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Diagnosis and management of patients with Marfan syndrome

Current medical and surgical treatments and multidisciplinary care are allowing people with this relatively common genetic disorder to live out a nearly normal life span.

CPT George S. Midla, MPAS, PA-C, CP

George Midla worked on the cardiothoracic surgery service at Madigan Army Medical Center, Tacoma, Washington, when he wrote this article. He has indicated no relationships to disclose relating to the content of this article.

In 1896, Antoine Bernard-Jean Marfan presented a case to the Medical Society of the Hospitals of Paris involving a 5-year-old girl with long limbs, long fingers, slender build, and muscular weakness.¹ In 1902, when additional patients who displayed similar findings along with cardiovascular and ocular manifestations were identified, Marfan syndrome (MFS) was finally described. MFS is an autosomal dominant disorder of the connective tissue caused by a defect in the fibrillin gene on chromosome 15.² Fibrillin is a large glycoprotein that is a component of the microfibrils in a variety of connective tissue; microfibrils are essential for the integrity of elastic fibers.

MFS is a relatively common disorder affecting 2 to 3 in 10,000 persons.³ Approximately 200,000 Americans are believed have the syndrome.⁴ MFS afflicts both sexes and all races equally.⁵ Although it produces the most significant changes to the connective tissue of the musculoskeletal, cardiovascular, and ocular systems, it may also affect the pulmonary, nervous, and integumentary fibrils.

MANIFESTATIONS

Musculoskeletal A variety of skeletal findings are associated with MFS, but the most recognizable is abnormal height. Men with MFS are often taller than 6 ft 5 in, and women are often taller than 6 ft. Dolichostenomelia (having long thin extremities) is also pronounced (see Figure 1). During the physical examination, a patient suspected to have this irregularity is asked to stand with arms fully extended out to the sides. A measurement is then taken of the span, from the tip of the middle finger of each hand. In affected patients, the measured length will be greater than the person’s height (see Figure 2). Arachnodactyly (elongated fingers and toes) is also associated with MFS, along with pectus excavatum or pectus carinatum. Excavatum is the more common of the two pectus deformities.

Joint laxity may be identified. The locations where this is best examined are the knees, wrists, and fingers. When a patient with MFS stands with knees locked, the legs will appear to be bending slightly backwards. The examiner can actively hyperextend the fingers and wrists with little effort and with no discomfort to the patient. In fact, the examiner will often find that the patient enjoys demonstrating these hyperextendable joints.

Distinctive facial features are related to MFS, including dolichocephaly (long head), malar hypoplasia (underdevelopment of the buccal area), enophthalmos (backward displacement of the eyeball into the orbit), retrognathia (posterior positioning of the jaw), and down slanting palpebral fissures. A high arched palate and dental crowding may also occur.

Pes plantus is another possible finding. Kyphoscoliosis and both abdominal and inguinal hernias have also been reported.

Cardiovascular The most worrisome abnormalities associated with MFS are those affecting the cardiovascular system. Because of the weakened development of vascular tissue, the aorta may dilate, and 80% of Marfan syndrome morbidity is linked to aortic aneurysm and dissection.⁶

An aortic aneurysm may manifest as sternal, back, or neck pain. Dyspnea, stridor, and cough due to pressure on the trachea can occur. If the aneurysm is placing pressure on the esophagus, dysphagia may be the initial manifestation. Hoarseness from pressure on the laryngeal nerve is another possibility. Finally, arm or neck edema second to the aneurysm encroaching on the superior vena cava has been documented.

Although all the heart valves can be affected by MFS, aortic root dilatation is of greatest concern. This structural change to the root leads to improper alignment of the valve cusps, causing regurgitation. The development of aortic root dilatation will vary greatly with each patient; but if the condition is allowed to progress, left-sided heart failure and, eventually, death will follow. During auscultation, aortic regurgitation will best be heard with the patient sitting and leaning forward. The diaphragm of the stethoscope should be placed over the right side of the second intercostal space along the sternal border. A high pitch blowing during early diastole is appreciated. Patients will complain of fatigue and shortness of breath. Aortic regurgitation may affect the ECG, which will demonstrate left ventricular hypertrophy (LVH) as a deep S wave viewed in the lead V₁.

