Abstract
The insulin-like growth factor 1 receptor (IGF1R) is a key factor in intrauterine
and postnatal growth by mediating the biological function of IGF-I. Mutations of IGF1R gene are usually associated with growth retardation, but the clinical picture of
IGF1R mutation carriers is heterogeneous. Indeed, these patients show clinical signs
compatible with Silver-Russell syndrome (SRS), and some IGF1R mutation carriers have
been identified in SRS cohorts. We therefore investigated deoxyribonucleic acid samples
of 19 growth-retarded patients with SRS features. Apart from 8 non-pathogenic variants,
we detected heterozygosity for the unknown duplication, c.1056_1057dup, leading to
a premature termination in one patient and his growth retarded sister. Due to its
nature, we assumed that this variant is probably pathogenic. However, the patient
and his sister exhibited spontaneous catch-up growth in later life. We therefore hypothesize
that the c.1056_1057dup does not result in a significant disruption to the GH-IGFI
axis. Thus, this IGF1R mutation without obvious clinical consequence might challenge
the actual concept of IGF1R haploinsufficiency as a general cause for disturbed growth
in IGF1R mutation carriers. In the future, mutation analysis of IGF1R should be considered
in growth-retarded patients with microcephaly and minor SRS features, but not in probands
with the characteristic SRS phenotype including macrocephaly.
Keywords
IGF1R mutations - growth retardation - Silver-Russell syndrome
