HLSU230 Biomedical Science

Introduction:

 With the global burden of genetic disorder, Marfan syndrome has gained increased attention due   to mortality rate and high health care expenditure (Meester et al. 2017).   Marfan syndrome is highlighted as a rare autosomal dominant disorder of the connective tissue where   patients with the disease often exhibit various clinical manifestations in domains such as skeletal, ligamentous, orooculofacial, abdominal, neurological and cardiovascular manifestations (Aubart et al. 2018).  While researchers has no specific cure, early diagnosis as well as regular monitoring and lifestyle intervention can address delay health disease. The case study represents a 13-year-old girl   who presented with a painful tooth in the upper left back region.  While assessing the medical history of the patient, the history suggested that she suffered from patent ductus arteriosus which was surgically closed when she was 6 years (Bitterman and Sponseller 2017).  Currently she presented in the clinical setting with heart murmuring and tooth pain.  She appeared to be slender and too thin   compared to her age and sex. She also exhibited to have long arms as well as    legs with elongated finger.  Physical examination confirmed that she has subtly sunken chest along with mild hunching of the back.    Narrow cranium with dolicocephaly as well as leptoprosopic facial features were observed in the extraoral examination. Similarly, she exhibited to have poor oral hygiene and minor gingivitis.  Physical examination suggested that she had abnormally curved which justified the presence of marfan syndrome (Bitterman and Sponseller 2017). Her oral examination where she reported to have Marfan syndrome as oral X-ray reported the presence of arched palate and crowded teeth.   ECG results suggested her heart murmuring.  Mutation screening strategy is the underlying screening strategy that identified dominant negative (DN) as well as  haploinsufficient (HI) mutations of the FBN1 gene (Kuehn et al. 2021).  Therefore, this paper aims discuss three areas such as Pathogenesis, Aetiology and Epidemiology along with Variant specific investigation in following paragraphs.

Epidemiology:

Pathogenesis:

Classic Marfan syndrome, also called type I often encompasses mutation in FBN1 gene on chromosome 15 (Bitterman and Sponseller 2017). The chromosome encodes for a specific microfibrillar glycoprotein fibrillin. Therefore, any alteration in classic fibrillin often induce the connective tissue to normal tissue stress (Bitterman and Sponseller 2017). Therefore, the patients with Marfan syndrome often exhibit clinical manifestations on skeleton, lungs, eyes, heart and aorta. As discussed by Aubart et al. (2018), affected individuals  are portrayed as tall, slender, sunken chest, long, thin extremities along with joint instability. Such clinical deformities are subjected to obvious recognition. However, degree of expressivity as well as penetrance often differs, cases where patients with Marfan syndrome often go unnoticed unless there is severe clinical manifestations that cause clinical emergency as discussed in this case scenario (Bitterman and Sponseller 2017).  

Marfan syndrome exhibit significant progression as individuals grow older gradually. However, it is also common instances where   in some infants, the disease exhibit rapidly progressive complications during at the age of 2 to 3 years. In such cases, multiple organ systems early in life become damage (Grange et al. 2016).  The research suggested that frequent abnormalities are observed for abnormalities. Therefore, if they left untreated Marfan syndrome can cause life-threatening complications. The   presence of congestive heart failure as well as aorta is also observed for the patients (Inayet et al. 2018). Individuals with Marfan syndrome may   have widening of the main artery of the lungs which can cause respiratory and lungs disease.  Congenital contractural arachnodactyly is also rarest disease observed as a complication of Marfan syndrome.

