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Marfan Syndrome

Marfan's Syndrome

Marfan syndrome is an autosomal dominant disorder of the connective tissue. It was first described by the French pediatrician Antoine Marfan in 1896.


Presentation

There are more than 25-30 different signs and symptoms in Marfan syndrome which can be of variable intensity and differ from patient to patient. Some people may not show any signs and symptoms. This condition worsens with age. Marfan syndrome becomes more obvious as changes occur in connective tissue.

The major systems affected are:

Skeletal system

The facial appearance of affected patients may be distinctive, with elongation and asymmetry. Sometimes there may be a high arched palate resulting in speech disorders [4]. Tall stature along with long thin digits and alteration in body proportions are seen. Wrists may be thin and weak. The arm span measured from the extended fingers often exceeds the height of the patient. Along with this the patient may show flat feet, hammer toes or stooped shoulders. There may be pain in joints, muscle and bones [5].

Eyes

Weakness of suspensory ligament of the eye may cause subluxation of lens, which is a common clinical feature in patients. Myopia and astigmatism may also be present.

Cardiovascular system

The most serious signs and symptoms of Marfan syndrome involve the cardiovascular system (CVS) which can lead to severe complications. Following degeneration in the media of the vessel wall, the aortic valve ring may dilate and produce an incompetent valve. Mitral valve is mainly involved resulting in mitral valve prolapse or regurgitation [6]. Typically, CVS symptoms present with fatigue, shortness of breath and tiredness. Heart murmur and angina pectoris may also be present. An aneurysm may occur in the ascending aorta leading to dissection or rupture.

Spinal affections

People with Marfan syndrome have a risk of developing scoliosis.

Skin

Striae distensae are very common and usually occur over shoulders and hips.