Mitral valve prolapse (MVP) is not as significant as aortic regurgitation, but it is still a concern. The valve leaflets of the mitral complex are supported by the chordae tendineae. If affected by MFS, the chordae may elongate or even rupture as a result of the high pressures they are exposed to during systole. Defects in the chordae cause the leaflets to prolapse back into the left atrium. This leads to diminished cardiac output and pulmonary hypertension, depending on the severity. MVP is the most common type of valve disorder associated with MFS and is found in more than 80% of persons with the syndrome.⁷

MVP can be detected when the stethoscope is placed over the apex. The murmur appreciated will vary with progression of the disease. If the regurgitation is mild, a late systolic murmur will be audible; in severe cases, the murmur will be identified early in the heart cycle. The murmur will also radiate to the axilla. As with aortic regurgitation, the patient will complain of fatigue and shortness of breath.

ECG findings in MVP may include left atrial abnormalities such as atrial fibrillation and LVH. Atrial fibrillation is identified by an absence of P waves, a wavy baseline, and an irregularly irregular QRS response.

Ocular The patient with MFS tends to be myopic. Severe myopic conditions are associated with degenerative changes to the peripheral retina. A retina damaged in this way may allow fluid to leak behind it, causing detachment and loss of vision. This is often more worrisome to the patient than the cardiac malformations.

Other ocular conditions include dislocated or subluxed lenses (ectopia lentis). Unlike in patients with homocystinuria, where the lens displaces downward and posteriorly, in patients with MFS, an upward and anterior trend is observed. An abnormally flat cornea, glaucoma, and cataracts have also been observed in persons with the syndrome.

Pulmonary MFS can cause decreased elasticity of the pulmonary tissue, a condition that can lead to a spontaneous pneumothorax. Patients suffering from a spontaneous pneumothorax will present with an acute onset of shortness of breath, a dry cough, or thoracic pain made worse by deep breathing.

Nervous system The dura covering the spinal cord is sometimes found to be weakened in persons with MFS. If the dura is affected this way, dural ectasia may develop. The diagnosis of this condition is based on the following criteria: bulging of the dural sac, lack of epidural fat, presence of radicular cysts, or an anterior sacral meningocele seen on CT or MRI.⁸ The patient may present with any number of neurologic complaints associated with the lumbar spinal area where this condition usually manifests. These complaints include low back pain, radicular pain in the buttocks or legs, leg weakness, and urinary incontinence. A good neurologic examination for lumbar etiologies will produce findings consistent with the level of the spine that is affected.

Integument Striae atrophicae (stretch marks) may develop at any age in persons with MFS. These striae are not associated with weight changes, pregnancy, or repeated stressors. They most often occur on the shoulders, mid-back, and thighs and do not pose a health risk.

DIAGNOSIS

Although MFS was first described more than 100 years ago, diagnosis of the syndrome is still made clinically. The criteria for a clinical diagnosis have evolved as medical testing and documentation have improved. Until recently, the Berlin nosology was used as the standard for identification, but flaws in this system have since been debated and the Ghent nosology, described in 1996, is now accepted.⁹ The Ghent system levies more restrictions on diagnosis when considering skeletal and genetic testing criteria and relatives positively identified with the syndrome. The Ghent classification is based on family history, genetic testing, and the review of six organ systems: skeletal, cardiovascular, ocular, pulmonary, nervous, and integument (see Table 1).

Children do not exhibit many of the Ghent criteria and as a result will not receive a diagnosis until later in life. Until that time they are described as having emerging MFS and are monitored regularly.

