Insulin-Like Growth Factor I Deficiency

A number sign (#) is used with this entry because insulin-like growth factor I deficiency is caused by homozygous mutation in the IGF1 gene (147440) on chromosome 12q22.

Clinical Features

Woods et al. (1996) described a 15-year-old boy, born of consanguineous parents, who had severe prenatal and postnatal growth failure, sensorineural deafness, and mental retardation. He was delivered at 37 weeks' gestation by cesarean section because of poor fetal growth, and showed symmetric growth retardation at birth, with a weight of 1.4 kg, length of 37.8 cm, and head circumference of 27 cm. Severe growth failure continued throughout infancy and childhood. He also had profound bilateral sensorineural deafness and moderately delayed motor development, with behavioral difficulties including hyperactivity and short attention span. Mild facial dysmorphism was also noted. Serum basal and stimulated growth hormone (GH; 139250) levels were increased and serum IGF1 was decreased. There was no response to therapy with human growth hormone administered from the age of 11 to 12 years. Woods et al. (1996) noted that patients with GH insensitivity (Laron dwarfism; 262500) also have high serum GH concentrations and low serum IGF1 concentrations, as well as insulin (176730) sensitivity and episodes of hypoglycemia, especially during infancy. By contrast, the patient reported by Woods et al. (1996) did not have hypoglycemia, perhaps because of resistance to insulin resulting from excess growth hormone secretion, and had neurologic involvement, which is not found in GH insensitivity.

Bonapace et al. (2003) reported a patient with IGF1 deficiency who was born at 39 weeks' gestation by cesarean section because of poor fetal growth. Birth weight, length, and head circumference were severely decreased. The parents, who were second cousins, were both at the 5th percentile for height. The patient continued to show poor growth and delayed bone age, as well as delayed psychomotor development and sensorineural deafness. Serum IGF1 levels were decreased. Bonapace et al. (2003) noted the striking phenotypic similarities to the patient reported by Woods et al. (1996).

Clinical Management

Camacho-Hubner et al. (1999) investigated the effects of recombinant human IGF1 therapy on the growth hormone-IGF system of the patient with severe growth retardation due to partial deletion of the IGF1 gene reported by Woods et al. (1996). GH profiles showed a decrease in peak amplitude, from 342 to 84 mU/L at 1 month, to 67 mU/L at 6 months, and to 40 mU/L at 1 year of therapy, with no significant changes in peak number. A significant increase in IGF-binding protein-1 (IGFBP1; 146730) levels was observed during treatment with 80 microg/kg-day IGF1, reflecting the inhibitory effect of recombinant human IGF1 on insulin secretion. The clinical response to recombinant human IGF1 therapy was an increased height velocity, from 3.8 cm/yr before treatment to 6.6 cm/yr. Increased lean body mass correlated with changes in the doses of recombinant human IGF1 and, in turn, with the biochemical changes in the GH-IGF axis. The authors concluded that recombinant human IGF1 treatment improved linear growth and insulin sensitivity in this patient by restoring IGF1 levels and by normalizing circulating GH, IGFBP, and insulin levels.

Woods et al. (2000) reported results of 1-year recombinant human IGF1 therapy on body composition, bone mineral density (BMD), insulin sensitivity, and linear growth in the patient reported by Woods et al. (1996). Recombinant human IGF1 therapy was initiated at age 16.07 years (bone age, 14.2 years) at a starting dose of 40 microg/kg daily, increasing after 3 months to 80 microg/kg daily. Body composition, BMD, markers of bone mineralization, and auxologic parameters (height and weight) were measured at 0, 6, and 12 months after start of therapy. On IGF1 therapy, body mass index increased from 17 kg/m2 to 18.6 kg/m2. Body composition studies revealed an initial decrease in total body fat, from 19.9% at baseline to 15.1% at 6 months. By 12 months of therapy, however, this had reversed, with an increase to 21.8%.

Molecular Genetics

In a patient with severe intrauterine and postnatal growth retardation, Woods et al. (1996) identified a homozygous deletion in the IGF1 gene (147440.0001), resulting in a truncated protein. Genomic studies showed that both parents were heterozygous for the deletion. The patient's mother and father were 154 cm and 163 cm tall, and the authors speculated that their short stature and borderline low serum IGF1 concentrations might represent a heterozygous effect.

In a patient with IGF1 deficiency, Bonapace et al. (2003) identified a homozygous mutation in the IGF1 gene (147440.0002). Both of his parents were heterozygous for the same mutation.

In a 55-year-old male with IGF1 deficiency who was the first child of consanguineous parents, Walenkamp et al. (2005) found a homozygous missense mutation in the IGF1 gene (V44M; 147440.0003). The phenotype included severe intrauterine growth retardation, deafness, and mental retardation, reflecting the GH-independent secretion of IGF1 in utero. Additional investigations revealed osteoporosis, a partial gonadal dysfunction, and a relatively well-preserved cardiac function. The postnatal growth pattern, similar to growth of untreated GH-deficient or GH-insensitive children, is consistent with the hypothesis that IGF1 secretion in childhood is mainly GH-dependent.

Exclusion Studies

Some studies of African Pygmies (265850) found decreased levels of serum IGF1 as a potential cause of their short stature (Merimee et al., 1981), but Bowcock and Sartorelli (1990) found no difference in the distribution of IGF1 RFLPs in Pygmies versus non-Pygmy black Africans, and no mutations in a DNA region 330-bp upstream of the IGF1 initiation site in Pygmies.