Thrombocytopenia absent radius syndrome Symptoms and Causes

causes

General: The development of thrombocytopenia absent radius (TAR) syndrome is poorly understood. Bone marrow samples from TAR patients show either decreased or absent megakaryocytopoiesis, the process of creating and specializing cells that make platelet cells (megakaryocytes). This indicates that thrombocytopenia in TAR syndrome is due to defective platelet production, which usually occurs when cells that have not yet developed to perform a specialized function are injured, or when the growth of these undeveloped cells is specifically prevented in bone marrow.
Inheritance: The causes of TAR syndrome are not fully understood and genetic research is still underway. However, the general theory is that it is inherited as an autosomal recessive trait. This theory has been based, in part, on the observation that TAR syndrome has affected more than one member of some families with unaffected parents. However, further research is needed to confirm this genetic link, as evidence has suggested that TAR syndrome may be the result of a more complex inheritance pattern.
Some have suggested that the inheritance pattern may be autosomal dominant with variable expressivity. This means that only one abnormal gene is needed to inherit the disorder, but symptoms and severity of the disease vary among patients.
Other theories: Another theory suggests that TAR syndrome may be the result of allelic heterogeneity, a single disorder caused by different mutations within one gene. However, non-genetic or environmental factors cannot be ruled out.
Some research has shown that a region of chromosome 1, which contains 11 genes, is mutated in TAR patients and in some percentage of their unaffected family members. This would indicate that this mutation is related to the development of TAR syndrome, but that the mutation alone cannot cause the disorder to be expressed. No specific mutation has been identified as the cause of disease in patients with TAR.
Some researchers have proposed that TAR syndrome is the result of cellular injury to an unborn child during the period of development in which the systems affected by TAR syndrome are developing. Athough the bone and blood abnormalities present in TAR syndrome appear to be completely different, they may be related in that the heart, the radii, and the megakaryocytes (platelet forming cells) all begin to form between weeks six and eight of development. These malfunctions occurring together to cause TAR syndrome may be explained by cellular injury.
Several genetic theories of inheritance have also been proposed because TAR syndrome has been observed to be very similar to congenital rubella and Robert's syndrome. However, a common genetic cause has not been identified. Further research is necessary to confirm these theories.

diagnosis

There are many disorders besides thrombocytopenia absent radius (TAR) syndrome that cause blood and bone problems. To accurately diagnose TAR syndrome, it is important to distinguish it from disorders with similar symptoms.
TAR syndrome is characterized by very low levels of platelet-producing cells, called hypomegakaryocytic thrombocytopenia. In addition, TAR syndrome is marked by lack of growth of the forearm bone connecting to the thumb (bilateral radial aplasia) in both arms. Diagnosis is based on the observation of these features. Patients are almost always diagnosed at birth.
Physical examination and imaging: X-rays and computed tomography (CT) scans are imaging techniques used to view the internal organ and bone structures. These techniques allow a medical professional to observe abnormalities in the physical development of a TAR syndrome patient. Characteristic skeletal abnormalities are detectable during prenatal ultrasound imaging, as early as thirteen weeks into the pregnancy. Ultrasound is another imaging technique that can also be used to examine kidneys, facial features, and extremities in developing fetuses that are suspected to have TAR syndrome.
The most consistent skeletal abnormality observed in TAR syndrome patients is the absence of both radii but presence of the thumbs. Other potential bone abnormalities include growth of the radius bone in just one forearm (unilateral radial aplasia), other bones in the forearm failing to grow or fully develop, the wrist being permanently bent towards the radius bone (radial club hand), a flipper-like appearance caused by the hands being connected to shorter arms (phocomelia), and various conditions resulting in underdeveloped or abnormal upper arm, wrist, finger, and toe bones.
Lower limb abnormalities have been observed in almost half of all cases of TAR syndrome, and at least 20% of TAR patients experience significant lower limb involvement. These are usually less severe than those of the upper limbs and include hip dislocation, turning inward or outward of either the upper leg bone or the shin bone, absence of lower leg bones, abnormal toe positions, and deformities of the knee, which cause abnormal bending positions of the leg, loose kneecaps, or fused knee bones. Lower limb defects do not generally affect the structure of the toes or feet.
Other more visible characteristics of TAR syndrome include various facial abnormalities. These include an unusually prominent forehead, a very small lower jaw, increased distance between the eyes, lumps of built up blood vessels in the face, low set ears (often resulting in hearing loss), flattened cheek bones, cleft palate, and downward displacement of the tongue. Patients may also show signs of a neurological disorder in which the head is significantly smaller than average (microcephaly).
Red and purple pinpoint spots called petechiae may be visible. These sometimes group together to form larger bruises and can occur anywhere on the body following a traumatic injury.
A thorough physical examination should also include observations of the size of the spleen, as many TAR syndrome patients have an enlarged spleen due to thrombocytopenia.
Lab studies: The most common finding in lab studies of TAR syndrome patients is that platelet count may be very low, indicating thrombocytopenia. However, thrombocytopenia can fluctuate over time. If TAR syndrome is strongly suspected on the basis of one platelet count, repeating the blood work is recommended.
Levels of certain white blood cells are elevated in about 50% of patients. Anemia may be present after an episode of bleeding.
Thrombocytopenia can occur as a separate condition and may be the result of causes other than TAR syndrome. A thorough medical history must be taken to rule out these possibilities. A person with thrombocytopenia may complain of general discomfort (malaise), fatigue, and weakness.
Platelet defects can be diagnosed using a bone marrow sample or biopsy. These samples are examined for the number, size, and maturity of platelet-producing cells, called megakaryocytes. Thrombocytopenia is generally characterized by low levels of small, immaturely developed megakaryocytes.
Genetic testing: Cordocentesis is a type of genetic testing that analyzes blood from the umbilical cord before a baby is born. This test can be used to confirm known genetic conditions. However, cordocentesis poses a 1-2% risk of miscarriage as well as a risk of prolonged bleeding from the umbilical cord at the test site.
It is useful for prenatal diagnostic methods to be performed, which can examine cells for genetic abnormalities before birth, to determine whether or not a child is affected. TAR syndrome infants should be delivered by cesarean section to avoid bleeding, bruising, and intracranial bleeding.

