Loeys-Dietz syndrome is a recently-discovered autosomal dominant genetic
syndromeIn medicine and psychology, the term syndrome refers to the association of several clinically recognizable features, signs , symptoms , phenomena or characteristics that often occur together, so that the presence of one feature alerts the physician to the presence of the others...
which has many features similar to
Marfan syndromeMarfan syndrome is a genetic disorder of the connective tissue.It is sometimes inherited as a dominant trait. It is carried by a gene called FBN1, which encodes a connective protein called fibrillin-1. People have a pair of FBN1 genes. Because it is dominant, people who have inherited one affected...
, but which is caused by
mutationIn biology, a mutation is a randomly derived change to the nucleotide sequence of the genetic material of an organism.Mutations can be caused by copying errors in the genetic material during cell division, or by exposure to mutagens , or can be induced by the organism itself, by cellular processes...
s in the genes encoding
transforming growth factorTransforming 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
BelgianThe Kingdom of Belgium is a country in northwest Europe. It is a founding member of the European Union and hosts its headquarters, as well as those of other major international organizations, including NATO...
physician Bart L. Loeys, for whom it is named.
There are currently two forms of Loeys-Dietz syndrome which are further subdivided into another two forms. The table below will better summarize this:
The main clinical characteristics include:
- Widely spaced eyes (orbital hypertelorism
Hypertelorism is an abnormally increased distance between two organs or bodily parts, usually referring to an increased distance between the eyes , seen in a variety of syndromes, including Basal Cell Nevus syndrome, DiGeorge syndrome and Loeys-Dietz syndrome...
)
- 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 tortuosity
Tortuosity 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:
- Scoliosis
Scoliosis is a medical condition in which a person's spine is curved from side to side, shaped like an "s", and may also be rotated. To adults it can be very painful. It is an abnormal lateral curvature of the spine...
- Indented or protruding chest wall (pectus excavatum
Pectus 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 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 (camptodactyly
Camptodactyly 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 foot
A clubfoot, Giles Smith syndrome or talipes equinovarus , is a birth defect. TEV is classified into 2 groups: Postural TEV or Structural TEV. Without treatment, persons afflicted often appear to walk on their ankles, or on the sides of their feet. It is a common birth defect, occurring in about one...
- Premature fusion of the skull bones (craniosynostosis
Craniosynostosis, is a medical condition in which some or all of the sutures in the skull of an infant or child close too early, causing problems with normal brain and skull growth. It can result in craniostenosis, which is the skull deformity caused by the premature closure of the cranial sutures...
)
- Joint hypermobility
- Congenital heart problems including patent ductus arteriosus
Patent ductus arteriosus is a congenital heart defect wherein a neonate's ductus arteriosus fails to close after birth. Symptoms are uncommon but in the first year of life include increased work of breathing and poor weight gain. With age, the PDA may lead to congestive heart failure if left...
(connection between the aorta and the lung circulation) and atrial 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 malformation
Arnold-Chiari malformation is a malformation of the brain. It consists of a downward displacement of the cerebellar tonsils and the medulla through the foramen magnum, sometimes causing 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 dissectionAortic dissection is a tear in the wall of the aorta that causes blood to flow between the layers of the wall of the aorta and force the layers apart. Aortic dissection is a medical emergency and can quickly lead to death, even with optimal treatment. If the dissection tears the aorta completely...
, abnormally long limbs and fingers, and
dural ectasiaDural 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...
(a gradual stretching and weakening of the
dura materThe dura mater , or dura, is the outermost of the three layers of the meninges surrounding the brain and spinal cord. 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 keeping in the cerebrospinal fluid...
that can cause abdominal and leg pain).
Loeys-Dietz syndrome is a recently-discovered autosomal dominant genetic
syndromeIn medicine and psychology, the term syndrome refers to the association of several clinically recognizable features, signs , symptoms , phenomena or characteristics that often occur together, so that the presence of one feature alerts the physician to the presence of the others...
which has many features similar to
Marfan syndromeMarfan syndrome is a genetic disorder of the connective tissue.It is sometimes inherited as a dominant trait. It is carried by a gene called FBN1, which encodes a connective protein called fibrillin-1. People have a pair of FBN1 genes. Because it is dominant, people who have inherited one affected...
