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This version published online on March 15, 2005
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-1254
A more recent version of this article appeared on May 1, 2005
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Submitted on June 30, 2004
Accepted on February 22, 2005

HOMOZYGOUS AND HETEROZYGOUS EXPRESSION OF A NOVEL IGF-I MUTATION

M. J.E. Walenkamp*, M. Karperien, A. M. Pereira, Y. Hilhorst-Hofstee, J. van Doorn, J. W. Chen, S. Mohan, A. Denley, B. Forbes, H. A. van Duyvenvoorde, S. W. van Thiel, C. A. Sluimers, J. J. Bax, J. A.P.M. de Laat, M. B Breuning, J. A. Romijn, and J. M. Wit

Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands; Department of Endocrinology and Metabolism, Leiden University Medical Center, Leiden, The Netherlands; Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands; Department of Metabolic and Endocrine diseases, University Medical Center Utrecht, Utrecht, The Netherlands; Medical Research Laboratories and Medical Department, Aarhus University Hospital, Aarhus, Denmark; Department of Medicine, Biochemistry and Physiology, Loma Linda University, Loma Linda, CA, United States; Department of Molecular and Biomedical Science, University of Adelaide, Australia; Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands; Department of Audiology, Leiden University Medical Center, Leiden, The Netherlands; Medical Center, Leiden, The Netherlands

* To whom correspondence should be addressed. E-mail: m.j.e.walenkamp{at}lumc.nl.

Insulin-like growth factor I (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 growth hormone (GH), whereas in childhood and in adult life IGF-I secretion seems to be mainly controlled by GH, as revealed from studies on patients with GH-releasing hormone receptor (GHRH-R) and GH-receptor (GHR) 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 (V44M). The inactivating nature of the mutation was proven by functional analysis demonstrating a 90-fold reduced affinity of recombinantly produced V44M 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 non-carriers.

In conclusion, the phenotype of our patient consists of severe intrauterine growth retardation, deafness and mental retardation reflecting the growth hormone (GH) independent secretion of IGF-I in utero. The postnatal growth pattern, similar to growth of untreated GH deficient or 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.
Key words: IGF-I • mutation • intrauterine growth retardation • postnatal growth failure • microcephaly




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