signs and symptoms

General: Thrombocytopenia absent radius (TAR) patients typically have very low blood platelet levels associated with clotting problems. The other main feature of the condition is that the forearm bone that connects the elbow to the thumb-side of the wrist (called the radius) fails to grow in both arms. These main characteristics differentiate TAR syndrome from other conditions affecting blood platelet levels and the radius bone.
Other conditions affecting the radius usually involve lack of growth or incomplete growth of thumbs as well as the radius, in one or both arms. This is not generally the case in TAR syndrome patients, most of whom have both of their thumbs.
Most individuals with TAR syndrome are shorter than average for their age and gender. No important hormonal abnormalities or growth hormone deficiencies have been observed to be associated with TAR syndrome. Fifty percent of affected infants show symptoms during the first week of their lives. Ninety percent are symptomatic within the first four months of their lives. Most affected individuals have significant bruising at birth.
Bone abnormalities: The most consistent skeletal abnormality observed in TAR syndrome patients is the absence of both radii but presence of the thumb. Other potential bone abnormalities include: the radius bone failing to grow in just one forearm (unilateral radial aplasia), other bones in the forearm failing to grow or fully develop, the wrist being permanently bent towards the radius bone (radial club hand), a flipper-like appearance caused by the hands being connected to shorter arms (phocomelia), and various conditions resulting in underdeveloped or abnormal upper arm, wrist, finger, and toe bones.
Generally, the more severely affected the upper limbs are in TAR syndrome patients, the more likely it is that the lower limbs will be affected as well. Lower limb abnormalities have been observed in almost half of all cases of TAR syndrome and at least 20% of TAR patients experience significant lower limb involvement. These are usually less severe than those of the upper limbs and include hip dislocation, turning inward or outward of either the upper leg bone or the shin bone, absence of lower leg bones, abnormal toe positions, and deformities of the knee, which cause abnormal bending positions of the leg, loose kneecaps, or fused knee bones. Lower limb defects do not generally affect the structure of the toes or feet.
Hematologic (blood-related) problems: Thrombocytopenia is a general term for any blood disorder resulting in low levels of blood platelets. Platelets are blood cells that cause the blood to clump together where a blood vessel injury occurs. Clotting helps to prevent blood loss. Therefore, thrombocytopenia is often associated with abnormal bleeding.
Symptoms include bruising easily, purple-colored spots and patches, and small red or purple pinpoint spots on the skin (purpura and petechiae). Additional symptoms include bleeding in the mouth, bloody nose, coughing up blood, and blood in the urine. Bleeding in the stomach and intestines may cause a patient to vomit blood. In more serious cases, life-threatening bleeding into the brain (intracranial hemorrhage) may occur. Symptoms of severe intracranial hemorrhage in an infant are associated with poor feeding, lethargy, irritability, and variable levels of consciousness.
Almost all patients with TAR syndrome begin to show symptoms of thrombocytopenia during the first year of life. Periods of very low platelets, called thrombocytopenic episodes, are common during the first two years of life. However, these episodes occur less frequently and platelet counts become more stable with age. The platelet counts may become normal in TAR patients by age four or five. Eventually, most affected individuals outgrow the risk of bleeding related to their low platelet levels.
Facial irregularities: Facial anomalies occur in approximately half of TAR syndrome patients. These include an unusually prominent forehead, a very small lower jaw, increased distance between the eyes, lumps of built up blood vessels in the face, low set ears (often resulting in hearing loss), flattened cheek bones, cleft palate, and downward displacement of the tongue.
In some cases, patients may be born with a neurological disorder in which the head is significantly smaller than average for the person's age and sex (microcephaly).
Heart problems: Heart problems occur in about one-third of TAR syndrome patients. These can include conditions such as tetralogy of Fallot, a heart defect with four characterizing structural abnormalities that is present at birth. Other congenital heart defects that allow irregular blood flow between the right and left sides of the heart, or any structural defect causing this blood flow, may also occur.
The most frequent other type of anomaly found in individuals with TAR syndrome is a hole in the heart. About 30% of affected individuals have some kind of structural abnormality of the heart.
Other: Cow's milk intolerance is associated with almost half of all cases of TAR syndrome, and usually develops during infancy. Patients may experience vomiting and bloody diarrhea after consuming products made with cow's milk. Kidney defects are also a common occurrence in TAR patients.
Other anomalies commonly associated with TAR syndrome include nuchal folds (excess skin on the back of the neck), excess fluid retained in the tissues of the feet, presence of skin moles, and excessive perspiration.
Infants in particular may experience difficulty feeding due to small lower jaw structure and other gastrointestinal complications, especially underdevelopment of the esophagus.

