To Örebro University

Retinoic acid receptor agonists can have dramatic negative effects on growth and even induce premature growth cessation and epiphyseal fusion (1, 2).

An 11 5/12-year-old, prepubertal girl with fibrodysplasia ossificans progressiva presented in our pediatric skeletal disorders clinic with the concern of early growth cessation. She had participated in a clinical trial of Palovarotene (“MOVE”, NCT03312634), a retinoic acid receptor-gamma agonist, since the age of 9 10/12 years. At the visit, she had recently discontinued her participation in the study. During the 19 months since starting on Palovarotene, her height had only increased 1.9 cm to 136.4 cm. A skeletal survey detected fusion of several growth plates that normally remain open until the end of puberty including the growth plates of proximal humerus, distal ulna and distal radius. One year after stopping Palovarotene, she was in early puberty and her height had increased another 3.9 cm to 140.3 cm (-2.6 SDS). Measurements of height, sitting height, and arm span confirmed that growth of arms and legs had ceased, whereas growth of the spine continued.

This report supports previous findings indicating that highdose retinoic acid receptor agonists can induce premature epiphyseal fusion even before puberty and may therefore cause significant, disproportionate short stature if used in young children. The finding that growth of the spine, but not legs and arms, resumed after the treatment was discontinued suggests that long bones are more susceptible than vertebrae to retinoic acid-induced epiphyseal fusion.

1. De Luca F, Uyeda JA, Mericq V, Mancilla EE, Yanovski JA, Barnes KM, et al. Retinoic acid is a potent regulator of growth plate chondrogenesis. Endocrinology. 2000;141(1):346–53.

2. Pease CN. Focal retardation and arrestment of growth of bones due to vitamin A intoxication. JAMA. 1962;182:980–5.