Marfan Syndrome: Identification And Management

Marfan Syndrome: Identification And Management

Leann Eaton

Case in Point

Julian Kincaid was at the peak of recognition for his athletic abilities in several sports at a local high school. The community newspaper published stories about major league sports scouts attending the recent playoff games. The scouts represented professional teams in basketball and track. The annual physical examinations for high school sports participation had been fairly general. Historically no one had been denied a place on team sports due to failing the annual brief physical examination each year.

During the last few minutes of the final basketball game of Julian Kincaid’s senior year, he collapsed on the court. After unsuccessful attempts to resuscitate Julian, he was pronounced dead. On the autopsy, he was found to have died of a ruptured aortic aneurysm. His complete diagnosis included Marfan’s syndrome.

Introduction

The identification of milder forms of Marfan’s syndrome is often overlooked in the young adult male population. The description of the Lincolnesque appearance with excessive height, long fingers and toes is commonly seen in young male athletes involved in competitive sports such as basketball. While the triad of symptoms of Marfan’s syndrome might be recognized during an extensive physiC:al examination, the disproportionately long limbs usually do not call attention to the syndrome in the sports arena. This may be due to the number of extremely tall athletes competing. Other reasons for misdiagnosis can include complacency of the young athlete to disclose physical pain or explicit symptoms to a health care provider during the required physical review, for fear of not being able to continue in the sport of choice. The triad of symptoms includes abnormal cardiovascular, musculoskeletal, and/or ocular findings.

An understanding of this connective tissue disorder is important for advanced practice nurses/nurse practitioners working in a primary care setting, as well as other adult health nurses. Correct identification of the disease is necessary to prevent the catastrophic and often fatal consequences which can occur when cardiovascular and musculoskeletal emergencies arise. Knowing what to look for during the routine physical examination, and knowing the correct questions to ask regarding past and cur rent health status, can lead to a purposeful plan of care. Planning will provide the patient and family with an opportunity to prepare for any limitations in daily activities that Marfan’s syndrome causes. Criteria for evaluating athletes with potential signs and symptoms were developed following the tragic death of a University of California at Los Angeles sports star due to this disorder, and are also included and discussed in this review (see Table 1).

Table 1.

Screening Criteria for Athletes

Following the untimely death of athletes undiagnosed with Marfan’s

syndrome, the University of California at Los Angeles (UCLA)

established criteria to screen athletes. The screening criteria

for athletes includes:

1. A positive family history of Marfan’s syndrome.

2. Positive findings for ectopic lens.

3. Identifying men taller than 6 feet and women

taller than 5 feet 10 inches, who also have two of

the following criteria:

a. Significant cardiac murmur (III/IV or higher) or a

midsystolic click.

b. Kyphoscoliosis.

c. Anterior thoracic deformity.

d. Arm span greater than height.

e. Upper-to-lower body ratio more than one standard deviation

below the mean.

f. Significant myopia.

If the criteria are identified, the patient should be

referred for echocardiography and slit lamp evaluation.

Participation in sports activities should be placed on

hold until further evaluation is completed.

Adapted from: Mellion, M. (1994).

Etiology

Marfan’s syndrome is an autosomal dominant disorder of connective tissue. The classical presentations primarily involve the cardiovascular, musculoskeletal, and ocular systems (Francke & Furthmayr, 1994). Cardiovascular complications are the leading cause of death. Marfan’s is termed a pleiotropic disorder because of the variable expression of symptoms (Pyeritz, 1993). Many organ systems and tissues are affected and each patient expresses the disease differently. Family members who share the same genetic pattern may have different manifestations of the disorder. This further complicates the clinical picture if symptoms are not identified in the family history. The incidence of Marfan’s syndrome is 1 in 10,000 (Francke & Furthmayr, 1994). There are no recorded racial, gender, or ethnic variables. New genetic mutations occur in 5% to 35% of individuals with no family history of Marfan’s syndrome (Manusov & Martucci, 1994).

Pathogenesis

In 1891, Antoine Marfan described a young girl with spider-like fingers and other skeletal anomalies. In the 1930s, Marfan recognized the disease was transmitted by a Mendelian dominant inheritance, and by 1949, the disorder was shown to be caused by a single mutant gene. In 1955, Musksick identified aortic dissection as the most prevalent cause of death from Marfan’s, but it was not until 1990 that the defective gene was isolated on the long arm of chromosome 15. Chromosome 15 contains genes that code for type I collagen receptors and cardiac and muscle actin (Manusov & Martucci, 1994).

