Marfan syndrome

• 1. Introduction

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  Marfan syndrome takes its name from Antoine Marfan, a French pediatrician who described it in 1896 after noticing striking features in a five-year-old girl. More than a century later, somewhere between 1 in 5,000 and 1 in 10,000 people live with the condition. The rate looks much the same in every region of the world. It is a genetic disorder of connective tissue, the fibrous material that holds the body together. Because that tissue runs everywhere, one inherited change can show up in the hands, the eyes, the spine, the lungs and the aorta. Why does a single gene reach so many parts of the body? How do doctors recognize the condition, especially in children? And how did a disorder that once shortened lives become one that many people manage for a normal span of years?

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• 2. The Visible Signs

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  Height is the sign most people notice first. Many people with Marfan syndrome grow taller than average, with slender arms and legs, long fingers and toes, and thin, weak wrists.

  The chest wall can sink inward, which is called pectus excavatum, or push outward, which is called pectus carinatum. The spine may curve sideways in scoliosis, and the shoulders often stoop. The roof of the mouth can be high and arched, which crowds the teeth and produces an overbite. For some people, a high palate and a small jaw also lead to speech disorders.

  Flat feet, hammer toes and joints that bend unusually far are common. So are stretch marks with no obvious cause, and pain in the joints, bones and muscles. Early osteoarthritis may follow. In the hips, the rounded top of the thigh bone can protrude into sockets that are unusually deep, which limits how far the hip can move.

  More than 30 signs and symptoms have been linked to the syndrome, and no two people are affected in quite the same way. Some signs cannot be seen from across a room at all, because they sit inside the eye, where a lens hangs on fine strands of connective tissue.

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• 3. The Eye

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  About 60% of people with Marfan syndrome have a lens that has partly slipped out of its normal position, and a slit-lamp biomicroscope can detect it. Doctors call this partial dislocation lens subluxation.

  The lens is suspended inside the eye by strands of connective tissue called ciliary zonules. The mutations behind Marfan syndrome weaken these strands and let them stretch. The lower strands are stretched most often, so the lens usually drifts upward and outward, although it can move in other directions. When the shift is subtle, high-resolution ultrasound biomicroscopy may be used to see it.

  Nearsightedness and blurred vision are common. Farsightedness can appear instead, particularly when the lens is badly displaced. The eyeball can also lengthen along one axis, the cornea can be unusually flat, and the eyes can turn inward or outward.

  People with the syndrome face a high risk of early glaucoma and early cataracts. They also face a risk of retinal detachment, which is one reason they may be advised to avoid contact sports and activities with a danger of falls. Surgery can often treat these complications, and artificial lenses can be implanted when the natural lens has moved.

  Servious as they can be, these eye problems do not threaten life. The cardiovascular signs can.

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• 4. Heart and Lungs

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  Undue fatigue, shortness of breath, racing heartbeats and chest pain that radiates to the back, shoulder or arm are the cardiovascular warnings that matter most. Cold arms, hands and feet can also point to poor circulation. A heart murmur, an abnormal ECG reading or symptoms of angina may prompt a closer look.

  Leaking of the mitral or aortic valves can arise from cystic medial degeneration, a weakening of the valve tissue that often accompanies the syndrome. Yet the finding most likely to make a doctor suspect an underlying condition is a dilated aorta or an aortic aneurysm.

  Sometimes nothing seems wrong until the weakened wall of the ascending aorta produces an aneurysm or an aortic dissection, which is a surgical emergency. A dissection announces itself with pain that radiates down the back and feels like tearing. It may be fatal, especially when diagnosis is delayed.

  Even after the aortic root has been operated on, a Type B dissection can occur in the descending aorta. That type is less likely to need surgery but can still kill. The abnormal tissue also makes a prosthetic mitral valve more likely to pull loose, so surgeons are advised to repair damaged valves rather than replace them.

  The lungs are touched less dramatically. A spontaneous pneumothorax can occur, though it is not common. Air escapes from a lung into the space between the lung and the chest wall, and the lung partly compresses or collapses. Pain, shortness of breath and a bluish tint to the skin can result, and untreated it can cause death.

