Metaphyseal chondromatosis with hydroxyglutaric aciduria (MC-HGA) is a
generalized skeletal dysplasia, accompanied by urinary excretion of D-2-
hydroxyglutarate (HGA), and variable cerebral involvement. By wholeexome
sequencing 2 unrelated patients with MC-HGA, we have found mutations
in isocitrate dehydrogenase 1 (IDH1) at codon 132, as apparent somatic
mosaicism. IDH1 is a key enzyme of the Krebs cycle, which converts isocitrate
into alpha-ketoglutarate (a-KG). Mutations at IDH1 Arg132 residue have
originally been identified in different tumour types (isolated gliomas, leukemias,
and chondrosarcomas). These mutations trans-specify the enzyme activity
resulting in HGA accumulation and a-KG depletion. This induces activation of
hypoxia-inducible factor 1-alpha (HIF-1a), an important regulator of chondrocyte
proliferation at the growth plate. Differently from Arg132 somatic mutations
found in isolated tumours, themutation in our patientsmust have occurred
very early in embryogenesis to cause a generalized dysplasia with involvement
of all long bones metaphyses and mutation detectability in blood. Identical
mutations have subsequently been identified in chondromas excised from
patients with multiple chondromatosis (Ollier disease). Tissue distribution of
themutationmay explain variable cerebral involvement and the susceptibility to
develop tumours in other organs. The postulated pathophysiology ofMC-HGA
points out the link between Krebs cycle, hypoxia sensing and bone growth.