Marfan syndrome and its relatives

In 1896, Dr Antoine Marfan – a French paediatrician working in the Faculty of Medicine in the University of Paris – presented a young girl called Gabrielle P to his colleagues: she had features of a connective tissue disorder characterised by long, slender limbs and joint contractures. He called the condition dolichostenomelia (which is Greek for slender limbs).

In 1902, Gabrielle P was studied using the new technology of X-rays by Drs Henri Mery and Leon Babonneix. She was noted to have abnormalities of her thoracic spine and her diagnosis was changed to hyperchondroplasia – effectively the opposite of the condition ‘achondroplasia’.

In the same year, Dr Emile Achard – also a Parisian doctor – reported a patient with similar physical features and used the term ‘arachnodactylie’. Dr Achard reported that his patient was hypermobile and noted a positive family history of similar features.

Gabrielle P died in adolescence, possibly from tuberculosis, a common infection in 19th century Europe. Interestingly, Dr Marfan went on to become a specialist in children’s infectious disease and hygiene.

Several people with similar features and, importantly, complications affecting the eye or aorta, were described in the early part of the 20th century, although the term ‘Marfan syndrome’ was only proposed for the first time (in the journal ‘Le Nourisson’ – ‘the infant’) in 1929 by Dr Carrau (who used the term ‘maladie de Marfan’). Ironically, then, it was probably Dr Achard who described the first case of what we now call Marfan syndrome (although this is a matter of debate); Gabrielle P may not have had Marfan syndrome at all, but a related condition we now call Beal’s syndrome (or congenital contractural arachnodactyly).

In the 1950s, Dr Victor McKusick summarised the collective experience of many different clinicians and wrote what is probably the first modern account of Marfan syndrome in his ground-breaking book ‘Heritable Disorders of Connective Tissue’. He pondered on the link between lens dislocation and aortic aneurysm.

Since the 1950s, diagnostic criteria for Marfan syndrome have been refined and, in 1991, mutations were first reported by Dr Hal Dietz in a gene known as FBN1 in patients with the condition. FBN1 encodes a protein called fibrillin. Over the following decades, the link between FBN1 mutations and Marfan syndrome was slowly unpicked, leading to new therapeutic opportunities.

In the first decade or so of the 21st century, patients with similar features to Marfan syndrome were described but without characteristic FBN1 mutations. Instead, they people were found to have mutations in different genes. Most of the molecules encoded by these additional genes were found to interact with fibrillin. Marfan syndrome is therefore the senior member of a family of rare connective tissue diseases that share a common feature: aortic aneurysm. These diseases are generally called either Loeys Dietz syndrome or familial thoracic aortic aneurysm.