  Sleep apnea, usually treated with BiPAP, and a form of obstructive lung disease with no known cause are other possibilities. Researchers have also described cysts, emphysema, bronchiectasis and a malformation called middle lobe hypoplasia. Every one of these problems traces back to a single protein.

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• 5. The Fibrillin Gene

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  In 1991, Francesco Ramirez at the Mount Sinai Medical Center in New York City identified the gene linked to Marfan syndrome. The gene is called FBN1 and sits on chromosome 15. It carries the instructions for fibrillin-1, a glycoprotein the body needs to build its extracellular matrix, including the elastic fibers within it.

  Elastic fibers are found throughout the body, but they are especially abundant in the aorta, the ligaments and the zonules of the eye. That distribution explains why those places are among the worst affected.

  Inheritance is autosomal dominant. A parent with the condition has a 50% chance of passing it to each child. About 75% of cases are inherited, and most affected people have another affected relative. The remainder arise as new mutations, which occur in roughly one in 20,000 births. The same mutation can produce mild disease in one person and severe disease in another.

  A transgenic mouse carrying one copy of a mutant fibrillin-1 reproduces many features of the human disease. Lowering the level of normal fibrillin-1 in mice also produces a Marfan-related disorder.

  Fibrillin-1 normally binds a dormant form of transforming growth factor beta, or TGF-β, and holds it in check. The simplest model says that less fibrillin-1 lets TGF-β levels rise. Exactly how that rise causes the damage is not proven. An inflammatory reaction that releases enzymes called proteases, which slowly break down elastic fibers, is known to occur.

  The importance of this pathway was confirmed by the discovery of Loeys-Dietz syndrome, which involves the TGFβR2 gene on chromosome 3. Doctors have often confused the two conditions because their symptoms overlap so much.

  Since 2010, evidence has pointed to a variant called marfanoid-progeroid-lipodystrophy syndrome. It is linked to mutations near the 3' end of FBN1. People with it have Marfan features along with reduced white fat tissue, as seen in neonatal progeroid syndrome. They are also short of asprosin, a hormone that helps regulate glucose and is cut from profibrillin. Because so many conditions resemble Marfan syndrome, naming it correctly is a task of its own.

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• 6. Reaching a Diagnosis

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  In 1996, doctors agreed on international diagnostic criteria for Marfan syndrome, and in 2010 a revised version of the Ghent nosology replaced them. Children are hard to diagnose because they typically show no symptoms until puberty.

  The 2010 rules offer seven routes to a diagnosis. With no family history, an aortic root Z-score of at least 2 counts when paired with a displaced lens, an FBN1 mutation, or a systemic score above 7. A displaced lens together with an FBN1 mutation known to accompany aortic disease also qualifies. With a family history, any one of three findings is enough: a displaced lens, a systemic score of at least 7, or an aortic root Z-score of at least 2.

  The systemic score is a points tally across the body. A positive wrist sign and thumb sign together earn 3 points. Pectus carinatum, a hindfoot deformity, dural ectasia, protrusio acetabuli and pneumothorax earn 2 points each. Scoliosis, stretch marks, nearsightedness beyond 3 diopters and mitral valve prolapse earn 1 point each.

  Two of those signs can be checked in seconds. For the thumb sign, also called Steinberg's sign, the person flexes the thumb as far as possible and closes the fingers over it. The sign is positive when the whole end bone of the thumb shows beyond the edge of the hand. That happens when the thumb is both unusually mobile and longer than usual.

  For the wrist sign, named for Walker and Murdoch, the person curls the thumb and fingers of one hand around the opposite wrist. It is positive when the little finger and thumb overlap, a result of thin wrists and long fingers.

  Many other disorders can produce a similar build, and doctors call these marfanoid. They include Ehlers-Danlos syndrome, homocystinuria, Stickler syndrome, Shprintzen-Goldberg syndrome, multiple endocrine neoplasia type 2B and congenital contractural arachnodactyly, also known as Beals-Hecht syndrome. Genetic testing and a search for other signs help tell them apart. For a confirmed case, the next step is regular checkups of the heart valves and the aorta.

