MARE-study: Metabolic derAngements in heReditary multiple Exostoses (HME) subjects with either heterozygous EXT1 or EXT2 mutations; a clinical cohort study.

To relate clinical phenotype of subjects with Hereditary Multipele Exostoses to EXT genotype in relation to:

1. Glycemic control (HbA1c, fasting glucose and insulin, OGTT and HOMA-r);

2. Cardiovascular risk profile including baseline ECG, dyslipdemia (fasting lipid profiles) and microalbuminuria;

3. Adrenal gland function (synacthen test).



We will study subjects with hereditary multiple exostoses (HME) who are frequently seen at the outpatient clinic of orthopaedic surgery at the OLVG. Patients as well as unaffected family members will be contacted by mail one month before their regular visit to treating physician dr Ham/dr van der Zwan for their consent to participate in these clinic study and to arrive at the OLVG fasted. All studies/measurements will be performed at the OLVG.

A recent Genome Wide Association Study (GWAS) identified novel risk loci for type 2 diabetes including EXT-2. This gene codes for exostosin, which is an enzyme involved in the elongation of heparan sulfate, a glycosaminoglycan present in all cells throughout the human body. Patients with EXT-1 and EXT-2 mutations are phenotypically characterized by the hereditary multiple exostoses/ multiple osteochondromas (HME/MO) syndrome, an autosomal dominant syndrome causing multiple epiphysial bone tumors due to a reduction in heparan sulfate synthesis. Thus, these subjects are solely seen in the orthopaedic outpatient clinic. However, preliminary data show that mice with identical EXT mutations are also characterized by insulin secretion problems and anatomic smaller pancreas, dyslipidemia and adrenal insufficiency. This is most likely induced due to impaired heparan-sulfate orchestrated organ development and cell to cell signalling.

One measurement period.

1. Orale glucose tolerance test (OGTT) for glucose disposal;

2. Synacthen test for adrenal gland function.