Many studies show that there are no deletions or rearrangements of genes causing Marfan’s. Instead, it is believed that a point mutation causes the syndrome. It is also believed that mutations occur at different sites on the gene (McKuscick, 1991). This is what gives the syndrome the variability of clinical presentations. Members of the same family diagnosed with Marfan’s can have different genetic sites affected.

Marfan’s syndrome is linked to the gene labeled as FBN1 (Finkbohner et al., 1995). Mutations of this gene cause a decreased production of fibrillin, a large glycoprotein in microfibrils. Microfibrils are structural components in many tissues including the suspensory ligament of the lens, cornea, skin, lung, and media of the aorta (Milewicz, 1994). Deficiency of fibrillin results in skin striae, skeletal overgrowth, pulmonary bullae, and dural ectasis (enlarged air spaces in pulmonary system and thinning of the dura matter) (Mellion, 1994).

The clinical manifestations of the disease are varied because,, fibrillin is present in so many structures of the body.

Clinical Presentation

There are many clinical presentations of this disorder and not all are expressed in every affected individual. Four subgroups of systems disorders represent the classical clinical manifestations: cardiovascular, skeletal, ocular, and cutaneous.

Microfibrils are abundant in the large blood vessels. The mutant gene is associated with the major component of elastin-associated microfibrils. While some of these fibers appear in the suspensory ligaments of the lens, the major affected system is cardiovascular. Cardiovascular symptoms are the cause of 90% of early morbidity and mortality (Manusov & Martucci; 1994). Mitral valve prolapse and regurgitation causing systolic murmurs are commonly seen.

Progressive dilation of the aortic root and ascending aorta is the primary reason for decreased life expectancy and is cause by weakness of the media of the blood vessels. This leads to aortic valve regurgitation and aortic dissection. Symptoms associated with aortic dissection are severe midline pain, pain in the front or back of chest, or abdomen pain. Small dissections may be painless (Tsipouras & Devereux, 1993). Aortic root enlargement is most marked at the level of the sinus of Valsalva. Eighty percent of adults with Marfan’s have aortic enlargement (Tsipouras & Devereux, 1993).

Mitral valve problems progress more rapidly and are more life threatening if the cardiovascular manifestations occur in childhood (Mellion, 1994). This includes mitral valve prolapse that causes mitral regurgitation and congestive heart failure. Cardiovascular deterioration may be extremely advanced in spite of less obvious skeletal and/or ocular problems. An example of this is the death of athletes who were not diagnosed or suspected of having Marfan’s syndrome.

Musculoskeletal

Skeletal changes are the most obvious symptoms. Arachnodactyly or long thin fingers are a common skeletal finding. One study found this feature in 88% of patients (Manusov & Martucci, 1994). One method to detect this is the wrist sign of Walker and Murdoch (Tsipouras & Devereux, 1993). This is positive when the thumb and little finger overlap when wrapped around the opposite wrist. Another symptom is the Steinberg thumb sign (Tsipouras & Devereux, 1993). This is positive when the thumb extends beyond the ulnar edge of the clenched fist.

Dolichostenomelia or long limbs and a tall stature are skeletal features of Marfan’s syndrome. Decreased microfibrils cause perichondral and periosteal membranes to function poorly. These affect bone growth resulting in long and often misshaped bones. This is measured by comparing the upper segment (head to pubic bone) with lower segment (pubic bone to floor). The individual with Marfan’s has an abnormally low upper-segment to lower-segment ratio. Limbs are also considered long if the ratio of arm span to height is greater than 1.00 to 1.03 (Mellion, 1994). Height above the 95th percentile is also a marker (Manusov & Martucci, 1994).

Other skeletal manifestations include pectus excavatum (funnel chest), carinatum of the sternum (pigeon breast), and rib deformities from bone overgrowth. A higharched narrow palate can occur. Kyphoscoliosis occurs in 30% to 35% of individuals (Manusov & Martucci, 1994). It is not unusual for joints to subluxate or dislocate quite easily.