Etiology:

Marfan’s syndrome is considered as the disorder associated connective tissue which often have severe impact on multiple organs. Due to presence of risk factors, mutation in FBN1 gene on chromosome 15 observed amongst patients. Due to potential mutation, microfibrillar glycoprotein fibrillin induce stress in connective tissue (Bitterman and Sponseller 2017). Moreover, the mutation in the mentioned gene often results in an upsurge in a   generation of protein called transforming growth factor beta, or TGF-β (Bitterman and Sponseller 2017).   Extensive research on the syndrome suggested that Marfan syndrome is considered as autosomal dominant trait. Therefore, only one unusual copy of the Marfan gene (mutation in FBN1 gene on chromosome 15 inherited from one parent is sufficient in order to develop Marfan syndrome (Bitterman and Sponseller 2017).

Epidemiology of Marfan Syndrome:

Even though, Marfan syndrome is rare connective tissue, the disorder often exhibit common incidence in United Kingdom. For example, approximately 1 in 5,000 individuals are suffering from Marfan syndrome in the UK (Bitterman and Sponseller 2017). Therefore, it is considered as one of the most common connective tissue disorders which affected both the genders equally.  On the other hand, NHS data suggested that about three-quarters of cases with  Marfan syndrome, children are   inherited  the disease from  only one  parent accounting for  75% of cases with  Marfan syndrome. Such data suggested that only 1 children out of 2 (50%) inherited chance that the child of a parent with Marfan syndrome. The researchers also suggested that the mean survival of the disease for the patient is usually 45years in   rare cases where complications started from 17 years (Grange et al. 2016). On the other hand, incidence of Marfan's syndrome in United Kingdom is about 2 to 3 children per 10 000 individuals. While considering the risk factor of the child to inherited the disease from only one parent, it can be said that   having one child with Marfan's syndrome is considered as the major risk factor for Marfan's syndrome (Bitterman and Sponseller 2017). Therefore, patients with Marfan's syndrome exhibit heart defects, lens dislocation along with other symptoms mentioned above. Treatments for Marfan syndrome is not available. Therefore, diagnosis of the treatment   often targets many organs (Bitterman and Sponseller 2017).

Classification of the Marfan Syndrome

Considering the differences of the genetical mutation differences there are different types of Marfan Syndrome such as pathogenic Marfan syndrome, likely pathogenic, uncertain significance”, “likely benign” or “benign”. The mutation in the FBN1 gene is mainly associated with the different segregation of the disease conditions among the individuals. In this context, it is very essential to mention that based on the different types of mutation in the specified gene. FBN1 mutations are reported in almost 90 per cent of the Marfan patients. Presently, more than 3000 alterations in the FBN1 gene have been recognized by the researchers, and nearly all of the mutations are exceptional to an affected family or individual. The study of Jessurun, Bom and Franken (2016), reported about of large study including 1013 probands of the disorder. Among these large number of probands approximately 803 different pathogenic mutations were reported by the researchers. Among these mutations 56 per cent were missense mutations, 14 per cent were nonsense mutations, 11 per cent splicing mutations, 17 per cent were frameshift mutations, and 2 per cent were in-frame deletions/insertions. The mutation in the FBN1 gene is associated with the coding of the extracellular matrix protein fibrillin-1 and it is related with the mutation of the encoded genes. Henceforth, the above conditions are mainly associated with the pathogenic Marfan syndrome. However, there are a few criteria for recognizing the disease as the pathogenic and they are mainly the presence of the PSV1 null variants including the nonsense, frameshift mutations, splice sites and based on the criteria these type of disease is marked as pathogenic disease (Jessurun, Bom and Franken 2016). On the other hand, in case of the likely pathogenic disease condition the mutation in the MYH11 can be reported. The Benign disease also has some criteria and they are mainly 1 stand-alone (BA1) and less than 2 strong presence of BS1- BS4 genes. The presence of the very strong (PSV1) and 1 moderate (PM1-PM6) and 2 moderate (PM1-PM6). In case of the likely benign the presence of the 1 strong (BS1-BS4) and 1 supporting (BP1-BP7) are considered in terms of the genetic variations of the disease conditions (Richards et al. 2015).

