Supplementary Material for: Five-Year Therapy with Recombinant Human Insulin-Like Growth Factor-1 in a Patient with PAPP-A2 Deficiency

Introduction: The metalloproteinase pregnancy-associated plasma protein A2 (PAPP-A2) cleaves insulin-like growth factor (IGF) binding proteins 3 and 5 to release bioactive IGF-I from its ternary complex. Patients with mutations in PAPP-A2 have growth failure and low free IGF-I despite elevated total IGF-I. We describe five-year treatment response to recombinant human IGF-1 (rhIGF-1) in a patient with PAPP-A2 deficiency, and the phenotype of PAPP-A2 deficiency in three siblings. Methods: Two siblings (P2, P3) with PAPP-A2 deficiency were recruited for rhIGF-1 therapy at 120 mcg/kg subcutaneous twice daily, along with a third sibling (P1) for phenotyping. We evaluated efficacy and safety of rhIGF-1 therapy, including effect on metabolic measures and bone mineral density (BMD). Results: Treatment with rhIGF-1 was started in 10.4y (P3) and 14.5y (P2) old brothers. P2 discontinued therapy due to pseudotumor cerebri. P3 continued rhIGF-1 for 5 years; HV increased (3.0 cm/y at baseline; 5.0-7.6 cm/y thereafter) as did height SDS (+0.6). P3’s pubertal onset was at 12.4y. BMD height-adjusted-Z-score modestly improved for lumbar spine (+0.4), and decreased in forearm (-0.2) and hip (-0.3). All siblings had hyperinsulinemia. Impaired glucose tolerance (IGT) resolved in P1. P2 showed worsening glucose tolerance (2-hr glucose: 225 mg/dL). Impaired fasting glucose and hyperinsulinemia initially resolved for P3, but IGT (2-hr glucose: 152 mg/dL) developed during puberty. Conclusion: Therapy with rhIGF-1 modestly improved linear growth in one patient with PAPPA-2 deficiency, but without true catch-up. Therapy was associated with pseudotumor cerebri in a sibling. Initial improvement in BMD and glycemic pattern on rhIGF-1 was not sustained during puberty.