scholarly journals Recommended IGF-I Dosage Causes Greater Fat Accumulation and Osseous Maturation Than Lower Dosage and May Compromise Long-term Growth Effects

2013 ◽  
Vol 98 (2) ◽  
pp. 839-845 ◽  
Author(s):  
Jaime Guevara-Aguirre ◽  
Arlan L. Rosenbloom ◽  
Marco Guevara-Aguirre ◽  
Jannette Saavedra ◽  
Patricio Procel
Keyword(s):  
Growth Promotion ◽  
Receptor Gene ◽  
Splice Site Mutation ◽  
Bone Age ◽  
Abdominal Ultrasound ◽  
Height Velocity ◽  
High Dose ◽  
Site Mutation ◽  
Percentage Body Fat ◽  
Igf I

Abstract Context: The maximum dose of IGF-I recommended for treatment of GH insensitivity is commonly used. Objective: The aim was to test the hypothesis that a lower dose is as effective as a high dose of IGF-I in growth promotion and has fewer deleterious effects. Design and Setting: Subjects were treated for 3 years with regular examinations including bone age and dual energy x-ray absorptiometry and for 1 year with abdominal ultrasound studies at a clinical research institute in Quito, Ecuador. Subjects: The study included 21 subjects ages 3.2–15.9 years with GH insensitivity due to the same splice site mutation on the GH receptor gene. Interventions: Subjects were allocated to receive 120 (n = 14) or 80 (n = 7) μg/kg IGF-I twice daily. Main Outcome Measures: Height velocity, osseous maturation, height SD scores (SDS), body composition, abdominal organ growth, and side effects were assessed. Results: There were no differences in growth velocity or height SDS increment by dosage, and the SDS increase was greater than in other reported series. Osseous maturation over 3 years with the high dose was nearly twice as rapid as with the lower dose (P < .001) and correlated with an increase in percentage body fat (r = .64; P < .001) and with adrenal size increase over 1 year (r = .32; P = .03). The ratio of bone age to height age was lower in the high-dose group after 3 years of treatment (P = .007). Conclusions: The commonly used IGF-I dosage of 120 μg/kg twice a day is excessive in comparison to a dose of 80 μg/kg twice a day, disproportionately accelerating osseous maturation, probably from the combined effects of obesity and inappropriate adrenal growth, thus likely compromising adult height potential. Moreover, the lower dose decreases direct treatment cost by one-third.

scholarly journals LUM-201 Elicits Greater GH Response than Standard GH Secretagogues in Pediatric Growth Hormone Deficiency

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A679-A680
Author(s):  
George Bright ◽  
Roy Smith ◽  
Michael O Thorner
Keyword(s):  
Single Dose ◽  
Bone Age ◽  
Interquartile Range ◽  
Hormone Deficiency ◽  
Height Velocity ◽  
Gh Secretagogues ◽  
Moderate Growth ◽  
Igf I ◽  
Stimulation Tests ◽  
The Difference