complications

General: The most serious complications of thrombocytopenic absent radius (TAR) syndrome occur during the first two years of a patient's life. This is also when mortality rates are highest. If a patient survives the initial two years of life, life expectancy is generally normal.
Hemorrhage: The major cause of death in TAR syndrome patients is hemorrhage due to an episode of dramatically low blood platelet levels. The incidence of death as a result of hemorrhage is almost completely limited to patients in their first year of life.
Children with TAR syndrome who are not delivered by cesarean section have an increased incidence of death due to bleeding, severe bruising, and intracranial hemorrhage (bleeding into the brain).
Bleeding and hemorrhage, especially intracranial hemorrhage, can also result in other serious complications, including brain damage.
Thrombocytopenic episode: Episodes of low platelets occur most often before age one, greatly increasing the risk of severe bleeding. Bleeding into the brain (intracranial hemorrhage) is the most common complication of these episodes.
The frequency of thrombocytopenic episodes decreases with age. By school age, patients can be expected to have near-normal platelet counts.
Thrombocytopenia may be accompanied by varying degrees of anemia or a decrease in hemoglobin in red blood cells. Since hemoglobin carries oxygen from the lungs to the tissues and organs of the body, individuals with anemia experience weakness, general fatigue, exercise-induced fatigue, shortness of breath, general discomfort, and poor concentration. Anemia in TAR syndrome patients is generally associated with severe bleeding caused by thrombocytopenic episodes. Affected individuals tend to outgrow anemia.
Episodes can be triggered by nonspecific stress, diarrheal illness (which is common during infancy), infection, or elements of an individual's diet, especially since a number of TAR syndrome patients have intolerance to cow's milk.
Gastrointestinal problems: Several severe gastrointestinal problems may occur in TAR syndrome patients. During episodes of thrombocytopenia, individuals may experience blood in the stool and/or urine or may vomit blood due to gastrointestinal tract bleeding.
TAR syndrome patients may also experience congenital (present at birth) gastrointestinal complications. Esophageal atresia is a disorder in which the esophagus does not develop properly. This causes bluish skin color when feeding, as well as choking, coughing or gagging, and drooling. Esophageal atresia may lead to serious feeding problems, especially in infants, which can affect nutrition.
Tracheoesophageal fistula is a disorder in which the trachea (or windpipe) is connected to the esophagus, often leading to fatal pulmonary complications. Anal atresia is the absence of an opening at the bottom of the intestinal tract, which can be fatal without corrective surgery.
Leukemia and leukemoid reaction: In addition to platelet problems, individuals with TAR syndrome may experience what is called a leukemoid reaction. This consists of the production of too many white blood cells. White blood cells help to protect the body from infection and other foreign materials. Leukemoid reactions alone are not generally dangerous. However, they are usually the result of a more serious disease state. Leukemoid reaction, not to be confused with leukemia, most often occurs in response to stress or infection during early infancy along with thrombocytopenic episodes in more severe cases of TAR syndrome. It can also be the result of bleeding into the brain caused by an episode of thrombocytopenia.
A leukemoid reaction may also be associated with cow's milk intolerance. TAR syndrome patients tend to have elevated levels of eosinophils, which are white blood cells usually associated with allergies and asthma.
In some cases, acute leukemia has been observed in both pediatric and adult patients with TAR syndrome. However, is not yet clear whether patients with TAR syndrome are at an increased risk of developing cancer.
Functional and developmental problems: Individuals with TAR often have delayed motor skill development because of their short arms. Hand and arm function is usually good if radial aplasia is the only skeletal abnormality.
