Two patients with a complete absence of biologically active IGF-1 showed severe pre- and postnatal growth, extreme microcephaly, sensorineural deafness and failure to thrive.
Genetic abnormalities causing growth failure that is less severe than the extreme phenotype are emphasized, together with an analysis of height and serum IGF-I across the spectrum of different types of GHR defects.
The spectrum of associated anomalies in this newly recognised phenotype complex consists of growth failure, typical facial anomalies with additional (previously unreported) nervous system abnormalities (e.g. sensorineural deafness) and somatomedin C deficiency.
During follow-up he manifested complications from the hydrocephalus and NDI including global developmental delay and growth failure with low IGF-1 and hypothyroidism.
A small number of children (to date 10) with modest growth failure and in the majority delayed puberty, a phenotype similar to that of CDGP, have been reported to carry mutations in the IGF acid labile subunit (IGFALS) gene which encodes the ALS, a part of the ternary complex carrying IGF-I in the circulation.
Finally, we clearly demonstrate that GH-R77C is not invariably associated with short stature, but that great care needs to be taken in ascribing growth failure to various heterozygous mutations affecting the GH-IGF axis and that careful functional studies are mandatory.
Primary GH insensitivity (GHI) or Laron syndrome, caused by mutations of the GH receptor (GHR) gene, has a clinical phenotype of postnatal growth failure associated with normal elevated serum concentrations of GH and low serum levels of IGF-I.
Because IGF-I, which circulates as part of a ternary complex with IGF binding protein (IGFBP)-3 and acid-labile subunit (ALS), mediates the growth-promoting effects of GH, IGFD is associated with severe growth failure in humans.
The identification of a second case of severe growth failure associated with STAT5b mutation implicates a unique and critical role for STAT5b in GH stimulation of IGF-I gene expression and statural growth.
Categorization of the causes for ISS by insulin-like growth factor I (IGF-I) concentrations provides a basis for speculation about the potential for IGF-I gene polymorphisms or binding protein abnormalities influencing the development of ISS-related growth failure.
IGF deficiency (IGFD) has emerged as an important clinical diagnosis: secondary IGFD results from insufficient production of GH and is characterized by postnatal growth failure; primary IGFD can result from abnormalities of the GH receptor or GH signaling cascade, or from mutations or deletions of the IGF-I gene.
GH insensitivity syndrome (GHIS; Laron syndrome) is clinically characterized by severe postnatal growth failure and very low serum levels of IGF-I despite increased secretion of GH.
Individuals with a deletion of 15q26.1-->qter which contains the insulin-like growth factor-I (IGF-I) receptor gene exhibit phenotypical similarities to patients with Silver-Russell syndrome (SRS) who represent a group of short children affected by pre- and postnatal growth failure and several dysmorphic features.
Growth failure in children with high growth hormone (GH) levels, low insulin-like growth factor 1 (IGF-1) levels, and accelerated linear growth in response to exogenous GH is presumed to result from biologically inactive GH.
The observed discrepancy between the very homogeneous hormone data proving severe GH and IGF-I deficiencies and the high variability of growth failure even within the same family suggests that the onset and predominance of GH-dependent growth during infancy are individually different and modified by as yet unknown factors.
Patients with single allele defects in the gene encoding the type 1 IGF receptor have been reported to have growth failure, but fibroblasts from affected patients have not exhibited insensitivity to the effects of IGF-I in vitro.
The differences from patients with GHRD include normal hand and foot length in seven of eight, normal arm span with relatively long legs, and persistence of extremely low levels of IGF-I into adulthood; similarities include the degree of growth failure, frequent but not uniform increased body weight for height or body mass index, and the presence of limited elbow extensibility and blue scleras in six of eight.
IGF-I deficiency is associated with prenatal and post-natal growth failure and may arise primarily as a result of GH receptor/post-receptor abnormalities or defects in the synthesis and transport of IGF-I.
Our results suggest that there is minimal DNA sequence variability in the human IGF-I gene and that mutations in IGF-I exons are infrequent causes of growth failure.