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Thrombocytopenia Absent Radius Syndrome

2011; American Academy of Pediatrics; Volume: 32; Issue: 9 Linguagem: Inglês

10.1542/pir.32.9.399

1529-7233

Lisa de Ybarrondo, Michelle S. Barratt,

Congenital heart defects research

Thrombocytopenia absent radius (TAR) syndrome (MIM #2740000) is a rare condition characterized by bilateral absence of radii, severe thrombocytopenia with platelet counts less than 50×103/μL (50×109/L), and the presence of both thumbs. Associated multisystem congenital abnormalities frequently affect the gastrointestinal, skeletal, genitourinary, and cardiac systems. TAR syndrome was first described in 1959 and defined as a syndrome in 1969 by Hall and associates.The inheritance pattern of TAR is uncertain. Autosomal recessive inheritance was inferred from reports of families having several affected children born to unaffected parents, but other reports suggested autosomal dominance with variable penetrance. In a study by Klopocki and colleagues, all 30 individuals born with TAR syndrome who were studied manifested a microdeletion of the 200-kb region at chromosome band 1q21.1. Analysis revealed that 75% of unaffected parents in this cohort had the microdeletion, and the deletion occurred de novo in 25%. Deletion of this segment on chromosome 1q21.1 is necessary but not sufficient to cause the phenotype, suggesting an additional modifier gene for disease expression. In individuals born with bilateral absence of the radius and the presence of thumbs, the identification of this microdeletion is proposed to be sufficient to verify the diagnosis of TAR syndrome.The diagnosis classically is based on clinical characteristics. Newborns born with bilateral radial aplasia who have thumbs should be evaluated for thrombocytopenia, and the platelet measurement should be repeated whenever there is physical evidence of increased bleeding (eg, bruising, petechiae). More than 50% of affected infants are symptomatic and have severe thrombocytopenia in the first week after birth (10 to 100×103/μL [10 to 100×109/L]). More than 90% become symptomatic within the first 4 postnatal months. Platelet counts improve over the first year and can recover spontaneously to near-normal values as the child gets older. Platelets are normal in size and granularity. Bone marrow examination shows reduction in the size and number of megakaryocytes. The hypomegakaryocytic thrombocytopenia is associated with a dysmegakaryocytopoiesis characterized by a blockage of cellular differentiation at an early stage. There is a lack of response to thrombopoietin despite normal receptors on the megakaryocytes.Gastroenteritis related to ingestion of cow milk can precipitate symptomatic thrombocytopenia. Transient leukemoid reactions with white blood cell counts greater than 35×103/μL (35×109/L) have been reported, as have case reports of leukemia but not of bone marrow failure.The primary conditions that must be considered in the differential diagnosis of TAR syndrome are Fanconi anemia (thrombocytopenia usually presents later than in TAR syndrome), Holt-Oram syndrome (thumb often absent), Roberts syndrome (microcephaly and intellectual disability), and RAPADILINO syndrome (radial hypoplasia, absent thumbs, other anomalies, diarrhea in infancy).Other clinical manifestations of TAR syndrome include additional skeletal abnormalities of the upper extremity (phocomelia, hypoplasia of the ulna or humerus, club hand, syndactyly, clinodactyly). Although lower extremity anomalies occur in 47% of cases, usually these are less severe than the upper limb anomalies. Cardiac anomalies occur in 15% to 33% of cases (septal defects most commonly). Facial anomalies occur in 53% of patients (micrognathia, tall and broad forehead, low and posteriorly rotated ears). Macrocephaly is seen in 76% of patients, and 95% have short stature. Problems with gastroenteritis caused by cow milk intolerance are common in 47% to 62% of patients, presenting with vomiting, diarrhea, and failure to thrive. Genitourinary anomalies with renal involvement occur in 23%. Learning difficulties are rare.Platelet transfusion is the mainstay of treatment for thrombocytopenia. Mortality is due primarily to intracranial hemorrhage during the neonatal and early infancy period, with the highest risk in the immediate perinatal period. Maintaining platelet counts within safe ranges for the first 72 to 96 hours after birth with prophylactic transfusions may be needed. Leukocyte-reduced platelet concentrates are recommended to minimize the risk of human leukocyte antigen (HLA) alloimmunization. Alloimmunization also can be delayed by giving single-donor platelets or by using a limited number of dedicated HLA-matched donors.Because thrombocytopenia usually resolves spontaneously after the first postnatal year, bone marrow transplantation is not indicated. Precautions should be used to avoid trauma, including use of a soft helmet. Prolonged pressure on immunization injection sites and local pressure with bleeding, such as with epistaxis, is recommended. Avoidance of medications that impair platelet function, such as nonsteroidal anti-inflammatory drugs, also is important. Alternative treatments with interleukin-6 and erythropoietin have been used to reduce thrombocytopenia.Orthopedic interventions to maximize function include prostheses, orthotics, adaptive devices, and surgery. Delaying surgery for repair until a patient is older and has less risk of thrombocytopenia is prudent. Adaptive devices provide independence in feeding, dressing, and toileting. Referral for genetic counseling for the family and patient is warranted. The prognosis for patients born with TAR syndrome is very good, including a normal life span if they survive the first year after birth.Comment: I remember attending a delivery in which the patient's father appeared to have absent radii syndrome. Prenatal ultrasonography had not revealed any problem, but the precision of ultrasonography at that time was not very good. The infant's father ran over to the warmer to view the infant as I examined her. His tears of joy that she appeared to have normal extremities led to a fairly emotional experience for all the clinicians in the delivery room. This case demonstrated to me both the functional challenges this man must have faced during his life with this condition and the uncertainty of the genetic inheritance. Fortunately, prenatal testing and more sensitive ultrasonography now are available, helping families to gain more information during the pregnancy.The potential for multiple organ involvement in TAR syndrome makes it prudent to examine the extremities closely in addition to the cardiac, gastrointestinal, and genitourinary systems of affected patients. Pediatricians should involve genetic counselors to provide families the best information about inheritance patterns. Current research is investigating the genetic transmission patterns and new therapies for early treatment of the thrombocytopenia.Janet R. Serwint, MDConsulting Editor, In Brief