Loeys-Dietz syndrome
Encyclopedia
Loeys-Dietz syndrome is a recently-discovered autosomal dominant genetic syndrome
which has many features similar to Marfan syndrome
, but which is caused by mutation
s in the genes encoding transforming growth factor
beta receptor 1 (TGFBR1) or 2 (TGFBR2).
It was identified and characterized by American physician Harry C. Dietz and Belgian
physician Bart L. Loeys, for whom it is named.
Other findings can include:
Many of the physical findings typical in Loeys-Dietz syndrome are also found in Marfan syndrome cases, including increased risk of ascending aortic aneurysm and aortic dissection
, abnormally long limbs and fingers, and dural ectasia
(a gradual stretching and weakening of the dura mater
that can cause abdominal and leg pain). However, it also has some additional traits not typical of Marfan patients, including widely spaced eyes, a split uvula
in the back of the throat, and skin findings such as easy bruising
or abnormal scar
s.
.
Previous research in laboratory mice
has suggested that the angiotensin II receptor antagonist
losartan
, which appears to block TGF-beta activity, can slow or halt the formation of aortic aneurysms in Marfan syndrome. A large clinical trial
sponsored by the National Institutes of Health
is currently underway to explore the use of losartan to prevent aneurysms in Marfan syndrome patients. Both Marfan syndrome and Loeys-Dietz syndrome are associated with increased TGF-beta signaling in the vessel wall. Therefore, losartan also holds promise for the treatment of Loeys-Dietz syndrome.
Syndrome
In medicine and psychology, a syndrome is the association of several clinically recognizable features, signs , symptoms , phenomena or characteristics that often occur together, so that the presence of one or more features alerts the physician to the possible presence of the others...
which has many features similar to Marfan syndrome
Marfan syndrome
Marfan syndrome is a genetic disorder of the connective tissue. People with Marfan's tend to be unusually tall, with long limbs and long, thin fingers....
, but which is caused by mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in the genes encoding transforming growth factor
Transforming growth factor
Transforming growth factor is used to describe two classes of polypeptide growth factors, TGFα and TGFβ....
beta receptor 1 (TGFBR1) or 2 (TGFBR2).
It was identified and characterized by American physician Harry C. Dietz and Belgian
Belgium
Belgium , officially the Kingdom of Belgium, is a federal state in Western Europe. It is a founding member of the European Union and hosts the EU's headquarters, and those of several other major international organisations such as NATO.Belgium is also a member of, or affiliated to, many...
physician Bart L. Loeys, for whom it is named.
Types
There are currently two forms of Loeys-Dietz syndrome which are further subdivided into another two forms. The table below will better summarize this:| Type | Gene | Locus Locus (genetics) In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map... |
OMIM | Description >- | 1A |
TGFBR1 | 9q22 | >- | TGFBR2 | 3p22 | >- | TGFBR1 | 9q22 | >- | TGFBR2 | 3p22 | >- |
Symptoms
The main clinical characteristics include:- Widely spaced eyes (orbital hypertelorismHypertelorismHypertelorism is an abnormally increased distance between two organs or bodily parts, usually referring to an increased distance between the orbits . In this condition the distance between the inner eye corners as well as the distance between the pupils is greater than normal...
) - Cleft palate or bifid uvula (a split in the tissue that hangs down in the back of the throat)
- Aortic and arterial aneurysms/dissections with tortuosityTortuosityTortuosity is a property of curve being tortuous . There have been several attempts to quantify this property. Tortuosity is commonly used to describe diffusion in porous media...
(corkscrew structure) of the arteries.
Other findings can include:
- ScoliosisScoliosisScoliosis is a medical condition in which a person's spine is curved from side to side. Although it is a complex three-dimensional deformity, on an X-ray, viewed from the rear, the spine of an individual with scoliosis may look more like an "S" or a "C" than a straight line...
- Indented or protruding chest wall (pectus excavatumPectus excavatumPectus excavatum is the most common congenital deformity of the anterior wall of the chest, in which several ribs and the sternum grow abnormally. This produces a caved-in or sunken appearance of the chest...
or pectus carinatumPectus carinatumPectus carinatum, , also called pigeon chest, is a deformity of the chest characterized by a protrusion of the sternum and ribs. It is the opposite of pectus excavatum.-Causes:...
) - Contractures of fingers and toes (camptodactylyCamptodactylyCamptodactyly is a medical condition involving fixed flexion deformity of the interphalangeal joints of the little finger. This involves permanent flexure of one or more phalanges...
) - Long fingers and lax joints
- Club footClub footA club foot, or congenital talipes equinovarus , is a congenital deformity involving one foot or both. The affected foot appears rotated internally at the ankle. TEV is classified into 2 groups: Postural TEV or Structural TEV....
