Skeletal Phenotype in Mulibrey Nanism, A Monogenic Skeletal Dysplasia With Fibrous Dysplasia

Mulibrey nanism (MUL) is a monogenic growth disorder caused by mutations in TRIM37, with pre-and postnatal growth failure, typical craniofacial features, perimyocardial heart disease, infertility and predisposition to tumors. Clinically, patients are gracile with relative macrocephaly, thin extremities, and narrow shoulders, but the full spectrum of skeletal features remains unknown. We conducted a cross-sectional study in order to further clarify the skeletal phenotype. We assessed radiographs of the long bones and spine in 33 MUL patients, aged 4.5-48 years (14 females and 19 males, median age 16.7 years) for skeletal features. Hospital records were reviewed for clinical characteristics and fractures. Results confirmed significant skeletal abnormalities related to MUL. Skeletal changes were present in all patients; long bones were slender and bowed with broad metaphyses and narrow diaphysis, the cortices were thick, and medullary cavities were narrow. The vertebral bodies were tall. Fibrous dysplasia was found in 19/33 patients (58%); changes were monostotic in 58% and polyostotic in 42%. Altogether 17/33 patients (52%) had a history of fractures. This study confirms that in addition to short stature, patients with MUL have a specific skeletal dysplasia. Our findings suggest an important role for TRIM37 in cellular functions governing skeletal modelling and remodelling.