Ocular changes include dislocated or subluxed lenses (ectopia lentis). Bilateral dislocated lenses are found in 79% of patients and are usually displaced superiorly. This abnormality is usually diagnosed by 5 years of age (Manusov & Martucci, 1994). Patients with dislocated lenses may be at an increased risk for retinal detachment (Godfrey, 1994). The globe of the eye becomes elongated and the cornea is flat. Myopia can be seen in some cases.

Cutaneous symptoms include striae on pectoral, deltoid, and/or thighs which are unrelated to weight change. Striae occur in 25% of the patients (Manusov & Martucci, 1994) and are caused from defective elastic tissue. Other cutaneous symptoms include hernias, usually inguinal. Blebs have been identified in the pulmonary system, while some patients develop spontaneous pneumothorax. The usual appearance is that of a thin person with little subcutaneous fat. Some adults do develop areas of fat accumulation.

Early Diagnosis

Awareness of the varied clinical manifestations is imperative for practitioners and early diagnosis is crucial for preventing serious complications of this syndrome. Marfan’s syndrome is not usually diagnosed at birth. However there is a form of Marfan’s called neonatal Marfan’s syndrome which is obvious at birth. The neonate is born with severe mitral valve regurgitation and progressive aortic root dilation, and ocular features typical of Marfan’s syndrome. Congenital contractures, loose skin, and pulmonary emphysema are also present. These infants usually die within the first year of life (Milewicz, 1994).

Diagnosis of Marfan’s syndrome is based on clinical findings which can be difficult because of the varied expression of the disorder. The baseline evaluation includes history and physical examination, echocardiogram, ophthalmology examination, and a chest x-ray. The echocardiogram and eye examination are imperative for diagnosis. Diagnostic criteria known as the Berlin Nosology was established at a workshop held during the 7th International Congress of Human Genetics in Berlin, Germany September 1986. Later that year, Pyeritz published a simplified version which includes checking the family history to see if a first-degree relative has Marfan’s. If there is a positive family history, the patient should show manifestations of two systems. If there is no family history, the patient should have symptoms in the skeletal system and at least two other systems to be diagnosed with Marfan’s syndrome (Mellion, 1994).

Some syndromes have features similar to Marfan’s syndrome, but can be distinguished from Marfan’s due to a lack of other features required to make the definitive diagnosis. One case is that of ectopia lentis as the result of familial traits alone, without involvement of other systems. Another case is that of Ectopia lentis that is caused by homocystinuria. Although some musculoskeletal changes are present, none of the other features can be isolated. Without the classical manifestations, the diagnosis of Marfan’s syndrome cannot be made. Aortic aneurysms can be the result of another familial autosomal dominant trait that is not related to Marfan’s syndrome or any other connective tissue disorder.

Immunochemical studies on skin and dermal fibroblast cultures show the role of fibrillin in Marfan’s. Monoclonal antibodies to fibrillin show reduced immunostaining at the dermal/epidermal junction and in the dermis of skin sections from individuals with Marfan’s compared to controls. Also, fibroblast cultures demonstrate a reduced accumulation of immunostainable fibrils in Marfan patients (Godfrey, 1994). A specific test result from a sterile catheterized urine specimen can rule out Marfan’s syndrome when ectopia lentis is present. Homocystinuria can be ruled out by a negative cyanide-nitroprusside test for disulfides in the urine.

Patient Management and Outcomes

While no treatment protocol has been established, management is aimed at preventing lifethreatening complications. As stated earlier, cardiovascular complications are the most common cause of morbidity and mortality. In 1972, a study by Murdoch showed a survival rate of 41 years in patients with Marfan’s syndrome (Silverman et al., 1995). In 1968, the composite valve graft technique was introduced to repair proximal aortic aneurysms (Finkbohner et al., 1995). This procedure replaces the aortic valve, and tubular and sinus segments of the ascending aorta. Coronary artery ostial reattachment is made in openings in the graft. This procedure has low hospital mortality rates and a 5 to 10 year survival rate. The procedure is recommended for an aortic diameter of 5.5 cm as a prophylactic measure to prevent aortic dissection and rupture (Finkbohner et al., 1995).

Surgical procedures that will replace the aorta, aortic valve, and mitral valve have been successful in some patients. Following these surgical interventions, lifelong followup with echocardiography is needed to evaluate further cardiac changes that might occur (Isselbacher et al., 1994).