Tall Stature
  • A nine-year-old girl was referred to our pediatric endocrinology clinic for tall stature. Physical examination revealed a lens dislocation with strabismus, high palate, positive wrist and thumb signs, joint hypermobility, and pes planus.[ncbi.nlm.nih.gov]
  • Her father, aunt and grandfather were of tall stature, characteristic of Marfan syndrome. On systemic evaluation, the patient was diagnosed as Marfan syndrome. After surgical correction she achieved vision of 6/6 in both eyes.[ncbi.nlm.nih.gov]
  • This variant has been previously reported in association with some skeletal features of Marfan syndrome in the absence of both tall stature and non-skeletal features. These features are consistent with the presentation of the siblings reported here.[ncbi.nlm.nih.gov]
  • It is characterized by tall stature, elongated extremities, mitral valve prolapse, aortic dilatation, aortic dissection, and sublaxation of the lens.[icd10data.com]
  • MARFAN SYNDROME: - A HARD LOOK - (Excerpts from the Marfan Foundation) MARFAN SYNDROME is a progressive, incurable, genetic disorder of the connective tissue, frequently characterized by tall stature, long limbs and fingers, scoliosis, complications and[jrmarfan58.com]
Marfanoid Habitus
  • On physical examination he presented with marfanoid habitus. Pneumothorax was managed conservatively with resolution.[ncbi.nlm.nih.gov]
  • The emergence of additional clinical signs (marfanoid habitus, severe myopia and dilatation of the aortic bulb) lead to consider the diagnosis of the progeroid variant of Marfan syndrome.[ncbi.nlm.nih.gov]
  • One such syndrome is multiple endocrine neoplasia type 2B (MEN2B), which is a cancer syndrome characterized by mucosal neuromas, medullary thyroid cancer, pheochromocytoma, and marfanoid habitus.[clinicalcorrelations.org]
  • People with Marfan syndrome tend to have what is called a Marfanoid habitus . This term refers to tall stature, long limbs (arm span is usually greater than height), long fingers, crowded teeth, a high-arched palate, and loose/lax joints.[forgottendiseases.org]
  • Habitus (Marfan Body Type) Skeletal findings At least sometimes Mitral Valve Prolapse Syndrome Mitral valve prolapse Variable skeletal findings At least sometimes Congenital Contractural Arachnodactyly (CCA or Beals syndrome) Mitral valve prolapse Variable[physio-pedia.com]
High Arched Palate
  • […] by , Last updated January 12, 2013 OVERVIEW connective tissue disorder autosomal dominant CLINICAL FEATURES GENERAL: tall, long thin fingers AIRWAY: cervical spine/ligamentous abnormality, high arch palate, crowded teeth RESP: emphysema, spontaneous pneumothorax[lifeinthefastlane.com]
  • Potentially important abnormalities include hyperextensible joints (possible positioning implications), high arched palate (airway implications), pectus excavatum , and kyphoscoliosis (difficulties with neuraxial anesthesia).[openanesthesia.org]
  • Patients with Marfan syndrome may have the following symptoms and signs on history and examination: general tall stature long arm-span (often exceeding the height of the patient) joint laxity resulting in recurrent dislocations spine/skull high arched[radiopaedia.org]
Mitral Valve Prolapse
  • Mitral valve prolapse (MVP), however, has remained poorly documented.[ncbi.nlm.nih.gov]
  • FBN1 variants are responsible for the related connective tissue disorders, grouped under the generic term of type-1 fibrillinopathies, which include Marfan syndrome (MFS), MASS syndrome (Mitral valve prolapse, Aortic enlargement, Skin and Skeletal findings[ncbi.nlm.nih.gov]
  • It is characterized by tall stature, elongated extremities, mitral valve prolapse, aortic dilatation, aortic dissection, and sublaxation of the lens.[icd10data.com]
  • Valve Prolapse, Myopia Borderline aortic enlargement Skin and skeletal findings At least sometimes Marfanoid Habitus (Marfan Body Type) Skeletal findings At least sometimes Mitral Valve Prolapse Syndrome Mitral valve prolapse Variable skeletal findings[physio-pedia.com]
  • Individuals with Marfan syndrome may have significant cardiovascular problems such as a common heart defect known as mitral valve prolapse.[rarediseases.org]
Heart Murmur
  • Leaky heart valves that can cause a heart murmur are also among the symptoms. As devastating as the news may be for Austin, getting this diagnosis now may be a lifesaver.[cnn.com]
  • In about ⅓ of people with MVP, blood leaks backward through the valve (mitral valve regurgitation), producing a heart murmur that can also be heard through a stethoscope.[aapos.org]
  • murmurs, irregular heartbeat, or in severe cases aortic aneurysm (potentially fatal heart condition).[dermnetnz.org]
Long Arm
  • He is extremely tall with a thin physique, a protruding chin and disproportionately long arms. Great attributes to be an Olympic swimmer. These physical attributes are also associated with the rare disease, Marfan syndrome.[raredr.com]
  • People with Marfan syndrome are usually tall and thin with disproportionately long arms, legs, fingers and toes. The damage caused by Marfan syndrome can be mild or severe.[mayoclinic.org]
  • This gene is localized to chromosome #15 on the long arm (q) at 15q21.1. Common findings in individuals with Marfan syndrome include those related to connective tissue disorders.[stanfordchildrens.org]
  • Children who have Marfan syndrome are usually tall and thin, with long arms, long double-jointed fingers, a short torso and very long legs. They often have an abnormally shaped chest, which increases the risk of developing lung problems.[childrenshospital.org]
Long, Thin Fingers
  • People with Marfan tend to be unusually tall, with long limbs and long, thin fingers.[snpedia.com]
  • […] by , Last updated January 12, 2013 OVERVIEW connective tissue disorder autosomal dominant CLINICAL FEATURES GENERAL: tall, long thin fingers AIRWAY: cervical spine/ligamentous abnormality, high arch palate, crowded teeth RESP: emphysema, spontaneous pneumothorax[lifeinthefastlane.com]
  • They may have long, thin fingers. Some people with Marfan syndrome have few health problems, while others are seriously affected by troubles with their heart and blood vessels, as well as their eyes.[healthdirect.gov.au]
  • The signs may include: Tall and slim build Long, thin limbs Large, flat feet Long, thin fingers Loose and flexible joints Scoliosis Breastbone protrusion or indentation Crowded teeth Marfan syndrome can cause scoliosis, which is a health condition involving[news-medical.net]
  • Since Marfan syndrome is partly caused by changes in growth regulation, people with the disorder can often have some of the following traits: They are taller than people in their family who do not have Marfan syndrome They may have long, thin fingers[ucsfhealth.org]
Long Leg
  • Children who have Marfan syndrome are usually tall and thin, with long arms, long double-jointed fingers, a short torso and very long legs. They often have an abnormally shaped chest, which increases the risk of developing lung problems.[childrenshospital.org]
  • Some of the features are easier to see, like long arms, long legs, long fingers. Usually, but not always, this means a tall and thin body type. It could mean a curved spine, a sunken in chest, and flexible joints.[ourdailybears.com]
  • Physical Signs The Skeleton : People with Marfan syndrome often have a tall, thin body build with long arms and long legs. They are often quite flexible or have “loose” joints.[luriechildrens.org]
  • The signs and symptoms of Marfan Syndrome include: Disproportionately long legs, arms, toes and fingers Extremely tall and slender build Long, narrow face High arched neck and crowded teeth Indented or protruding sternum (breastbone) Dislocated lenses[epainassist.com]
Hyperextensible Joints
  • Potentially important abnormalities include hyperextensible joints (possible positioning implications), high arched palate (airway implications), pectus excavatum , and kyphoscoliosis (difficulties with neuraxial anesthesia).[openanesthesia.org]
Blue Sclera
  • LDS patients may also have widely spaced eyes, cleft palate, blue sclerae, and type 1 Chiari malformations (in which a portion of the cerebellum descends out of the skull into the area where the spinal cord is located).[forgottendiseases.org]
Iridodonesis
  • Ocular system Findings include ectopia lentis (subluxation or upward dislocation of the lens) and iridodonesis (tremulousness of the iris). The margin of the dislocated lens can often be seen through the undilated pupil.[merckmanuals.com]

