"While some individuals enjoy a natural advantage in sports due to their long limbs, others face daily challenges posed by the abnormally long and hyperextensible limbs and fingers characteristic of Marfan syndrome, a lesser-known genetic condition. Imagine navigating through routine tasks with limbs that seem too long, causing constant difficulties, discomfort, and coordination problems. Yet, the real surprise lies in the increased risk of life-threatening heart complications and severe bone and spine deformities that accompany this condition."
Overview
Marfan syndrome (MFS), a rare, less known, genetic condition, affects the body's connective tissue. Connective tissue includes: Bones, ligaments, tendons and others that support body organs. A network of fibers that provide structure and support to our organs, bones, skin, and blood vessels. This, among other fibers, includes fibrillin, whose genetic mutation is known to be primarily responsible for the condition. When a mutation occurs in the FBN1 gene, it creates faulty fibrillin-1 protein, leading to the characteristic features of Marfan syndrome.
Some Historical Facts!! It was first described by Antoine Bernard-Jean Marfan in 1896 in a 5-year-old girl with peculiarly long and thin digits, hence named after him. Before the availability of the Bentall composite graft procedure in 1968, the operative results were very poor.
Incidence:
While not as common as some other genetic conditions, Marfan syndrome affects an estimated 1 in 5,000 people globally affecting people from all races and ethnicities. Interestingly, it affects both males and females equally as against many other genetic disorders that usually have a propensity to occur more in a specific gender. A person with Marfan's syndrome has a 50% probability of passing on the illness to their offspring. Individuals who have Marfan syndrome are born with the condition, even though they might not receive a diagnosis right away.
One should be aware that at times genetic tests for FBN1 gene mutation, might at times, show negative results, but the child may still have it, this could happen because of another genetic alteration that was not checked for.
Does It Have A Known Cause?
Marfan syndrome stems from a genetic mutation in a gene located on chromosome 15, named the FBN1 gene. This gene is responsible for the production of fibrillin-1, a crucial protein in the formation of elastic fibers. When mutated, it leads to weak and disorganized connective tissue, this gives rise to the various signs and symptoms associated with the syndrome.
In almost 75% of cases, the syndrome is inherited from one of the parents who also carries the defective gene. The remaining 25% of cases will have no family history but arise from sudden chance mutations in the FBN1 gene.
In advanced cases aorta may widely stretch, tear (dissection) or burst ( rupture) which can be fatal.
Symptoms: A Spectrum of Manifestations
Different people will experience the illness in different ways, and the severity of the symptoms can vary. Some of the shared features include:
● Bone Abnormalities: Tall and slender build( lean body type), long limbs(due to overgrowth of long bones), abnormally long toes and fingers (arachnodactyly), curved spine (scoliosis), flat feet, chest wall deformity ( chest wall protruding outwardly ( pectus excavatum) or inwardly(pectus carinatum)), flexible joints.
● Hypermovable joints: Defective fibrillin protein production resulting in parts of the body being able to stretch abnormally when placed under any kind of stress for instance affected individuals show can easily protrude their thumb past the palm of the hand while making a fist, wherein thumb extends beyond the little finger (Hand sign of marfan syndrome).
● Eye Problems: Nearsightedness (myopia), detached retina, and dislocation of the lens (ectopia lentis).
● Heart Related Complications: Abnormal heart sounds ( Heart murmurs, flutters, skipped beats, depicting leaking heart valves), bulging and dilation of the aortic vessel wall described as aortic aneurysm (“Aorta” is the main artery arising from heart), and valve abnormalities ( valves become floppy, fail to close adequately, leading to backward leaking of blood (termed as regurgitation). In advanced cases aorta may widely stretch, tear (dissection) or burst (rupture) which can be fatal.
● Impact on Lung : Weakening of the lung tissue leading to collapsed lung (spontaneous pneumothorax) and breathing difficulties.
● Unexplained Stretch Marks (striae) on the skin, without any gain in weight, stress or pregnancy.
● Cerebrovascular accidents: According to latest research, there is increased risk of localized ischemia( decreased blood flow ), bleeding (hemorrhages) in brain, in patients with marfan syndrome.
● Oral Features: Crowded Teeth, bifid uvula, high arched palate, backwardly placed jaws.
● Aches and Pains: Headaches, lower back pain and leg numbness.
Diagnosis: How to know if someone has marfan syndrome?