Abstract Presentation Type: OralScience Type and Topic: Clinical Trial Introduction: LUM-201 (ibutamoren, formerly MK-0677) is an orally administered GH-secretagogue that stimulates the GH secretagogue receptor (GHSR1a) in the hypothalamus and pituitary. LUM-201 is in development for long-term use in a subset of PGHD patients with moderate growth deficiencies. A diagnosis of PGHD is confirmed by low GH responses to standard GH secretagogues (clonidine, arginine, L-dopa, glucagon, insulin) so it is somewhat counter-intuitive to suggest that children who cannot respond to one GH secretagogue might have favorable responses to LUM-201. Objective: To determine if LUM-201 stimulates GH responses differently than standard GH secretagogues. Methods: 68 naïve-to-treatment, prepubertal children with GHD received two standard GH stimulation tests and a test with a single 0.8 mg/kg dose of LUM-201. The 68 subjects included 20 girls and 48 boys. The median (interquartile range) age was 9.2 years (7.2,10.8), bone age 6.0 years (4.5, 7.9), height SDS -3.3 (-4.5, -2.5), pretreatment height velocity 4.0 cm/y (3.2, 4.6), and baseline IGF-1 51 ng/mL (24,111). Results: The median (interquartile range) of maximal GH response to single dose LUM-201 was 15.0 ng/mL (3.5, 49) and to various pairs of standard stimuli was 5.4 ng/mL (1.8-7.6) (p< 0.00001). The median (IQR) for the difference between GH responses to LUM-201 and standard stimuli was 9.6 ng/ml (1.9, 42). In a multivariate analysis (r2 =0.73) differential GH increased with higher values of baseline IGF-I (p < 0.00001) and standard GH stimulation test (p = 0.047) but was not influenced by age (p = 0.16), sex (p = 0.28), baseline HV (p = 0.24), age-bone age differences (p = 0.33) or height-SDS (p = 0.75). Conclusion: In GHD children, the GH response to single dose LUM-201 greatly exceeds that observed with standard GH testing agents. The difference is greatest among patients with higher baseline values of IGF-I and higher GH responses to standard stimuli. The synergistic actions of LUM-201 on the physiological mechanisms regulating GH release explain why GH responses are greater in response to LUM-201 compared to traditional tests used to diagnose PGHD. Key words: LUM-201, GH deficiency, GH secretagogues, pediatrics, stimulation tests, short stature, pituitary, hypothalamus

Idiopathic infantile hypercalcemia: mutations in SLC34A1 and CYP24A1 in two siblings and fathers

2020 ◽  
Vol 33 (10) ◽  
pp. 1353-1358
Author(s):  
Ayla Güven ◽  
Martin Konrad ◽  
Karl P. Schlingmann
Keyword(s):  
Vitamin D ◽  
Stop Codon ◽  
Gene Mutations ◽  
Splice Site Mutation ◽  
Heterozygous Mutation ◽  
High Dose ◽  
Loss Of Function ◽  
Site Mutation ◽  
Medullary Nephrocalcinosis ◽  
Idiopathic Infantile Hypercalcemia

AbstractObjectivesBoth CYP24A1 and SLC34A1 gene mutations are responsible for idiopathic infantile hypercalcemia, whereas loss-of-function mutations in CYP24A1 (25-OH-vitamin D-24-hydroxylase) lead to a defect in the inactivation of active 1.25(OH)2D; mutations in SLC34A1 encoding renal sodium phosphate cotransporter NaPi-IIa lead to primary renal phosphate wasting combined with an inappropriate activation of vitamin D. The presence of mutations in both genes has not been reported in the same patient until today.Case presentationHypercalcemia was incidentally detected when a 13-month-old boy was being examined for urinary tract infection. After 21 months, hypercalcemia was detected in his six-month-old sister. High dose of vitamin D was not given to both siblings. Both of them also had hypophosphatemia and decreased tubular phosphate reabsorption. Intensive hydration, furosemide and oral phosphorus treatment were given. Bilateral medullary nephrocalcinosis was detected in both siblings and their father. Serum Ca and P levels were within normal limits at follow-up in both siblings. Siblings and their parents all carry a homozygous stop codon mutation (p.R466*) in CYP24A1. Interestingly, both siblings and the father also have a heterozygous splice-site mutation (IVS6(+1)G>A) in SLC34A1. The father has nephrocalcinosis.ConclusionsA biallelic loss-of-function mutation in the CYP24A1 gene was identified as responsible for hypercalcemia, hypercalciuria and nephrocalcinosis. In addition, a heterozygous mutation in the SLC34A1 gene, although not being the main pathogenic factor, might contribute to the severe phenotype of both patients.

A splice site mutation in the human glucagon receptor gene abolishes function and causes pancreaticβ-cell hyperplasia and hyperglucagonemia

2000 ◽  
Vol 94 (1-3) ◽  
pp. 2
Author(s):  
Erica Nishimura ◽  
Lars H. Hansen ◽  
Etienne Larger ◽  
Richard W. Gelling ◽  
Jean-Claude Chaput ◽  
...  
Keyword(s):  
Splice Site ◽  
Receptor Gene ◽  
Splice Site Mutation ◽  
Site Mutation ◽  
Cell Hyperplasia ◽  
Glucagon Receptor ◽  
Glucagon Receptor Gene
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