[Compiled by GenePool] [May 2006] [ Author : June-Anne Gold- Specialist Registrar Clinical Genetics]
The Least You Need to Know
1.It can present at any age – (rarely as a severe neonatal form.)
2.Any one of the systems may make you think of the diagnosis. o Eyes- myopia/lens dislocation/detached retinao Heart- dilatation, dissection or rupture of the aortao Lungs- spontaneous pneumothorax.o Skeleton- tall and thin, long limbs and fingers and toes, spinal curvature.
3.Sudden early death due to cardiac cause in family history.
4.Definitive diagnosis may be made by a cardiologist, but referral to a clinical genetics centre is advisable in order to counsel the whole family.
Sunday, 18 November 2007
Marfan Syndrome
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Coffee Break Summary
Synonyms: Marfan Disease; OMIM #154700; FBN1
Overview
Marfan syndrome is a genetic disease of connective tissue, inherited in an autosomal dominant manner.
There is variable expression (manifestations are different in each individual) which can mean that diagnosis may be challenging. The diagnosis is a clinical one, based on typical characteristic findings in different organ systems and a detailed family history.
Inheritance
The abnormal gene in Marfan syndrome is FBN1, which is found on chromosome 15. The mode of inheritance is autosomal dominant. Men and women are equally affected. Three out of four people with Marfan have inherited it from a parent who is also affected. This diagnosis may have come to light due to the diagnosis in a more severely affected individual. One out of four people who have Marfan syndrome that is caused by a de novo (new) mutation in the FBN1 gene.
An affected individual has a 50% chance of passing the abnormal gene on to each of their children.
Sometimes the first diagnosis in a family is made in a child. Subsequently the diagnosis is also made in a parent.
The gene FBN1 codes for a protein known as ‘fibrillin-1’. This protein contributes to the strength of connective tissue. In Marfan syndrome the protein has altered properties and does not function correctly, weakening the structure of the connective tissue.
Features – signs, symptoms & complications
The systems of the body affected by Marfan syndrome include
Skeletal (bones and ligaments)-bone overgrowth, joint laxity. Disproportionate long limbs to trunk. Scoliosis, curvature of the spine can be mild or severe.
Cardiovascular (heart and blood vessels)
Pulmonary (lungs)
Ocular (Eyes)
Skin
Complications related to the affected system
Cardiac –Aortic dilatation, dissection of the aorta, mitral valve prolapse
Skeletal- Scoliosis which can be severe and need orthopaedic intervention. Rib overgrowth can give rise to thorax malformation pectus excavatum – (ribcage caved in) or pectus carinatum (‘pigeon chest’) Pes planus (flat feet)
Eyes- lens dislocation in an upwards direction, myopia (short-sightedness) may be familial and unrelated.
Pulmonary –spontaneous pneumothorax, apical blebs
Skin – stretch marks and herniae
Testing
FBN1 is a large gene consisting of 65 exons (coding regions); approximately 200 mutations have so far been described. There is some correlation between the severe neonatal form of the syndrome and mutations that occur between exons 24 and 32.
Even though the gene is has been identified, testing is not available on a routine clinical basis. Mutation testing is time-consuming and expensive. Diagnosis can usually be made on clinical grounds, so DNA testing may not add useful information.
In cases where pre-natal diagnosis is sought, mutation testing may be possible, but this must be discussed with a genetics centre well in advance. Even where genetic tests cannot be offered, prenatal assessment by ultrasound scanning may be possible, but needs to be discussed in each individual case and is insensitive in the first two trimesters.
Prenatal diagnosis is possible in families where the gene mutation is known. This can be done either by chorionic villus sample(CVS) at about 10-12 weeks gestation or amniocentesis at 16-18 weeks gestation. Linkage analysis may be possible in some families, but should be used with caution. Prenatal diagnosis, which cannot predict the severity of the condition, may be controversial for an adult onset disease.
Referral –for definitive diagnosis
Diagnosis in cases with an affected parent and clear-cut clinical signs may be straightforward, but many cases need combined clinical and radiological assessment by experienced specialists. Referral to a specialist clinical genetics centre is advisable.
