Circulating IGF-I Deficiency and Inactivation of the Acid-Labile Subunit Gene
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《新英格兰医药杂志》
To the Editor: Domené et al. (Feb. 5 issue)1 describe a boy with homozygous inactivation of the IGFALS gene, which encodes the acid-labile subunit (ALS) of insulin-like growth factor I (IGF-I) who had delayed puberty and moderate growth impairment. However, his height, when considered as a function of bone age, was only about 1 SD below the mean normal. The association of this gene defect with delayed puberty may prove fortuitous. In other rare cases, persons with inactivation of the IGFALS gene may not be considered short, and their total IGF-I may not be measured. Changes in height and progression of puberty between the ages of 14.6 and 17 years were not reported.
The failure to measure serum free IGF-I is unfortunate. In view of the boy's near-normal growth and only moderately increased serum growth hormone level, the free IGF-I level must have been nearly normal. Inactivation of the IGFALS gene in mice and humans probably leads to increased IGF-I turnover, which is easily compensated for by an increase in growth hormone secretion. In mice, when igfals deletion is combined with selective hepatic deletion of the igf1 gene, extrahepatic secretion of IGF-I is deficient, despite markedly increased growth hormone secretion, and growth failure results.2,3
William H. Daughaday, M.D.
P.O. Box 157
Newport Beach, CA 92662
wdmd@aol.com
References
Domené HM, Bengolea SV, Martínez AS, et al. Deficiency of the circulating insulin-like growth factor system associated with inactivation of the acid-labile subunit gene. N Engl J Med 2004;350:570-577.
Yakar S, Rosen CJ, Beamer WG, et al. Circulating levels of IGF-1 directly regulate bone growth and density. J Clin Invest 2002;110:771-781.
Daughaday WH. Free insulin-like growth factor (IGF) in disorders of IGF binding protein 3 complex formation. J Clin Endocrinol Metab 2004;89:3-5.
The authors reply: We are in agreement with Dr. Daughaday's comments regarding the impairment of growth and pubertal delay in our patient. At 19 years of age, the patient has spontaneously completed puberty and has a testicular volume of 20 ml, serum testosterone levels in the low-normal range for adults, and a height of 166.4 cm (0.94 SD below the local mean). The combination of normal growth with marked reductions in total circulating IGF-I could be explained by normal plasma levels of free IGF-I, as observed in mice with inactivation of the igfals gene (ALS-knockout mice).1 Alternatively, it is possible that linear growth is maintained by the production of cartilage IGF-I that acts through an autocrine or paracrine mechanism. To address this issue, we have started a collaborative study involving the measurement of free as well as bioactive IGF-I2,3 in our patient with acid-labile–subunit deficiency. Preliminary results indicate that the serum levels of free IGF-I are subnormal in the basal state. If these results are confirmed, they suggest that IGF-I produced at the cartilage level, stimulated by increased growth hormone secretion, is responsible for the normal growth and the normal near-final height attained by our patient.
Horacio M. Domené, M.S.
Alicia S. Martínez, M.D.
Héctor G. Jasper, M.D.
Centro de Investigaciones Endocrinológicas
1425 Buenos Aires, Argentina
References
Yakar S, Rosen CJ, Beamer WG, et al. Circulating levels of IGF-1 directly regulate bone growth and density. J Clin Invest 2002;110:771-781.
Frystyk J, Ivarsen P, Stoving RK, et al. Determination of free insulin-like growth factor-I in human serum: comparison of ultrafiltration and direct immunoradiometric assay. Growth Horm IGF Res 2001;11:117-127.
Chen JW, Ledet T, Orskov H, et al. A highly sensitive and specific assay for determination of IGF-I bioactivity in human serum. Am J Physiol Endocrinol Metab 2003;284:E1149-E1155.
The failure to measure serum free IGF-I is unfortunate. In view of the boy's near-normal growth and only moderately increased serum growth hormone level, the free IGF-I level must have been nearly normal. Inactivation of the IGFALS gene in mice and humans probably leads to increased IGF-I turnover, which is easily compensated for by an increase in growth hormone secretion. In mice, when igfals deletion is combined with selective hepatic deletion of the igf1 gene, extrahepatic secretion of IGF-I is deficient, despite markedly increased growth hormone secretion, and growth failure results.2,3
William H. Daughaday, M.D.
P.O. Box 157
Newport Beach, CA 92662
wdmd@aol.com
References
Domené HM, Bengolea SV, Martínez AS, et al. Deficiency of the circulating insulin-like growth factor system associated with inactivation of the acid-labile subunit gene. N Engl J Med 2004;350:570-577.
Yakar S, Rosen CJ, Beamer WG, et al. Circulating levels of IGF-1 directly regulate bone growth and density. J Clin Invest 2002;110:771-781.
Daughaday WH. Free insulin-like growth factor (IGF) in disorders of IGF binding protein 3 complex formation. J Clin Endocrinol Metab 2004;89:3-5.
The authors reply: We are in agreement with Dr. Daughaday's comments regarding the impairment of growth and pubertal delay in our patient. At 19 years of age, the patient has spontaneously completed puberty and has a testicular volume of 20 ml, serum testosterone levels in the low-normal range for adults, and a height of 166.4 cm (0.94 SD below the local mean). The combination of normal growth with marked reductions in total circulating IGF-I could be explained by normal plasma levels of free IGF-I, as observed in mice with inactivation of the igfals gene (ALS-knockout mice).1 Alternatively, it is possible that linear growth is maintained by the production of cartilage IGF-I that acts through an autocrine or paracrine mechanism. To address this issue, we have started a collaborative study involving the measurement of free as well as bioactive IGF-I2,3 in our patient with acid-labile–subunit deficiency. Preliminary results indicate that the serum levels of free IGF-I are subnormal in the basal state. If these results are confirmed, they suggest that IGF-I produced at the cartilage level, stimulated by increased growth hormone secretion, is responsible for the normal growth and the normal near-final height attained by our patient.
Horacio M. Domené, M.S.
Alicia S. Martínez, M.D.
Héctor G. Jasper, M.D.
Centro de Investigaciones Endocrinológicas
1425 Buenos Aires, Argentina
References
Yakar S, Rosen CJ, Beamer WG, et al. Circulating levels of IGF-1 directly regulate bone growth and density. J Clin Invest 2002;110:771-781.
Frystyk J, Ivarsen P, Stoving RK, et al. Determination of free insulin-like growth factor-I in human serum: comparison of ultrafiltration and direct immunoradiometric assay. Growth Horm IGF Res 2001;11:117-127.
Chen JW, Ledet T, Orskov H, et al. A highly sensitive and specific assay for determination of IGF-I bioactivity in human serum. Am J Physiol Endocrinol Metab 2003;284:E1149-E1155.