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Homozygous and Heterozygous Expression of a Novel Insulin-Like Growth Factor-I Mutation

Departments of Pediatrics (M.J.E.W., M.K., H.A.v.D., C.A.S., J.M.W.), Endocrinology and Metabolism (M.K., A.M.P., S.W.v.T., J.A.R.), Cardiology (J.J.B.), and Audiology (J.A.P.M.d.L.) and Center for Human and Clinical Genetics (Y.H.-H., M.B.B.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands; Metabolic and Endocrine Diseases (J.v.D.), University Medical Center, Utrecht, The Netherlands; Medical Research Laboratories and Medical Department (J.W.C.), Aarhus University Hospital, DK 8000 Aarhus, Denmark; Department of Medicine, Biochemistry, and Physiology (S.M.), Loma Linda University, Loma Linda, California 92350; and Department of Molecular and Biomedical Science (A.D., B.F.), University of Adelaide, SA 5005 Adelaide, Australia

Address all correspondence and requests for reprints to: M. J. E. Walenkamp, Department of Pediatrics J6-S, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: m.j.e.walenkamp{at}lumc.nl.

IGF-I is a key factor in intrauterine development and postnatal growth and metabolism. The secretion of IGF-I in utero is not dependent on GH, whereas in childhood and adult life, IGF-I secretion seems to be mainly controlled by GH, as revealed from studies on patients with GHRH receptor and GH receptor mutations.

In a 55-yr-old male, the first child of consanguineous parents, presenting with severe intrauterine and postnatal growth retardation, microcephaly, and sensorineural deafness, we found a homozygous G to A nucleotide substitution in the IGF-I gene changing valine 44 into methione. The inactivating nature of the mutation was proven by functional analysis demonstrating a 90-fold reduced affinity of recombinantly produced for the IGF-I receptor. Additional investigations revealed osteoporosis, a partial gonadal dysfunction, and a relatively well-preserved cardiac function. Nine of the 24 relatives studied carried the mutation. They had a significantly lower birth weight, final height, and head circumference than noncarriers.

In conclusion, the phenotype of our patient consists of severe intrauterine growth retardation, deafness, and mental retardation, reflecting the GH-independent secretion of IGF-I in utero. The postnatal growth pattern, similar to growth of untreated GH-deficient or GH-insensitive children, is in agreement with the hypothesis that IGF-I secretion in childhood is mainly GH dependent. Remarkably, IGF-I deficiency is relatively well tolerated during the subsequent four decades of adulthood. IGF-I haploinsufficiency results in subtle inhibition of intrauterine and postnatal growth.

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