, but which is caused by
mutationIn biology, a mutation is a randomly derived change to the nucleotide sequence of the genetic material of an organism.Mutations can be caused by copying errors in the genetic material during cell division, or by exposure to mutagens , or can be induced by the organism itself, by cellular processes...
s in the genes encoding
transforming growth factorTransforming 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
BelgianThe Kingdom of Belgium is a country in northwest Europe. It is a founding member of the European Union and hosts its headquarters, as well as those of other major international organizations, including NATO...
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 In the fields of genetics and evolutionary 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 |
| |
>-
| 1B
TGFBR2 |
3p22 |
| |
>-
| 2A
TGFBR1 |
9q22 |
| |
>-
| 2B
TGFBR2 |
3p22 |
| |
>-
Symptoms
The main clinical characteristics include:
- Widely spaced eyes (orbital hypertelorism
Hypertelorism is an abnormally increased distance between two organs or bodily parts, usually referring to an increased distance between the eyes , seen in a variety of syndromes, including Basal Cell Nevus syndrome, DiGeorge syndrome and Loeys-Dietz syndrome...
)
- 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 tortuosity
Tortuosity 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:
- Scoliosis
Scoliosis is a medical condition in which a person's spine is curved from side to side, shaped like an "s", and may also be rotated. To adults it can be very painful. It is an abnormal lateral curvature of the spine...
- Indented or protruding chest wall (pectus excavatum
Pectus 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 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 (camptodactyly
Camptodactyly 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 foot
A clubfoot, Giles Smith syndrome or talipes equinovarus , is a birth defect. TEV is classified into 2 groups: Postural TEV or Structural TEV. Without treatment, persons afflicted often appear to walk on their ankles, or on the sides of their feet. It is a common birth defect, occurring in about one...
- Premature fusion of the skull bones (craniosynostosis
Craniosynostosis, is a medical condition in which some or all of the sutures in the skull of an infant or child close too early, causing problems with normal brain and skull growth. It can result in craniostenosis, which is the skull deformity caused by the premature closure of the cranial sutures...
)
- Joint hypermobility
- Congenital heart problems including patent ductus arteriosus
Patent ductus arteriosus is a congenital heart defect wherein a neonate's ductus arteriosus fails to close after birth. Symptoms are uncommon but in the first year of life include increased work of breathing and poor weight gain. With age, the PDA may lead to congestive heart failure if left...
(connection between the aorta and the lung circulation) and atrial 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 malformation
Arnold-Chiari malformation is a malformation of the brain. It consists of a downward displacement of the cerebellar tonsils and the medulla through the foramen magnum, sometimes causing 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 dissectionAortic dissection is a tear in the wall of the aorta that causes blood to flow between the layers of the wall of the aorta and force the layers apart. Aortic dissection is a medical emergency and can quickly lead to death, even with optimal treatment. If the dissection tears the aorta completely...
, abnormally long limbs and fingers, and
dural ectasiaDural 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...
(a gradual stretching and weakening of the
dura materThe dura mater , or dura, is the outermost of the three layers of the meninges surrounding the brain and spinal cord. 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 keeping in the cerebrospinal fluid...
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
uvulaThe 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 voice:...
in the back of the throat, and skin findings such as easy
bruisingA 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 extracellular space. Bruises can involve capillaries at the level of skin, subcutaneous tissue, muscle,...
or abnormal
scarScars are areas of fibrous tissue that replace normal skin after injury. A scar results from the biologic 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 Scars (also...
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 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
miceA 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. The American white-footed mouse and the deer mouse also sometimes live in houses. In some places, certain kinds of field mice are also common...
has suggested that the
angiotensin II receptor antagonistAngiotensin 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...
losartanLosartan 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. It is currently marketed by Merck & Co...
, which appears to block TGF-beta activity, can slow or halt the formation of aortic aneurysms in Marfan syndrome. A large
clinical trialClinical trials are conducted to allow safety and efficacy data to be collected for new drugs or devices. These trials can only take place once satisfactory information has been gathered on the quality of the product and its non-clinical safety, and Health Authority/Ethics Committee approval is...
sponsored by the
National Institutes of HealthThe National Institutes of Health is an agency of the United States Department of Health and Human Services and is the primary agency of the United States government responsible for biomedical and health-related research. It consists of 27 separate institutes and centers which includes the Office...
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.
External links