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• 7. Care and Surgery

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  Before modern heart surgery and drugs such as losartan and metoprolol, many people with Marfan syndrome died in their teens and twenties. Lifespan was reduced by at least a third. Life expectancy has risen significantly since the 1970s and is now similar to that of the average person. Women with the syndrome live longer than men, and more manifestations of the disease are being found as more patients survive.

  There is still no cure. Care means treating each problem as it arises, along with preventive medication, even in young children, to slow the widening of the aorta. The goals are to calm heart rhythm problems, lower the heart rate and bring down blood pressure. Beta blockers such as propranolol ease the stress on the aorta. When they are not tolerated, doctors turn to calcium channel blockers, ACE inhibitors or angiotensin receptor blockers.

  The American Heart Association has sorted activities for people with no or mild aortic dilation. Bowling, golf, brisk walking, snorkeling, stationary biking and tennis are probably permissible. Basketball, running, downhill skiing, soccer and lap swimming carry intermediate risk. Weightlifting, ice hockey, rock climbing, surfing, windsurfing and scuba diving are high risk.

  Surgery becomes necessary when the aorta swells into a large aneurysm, dissects or ruptures, or when a valve fails. Options include a composite aortic valve graft or a valve-sparing aortic root replacement. Elective operations are generally successful, while surgery during an acute dissection or rupture is far more problematic. Surgeons usually consider an elective operation when the aortic root reaches 50 mm, though each case needs its own evaluation by a cardiologist.

  Custom-built supports for the aortic root offer an alternative. The first was placed in 2004, and by 2020 the procedure had been used in over 300 people. As patients survive enlarged roots and dissections, repairs elsewhere are becoming more common, including descending thoracic aneurysms and aneurysms of the subclavian arteries.

  Spinal surgery calls for detailed imaging and careful planning, because the syndrome can cause spinal abnormalities that produce no symptoms. A small pneumothorax may clear up without treatment in one to two weeks. A moderate one may need a chest drain for several days, and a large one is likely to be an emergency.

  Pregnancy brings a significant risk of aortic dissection, which is often fatal even when treated quickly. Women with the syndrome should be assessed thoroughly before conception, and echocardiography should be done every six to 10 weeks during pregnancy. For most women, safe vaginal delivery is possible.

  Prenatal testing can show whether a child inherited the condition. Chorionic villus sampling can be done at 10 to 12 weeks, and amniocentesis at 16 to 18 weeks. In 1996, the first preimplantation genetic testing for Marfan syndrome was carried out, checking early IVF embryo cells and discarding those with the mutation.

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• 8. Famous and Disputed Cases

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  Portraits of Akhenaten show an elongated skull, a larger pelvis, enlarged thighs and spindly calves, and these features have long invited a Marfan diagnosis. As of 2021, most Egyptologists argue that the images are stylized portrayals shaped by Atenism, not evidence of a medical condition.

  The list of people who have or had Marfan syndrome is firmer. It includes Isaiah Austin, Javier Botet, Austin Carlile, Bradford Cox, Euell Gibbons, Flo Hyman, Jonathan Jeanne, Skinny Dennis Sanchez, Vincent Schiavelli, Troye Sivan, John Tavener, Chris Turner and Matty Cardarople.

  Other names turn up on lists of historical figures and celebrities, but the evidence is speculative, questionable or refuted. Abraham Lincoln's diagnosis is disputed and rests on his physical characteristics and family history. Rumors about Osama bin Laden were judged likely false by journalists. Michael Phelps disputes the claim himself. Niccolò Paganini, Robert Johnson, Jonathan Larson, Joey Ramone and Hank Williams are all speculative cases.

  Sergei Rachmaninoff is a disputed case with a pointed rebuttal: "Rachmaninov did not clearly exhibit any of the other clinical characteristics typical of Marfan's. (...) Nor did he express any of the clinical effects of a Marfan-related syndrome".

  The last name is the most definite. Tutankhamen appears among the doubtful cases only to be struck off, because he did not have Marfan syndrome.

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