Five affected subjects from two families presenting moderate growth retardation and elevated circulating levels of IGF1, IGF2, IGFBP-3, IGFBP-5, and ALS were found to be homozygous for two different variants in the PAPPA2 gene (p.D643fs25* and p.A1033V) [92]. Here, IGFBP3 is linked to amyotrophic lateral sclerosis.