Management
Genetic counselling
Children of individuals affected by Marfan syndrome are at 50% risk of inheriting the causative genetic mutation. The risk to their brothers or sisters of affected individuals depends on the status of their parents; if the parents are affected, the risk is also 50%. If the parents are unaffected the risk is much less than 50%, but greater than the population risk. This is due to rare germline mosaicism when the gene change has occurred in a proportion of either the sperm or the eggs of an unaffected parent.
Treatment
Active management is important because early treatment can prevent serious complications.
As Marfan syndrome affects many systems of the body a number of specialists may need to be involved, depending on the severity of the symptoms in an individual. One doctor should have a co-ordinating role ensuring that all areas of the syndrome are covered. This could be the clinical geneticist or a cardiologist with an interest in Marfan syndrome. This condition needs a true multidisciplinary approach. Clinicians that may be involved will include geneticists and genetic counsellors, cardiologists, ophthalmologist, orthopaedic surgeons and general paediatricians.
Pitfalls to Avoid
Offering a ‘routine DNA test’ for diagnosis of a new case of Marfan syndrome.
Not arranging multidisciplinary follow up (cardiology, ophthalmology, growth & spinal monitoring in children) or referral to Marfan Syndrome clinic where available.
Forgetting to offer assessment of relatives.
Offering routine antenatal care to women with Marfan syndrome (need liaison with cardiologist due to increased risk of cardiac complications during pregnancy).
Clinical Scenarios
Scenario 1
Mr Goldberg comes to see you. He is 19 years old and has had 2 spontaneous pneumothoraces. Apart from mild asthma he has always been healthy. He would like to know if he could have Marfan syndrome as he saw a recent programme on the T.V. and he feels he looks like some of the people on the programme. He is tall (6’3”) and so is his mother (6’1”) and one of his sisters, but not his other sister or brother. He is concerned about sudden death as his grandfather died unexpectedly in his early thirties. He would like a gene test to see if he has the condition.
Marfan syndrome is a connective tissue disorder which can affect people in different ways and severity. First presentation can be a pneumothorax. It is inherited in an autosomal dominant manner; if a parent is affected the risk of having an affected child is 50% or 1 in 2.
You examine him. He is tall and thin, has typical Marfanoid face with high arched palate; he has long fingers and toes. His arm span is greater than his height. He has a positive wrist and thumb sign. There is mild scoliosis and joint laxity. He wears glasses for short-sightedness. Blood pressure is normal and you cannot hear a murmur. You explain that he may have Marfan syndrome, which is a clinical diagnosis, and you will refer him to his local clinical genetics department to confirm the diagnosis. At present there is no simple gene test to tell him that he does or does not have the condition. His options can be discussed with the clinical geneticist. In the interim it is important to book an echocardiogram and refer him to the cardiologist for evaluation. Reassure him that although there is no cure for Marfan syndrome, there are several treatments to help with some of the complications and also help prevent some of the problems. He will also need to have an ophthalmological and orthopaedic review.
The skeletal features and the history of a pneumothorax with a possible family history of sudden early death make the diagnosis likely. The family are all patients in your practice and it would be important for you to suggest that you see the other members of the family for evaluation.
Scenario 2
Mrs Raymond visits the surgery. She is the older sister of Mr Goldberg and is concerned that she might also be at risk and wants to know the chance of her children getting Marfan syndrome.
Marfan syndrome is inherited in an autosomal dominant inheritance so all of Mr Goldberg’s siblings have a 1 in 2 or 50% risk of being affected. You examine her and she is 5’ 4” and has normal examination findings. You reassure her that she is unlikely to have Marfan syndrome and therefore her risk of having a of having a child with Marfan syndrome which is very low. It is estimated that about 1 in 5,000 people have Marfan syndrome. She may wish to see a clinical geneticist to rule out the diagnosis with more certainty.
Scenario 3
Ms Goldberg visits you. She is the 17 year old sister of Mr Goldberg and is extremely concerned as she is 8 weeks pregnant and wonders if her baby could be affected. You examine her; she is 6’2” and looks similar to her brother.
You refer her as an urgent prenatal case to the local genetics department for advice, diagnosis, evaluation of the risks for her and her baby, and to discuss the options available. You also refer her to the cardiologist for an urgent echocardiogram and assessment. You know that if she does have Marfan syndrome she is also at increased risk in pregnancy. Sudden death due to dissection of the aorta can occur during pregnancy.
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