Many persons presenting "Marfan-like" features do not really have it, but exhibit a large spectrum of other syndromes. The multiplicity of symptoms and resemblance of features with other connective tissue disorders makes diagnosis difficult. Most of the signs and symptoms do not usually appear until later childhood and the teenage years. See your physician for a precise diagnosis. Your physician may take into account a number of things, such as:
● A thorough medical and family history.
● Imaging tests like:
a) X-rays to see skeletal abnormalities;
b) Echocardiogram for heart sounds;
c) MRI to check aorta and other blood vessels;
d) CT Scan: to detect spinal ectasia
● Physical examination to evaluate skeletal and other physical aspects;
● Genetic testing to confirm the presence of the FBN1 mutation [10]
● Eye examination by ophthalmologist to see eye changes such as: myopia and lens dislocation.
For the purpose of starting therapy and avoiding problems, early diagnosis is essential.
Ghent Criteria
The diagnostic checklist that helps healthcare professionals tell the difference between Marfan syndrome and other similar syndromes, is the Ghent Criteria which further consists of major and minor criteria.
The major criteria are the more severe symptoms that are only present in affected individuals. Major criteria can include:
● An enlarged aorta
● A tear in the aorta
● Dislocation of the lens of the eye
● A family history of the syndrome
● At least 4 skeletal problems, such as flat feet or a curved spine (scoliosis).
● Enlargement of the lining that surrounds part of the spinal cord (dural ectasia).
Minor criteria are the less severe symptoms present even in general population in addition to affected people along with people with other conditions with similar symptoms. Minor criteria can include:[18]
● A high arched, narrow palate, with crowding of teeth.
● Unexplained stretch marks
● A long, thin face
● Loose joints
Each affected individual would usually have a unique combination of both major and minor symptoms.
Genetic testing
For children, genetic testing may be advised in a number of circumstances, such as:
● When a child has no symptoms but a parent with Marfan syndrome.
● When a youngster exhibits certain characteristics of Marfan syndrome but lacks a conclusive diagnosis
● In families with a history of aortic aneurysm or dissection.
Prenatal Testing
Prenatal genetic testing options to test if the unborn baby has the genetic mutation that causes Marfan syndrome are:
1) Chorionic villus sampling (CVS) at 11 to 14 weeks testing a small sample of placenta to detect genetic abnormalities.
2) Amniocentesis tests the amniotic fluid present around your unborn baby for genetic abnormalities. It is carried out at 15 to 20 weeks.
Nevertheless, the degree of symptoms cannot be predicted by these tests.
At times genetic tests for FBN1 gene mutation, might at times, show negative results, but the child may still have it, this could happen because of another genetic alteration that was not checked for.
**In almost 99 out of 100 affected individuals, the genetic mutation can be identified through genetic testing. But since the outcomes aren't always clear-cut, its better to see a medical geneticist or genetic counsellor for accurate diagnosis.
Treatment Options to Manage the Condition
Unfortunately, there's no cure for Marfan syndrome. Nonetheless, a range of therapeutic approaches can help in the management of its symptoms and decrease the risk of its associated complications. Among the effective therapy alternatives are:
● Medications: Beta-blockers or angiotensin receptor blockers ( ARB’s) to control your blood pressure and stop aortic dissection, medications to strengthen your lung tissue.
● Surgery: To manage aortic problems, your doctor may recommend aortic valve replacement or repair.
● Surgery to straighten your spine, will usually be needed if it curves by 40 degrees or more. This will provide necessary relief from problems such as restricted breathing and back pain. Scoliosis can be treated with a brace and/or a variety of surgical techniques, depending on your age and unique situation.
For surgery:
a) In young children ( under the age of 10), growing rods are inserted, which allow for ongoing growth while partially correcting the curvature of the spine.
b) In teenagers and young adults, a spinal fusion operation may be carried out, which involves spine straightening using metal rods that are attached with screws, hooks, and wires. Bone grafts are used to fuse the spine in place.
c) Surgery for adults with scoliosis is recommended only when the spinal curvature is severe, getting worse, or when patient is experiencing ongoing compression on the nerves in the spine. The 2 main types of surgery usually recommended here are: decompression surgery, where the disc or bone pressing on a nerve is removed, and spinal fusion surgery.
● Physical therapy: For the treatment of musculoskeletal conditions such as scoliosis.
● Lifestyle modifications: Avoiding strenuous physical activities that can put strain on the aorta. Additionally, routine expert monitoring can be beneficial.
● Annual Eye check up: eye problems associated with Marfan syndrome are potentially serious and may lead to a permanent loss of vision. Your doctor may suggest annual health checkups to monitor new developments.
● Genetic Counseling: For understanding the risks and for family planning.