Finkbohner’s 1995 study showed those undergoing aortic aneurysm repair had a median survival rate of 61 years. No difference in survival rates was noted between women and men. Those who did not undergo surgery had a median life expectancy of 30.4 years. Surgery was not performed because they died prior to an accurate diagnosis and treatment plan, or the surgery was not available. This same study revealed the majority of patients later developed vascular complications at other sites. The thoracic aorta was the most involved site. Surgical intervention to repair the aorta has greatly lengthened the life expectancy for Marfan patients.

Smoking has been associated with a need for a second aortic procedure in Marfan patients (Finkbohner et al., 1995). It is imperative that individuals diagnosed with Marfan’s do not begin or immediately stop smoking. Second hand smoke must be avoided as well.

The life expectancy has risen dramatically during the past 20 years. A 1995 study by Silverman and colleagues showed a median life expectancy of 72 years. The difference between the original 1972 study, and the 1995 study of life expectancy was attributed to four factors: (a) an overall improvement in the population life expectancy, (b) benefits arising from cardiovascular surgery, (c) increased proportion of milder cases due to increased frequency of diagnosis, and (d) medical therapy (Silverman et al., 1995). While all studies have looked at length of life, few have looked at the quality of life. The quality of life issue is ripe ground for future nursing research.

In 1971, Halpern advised using beta-adrenergic blocking agents to decrease the risk of aortic dissection (Shores, Berger, Murphy, & Pyeritz, 1994). The benefits of beta blocker therapy was reinforced by findings from a 1994 study by Shores and colleagues. This study showed that enlargement of the aortic root remained low with the use of propranolol (Inderal[R]) or atenolol (Tenormin[R]). Beta blockers act by decreasing the heart rate and forcing myocardial contractility, which decreases the strain on the aorta. These medications serve several purposes. In 1993, Tahernia found that no progression in aortic dilation was seen after 2 to 5 years of low-dose beta blocker therapy.

Other benefits of propranolol and atenolol include a decrease in arrhythmias produced by another frequently identified sequella of mitral valve prolapse. The patient with mitral valve regurgitation should receive prophylactic antibiotics prior to dental work and surgical procedures to prevent endocarditis.

Due to the familial transmission patterns, nurses should understand the pediatric implications of the disease to provide comprehensive patient education. Godfrey (1994) advises that a child with even mild symptoms of Marfan’s should avoid sports. This can be difficult because many of these children have skeletal structures conducive to sports. It is imperative to diagnose the syndrome early so that children’s abilities can be channeled from competitive sports into other activities. Sports that minimize stroke volume and cardiac output such as noncompetitive biking and swimming can be considered (Manusov & Martucci, 1994). Patients should avoid contact sports, isometric exercises, weightlifting, or physical exertion to the point of exhaustion (Fann & Dalman, 1993).

Genetic Counseling and Psychosocial Issues

Because most cases of Marfan’s are inherited, genetic counseling should be part of the treatment plan. Maurice Godfrey reported the first case of detecting Marfan’s syndrome for a woman diagnosed with Marfan’s in her 9th week of pregnancy using chrrirnic villus sampling (Goldsmith, 1992). Although this will tell parents if their child does or does not have the syndrome, it will not tell them how the child will be affected. The variation of intensity of the disease precludes the ability to determine severity, even within familial limits. A parent with Marfan’s has a 50% chance of passing the defective gene onto each newborn.

A woman of childbearing age should be counseled concerning the risks of pregnancy. According to Godfrey (1994), half of the pregnant women with moderate to severe Marfan-linked cardiovascular complications die just before, during, or after giving birth. This is attributed to the weakness of heart valves or aorta. Pregnancy increases the hemodynamic stress on the aorta. It is preferable for women with mild or no aortic dilation to have children early in life (Manusov & Martucci, 1994). The woman should be closely followed with echocardiograms during pregnancy.

Psychosocial and Economic Support

The patient with Marfan’s syndrome needs considerable reassurance about the progress of the disease. Career counseling or professional communication about job choices is necessary. The changing of a career or job may again become necessary, in the future, if physical changes increase in intensity over time. Medical care, insurance restrictions, and financial implications must be discussed openly with the patient, family, and/or significant others. Regional and national support can be obtained through the National Marfan’s Syndrome Foundation and its local branches located throughout the United States. This is a resource organization for both patient and family.

