CONTEXT: Pregnancy-associated plasma protein-A2 (PAPP-A2) is a metalloproteinase that specifically cleaves IGFBP-3 and IGFBP-5. Mutations in the PAPP-A2 gene have recently been shown to cause postnatal growth failure in humans, with specific skeletal features, due to the resulting decrease in IGF-I bioavailability. However, a pharmacological treatment of this entity is yet to be established.

CASE DESCRIPTION: A 10.5 year old girl and a 6 year old boy, siblings from a Spanish family, with short stature due to a homozygous loss-of-function mutation in the PAPP-A2 gene (p.D643fs25*) and undetectable PAPP-A2 activity, were treated with progressive doses (40, 80, 100 and 120 μg/kg) of recombinant human IGF-I (rhIGF-I) twice daily for one year. There was a clear increase in growth velocity and height in both siblings. Bioactive IGF-I was increased and spontaneous GH secretion was diminished after acute administration of rhIGF-I, while serum total IGF-I and IGFBP-3 levels remained elevated. No episodes of hypoglycemia or any other secondary effects were observed during treatment.

CONCLUSION: Short-term treatment with rhIGF-I improves growth in patients with PAPP-A2 deficiency.