Although MFS is a genetic disorder, genetic testing is not usually conducted. Because of the size of and variations in the affected gene, testing is often inaccurate; furthermore, when results are positive, testing can identify only those persons who are predisposed to MFS. Segregation or linkage analysis testing is sometimes applied to larger families where cases of MFS have been identified. Testing these high-risk patients is done so that monitoring programs and some treatments may begin early. Again, such testing is only a screening tool, which serves as an adjunct to the clinical examination.

TREATMENT

MFS has no cure. Patients are managed by a multidisciplinary approach, seeing a variety of specialists who record the progression of the disease and discuss and implement different treatment options.

Each year, an orthopedist evaluates spinal changes in the patient with MFS. Braces may be offered early to slow kyphoscoliosis. Development of a pectus deformity may interfere with cardiac function. Surgical correction for an excavatum, called a Nuss procedure, may be performed by a thoracic surgeon.

The patient should also be followed by a cardiologist with experience in treating MFS. Therapy with beta-blockers is still the standard of care.¹⁰ This class of medications has been shown to slow the progression of aortic dilatation by decreasing BP. In addition, echocardiography is performed to assess function and enlargement of the heart and aorta. Antibiotic prophylaxis against endocarditis is recommended before dental procedures for those patients who have valvular pathology. A medical alert identification bracelet is recommended for all patients with MFS but especially for those who have been identified with cardiac conditions.

Surgical correction of an enlarging aortic root has been shown to increase longevity when the procedure is done prophylactically rather than emergently.¹¹ The accepted degree of enlargement that warrants surgery is 5.5 cm in the adult and 5.0 cm in the child. Factors such as the rate of aneurismal growth and a family history of dissection are also considered. The surgery to replace the root and aortic valve is called the Bentall procedure. Aortic valve-sparing procedures are now more common, although not without some controversy.¹² Most experts agree that if the valve leaflets are closing properly, women considering pregnancy may retain their native heart valve to avoid having to take antiplatelet therapy during pregnancy. The valve is also spared in children to allow it to grow with the patient so it can meet the increasing demands of a larger body surface area.

Regular ophthalmologic visits are scheduled to screen for myopia, strabismus, and lens dislocations. Impaired pulmonary function or a pneumothorax will be compounded in smokers, and tobacco use should be strongly discouraged. Children with MFS may be underweight because of decreased muscle mass. Protein-rich supplements should be considered in this population to help increase muscle volume.

Counseling is an essential part of the treatment plan for all patients. The burden of MFS rests heavily on both the child and parents of those affected. A positive diagnosis will manifest itself psychologically, emotionally, socially, and economically.¹³ Children are asked to curb their athletics, must deal with the stigma of recurrent medical visits, and are likely to be uncomfortable with their body habitus. Adults may become angry or afraid. Parents of those with the syndrome might harbor feelings of guilt. For all of these reasons and more, regular counseling is advised. With the risk of transmitting MFS to a fetus being 50%, genetic counseling before the patient becomes sexually active is advised.

Exercise Patients with MFS are living into their 70s with current medical therapies. An exercise program is important, although training should be adjusted for the type and severity of organ system involvement. Patients should be evaluated for current health, medication use, and physical fitness before an exercise program is outlined.

A review of medications is important because beta-blockers may reduce a person’s ability to participate in strenuous activities. Those taking anticoagulants will be at an increased risk for bleeding episodes. Appropriate measures must be taken to reduce the chance of injuries in these patients.

Light to moderate activity levels and low-impact sports are generally suggested. Contact sports and weight lifting cause additional stress on the aorta and the skeletal system and should be avoided. Also, contact sports can precipitate an ocular emergency. Some activity suggestions for patients with MFS are walking, jogging, swimming, noncompetitive basketball, golf, and light tennis. Because of the increased risk of a pneumothorax, radical changes in atmospheric pressure, such as those experienced while scuba diving, flying in an unpressurized aircraft, or skydiving, should be avoided.