An essential element in performing a routine athletic physical examination is to administer as thorough an exam as possible. Be cognizant that the young athlete is excited about the prospect of the sport experience; parents are usually supportive with anticipatory excitement and coaches are delighted with the prospect of having another talented member of the sports team.

It is important for the primary care provider to recognize the characteristics of connective tissue disorders, such as Marfan’s syndrome, while obtaining a complete past and current health picture, and acquiring a directed family history. Referral to the cardiovascular specialist must be a consideration when any cardiovascular abnormality is suspected or detected due to the known cardiac risks with this disorder. Optimizing the support of psychological and social services to assist the patient and family in adjusting to a chronic incurable disorder is essential. Identifying mutual goals for short and medium time periods is more likely to achieve a greater commitment to the treatment plan.

Keeping abreast of new findings in the field of connective tissue disorders is important when developing screening protocols for athletic programs. Hopefully within the next few years diagnostic tests that can detect fibrillin defects in cultured skin fibroblasts, as well as analysis of a specific gene in the DNA chain, will be available. Referral for genetic counseling is important to the young man or woman desiring to have a family. A major objective to achieve with the patient with Marfan’s syndrome is to maximize his/her functional abilities, and avoid additional damage or injury to the cardiac, musculoskeletal, and ocular systems.

References

Fann, J., & Dalman, R. (1993). Heritable arteriopathy. Seminars in Vascular Surgery, 1(6), 46-54.

Francke, U., & Furthmayr, H. (1994). Marfan’s syndrome and other disorders of fibrillin. New England Journal of Medicine, 330(9), 1384-1385.

Finkbohner, R., Johnston, D., Crawford, S., Coselli, J., & Milewicz, D. (1995). Marfan’s syndrome long-term survival and complications after aortic aneurysm repair. Circulation, 91(3), 728-733

Godfrey, M. (1994). From fluorescence to the gene: The skin in the Marfan syndrome. Journal of Investigative Dermatology, Supplement 5-supp (103), 585-589.

Goldsmith, M. (1992). Marfan’s syndrome, hypertrophic cardiomyopathy findings underline avoidance of some sports. Medical News and Perspectives, 268(24), 3413-3414.

Isselbacher, K., Braunwald, E., Wilson, J., Martin, J., Fauci, A., & Kasper, D. (1994). Harrison’s principles of internal medicine (13th ed.). New York: McGraw-Hill, Inc.

Manusov, E., & Martucci, E. (t994). The Marfan’s syndrome an under diagnosed killer. Archives of Family Medicine, 3(9), 822-826.

McKuscick, V (1991). The defect in Marfan’s syndrome. Nature, 352, 279-280.

Mellion, M. (1994). Diagnosing Marfan’s syndrome. Heart Disease and Stroke, 3(5), 241-245.

Milewicz, D. (1994). Identification of defects in the fibrillin gene and protein. Texas Heart Institute Journal, 1(21), 22-29.

Pyeritz, R. (1993). Marfan’s syndrome: Current and future clinical and genetic management of cardiovascular manifestations. Seminars in Thoracic and Cardiovascular Surgery, 5(1), 11-16.

Silverman, D., Burton, K., Gray, J., Bosner, M., Kouchoukos, N., Roman, M., Boxer, M., Devereux, R., & Tsipouras, R (1995). Life expectancy in the Marfan syndrome. The American Journal of Cardiology, 75, 157-160.

Shores, J., Berger, K., Murphy, E., & Pyeritz, R. (1994). Progression of aortic dilation and the benefit of long-term beta adrenergic blockade in Marfan’s syndrome. New England Journal of Medicine, 330(19), 1335-1341.

Tahernia, A.(1993). Cardiovascular anomalies in Marfan’s syndrome: The role of echocardiography and beta blockers. Southern Medical Journal, 3(8), 305-309.

Tsipouras, R, & Devereux, R. (1993). Marfan’s syndrome: Genetic basis and clinical manifestations. Seminars in Dermatology, 2(12), 219-228.

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Leann Eaton, MSN, RN, is Assistant Professor, Jewish Hospital, College of Nursing and Allied Health, St. Louis, MO.

Sue Meiner, EdD, RN, CS, GNP, is Research Patient Coordinator and Nurse Practitioner, Washington University, School of Medicine, Division of Geriatrics/Gerontology, St. Louis, MO; and Associate Professor, Jewish Hospital College, St. Louis, MO.

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