For the purpose of starting therapy and avoiding problems, early diagnosis is essential.
Success Stories From the Marfan Community
There are numerous inspiring stories of individuals thriving with Marfan syndrome. Consider the example of Abraham Lincoln the 16th U.S. president.
Marla Runyan, a professional runner who went blind due to the condition but defied limitations to win multiple gold medals at the Paralympics. Her story exemplifies that Marfan syndrome doesn't have to hold you back.
Hunter Zolman: A professional volleyball player who was diagnosed with Marfan syndrome at a young age, competed at the highest level, demonstrating that athletic success is possible with proper management.
You may be advised by your cardiologist to refrain from engaging in certain competitive sports activities which can potentially strain your heart, increase your blood pressure. risk of heart tear or joint injury to already weak joints.
Living with Marfan Syndrome!
Individuals affected with the syndrome may have valid concerns about their appearance, self image, future marital life, career and so on.
You may also be advised by your cardiologist to refrain from engaging in certain competitive sports activities which can potentially strain your heart, raise your blood pressure, heart rate and thereby the tendency to increase your risk of heart tear in addition to increasing your risk of joint injury to already weak joints. These activities include:
● Long-distance running
● Intense weightlifting
● Scuba diving
● Gymnastics
● Climbing
However the good news is, early diagnosis and availability of advanced treatment options have greatly improved the outlook for those with Marfan syndrome. Most individuals with Marfan syndrome can lead quite normal and fulfilling lives if they receive the right care and support of their loved ones.
Quote from Expert Medical Professional
Recently, Dr. Yokesh Arul, an MD medicine resident, spoke about this rare genetic condition through an Instagram post, highlighting the features of this illness that, if undiagnosed, can be fatal. He created awareness by discussing a 17-year-old patient whose presenting complaints were vague. However, on careful examination, it was found that the patient had abnormally long limbs, flat feet, abnormal heart sounds (diastolic murmur), and typical hand and wrist features of Marfan syndrome, such as abnormally long fingers and toes, and extremely extendable joints. Her father had similar features as well.
According to Dr. Arul, the condition might be asymptomatic but can cause sudden cardiac death, potentially leading to death at a young age of 40 years or less. Early diagnosis and appropriate treatment are essential to prevent further damage to the heart and reduce the risk of associated dangerous complications.
The Latest Developments:
Researchers are constantly striving for advancements in Marfan syndrome treatment. Promising areas of exploration include gene therapy to potentially correct the genetic mutation and the development of new medications to target specific pathways involved in the disease process.
Conclusion
Marfan syndrome, once daunting, holds a brighter future thanks to medical advancements. While incurable, early detection and comprehensive management empower individuals to lead fulfilling lives. Proactive care by a specialist team minimizes complications, allowing patients to focus on well-being and embrace life's potential. The inspiring Marfan community showcases resilience, like Marla Runyan's achievements. Promising research on gene therapy and targeted medications paves the way for even better management strategies. With proper care, support of loved ones, and a positive outlook, individuals with Marfan syndrome can live normal and fulfilling lives.
1. Marfan Foundation: https://www.marfan.org/
2. National Marfan Foundation: https://www.marfan.org/
3. Marfan Trust: https://marfantrust.org/
References
1] Dietz HC, Cutting GR, Pyeritz RE, Maslen CL, Sakai LY, Corson GM, et al. (1991). Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature, 352(6333), 337-339. https://www.nature.com/articles/352337a0
[2] National Organization for Rare Disorders. (2020). Marfan Syndrome. Retrieved from https://rarediseases.org/gard-rare-disease/marfan-syndrome/
[3] Pyeritz RE, McKusick VA. (1989). Marfan syndrome and related disorders. Part 1: general features. JBMR Journal of Bone and Mineral Research, 4(1), 269-274. https://www.ncbi.nlm.nih.gov/books/NBK537339/
[4] Ramirez F, Dietz HC. (2007). Marfan syndrome: a review. Nature Clinical Practice Cardiovascular Medicine, 4(7), 398-406. https://www.ncbi.nlm.nih.gov/books/NBK537339/
[5] Pyeritz RE. (2010). Marfan syndrome. Arthritis Research & Therapy, 12(4), 212. https://www.ncbi.nlm.nih.gov/books/NBK537339/
[6] Dietz HC. (1998). The Marfan syndrome. New England Journal of Medicine, 339(25), 1757-1765. https://www.ncbi.nlm.nih.gov/books/NBK537339/
By Dr. Aditi Bakshi