Recommendations

While discussing about the medical management of the disease condition, it can be stated that the therapeutic strategies mainly focus on the reduction of the pressure in the aorta in order to prevent the aortic dissections. In this context, the use of the replacement strategy of the ascending aorta is considered as the most important and effective way to prevent the fatal complications associated with the aortic dissections and rupture as well. The use of the Prophylactic surgery is suggested in case of the aortic diameter of 50 mm, in case of ascending along with the descending aortic aneurysms. Though, the threshold span is 45 mm for the aortic root diameter among the patients having a family history of initial dissection, important mitral or aortic valve regurgitations, rapid aortic dilation (>2 mm/year) or a wish of pregnancy. Another important treatment process is the Personalized external aortic root support (PEARS) method.  According to the study of Izgi et al. (2018) the PEARS method is effective for managing the disease condition. In this study, the researchers reported the effectiveness of the external aortic root support system and this system was introduced in the year of 2004. The study reported the inclusion of the 24 consecutive patients suffering from the Marfan syndrome. The mean aortic diameter was approximately 45 ± 2.8 mm (range: 41 to 52 mm) and the follow ups were reported for 6.3 ± 2.6 years. The researchers did not report about no increase in the ascending aorta diameters and in the aortic root. The ascending aorta diameter was reported to be reduced to 32.4 ± 3.6 mm to 32.3 ± 3.7 mm (change −0.10 mm, 95 per cent CI: −0.92 to 0.74 mm). On the other hand, the descending aorta diameter in the same period of time enhanced to 24.2 ± 3.0 mm from 22.9 ± 2.4 mm (change 1.32 mm, 95% CI: 0.70 to 1.94 mm) along with a significant p value (p < 0.001). Hence, the study concluded that the surgery technique is effective in managing the disease condition.

The Conservative Aortic Valve surgery for aortic Insufficiency and Aneurysm of the Aortic Root (CAVIAAR) technique is another effective measure to preserve the root dynamics for providing long term results among the patients of this disease condition. For ensuring the sufficient hemodynamic function an expandable ring is rooted around in the remodelled aortic root ().

Another treatment strategy is the use of the endovascular stent grafting therapy and it is a minimally invasive surgery effective for the descending aortic aneurysms. Wen et al. (2018) also reported the effectiveness of the endovascular surgical process in treating and managing the aortic dissections and ruptures. The main aim of this current study was to assess the short term clinical outcomes of the patients operated with stents Marfan syndrome related cardiovascular problems. The study was conducted in between the October 2013 and December 2016 and in this study the researchers included 12 patients along with spontaneous isolated dissection of superior mesenteric artery or SMA. The study results reported that the for short term basis the use of the stent is an effective strategy for managing the cardiovascular problems caused by the Marfan syndrome.

In case of the medicine-based treatment of the cardiovascular problem caused by the Marfan syndrome the use of the beta-blockers can be recommended and in recent time use of this medicine has become very popular. The mechanism of action of the therapy is related to the decrease of tension on the proximal aorta. Reduction of stress condition on the aortic wall is comprehended by decreased chronotropy, decreased inotropy, reduced mean blood pressure, and enhancement of the stability of aorta by the cross-linking in between the collagen and elastin. Koo, Lawrence and Musini (2017) reported about the effective use of the beta blockers in treating the Marfan syndrome condition specifically for the prevention of the aortic dissection. In this current study the researchers aimed to assess the long-term effectiveness and safety of the beta blockers compared to the placebo or treatment among the patients of the Marfan syndrome. For meeting the goals of the study, the researchers basically performed a systematic review and performed a search process in different online databases such as MEDLINE, CENTRAL and Embase.  The review result reported that there was only one study that stated the effectiveness of the beta blockers and most of the studies selected for this review failed to show any significant effect of the beta blockers in terms of improving the incidence of aortic dissection, congestive heart failure, cardiovascular surgery and aortic regurgitation.