- Premature fusion of the skull bones (craniosynostosisCraniosynostosisCraniosynostosis is a condition in which one or more of the fibrous sutures in an infant skull prematurely fuses by ossification, thereby changing the growth pattern of the skull...
) - Joint hypermobility
- Congenital heart problems including patent ductus arteriosusPatent ductus arteriosusPatent ductus arteriosus is a congenital disorder in the heart wherein a neonate's ductus arteriosus fails to close after birth. Early symptoms are uncommon, but in the first year of life include increased work of breathing and poor weight gain...
(connection between the aorta and the lung circulation) and atrial septal defectAtrial septal defectAtrial septal defect is a form of congenital heart defect that enables blood flow between the left and right atria via the interatrial septum. The interatrial septum is the tissue that divides the right and left atria...
(connection between heart chambers) - Translucency of the skin with velvety texture
- Abnormal junction of the brain and medulla (Arnold-Chiari malformationArnold-Chiari malformationArnold–Chiari malformation, or often simply Chiari malformation, is a malformation of the brain. It consists of a downward displacement of the cerebellar tonsils through the foramen magnum , sometimes causing non-communicating hydrocephalus as a result of obstruction of cerebrospinal fluid outflow...
) - Bicuspid aortic valves
Many of the physical findings typical in Loeys-Dietz syndrome are also found in Marfan syndrome cases, including increased risk of ascending aortic aneurysm and aortic dissection
Aortic dissection
Aortic dissection occurs when a tear in the inner wall of the aorta causes blood to flow between the layers of the wall of the aorta and force the layers apart. The dissection typically extends anterograde, but can extend retrograde from the site of the intimal tear. Aortic dissection is a medical...
, abnormally long limbs and fingers, and dural ectasia
Dural ectasia
Dural ectasia is a widening or ballooning of the dural sac surrounding the spinal cord usually at the lumbosacral level. It is one of the major manifestations of Marfan syndrome. It may cause low back pain, headaches and neurological signs such as weakness and loss of bowel and bladder function,...
(a gradual stretching and weakening of the dura mater
Dura mater
The dura mater , or dura, is the outermost of the three layers of the meninges surrounding the brain and spinal cord. It is derived from Mesoderm. The other two meningeal layers are the pia mater and the arachnoid mater. The dura surrounds the brain and the spinal cord and is responsible for...
that can cause abdominal and leg pain). However, it also has some additional traits not typical of Marfan patients, including widely spaced eyes, a split uvula
Uvula
The palatine uvula, usually referred to as simply the uvula , is the conic projection from the posterior edge of the middle of the soft palate, composed of connective tissue containing a number of racemose glands, and some muscular fibers .-Function in language:The uvula plays a role in the...
in the back of the throat, and skin findings such as easy bruising
Bruise
A bruise, also called a contusion, is a type of relatively minor hematoma of tissue in which capillaries and sometimes venules are damaged by trauma, allowing blood to seep into the surrounding interstitial tissues. Bruises can involve capillaries at the level of skin, subcutaneous tissue, muscle,...
or abnormal scar
Scar
Scars are areas of fibrous tissue that replace normal skin after injury. A scar results from the biological process of wound repair in the skin and other tissues of the body. Thus, scarring is a natural part of the healing process. With the exception of very minor lesions, every wound results in...
s.
Treatment
As there is no known cure, Loeys-Dietz syndrome is a lifelong condition. Due to the high risk of death from aortic aneurysm rupture, patients should be followed closely to monitor aneurysm formation, which can then be corrected with vascular surgeryVascular surgery
Vascular surgery is a specialty of surgery in which diseases of the vascular system, or arteries and veins, are managed by medical therapy, minimally-invasive catheter procedures, and surgical reconstruction. The specialty evolved from general and cardiac surgery...
.
Previous research in laboratory mice
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...
has suggested that the angiotensin II receptor antagonist
Angiotensin II receptor antagonist
Angiotensin II receptor antagonists, also known as angiotensin receptor blockers , AT1-receptor antagonists or sartans, are a group of pharmaceuticals which modulate the renin-angiotensin-aldosterone system...
losartan
Losartan
Losartan is an angiotensin II receptor antagonist drug used mainly to treat high blood pressure . Losartan was the first angiotensin II receptor antagonist to be marketed. Losartan potassium is marketed by Merck & Co. Inc. under the trade name Cozaar...
, which appears to block TGF-beta activity, can slow or halt the formation of aortic aneurysms in Marfan syndrome. A large clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
sponsored by the National Institutes of Health
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
is currently underway to explore the use of losartan to prevent aneurysms in Marfan syndrome patients. Both Marfan syndrome and Loeys-Dietz syndrome are associated with increased TGF-beta signaling in the vessel wall. Therefore, losartan also holds promise for the treatment of Loeys-Dietz syndrome.