Abstract
Introduction
Marfan syndrome (MFS) is a common connective tissue disorder affecting one in 3300 people worldwide, and is caused by unique mutations in the 65 exon gene for fibrillin-1—an essential microfibril component of ligaments, tendons, and muscle. A recently discovered feature in the Marfan mouse model is increased concentrations of transforming growth factor β, resulting in overgrowth. 70% of patients with MFS have scoliosis of some degree. Can lessons be learned from MFS aetiology and treatment that apply to idiopathic adolescent scoliosis? We aimed to establish whether there is a relationship between the type and location of mutation, and the presence and degree of severity of scoliosis, in patients with MFS.
Methods
Of 181 consecutive patients with MFS with known causative fibrillin-1 mutations, 93 were male (51%) and 88 female (49%). 28 (15%; ten males, 18 females) of the total group had moderate to severe scoliosis, including two females and two males who had corrective surgery. Of the 16 patients with severe scoliosis (three males, 13 females), FBN1 mutations clustered in the latter half of the gene in exons 33–63. Of these 16 mutations, ten were severe (seven stop codons, three splice site mutations); the others were point mutations, three involving added cysteine and three substituted cysteine, in calcium-binding EGF-like regions.
Height A rapid adolescent growth spurt to excessive height is a documented clinical feature in MFS. The age of clinical diagnosis as an indication of severity was on average 11·3 years (range 2 days to 36 years), and ten patients were diagnosed before the age of 12 years.
Conclusions
Genotype-phenotype correlation for patients with MFS with moderate to severe scoliosis shows the trend/association of severe mutations in 25%, with 50% of the total in the latter half of the gene (exons 33–63) with stop codons and splice site mutations. Cysteine substitutions in calcium binding EGF-like regions occurred in a further 25% of mutations. Disruption of spinal support together with rapid excessive early pubertal growth presents a human model for production of scoliosis, and a rationale for attempted preventive irbesartan therapy in Marfan mouse models and human patients. The 21-centre national AIMS Trial of irbesartan in MFS commences in January, 2011, and skeletal measurements will be of interest.
