Genetic and other disorders related to Marfan syndrome
Although Loeys-Dietz syndrome (LDS) symptoms overlap with other disorders such as Marfan Syndrome (MFS), Ehlers-Danlos Syndrome (EDS), Shprintzen-Goldberg syndrome (SGS) and others, a variety of differential features set LDS apart from other disorders.
Individuals diagnosed with Marfan syndrome (MFS) exhibit several findings not found in LDS patients. These include:
- Ectopia Lentis (dislocation of the lens of the eye)
- Dolichostenomelia (prominently long limbs)
Individuals with LDS tend to have a more translucent quality to their skin, allowing veins to be easily visible. Abnormal scarring and easy bruising also may occur to a greater degree in individuals with LDS. Birth defects such as clubfoot, other structural heart defects and cleft palate (opening and obvious gap in the roof of the mouth) are also more likely to be associated with LDS.
It has also been discovered that the genetic cause for these two disorders is distinct. MFS is caused by a mutation (gene change) in the fibrillin-1 (FBN1) gene, while LDS is caused by a mutation the TGFBR1, TGFBR2, SMAD3 or TGFB2 gene.
Shprintzen-Goldberg syndrome (SGS) is characterised by craniosynostosis (premature fusing of the skull bones), neurologic and brain anomalies, distinctive craniofacial features, and skeletal changes. Cardiovascular problems may occur but aortic root dilatation is most likely not found in individuals with SGS. Minimal subcutaneous fat, abdominal wall defects, cryptorchidism in males, and myopia are also characteristic findings. Both males and females may be affected.
- Small, abnormally shaped skull, narrow face, small chin sometimes with cleft palate
- Tall stature with long, slim arms and legs with long, spider-like fingers and toes
- Joint hypermobility
- Developmental delay, learning problems
- Heart defects
Weill-Marchesani syndrome (WMS) is a connective tissue disorder characterized by abnormalities of the lens of the eye, proportionate short stature, brachydactyly, and joint stiffness. The ocular problems, typically recognized in childhood, include microspherophakia (small spherical lens), myopia secondary to the abnormal shape of the lens, ectopia lentis (abnormal position of the lens), and glaucoma, which can lead to blindness. Height of adult males is 142-169 cm; height of adult females is130-157 cm. Autosomal recessive and autosomal dominant WMS cannot be distinguished by clinical findings alone.
- Eye anomalies including microspherophakia and ectopia lentis
- Short stature
- Joint stiffness
- Heart defects (occasional)
Stickler syndrome is an autosomal dominant disorder caused by mutations in collagen genes.
- Ocular findings of myopia (nearsightedness), cataracts, and retinal detachment
- Hearing loss
- Facial abnormalities sometime including cleft palate
- Early onset arthritis
- Short stature in comparison to unaffected siblings
- Some individuals have body type similar to Marfan syndrome, but do not have tall stature
For more information about Stickler syndrome, visit the Stickler Involved People website.
Marfan Habitus (Marfan Skeletal Features)
Many individuals have skeletal features that are similar to Marfan syndrome, but do they not have the aortic and eye problems that are characteristic of Marfan syndrome. This is called Marfan Habitus (or Marfanoid or Marfan-like Habitus). Often the skeletal features are inherited in families and can result from mutations in the same gene that causes Marfan syndrome. Individuals who do not have Marfan syndrome can have one or many of these skeletal problems. These problems are not life-threatening, but some may cause discomfort and disability in affected individuals. Many of the skeletal features do not require treatment for most individuals unless they become symptomatic and interfere with daily routines. It is recommended that individuals with major skeletal manifestations of Marfan syndrome have a thorough evaluation for the condition, including echocardiogram and ophthalmologic examination. Continued cardiac follow-up with echocardiograms every few years is recommended.
Skeletal features include
- Long, thin arms and legs, which are out of proportion to the trunk causing the armspan to be greater than the height
- Long, thin fingers and toes
- Curvature of the spine (scoliosis)
- Chest wall abnormalities (pectus excavatum/or indented chestbone or pectus carinatum/protruding chestbone)
- Flat feet (pes planus)
- Loose or hyperextensible joints
- Highly arched roof of the mouth (palate) leading to crowding of the front teeth
Homocystinuria is an inherited metabolic disorder in which the body is unable to process certain building blocks of proteins (amino acids) properly. The most common form of the condition is caused by the lack of an enzyme called cystathionine beta-synthase. This form of homocystinuria is characterized by dislocation of the lens in the eye, an increased risk of abnormal blood clots, and skeletal abnormalities. Problems with development and learning are also evident in some cases. Less common forms of homocystinuria are caused by a lack of other enzymes involved in processing amino acids. These disorders can cause mental retardation, seizures, problems with movement, and a blood disorder called megaloblastic anemia. Homocystinuria can be diagnosed by urine and/or blood tests, and should be done on any individual with lens dislocation. It can be treated with dietary modifications and supplements in addition to medications, such as trimethylglycine (betaine) or vitamin B6 (pyridoxine).
