The Undiagnosed 8,000

From unifying a set of signs and symptoms behind a single diagnosis to finding the causative gene, awareness of Marfan syndrome has travelled a long, long way. But there is still so much to do and many (undiagnosed) people to find! Read our final take on the month:

The tip of the Iceberg – Marfan, Loeys-Dietz and related Conditions
by Angus McCrone

When a new iceberg is spotted, what is above the water is the conspicuous bit. What is below the water is less obvious, but it is usually much larger and will take a longer time to examine.

Something similar has happened with Marfan Syndrome and other genetic conditions that predispose people to increased risk of aortic aneurysm. The easiest diagnoses have always been of people with ‘classic’ indications, such as unusual height, thinness, long fingers and eye problems.

The advent of genetic testing in the 21st Century has revealed that the community of patients affected by these conditions is much larger than previously thought.

Dr Anne Child, medical director for the Marfan Trust, says: “There was a paper published in the 1970s, looking at the incidence of Marfan Syndrome in Northern Ireland. It estimated the prevalence at one in every 40,000 people.

“We now know the figure is one in 3,000 worldwide. It may even be a bit higher than that.”

Something similar is happening with the related condition of Loeys-Dietz Syndrome, which was only identified for the first time in 2005. Some health websites still say that its incidence is less than one in 100,000. “That must be too cautious,” says Anne.

Genetic testing for LDS only came in around six years ago, and since then numbers of cases have been rising fast. At the Marfan Symposium in London in August 2024, it was striking how many people attending picked up Loeys-Dietz badges to identify their condition.

Pinpointing different genetic markers for genetic conditions linked to aortic aneurysms is a major area of work for Dr Jose Antonio Aragon-Martin, director of the Sonalee Laboratory located at William Harvey Research Institute in Queen Mary University of London.

He says his team are focussing on three groups – people confirmed with Marfan Syndrome, people confirmed with LDS, and people that fit under the heading of Heritable Thoracic Aortic Aneurysms and Dissections, or HTAAD, but who have a genetic pattern that has not yet been identified.

Jose says: “Yes, we are talking about a larger number of people than previously thought. The genetic testing is addressing people who may not have the more obvious features associated with Marfan.”

One of the consequences of this expansion in the HTAAD ‘universe’ is that there is a gap between many of the milder and less obvious Marfan and LDS patients confirmed by genetic testing, and the descriptions of these conditions on medical websites.

Anne says: “The American Marfan Foundation website asks families to send in photos. Pictures that don’t exhibit outward signs of the condition don’t teach anyone anything, so for the sake of education they will select the more obvious features to display, thus raising awareness.”

Genetic research has greatly accelerated the effort to help alleviate the suffering of HTAAD patients. Anne says: “First we found the gene, then we were able to develop diagnostic techniques, and those now identify 97% of patients with Marfan Syndrome. Then the NHS adopted that on the list of its tests, then we got improvements in both medication and surgery, resulting in improvement in life expectancy and the quality of life. Then we will try to find a cure, using gene editing. We are on a pathway, and we are quite a long way along it.”