Workup

There is no objective diagnostic test of this condition. Since it affects multiple organ systems, a multidisciplinary approach is needed [7].

The diagnosis is done by a complete family history and a thorough examination of the patient’s eyes, heart and bone structure. The thumb sign and wrist sign are elicited for diagnosis.

An echocardiogram must be done to see the heart’s valves and aorta, a plain cardiogram is not sufficient. An echocardiogram will show images of heart in motion. A CT scan or MRI scan maybe done to visualise the heart.

An ophthalmologist will use a slit lamp examination to identify a dislocated lens along with other tests to check eye pressure and retina.

Genetic testing can be done by analysing the fibrillin gene-1 [8].

Treatment

Marfan syndrome is incurable, but treatment is focussed at reducing pain and preventing complications. The life expectancy has increased over the period of years [9]. An individualized treatment will be selected depending on the severity of symptoms.

Regular echocardiograms should be done to evaluate the status of the aorta and heart valves. Occasionally, a CT scan and MRI scan maybe required. Medications mainly beta blockers maybe given to reduce heart rate and keep blood pressure in control.
An ophthalmologist should regularly check eyes for any vision problems. Most cases can be corrected by glasses or corrective surgery.

If musculoskeletal system is affected patient should check on regular basis for any joint pains, or any deformity should be corrected by orthopaedic surgery as these deformities can limit functioning of the patient.

Surgery in Marfan syndrome is done in cases of aortic rupture or aortic dissection. Valve repair or replacement surgery may also be necessary [10].

Regular moderate physical exercise is recommended.

Prognosis

The prognosis of the disease has vastly improved and life expectancy of patient has also increased. The most important factor is early diagnosis, so that patient can benefit from lifestyle modifications thus increasing the life expectancy. Good medical care and social support can help both adults and children with Marfan syndrome. Average life expectancy of people with Marfan syndrome is about 70 years [3].

Etiology

Mutations in fibrillin gene (FBN1) [1] on chromosome 15 have been indicated to cause Marfan syndrome. Chromosome 15 encodes fibrillin gene which produces fibrillin, an important component of extracellular matrix as well as maintaining elastic fibres which provide strength and flexibility to the entire body.
Occasionally, mutations occur in Tumour growth factor-beta (TGF-β).

More than 500 fibrillin gene mutations have been identified out of which all are unique to the affected individual or family members. Different gene mutations are responsible for genetic heterogeneity.

As it is a genetic condition, the greatest risk factor for Marfan syndrome is having one parent with this condition [2].

Epidemiology

Marfan syndrome affects 1 in every 3000-5000 people, affecting males and females equally. It appears to be distributed equally among all races and backgrounds.

It is one of the more common inheritable disorders. Since it is autosomal dominant, it means that any parent who has it has 50% risk of giving it to the child. 3 out of 4 cases are inherited, which is due to defects or disruptions of fibrillin-1 gene (FBN-1).

There is a 25% chance of spontaneous mutations known as sporadic cases where a patient who presents with Marfan syndrome has no family history of the disorder. Another characteristic feature of this syndrome is variable expression which means different members of a family affected with Marfan syndrome will show varied symptoms of different severity.

Sex distribution
Age distribution

Pathophysiology

Marfan syndrome is caused by mutations in FBN1 gene present on chromosome 15, which encodes for fibrillin-1. Fibrillin is a type of glycoprotein which is an important component of extracellular matrix. This extracellular matrix is required for formation of connective tissue as well as maintaining it. Extracellular matrix is a storehouse of growth factors. Fibrillin helps in formation of microfibrils which give elasticity and strength to connective tissue.

Most mutations are unique and mainly affect a single amino acid of the protein. There is no particular spot for mutation to occur, the entire gene is affected. Severe cases of Marfan syndrome have been noted in the region encompassing exons 24 to 32.

Fibrillin mutations are seen in people who do not show Marfan syndrome but have related connective tissue disorder. Thus an abnormality in fibrillin gene leads to decreased production of microfibrils leading to resulting in connective tissue all throughout the body.