- Near-sightedness (myopia)
- Dislocated lens of the eye (ectopia lentis)
- Tendency to develop blood clots (thrombosis)
- Failure to thrive in newborns and/or developmental delays
- Tall stature with long thin limbs and fingers, chest deformities, scoliosis
Ehlers-Danlos syndrome (EDS) is a group of genetic connective tissue disorders characterized by unstable, hyper-mobile joints, loose, “stretchy” skin and tissue fragility. Like Marfan syndrome, it is caused by a defect in the connective tissue. The fragile tissues and skin and unstable joints found in EDS are due to faulty collagen, while the features of Marfan syndrome are due to faulty fibrillin-1 and an over-expression of TGFβ. Collagens and fibrillin-1 are proteins that add strength and elasticity to connective tissue. There are several different types of EDS, each with its own set of features and complications. Some forms of Ehlers-Danlos syndrome, notably the vascular and kyphoscoliosis types, can involve serious and potentially life-threatening complications. Blood vessels can tear (rupture) unpredictably, causing internal bleeding, stroke, and shock. The vascular type of Ehlers-Danlos syndrome is also associated with an increased risk of organ rupture, including tearing of the intestine and rupture of the uterus (womb) during pregnancy. People with the kyphoscoliosis form of Ehlers-Danlos syndrome experience severe, progressive curvature of the spine that can interfere with breathing.
- Joint hypermobility
- Loose/unstable joints which are prone to frequent dislocations
- Skin and joint hyper-extensibility
- Soft, velvety-like skin
- Fragile skin that tears or bruises easily
For more information about Ehlers-Danlos syndrome, visit the Ehlers-Danlos National Foundation website.
Bicuspid Aortic Valve
Bicuspid Aortic Valve (BAV) is an abnormality of the aortic valve in which the valve consists of only two leaflets (bicuspid) instead of the normal three leaflets (tricuspid). It is inherited in an autosomal dominant manner, meaning that if a person has bicuspid aortic valve, they have a 50-50 chance of passing it on to each child. In most cases, people with bicuspid aortic valves do not have any symptoms associated with it. However, aortic dilation occurs in a subset of individuals which can lead to a leaky aortic valve (aortic insufficiency) and an increased chance of aortic dissection. Severe cases of aortic insufficiency may require valve replacement surgery. Yearly monitoring by echocardiogram to assess valve function and aortic diameter (both aortic root and ascending aorta) is recommended. If good visualization through an echocardiogram is not possible, CT scan or MRI is recommended. Prophylactic antibiotics are recommended by the American Heart Association prior to dental or surgical procedures.
Identification and treatments include
- Accurate diagnostic testing
- Blood pressure management
- Comprehensive, individualized care
For more information about Bicuspid Aortic Valve, visit the Bicuspid Aortic Foundation website.
Beals syndrome and Marfan syndrome are similar in many ways, but there are also some important differences, specifically how the joints are affected. It is important for people with features of Beals syndrome to obtain an accurate diagnosis so they can benefit from treatments, such as physical therapy, to improve joint mobility as soon as possible. Beals syndrome is caused by a mutation in a gene that helps build connective tissue called fibrillin-2. It is closely related to the gene (fibrillin-1) that causes Marfan syndrome. Beals syndrome is also known as congenital contractural arachnoldactyly (CCA), which refers to the joint contractures (shortening).
People with Beals syndrome have many of the skeletal (bone) and aortic enlargement problems as people with Marfan syndrome, and treatments for these problems are the same. One difference from Marfan syndrome is that, in Beals syndrome, the eyes are not affected. Another major difference is the way in which Beals syndrome affects the body’s joints. People with Beals syndrome are unable to fully extend joints like their fingers, elbows, knees, toes, and hips. Their joints remain bent and deformed. When joints remain contracted for long periods of time, the muscles can become tight and short, restricting movement. When contractures are present at birth (congenital), they can delay motor development. People with Beals syndrome should also have their heart monitored on a yearly basis to check for cardiovascular complications that may arise.
- Long, slender fingers and toes
- Long, narrow body type
- Curved spine (scoliosis)
- Backward or lateral curved spine at birth or early childhood
- Chest sinks in or sticks out
- Reduced bone mass
- Facial abnormalities (unusually small jaws, high-arched palate)
- Crumpled appearance to the top of the ear
- Aortic enlargement and/or mitral valve regurgitation (occasionally)
Brugada Syndrome is a life threatening heart rhythm disorder. The condition is characterized by an abnormal heartbeat which is known as the Brugada sign, and is identified by an ECG. Brugada syndrome is an inherited disorder. Most people do not demonstrate any symptoms of the disease, and hence are unaware of their condition. The disorder is commoner in men than in women. It can be treated using a device called an implantable cardioverter-defibrillator.
- Pounding or fluttering in the chest
- Shortness of breath
- Fainting spells (syncope)
- Arrhythmias that occur during sleep
Information courtesy of the National Marfan Foundation, USA