Disorder Of Abnormal Connective Tissue Biology Essay

Published: Last Edited:

This essay has been submitted by a student. This is not an example of the work written by our professional essay writers.

Marfan syndrome is an autosomal dominant disorder of abnormal connective tissue that affects several body systems (Peters et al., 2005). Connective tissue is the type that binds and supports organs and structures within the body ("Marfan syndrome", n.d.). Connective tissue is found throughout the entire body; therefore, Marfan syndrome features have the potential to appear in several different parts of the body. Complications of the syndrome can be observed in the heart, bones, blood vessels, eyes and joints. Occasionally, the pulmonary and integumentary systems can also be affected (Gibaldi, 2010). The genetic mutation that causes Marfan syndrome expresses itself in several different ways in each individual, with symptoms and features that range in severity and may involve different organ systems in different individuals ("Marfan syndrome", n.d.). The disorder shows equal prevalence between genders, race and geographical backgrounds (Ho, Tran & Bektas, 2005). Approximately one in 5,000 people have Marfan syndrome. Marfan syndrome can be inherited from a parent or occur as a spontaneous mutation, meaning that the individual is the first in their family to have the condition. Individuals with Marfan syndrome have a one out of two chance of passing on the mutation with each offspring (Gibaldi, 2010). In 1972, the average age of death of patients with Marfan syndrome was thirty-two years. In 1993, the average age of death rose to forty-one years. The increased life expectancy from 1972 to 1993 may be credited to an increase in life expectancy in the general population, earlier diagnosis through screening and earlier medical intervention (Coons, Farley, Kim & Caputo, 2009). According to the Merck Manual of diagnosis and therapy, the life expectancy in 1996 increased to sixty-one years (Pessler, 2006).

In 1875, a physician named E. Williams described Marfan syndrome in a presentation given to the American Ophthalmological Society. Williams reported a gentleman and his two children to display similar unique physical characteristics that consisted of large, loose jointed extremities accompanied by dislocated lenses (Gonzales, 2008). In 1886, Antoine Bernard-Jean Marfan described a five year-old, Gabrielle, to have exceptionally long disproportionate limbs an digits. She also was described by Marfan to have a lanky build and poor muscular strength. He gave her spider-like fingers the name "pattes d'araignée" and termed the condition "dolichosténomélie", which means slender limbs. Six years later it was noted on radiographs that Gabrielle had spinal curvature and thoracic asymmetry. Other doctors documented the presence of ectopia lentis and cardiovascular abnormalities including a dissecting aorta (Ho et al., 2005). In 1902, following a group of patients with similar features and manifestations, the disorder was formally given the name Marfan syndrome. Over the next fifty years others described additional manifestations of the condition including ocular changes, cardiovascular disorders and skeletal system disorders (Gonzales, 2008).

Marfan syndrome is a result of a mutation within a chromosome. Human cells consist of twenty-three pairs of chromosomes. Twenty-two of the chromosome pairs are autosomal, which means they are the same in both genders. Due to Marfan syndrome being an autosomal disorder, it only takes one copy of the mutated gene to cause manifestations of the feature. Chromosomes consist of tightly coiled DNA, which stores genetic information. DNA is comprised of four chemical bases or nucleotides: adenine, guanine, cytosine and thymine. Each nucleotide joins with another to form a base pair. There are approximately three billion bases in the human DNA, ninty-nine percent of which are the same in each individual. However, changes in these sequences causes a mutation in the gene, similar to that of which causes Marfan syndrome (Gonzales, 2008).

Marfan syndrome is caused by a genetic mutation on chromosome fifteen affecting the FBN1 gene encoding fibrillin. Fibrillin is a large glycoprotein that is necessary to preserve the extracellular matrix which is accountable for the elasticity and strength of connective tissues throughout the body. Mutations located within the FBN1 gene are associated with approximately ninety percent of those individuals with Marfan syndrome. The remaining ten percent of individuals have no mutations on the FBN1 gene; however, they have Marfan syndrome phenotype. Some of these individuals have mutations on the fibrillin-2 gene which is located on chromosome five. Recent data indicates that the transforming growth factor-β (TGF-β) and mutations on TGFβR1 and TGFβR2 genes are also linked to Marfan syndrome (Gonzales, 2008).

There are believed to be more than 800 identified mutations in the FBN1 gene of those individuals with Marfan syndrome. Most of the mutations are inheritable and can be associated to an affected family member. However, twenty to thirty percent are a new genetic mutation, which means the mutation was not inherited from the parents. It is believed that genetic mutations that cause Marfan syndrome are expressed in one of three ways. Sixty-six percent are missense mutations, which mean there was a change in the protein that caused a small piece of information in the gene to be altered. Twenty percent are caused by frameshift mutations. This type of mutation changes everything that precedes the altered information and typically causes significant changes in the function of the protein. The final twelve percent are caused by splice site mutations. This occurs when a piece of information is inserted into or deleted from a gene (Gonzales, 2008).

