Table 2.
IGF-1 Mutation Case Report Summary
| Measures | Proband (present study) | First Author, Year (Ref.) |
||||||
|---|---|---|---|---|---|---|---|---|
| Fuqua, 2012 (5) | Van Duyvenvoorde, 2010 (10), Sibling 2 | Van Duyvenvoorde, 2010 (10), Sibling 1 | Netchine, 2009 (9) | Walenkamp, 2005 (11) | Bonapace, 2003 (8) | Woods, 1996 (7) | ||
| Birth weight SDS | −1.5 | −1.5 | −1.2 | −2.9 | −2.4 | −3.9 | −4.0 | −3.9 |
| Birth length SDS | −1.2 | −0.6 | −1.0 | −3.8 | −3.7 | −4.3 | −6.5 | −5.4 |
| HC SDS | −3.4 | No microcephaly | −1.6 | −2.4 | −2.5 | −8.0 | −7.5 | −4.9 |
| Height SDS | −2.7 | −4.2 | −4.6 | −4.1 | −4.9 | −8.5 | −6.2 | −6.9 |
| Phenotype | ||||||||
| IUGR | Yes | No | NR | NR | Yes | Yes | Yes | Yes |
| Hearing impaired | No | No | NR | NR | No | Yes | Yes | Yes |
| Cognitive delay | Yes | No | NR | Yes (details NR) | Yes (IQ 70–75) | Yes (IQ < 40) | Yes (details NR) | Yes (details NR) |
| Micrognathia | Yes | NR | NR | NR | NR | Yes | NR | Yes |
| Clinodactyly | Yes | NR | NR | NR | Yes | NR | NR | Yes |
| IGF-1 | Low-normal | Low-normal | Low | Low | Low | Very high | Low | Undetectable |
| IGFBP-3 | Normal | Normal | Normal | Normal | High (after GH) | Normal | Normal | Normal |
| ALS | High-normal | High-normal | Normal | Normal | High (after GH) | High | NR | Normal |
| GH | NR | Basal, 0.82 ng/mL (nl, <10); stim, 15 ng/mL (nl, >10) | Borderline GH during stim (actual value NR) | GH max during stim, 10.7 μg/L (nl, >6.7) | Basal, 0.7 ng/mL; stim, 26 ng/mL (nl, >7) | Basal,13 ng/mL (high); stim, 127 ng/mL (high) | Basal, 10 ng/mL; stim, 18 ng/mL (high) (nl, 10–12 ng/mL) | Basal, 18 ng/mL (high); stim, 94 ng/mL (high) |
| Bone age | Normal | Normal | Delayed | Delayed | Delayed | Delayed | Delayed | Delayed |
| IGF-1 abnormality | Heterozygous; IGF-1 gene deletion | Heterozygous; exon 4 splicing excision → frameshift mutation and early stop codon (c.402 + 1G>C, p.N74Rfs*8) | Heterozygous; 4 bp duplication → frameshift mutation and early stop codon (c.243–246dupCAGC, p.S83Qfs*13) | Heterozygous; 4 bp duplication → frameshift mutation and early stop codon (c.243–246dupCAGC, p.S83Qfs*13) | Homozygous; missense mutation with 4 × lower IGF1R affinity (p.R36Q) | Homozygous; missense mutation with 90 × lower IGF1R affinity (p.V44M) | Homozygous; T to A transversion of poly-A tail leading to truncated exon 6 | Homozygous; deletion of exons 4 and 5 |
| Parental height SDS | ||||||||
| Maternal | −1.3 | −4.6a | −3.5a | −3.5a | −2.9a | −2.4a | −1.6a | −1.4a |
| Paternal | −2.0a | +1.2 | −1.3 | −1.3 | −1.0a | +0.3a | −1.9a | −1.8a |
| Treatment response (rhGH vs rhIGF-1) | NR | After 9 mo rhGH (44 μg/kg/d): GV, 4.1 cm/y; height, SDS − 3.8 (from − 4.19). Followed by: 8 mo rhIGF-1 (120 mg/kg twice a day), GV, 6 cm/y; height, SDS − 3.5 | After 2 y rhGH (1.4 mg/m2/d): height SDS increased by +1.5; plasma IGF-1 SDS increased from −2.4 to +0.3 | After 2 y rhGH (1.4 mg/m2/d): height SDS increased by +1.0; plasma IGF-1 SDS increased from −2.6 to +0.6 | On rhGH 0.4 mg/kg/wk, GV increased to max 9–10 cm/y. On rhGH 0.2 mg/kg/wk, GV decreased to 5 cm/y | NR | After 6 mo rhIGF-1 (40 μg/kg/d): GV, 4.4 cm/y. Followed by rhIGF-1 (80 μg/kg/d): GV max 7.9 cm/y. On rhIGF-1, HC SDS improved (−7.5 to −4.3) | On rhGH × 1.7 y, no GV improvement. On rhIGF-1 (40 μg/kg/d): GV 4.2 cm/y. On rhIGF-1 (80 μg/kg/d), GV 7.3 cm/y. On rhIGF-1, insulin resistance improved |
Abbreviations: HC, head circumference; stim, stimulation; nl, normal; NR, not reported; GV, growth velocity.
a
Heterozygous carrier parent.