title: Homozygous and heterozygous expression of a novel insulin-like growth factor-I mutation.
abstract: 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.
authors.affiliation: Department of Pediatrics J6-S, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. m.j.e.walenkamp@lumc.nl
authors.forename: M J E
authors.initials: MJ
authors.lastname: Walenkamp
authors.forename: M
authors.initials: M
authors.lastname: Karperien
authors.forename: A M
authors.initials: AM
authors.lastname: Pereira
authors.forename: Y
authors.initials: Y
authors.lastname: Hilhorst-Hofstee
authors.forename: J
authors.initials: J
authors.lastname: van Doorn
authors.forename: J W
authors.initials: JW
authors.lastname: Chen
authors.forename: S
authors.initials: S
authors.lastname: Mohan
authors.forename: A
authors.initials: A
authors.lastname: Denley
authors.forename: B
authors.initials: B
authors.lastname: Forbes
authors.forename: H A
authors.initials: HA
authors.lastname: van Duyvenvoorde
authors.forename: S W
authors.initials: SW
authors.lastname: van Thiel
authors.forename: C A
authors.initials: CA
authors.lastname: Sluimers
authors.forename: J J
authors.initials: JJ
authors.lastname: Bax
authors.forename: J A P M
authors.initials: JA
authors.lastname: de Laat
authors.forename: M B
authors.initials: MB
authors.lastname: Breuning
authors.forename: J A
authors.initials: JA
authors.lastname: Romijn
authors.forename: J M
authors.initials: JM
authors.lastname: Wit
mesh_terms: D006579:Heterozygote; D019382:Human Growth Hormone / Q000097:blood; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree
chemical_list: D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I