The gene identified to cause Marfan syndrome was localized to chromosome 15q21 in 1990 and was replicated for further research in 1991. FBN1 is a rather large gene, 110 kb in size, containing genomic DNA and consisting of sixty-five exons. It encodes the microfibrillar protein fibrillin. Currently, scientists' knowledge of fibrillin biochemistry and microfibrillar assemblage is limited. However, studies performed on mice could provide insight into fibrillin pathogenesis and microfibrillar organization; thus, leading to a better understanding of the pleiotropic manifestations of Marfan syndrome and perhaps a development of a cure (Ho et al., 2005).

The diagnosis of Marfan syndrome is typically made based on the presence of typical musculoskeletal, ocular or cardiovascular features, the presence of a family history of Marfan syndrome, or a positive fibrillin mutation (Taub et al., 2009). The gold standard for the diagnosis of Marfan syndrome is the Ghent criteria, established in 1996 by a group of prominent geneticists (Nallamshetty et al., 2002). However, the diagnosis of Marfan syndrome can be difficult to make because several autosomal dominant, inheritable connective tissue disorders have some similar presenting features to those of Marfan syndrome. Some of the similarly related conditions include: familial mitral valve prolapsed syndrome, MASS phenotype, congenital contractual arachnodatyly, familial thoracic aortic aneurysm, familial aortic dissection and familial Marfan-like habitus. Also, the wide spectrum of presenting features has made diagnosing Marfan syndrome challenging. The mild phenotype of Marfan syndrome can share common characteristics with physical findings of the general public. Exceptionally receptive and precise criteria are needed to ensure that Marfan syndrome is diagnosed correctly. Although several clinical findings are associated with Marfan syndrome, a restricted combination of findings has been chosen to diagnosis Marfan syndrome. This compilation of observations, referred to as the Ghent nosology or Ghent criteria was initially expressed in 1996. The findings of the Ghent criteria were chosen because they are found less often in other connective tissue disorders or in individuals of the general public. The criteria involve several organ systems, reflecting widespread effects of Marfan syndrome. The Ghent criteria are based exclusively on expert opinion. The Ghent criteria has outperformed several previous nosologies and continues to be the basis of diagnosis used today (Iams, 2010).

The organ systems included in the Ghent criteria are ocular, skeletal, cardiovascular, pulmonary, integumentary and nervous. Genetic testing and family history are also taken into consideration within the Ghent criteria. To date, no laboratory test has been proven successful in identifying Marfan syndrome; therefore, the diagnosis relies heavily upon clinical findings. According to the Ghent criteria, to receive a diagnosis of Marfan syndrome, a patient must exhibit two major criterions in dissimilar organ systems and display involvement of a third organ system (Iams, 2010). Involvement is defined as demonstrating some of the less specific clinical manifestations. In the unusual case that a patient is positive to have a genetic defect that is known to cause Marfan syndrome, the patient needs to exhibit only one major criterion and the involvement of a second system for diagnosis. Additionally, if the patient has a relative with confirmed Marfan syndrome, then the patient needs to also have one major criterion and involvement of a second system for diagnosis (Iams, 2010).

The vast number of known mutations for Marfan syndrome is more than 800. In addition, twenty-five percent of cases of Marfan syndrome are as a result of new mutations, making genetic testing for diagnosis rather expensive and impractical. Genetic testing is used for helping relatives of patients with Marfan syndrome validate that they do not have the syndrome. Genetic testing within Marfan syndrome families still only identifies the genetic defect seventy to eighty percent of the time (Iams, 2010).

Marfan syndrome generally leads to weakened ligaments and abnormal bone growth. AS a result, it is associated with an assortment of skeletal irregularities such as loose-fitting and extremely flexible joints and inconsistent lengthening of the bones. Other skeletal abnormalities often present in patients with Marfan syndrome include an elongated, slender face; an elevated arching of the roof of the mouth, which could lead to crowding of the teeth; a protruding or depressed sternum; scoliosis; flat feet and hammertoes ("Marfan syndrome", n.d.).

Kyphosis and scoliosis usually develop subtly during childhood and tends to get worse during stages of growth (Ho et al., 2005). Scoliosis affects approximately 60% of patients with Marfan syndrome and may advance quickly during active growth periods, leading to marked deformity, pain and restricted ventilator deficit (Dean, 2007). Unlike patients with idiopathic scoliosis, the condition in Marfan syndrome patients generally responds unsuccessfully to bracing. Scoliosis that increases further than 40° can result in restrictive lung disease and cor pulmonale. Pectus excavatum is a compelling concern for younger patients; however, it hardly ever leads to complications early in life; therefore, surgery should be postponed. Surgical intervention during midadolescence or early adulthood is frequently accompanied by a more favorable prognosis with decreased possibility of recurrence. Pectus carinatum does not shrink the diameter of the chest between the spine and sternum; therefore, it does not shift the heart. It is typically repaired for cosmetic reasons only as it infrequently causes problems in childhood; therefore, surgery can be delayed (Ho et al., 2005). Back pain is believed to be more frequent in patients with dural ectasia; however, the evidence for this is difficult. Dural ectasia is present in sixty-nine percent of patients with Marfan syndrome. Treatment of dural ectasia to decrease back pain remains tentative. Bone mineral density appears to be diminished in the spine and hip in patients with Marfan syndrome. However, an associated increase in fracture occurrence was not observed in these patients (Dean, 2007).