Pregnancy Aortic dissection becomes more likely during pregnancy, and the threat is greater when the woman’s aortic root is 4 cm or larger before she conceives. The increased risk may be due to inhibition of collagen and elastin deposition in the aorta by estrogen, gestational hypertension, and preeclampsia. A cardiac evaluation and review by obstetrics is recommended before conception occurs. If required, beta-blocker therapy should continue throughout the pregnancy.

NEW DIRECTIONS

Recent studies have shown that losartan (Cozaar), an angiotensin II type 1 receptor antagonist, may have potential in the treatment of MFS.¹⁴ During studies involving mouse models, losartan demonstrated that it arrested the development of many manifestations of MFS by lowering the activity of transforming growth factor (TGF) beta. In some cases, the medication also reversed aortic pathology.¹⁵ The increase in TGF-beta is due to a signaling problem resulting from a lack of the fibrillin gene. Losartan has a safe record and is already approved for use in persons older than 6 years. A multicenter clinical trial to compare the beta-blocker atenolol (Tenormin) with losartan has been proposed.

Conclusion Without intervention, the life expectancy of the patient with MFS is 32 years, but current treatments are now enabling these patients to live out a nearly normal life span. As they grow older, this new generation of patients will create more challenges for clinicians since the long-term manifestations of Marfan syndrome have not been well documented. PAs should continually examine the literature for updates on this challenging group of patients. In the future, the use of losartan in treating MFS may give the medical community a powerful tool in which to combat this syndrome.

REFERENCES

	1.	Marfan AB. Un cas de déformation congénital des quatre membres plus prononcée aux extrémitiés caractérisée par l’allongement des os avec un certain degré d’amincissement. Bull Mém Soc Méd Hôp. Paris 1896;13:220-226.
	2.	Dietz HC, Loeys B, Carta L, Ramirez F. Recent progress towards a molecular understanding of Marfan syndrome. Am J Med Genet C Semin Med Genet. 2005;139(1):4-9.
	3.	Meijboom LJ, Nollen GJ, Mulder BJM. Prevention of cardiovascular complications in the Marfan syndrome. Vascular Disease Prevention. 2004;1(1):79-86.
	4.	Orenstein BW. Aortic dissection: problems at the pump. For the Record. 2004;16(15):34.
	5.	Grimes SJ, Acheson LS, Matthews AL, Wiesner GL. Clinical consult: Marfan syndrome. Prim Care. 2004;31(3):739-742, xii.
	6.	Porciani MC, Attanasio M, Lepri V, et al. Prevalence of cardiovascular manifestations in Marfan syndrome. Ital Heart J Suppl. 2004;5(8):647-652.
	7.	Nienaber CA, Von Kodolitsch Y. Therapeutic management of patients with Marfan syndrome: focus on cardiovascular involvement. Cardiol Rev. 1999;7(6):332-341.
	8.	Ahn NU, Sponseller PD, Nallamshetty L, et al. Dural ectasia in the Marfan syndrome: MR and CT findings and criteria. Genet Med. 2000;2(3):173-179.
	9.	De Paepe A, Devereux RB, Dietz HC, et al. Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet. 1996;62(4):417-426.
	10.	Sharkey AM. Cardiovascular management of Marfan syndrome in the young. Curr Treat Options Cardiovasc Med. 2006;8(5):396-402.
	11.	Kim SY, Martin N, Hsia EC, et al. Management of aortic disease in Marfan syndrome: a decision analysis. Arch Intern Med. 2005;165(7):749-755.
	12.	Patel ND, Williams JA, Barreiro CJ, et al. Valve-sparing aortic root replacement: early experience with the De Paulis Valsalva graft in 51 patients. Ann Thorac Surg. 2006;82(2):548-553.
	13.	Peters K, Apse K, Blackford A, et al. Living with Marfan syndrome: coping with stigma. Clin Genet. 2005;68(1):6-14.
	14.	Gleb B. Marfan’s syndrome and related disorders—more tightly connected than we thought. N Engl J Med. 2006;355(8):841-844.
	15.	Habashi JP, Judge DP, Holm TM, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science. 2006;312(5770):117-121.