Forteza et al. (2016) performed a comparative study to assess the effectiveness of losartan and atenolol. Losartan is considered as another potential treatment option and in this study the researchers stated about the use of the losartan. However, the research failed to show any significant differences among the two treatment groups in spite of showing a little difference.

For the ocular management in case of the Marfan syndrome the health care professionals may choose optical correction by using the contact lenses or the spectacles. In some cases, the researchers also have reported the use of the surgical interventions comprising of lens extraction and manipulations of the iris diaphragm.  Moreover, the use of the aphakic surgery can be recommended by diverse options of lens replacement (Jessurun, Bom and Franken 2016).

For managing the skeletal muscle related problems caused due to the presence of the Marfan syndrome. In most of the cases, the management of the scoliosis condition is based on the surgical stabilization specifically in case of the serious and progressive cases of the scoliosis and in such cases the use of surgery is most beneficial as the use of bracing technique is not at all adequate. Pectus excavatum or incavatum is the most common issue faced by the patients of the Marfan syndrome and for managing this condition nuss procedure can be used and it is a negligibly invasive restoration of pectus excavatum, by placing a substernal bar (Jessurun, Bom and Franken 2016). 

Conclusion

Hence, it can be concluded that the Marfan syndrome is greatly affecting the people around the world. Marfan syndrome is highlighted as a rare autosomal dominant disorder of the connective tissue where   patients with the disease often exhibit various clinical manifestations in domains such as skeletal, ligamentous, orooculofacial, abdominal, neurological and cardiovascular manifestations. While researchers have no specific cure, early diagnosis as well as regular monitoring and lifestyle intervention can address delay health disease. Affected individuals are portrayed as tall, slender, sunken chest, long, thin extremities along with joint instability. Marfan syndrome exhibit significant progression as individuals grow older gradually. Individuals with Marfan syndrome may   have widening of the main artery of the lungs which can cause respiratory and lungs disease. Congenital contractural arachnodactyly is also rarest disease observed as a complication of Marfan syndrome. Even though, Marfan syndrome is rare connective tissue, the disorder often exhibit common incidence. The mutation in the FBN1 gene is mainly associated with the different segregation of the disease conditions among the individuals. An important treatment process is the Personalized external aortic root support (PEARS) method.  The Conservative Aortic Valve surgery for aortic Insufficiency and Aneurysm of the Aortic Root (CAVIAAR) technique can also be used under the surgical treatment process. In case of the medicine-based treatment of the cardiovascular problem caused by the Marfan syndrome the use of the beta-blockers can be recommended. For the ocular management in case of the Marfan syndrome the health care professionals may choose optical correction by using the contact lenses or the spectacles. Finally, it can be stated that for more prominent referral to manage the disease condition more research is required as a lot of treatment options are not at all conclusive in terms of showing effective results.

References

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Aubart, M., Gazal, S., Arnaud, P., Benarroch, L., Gross, M.S., Buratti, J., Boland, A., Meyer, V., Zouali, H., Hanna, N. and Milleron, O., 2018. Association of modifiers and other genetic factors explain Marfan syndrome clinical variability. European Journal of Human Genetics, 26(12), pp.1759-1772.

Bitterman, A.D. and Sponseller, P.D., 2017. Marfan syndrome: a clinical update. JAAOS-Journal of the American Academy of Orthopaedic Surgeons, 25(9), pp.603-609.

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Inayet, N., Hayat, J.O., Kaul, A., Tome, M., Child, A. and Poullis, A., 2018. Gastrointestinal symptoms in Marfan syndrome and hypermobile Ehlers-Danlos syndrome. Gastroenterology research and practice, 2018.

Izgi, C., Newsome, S., Alpendurada, F., Nyktari, E., Boutsikou, M., Pepper, J., Treasure, T. and Mohiaddin, R., 2018. External aortic root support to prevent aortic dilatation in patients with Marfan syndrome. Journal of the American College of Cardiology, 72(10), pp.1095-1105.

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