Transforming growth factor beta plays an important role in this condition, wherein fibrillin-1 binds to an inactive form of TGF-β resulting in fibrillin being unavailable for biological activity. The simplest theory states that the decrease in fibrillin along with increased levels of TGF-β is responsible for the pathology. TGF-β results in release of inflammatory proteases which gradually destroy elastic fibres and extracellular matrix. As elastic fibres are richly found in the aorta, ligaments and ciliary zonules of the eye, these areas are the worst affected.

Prevention

Prevention is mainly for the complications which can occur. To prevent these early diagnoses helps to start treatment according to the patient’s severity of symptoms. Regular check-ups should be done especially of the eyes and heart. Spontaneous gene mutations cannot be prevented. Genetic counselling is recommended for couples with a history of this condition who wish to have children.

Summary

Marfan syndrome is a genetically inherited disorder that affects the human connective tissues. Since a major part of the body is made up of connective tissue, multiple organs are affected. Genetically, Marfan syndrome is autosomal dominant, where abnormality in the gene causes a myriad of clinical features mainly affecting the skeletal system-bones and muscle, cardiovascular system-heart and blood vessels and the ocular system.

Arachnodactyly which means spider like fingers in Greek is the hallmark of this condition due to the disproportionately long hands and fingers. Along with long and slender toes and fingers, there may be loose joints resulting in hypermobility. External manifestations are the main key in diagnosing this condition and even two patients from same family may look different. Intelligence is not affected.

Patient Information

Marfan syndrome is an inherited disorder that affects the connective tissue which is the material between cells. This connective tissue gives strength , flexibility and elasticity to the entire body. The condition affects many organs of the body, mainly the heart, eyes and skeleton.

The symptoms presented will vary from patient to patient. The severity increases with age. People with this syndrome tend to look unusually tall and thin. Patients show abnormally long fingers and toes. Most patients with Marfan syndrome may have a narrow face, along with curved spine or any other bony deformities. More than half of the patients will show blurring of vision for far away objects, or the lens may get dislocated from its normal position. Changes in heart and blood vessel may cause tiredness, shortness of breath. This is due to changes in the structure of the heart valves.

Genetic mutations are responsible for this syndrome due to which this condition has a high chance of being passed on to children.

Treatment mainly consists of relieving symptoms depending on the severity hence treatment plan will vary. The medical provider will take a complete history including family history and clinical examination to confirm this condition. Imaging techniques mainly echocardiogram to study the heart functioning are done. CT and MRI scans may also be suggested.

Marfan syndrome is incurable. The objective of the treatment is to prevent any complications and ensure that the patient can lead normal lives. Lifestyle modifications along with counselling help the patient.The most important aspect is early identification of this condition and treatment for prevention of complications.
Regular monitoring and modern treatment allows patients to lead a normal life span.

References

Article

  1. Kainulainen K, Karttunen L, Puhakka L, Sakai L, Peltonen L. Mutations in the fibrillin gene responsible for dominant ectopic lentis and neonatal Marfan syndrome. Nat Genet.1994 Jan; 6 (1): 64–9.
  2. McMillan JA, Feigin RD, DeAngelis C, Jones DM. (Eds). Oski'sPediatrics: Principles & Practice. Philadelphia, PA. Lippincott Williams & Wilkins. 2006.
  3. Fusar-Poli P, Klersy C, Stramesi F, Callegari A, et al. Determinant of quality of life in Marfan Syndrome. Psychosomatics.2008 May-Jun; 49 (3): 243–8.
  4. Kohlmeier L, Gasner C, Bachrach LK, Marcus R. The bone mineral status of patients with Marfan syndrome. J Bone Miner Res. 1995 Oct;10 (10): 1550–5.
  5. Van de Velde S, Fillman R, Yandow S. Protrusioacetabuli in Marfan syndrome. History, diagnosis, and treatment. J Bone Joint Surg Am. 2006 Mar; 88(3): 639–46.
  6. Zipes, Libby Bonow Braunwald. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. 7th Ed. USA: Elsevier Saunders; 2005; p. 1894
  7. Dean JC. Marfan syndrome: Clinical diagnosis and management. Eur J Hum Genet. 2007 Jul; 15(7): 724–33.
  8. De Paepe A, Devereux RB, Dietz HC, Hennekam RC, Pyeritz RE. Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet. 1996; 62 (4): 417–26.
  9. Keane MG, Pyeritz RE. Medical management of Marfan syndrome. Circulation. 2008 May 27; 117 (21): 2802–13.
  10. Gott VL, Cameron DE, Alejo DE, et al. Aortic root replacement in271 Marfan patients: a 24-year experience. Ann Thorac Sur. 2002 Feb; 73 (2): 438–43.

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Last updated: 2018-06-22 09:34