difference in HV LS means was 0.01 cm/y with no inferiority of group A. Conclusions: Patients with severe GHD often do not normalize their serum IGF-I with GH treatment; however, their growth response is not different from those who do normalize IGF-I. Therefore, titrating IGF-I into the normal range in children with severe GHD may be unnecessary and unhelpful. Instead, clinical endpoints such as HV should be the primary consideration for individualization of GH dose. P-61 KOREAN ADULT GROWTH HORMONE DEFICIENCY TREATMENT REGISTRY Yoon-Sok Chung1,2 ° , Sung-Woon Kim2 , Seong-Yeon Kim2 , Ahn Sang-Mi1,2 , Eun-Gyoung Hong2 , In-Kyung Jeong2 , Jong-Ryeal Hahm2 , Minho Shong2 , Dong-Sun Kim2 , SeongKeun Lee2 , Sungdae Moon2 , Hyun-Koo Yoon2 , Dooman Kim2 , Hye-Kyung Park2 , Hyun Kwak2 , Jung-Hyun Noh2 , Seong-Kyu Lee2 , Yun-Kyung Kim1,2 , Ui-Hyun Kim2 , Sang-Woo Kim2 , SunHye Jung1,2 . 1 Dept. Endocrinology and Metabolism, Ajou University School of Medicine; 2 The Korean Adult Growth Hormone Study Group of the Korean Endocrine Society, South Korea Adult growth hormone (GH) deficiency is related with decreased lean body mass, increased body fat, and poor quality of life. In western countries, adult growth hormone deficiency treatment registry provided database of effects and safety of GH. The Korean Adult Growth Hormone Study Group of the Korean Endocrine Society has begun to register patients with adult growth hormone deficiency since