Learning disabilities have been observed in TAR syndrome patients. However, they appear to occur only in individuals who have had an intracranial hemorrhage (bleeding into the brain). Intellectual disability (formerly called mental retardation) is associated with about seven percent of all cases of TAR syndrome. The association of TAR with intellectual disability is believed to be due to complications from intracranial hemorrhage caused by thrombocytopenia. Some patients may be at risk for intellectual disability and other neuropsychiatric disorders (psychosis) because of structural defects, although research on this theory is unclear.
Musculoskeletal symptoms of TAR syndrome may cause significant functional disabilities and cosmetic concerns for patients with the disorder.
Other: Women with TAR syndrome often have very heavy menstrual periods. This lowers platelet levels and may bring on an episode of thrombocytopenia or conditions of anemia.
The spleen works to filter unwanted materials from the blood. In TAR syndrome patients, the spleen collects platelet cells, becomes enlarged, and may be at risk for bursting. This may result in low blood platelet levels and cause a thrombocytopenic episode.
TAR syndrome patients may have large, horseshoe-shaped kidneys, which function abnormally in almost 25% of patients. They may also have a ring of pancreatic tissue that constricts or blocks blood flow to the lower intestines (annular pancreas). In addition, TAR syndrome patients may have a small bulge in the small intestine (Meckel's diverticulum). Patients may also develop urinary tract or uterine disorders.
Patients with TAR syndrome may have abnormalities in the structure of the ribs, including asymmetrical first rib or cervical (extra) rib. They may also have abnormalities of the spine, including spina bifida ("split" spine), scoliosis, and cervical spinal fusion. Depending on the severity of these abnormalities, they may create functional disabilities for the patient or require serious medical attention.
About 30% of individuals with TAR syndrome have some kind of structural abnormality of the heart, in some cases, a hole in the wall between the right and left sides of the heart. These abnormalities often require surgery. Due to the low platelet levels in TAR syndrome patients, however, individuals are at higher risk for complications during any type of heart surgery.

risk factors

Thrombocytopenia absent radius (TAR) syndrome is believed to be inherited in an autosomal recessive pattern. Autosomally inherited disorders are associated with abnormalities (mutations) in any of the first 22 non-sex chromosomes, which are the genetic structures that contain DNA. People inherit two copies of each autosomal gene (one from each parent). Recessive inheritance means that both copies of a gene must be defective to cause the disease. A person that has only one defective gene does not develop the disease, but is considered a carrier. Carriers can pass the abnormal gene to their children.
Children born to parents who are both carriers of an autosomal recessive gene each have a 25% chance of inheriting two copies of the abnormal gene, one from each parent, and developing the disease. These children would also have a 50% chance of inheriting just one abnormal gene, which would make them carriers.
If one parent has TAR and the other parent does not have TAR and is not a carrier of TAR, each of their children will be a carrier of TAR. Children who have one parent with TAR and one parent who is a carrier of TAR have a 50% chance of having TAR syndrome and a 50% chance of being a carrier of TAR. Many TAR patients have had children that did not develop the disease.
Patients usually show symptoms of thrombocytopenia (low blood platelet production) in the first week of life. However, improved blood platelet counts during infancy and normalization of platelet levels with increasing age is common.
TAR syndrome affects males and females equally, and the incidence is similar in most populations. For unknown reasons, TAR syndrome rarely occurs in the United States. The frequency is slightly higher in Spain, where TAR syndrome affects about four out of every one million babies.