ClinVar Genomic variation as it relates to human health

Salvatori et al. (1999) examined 22 affected members of a large extended Brazilian kindred (Itabaianinha cohort) containing at least 105 members with autosomal recessive short stature (IGHD4; 618157), formerly IGHD1B, Extensive endocrine evaluation confirmed markedly reduced or undetectable serum concentrations of GH that did not increase in response to different stimuli. Analysis of the GHRHR gene detected a novel homozygous 5-prime splice site mutation, a G-to-A transition at position +1 of intron 1. Thirty of the affected subjects tested were homozygous for this mutation, and of 64 clinically unaffected patients, 41, including 9 obligate carriers, were heterozygous for the mutation and 23 were homozygous for the wildtype sequence. Aguiar-Oliveira et al. (1999) measured insulin-like growth factor I (IGF1; 147440), IGF2 (147470), IGF-binding protein-1 (IGFBP1; 146730), IGFBP2 (146731), IGFBP3 (146732), and acid labile subunit (ALS; 601489) in 27 subjects with GHD (aged 5 to 82 years) from the Itabaianinha cohort with the intron 1 splice site GHRHR mutation and in 55 indigenous controls (aged 5 to 80 years). All components of the IGF axis, measured and theoretical, showed complete separation between GHD and control subjects, except IGFBP1 and IGFBP2 concentrations, which did not differ. The most profound effects of GHD were on total IGF1, IGF1 in the ternary complex, and ALS. The proportion of IGF1 associated with IGFBP3 remained constant throughout life, but was significantly lower in GHD due to an increase in IGF1/IGFBP2 complexes. As diagnostic tests, IGF1 in the ternary complex and total IGF1 provided the greatest separation between GHD and controls in childhood. The authors concluded that severe GHD not only reduces the amounts of IGFs, IGFBP3, and ALS, but also modifies the distribution of the IGFs bound to each IGFBP. Diagnostic tests used in the investigation of GHD should be tailored to the age of the individual. In particular, measurement of IGF1 in the ternary complex may prove useful in the diagnosis of GHD in children and older adults, whereas free ALS may be more relevant to younger adults. Gondo et al. (2001) compared the pituitary hormone response to GHRP-2, a potent growth hormone secretagogue, in 11 affected individuals from the Itabaianinha cohort with this mutation and in 8 normal unrelated controls. Basal serum GH levels were lower in the GHD group compared with controls. After GHRP-2 administration, there was a 4.5-fold increase in serum GH relative to baseline values in the GHD group, which was significantly less than the 79-fold increase in the control group. The authors concluded that an intact GHRH signaling system is not an absolute requirement for GHRP-2 action on GH secretion and that GHRP-2 has a GHRH-independent effect on pituitary somatotroph cells. Menezes Oliveira et al. (2006) studied the consequences of lifetime IGHD on the metabolic and cardiovascular status of adult members of the large Brazilian kindred (Itabaianinha cohort) with severe IGHD reported by Salvatori et al. (1999). GHD subjects had increased abdominal obesity, higher total and low density lipoprotein cholesterol, and higher C-reactive protein (123260) than controls. They did not have an increase in carotid wall thickness, and there was no evidence of premature atherosclerosis as evaluated by exercise echocardiography. The authors concluded that in this homogeneous cohort, untreated severe IGHD is not associated with evidence of premature atherosclerosis despite unfavorable cardiovascular risk profile. Pereira et al. (2007) compared 76 adult subjects (age, 25-75 years) from the Itabaianinha cohort who were heterozygous for the IVS1+1G-A mutation with 77 sex-matched controls from the same population who were homozygous for the wildtype GHRHR allele. They found no difference in adult height or SD score for serum IGF-I between the 2 groups. However, body weight, body mass index, skin folds, waist and hip circumferences, and lean mass were all reduced in heterozygous subjects. The authors concluded that heterozygosity for a null GHRHR mutation is associated with changes in body composition and possibly an increase in insulin sensitivity. Oliveira et al. (2007) reported that in patients with lifetime isolated GHD due to IVS1+1G-A homozygosity, 6-month treatment with GH had reversible beneficial effects on body composition and metabolic profile, but caused a progressive increase in intima-media thickness and in the number of atherosclerotic carotid plaques. (less)