Loeys Dietz Syndrome
What is Loeys Dietz Syndrome?
Loeys Dietz Syndrome is a genetic connective tissue disease, similar to Marfan syndrome and Ehlers-Danlos syndrome. This syndrome has four types and the general characteristics are very various between individuals affected with this disease.
This syndrome is caused by a mutation in specific genes that provide information for forming proteins. These proteins take part in regulation of cell growth, differentiation, division and death. Loeys Dietz syndrome is inherited in autosomal-dominant pattern (other autosomal dominant diseases see here: Liddle syndrome, Dubowitz syndrome).
That means that only one of the cells has to have the mutated gene for the disorder to be present. In most cases Loeys Dietz syndrome occurs as a new mutation, when no one else in the family is affected. The exact causes for mutation to occur are unknown.
There are four types of Loeys Dietz syndrome and they are distinguished by the mutated gene that causes this syndrome:
- Type I- TGFBR1 gene
- Type II- TGFBR2 gene
- Type III -SMAD3 gene
- Type IV- TGFB2 gene
The four genes, which mutations cause Loeys Dietz syndrome have a signaling role in promoting the growth and development of various tissue- blood vessel, bone, extracellular matrix. When these genes are mutated, they produce proteins with little or no function. Although their function is severely reduced, the signaling activity is increased. The exact mechanism of this activity is still unknown. The proteins start to work intensively and it disrupts the normal development of connective tissue in various organ systems .
Tgfbr1 gene and Tgffbr2 gene
Tgfbr1 gene is responsible for producing protein Tgfer proteins and forms a complex. Tgf-β receptor complex is responsible for cell growth, differentiation, development and death. Tgf-β receptor type 1 and 2 keeps the cells from growing and dividing uncontrollably therefore they also have anti-tumor growth function .
Smad3 gene is responsible for production of protein that transmits signals from cell surface to the nucleus. It is also a part of the Tgf-β signal transmitting pathway. The Smad protein complex in the nucleus controls the activity of certain genes and also regulates proliferation of cells .
Thfb2 gene is responsible for the production of Tgfβ-2 protein. This protein takes part in many functions in the body and is required from embryogenesis throughout all life. It takes part in regulating cell growth, differentiation, development and death.
It also takes part in forming blood vessels and regulating functions like muscle and fat cell development, healing of wounds, immune responses. It is especially important in skeletal tissue growth regulation.
There are four main features that suggest LDS. Not all of these features can be found in all patients. The main characteristics are:
- Aneurisms- widening of arteries, most often the aorta.
- Twisted or spiral arteries also known as arterial turtuosity. This symptom is most often present in the neck arteries.
- Hypertelorism- abnormally wide space between the eyes (also see Sotos syndrome)
- Split uvula- tissue that hangs down from the palate.
Since the genes involved in this syndrome have a role in connective tissue growth and development, many other body systems are involved [2,7].
- Flatness of cheak bones
- Downward angle of the eyes
- Skull bones fuse early after birth
- Cleft lip or palate (also see Stickler syndrome)
- Blue sclera
- Small or/and receding chin 
- Long fingers and toes
- Contracted fingers
- Clubfoot deformity
- Cervical vertebrae instability
- Abnormal flexibility of joints
- Chest wall deformities- pectus excavatum or pectus carinatum
- Height is usually normal 
- Pale, translucent, soft skin
- Bruises appear after minor trauma
- Abnormal scarring
- Possible hernias of the abdominal wall (see prune belly syndrome)
- Patent ductus arteriosus
- Defects of atrial or septal wall
- Bicuspid aortic valve
- Disorders of the eye muscles
- Detachment of retina that can cause vision loss
- More susceptible towards allergies
- Inflammatory disease of intestines, such as bacterial overgrowth syndrome
- Hollow organs are more prone to rupture- intestines, uterus
The diagnosis of Loeys Dietz syndrome can be made by clinical examination of the patient with further investigations for affected organ systems. The diagnosis can be determined by performing molecular genetic testing. Genetic testing is performed if there is high suspicion of Lds .
After thorough physical examination and detecting the possible organ system involvement, various tests can be performed:
- Echocardiography- examination of the heart with ultrasound can detect aortic aneurism and cardiac malformations.
- CT angiography- determination of blood vessel involvement. This method uses contrast substance that is injected and subsequent imaging.
- MR angiography- imaging of blood vessels with using magnetic rays. With this method a 3D image can be obtained to check for arterial turtuosity.
- Radiological imaging studies can also be used to determine possible skeletal deformations 
By obtaining blood samples from the patient molecular genetic testing can be performed. With this testing it is possible to determine which type of Loeys Dietz syndrome the patient has. The family members can also be tested, especially the children of a parent with Lds. If the child is born with Lds both parents should get tested to get information about possible recurrence .
Treatment of LDS includes conventional and surgical management of symptoms.
- Heart condition can be treated surgically. Blood vessel condition has to be frequently monitored to avoid aortic dissection and preventive surgery can be done. Medications are used to treat arrhythmia, thrombosis, maintain normal blood pressure.
- It is important for people with LDS to have regular but mild exercise. They should avoid contact sports
- In some cases surgery to correct scoliosis and chest wall deformity has to be done
- Other treatments include physical therapy, proper diet and orthosis .
Mostly people with Lds get diagnosed at an older age. On some occasions diagnosis is only made after some of the clinical characteristics have caused serious health problems, like artery dissection, subclavian steal syndrome. With early diagnosis and proper management, Lds patients can have a better quality of life. Many patients can live a normal life without knowing they have Lds therefore the exact statistics of life expectancy are not known .
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- Gene information see at: https://ghr.nlm.nih.gov/condition/loeys-dietz-syndrome#diagnosis
- Patient information : http://www.loeysdietz.org/en/medical-information/main-characteristics
- The Marfan foundation: https://www.marfan.org/loeys-dietz
- Detailed patient information http://www.medicinenet.com/loeys-dietz_syndrome/article.htm
- Detailed information for medical specialists: http://www.nature.com/gim/journal/v16/n8/full/gim201411a.html
- Imaging of LDS https://radiopaedia.org/articles/loeys-dietz-syndrome-2
- Aortic aneurism in LDS information: https://www.researchgate.net/publication/46256265_The_Loeys-Dietz_syndrome_An_update_for_the_clinician