Joint hypermobility is also a common manifestation among patients with Marfan syndrome, affecting eighty-five percent of children under eighteen and fifty-six percent of adults. Many of these patients suffer from arthralgia, myalgia or ligamentous injury (Dean, 2007).

According to a study reported in "The lumbar interpediculate distance is widened in adults with the Marfan syndrome: Data from 32 cases", the lumbar interpediculate distances in patients with Marfan syndrome were significantly larger than those of the general population at all levels of the lumbar spine (Ahn et al., 2001). It is therefore believed that the widened interpediculate distances may reflect irregular growth and formation of the vertebral elements secondary to the connective tissue disorder itself. In the same study, it was reported that the lumbar spine in patients with Marfan syndrome has a higher prevalence of developmental anomalies including biconcave vertebrae, transition vertebrae and lengthened transverse process distance (Ahn et al., 2001).

In a study conducted to determine the prevalence of protrusion acetabuli in patients with Marfan syndrome, reported in "Protrusio acetabuli in Marfan syndrome: Age-related prevalence and associated hip function", Sponsellar et al. concluded that acetabular protrusion is demonstrated in nearly thirty-four percent of adults with Marfan syndrome (2006). It was also determined that its occurrence increases during skeletal growth and seems to advance minimally after full skeletal maturity (Sponsellar et al., 2006).

Most individuals with Marfan syndrome have cardiovascular irregularities, such as a weakened aorta. As the walls of the aorta become weakened, they may dilate and lead to an aneurysm, which can result in death. Faulty heart valves constitute another cardiovascular complication commonly associated with Marfan syndrome. The dysfunctional heart valves may cause a heart murmur, difficulty breathing, fatigue, or an arrhythmia ("Marfan syndrome", n.d.).

Cardiovascular manifestations of Marfan syndrome include prolapse of the mitral valve and regurgitation, left ventricular dilatation and cardiac failure, pulmonary artery dilatation and aortic root dilatation. In addition, myocardial infarction may occur if an aortic root dissection occludes the coronary ostia. Marfan syndrome death from aortic complications has decreased

and life expectancy has increased due to increased medical and surgical intervention (Dean, 2007). Mitral valve prolapse and mitral valve regurgitation have been reported to be exceedingly

common in patients with Marfan syndrome and is the greatest cause of morbidity and mortality in infants and young children with Marfan syndrome. The incidence of mitral valve prolapse in patients with Marfan syndrome is less than previously reported. The large majorities of patients with mitral valve prolapse have bileaflet involvement and have significantly larger aortic root diameters. In addition, the indexed sinotubular junction dimension is larger in adult patients with Marfan syndrome than in younger patients (Taub et al., 2009). In patients with Marfan syndrome, more than ninety percent of known cause of death is due to cardiovascular complications. However, with rapid improvements in medical and surgical treatment, effective management of patients has resulted in increased life expectancy. Nevertheless, delayed diagnosis is still frequent; therefore, mortality remains high as a result (Ho et al., 2005).

Most individuals with Marfan syndrome have a vision irregularity such as a shift in one or both eye lenses. Other Marfan syndrome related eye complications that may occur include: myopia, glaucoma, cataracts and retinal detachment ("Marfan syndrome", n.d.). Highly myopic patients can achieve superior visual acuity through the use of glasses or contact lenses. In severe cases of myopia, retinal detachment becomes an essential concern. This is of great concern because the globe of the eye is elongated and the retina is subject to increased stretching; therefore, increasing the tendency to detach. Another feature of Marfan syndrome is ectopia lentis. Ectopia lentis refers to the dislocation of the lens within the eye. An estimated two-thirds of patients with Marfan syndrome have ectopia lentis. The management of ectopia lentis is through the use of miotic medicines to constrict the pupil. Glasses may also be prescribed to correct components of phakia and aphakia. Other forms of treatment include lens extraction and insertion of a prosthetic lens. Cataracts are fairly common and can appear early in the condition of Marfan syndrome. Glaucoma is a subtle but common complication among Marfan syndrome patients (Ho et al., 2005).

Currently, there is no cure for Marfan syndrome. According to Gonzales, without intervention the life expectancy of those with Marfan syndrome is approximately 37 years (2008). Marfan syndrome patients who seek medical intervention can expect to have a normal life span. The extent and severity of cardiovascular disorders normally determines the prognosis in individuals with Marfan syndrome. It is through thoughtful care and timely interventions that those individuals with Marfan syndrome have the possibility live a normal healthy life (Gonzales, 2008).

In conclusion, Marfan syndrome has the potential to affect a widespread amount of anatomy, due to the fact that connective tissue is plentiful throughout the body. As mentioned above, the more common manifestations of Marfan syndrome occur within the musculoskeletal, cardiovascular and ophthalmological systems. However, other features have been documented to occur within the respiratory and central nervous systems such as dura ectasia and spontaneous pneumothroax.