eMedicine Specialties > Pediatrics: General Medicine > Hematology

Thrombocytopenia-Absent Radius Syndrome

Author: John K Wu, MBBS, MSc, FRCP(C), Clinical Professor, Department of Pediatrics, Division of Hematology-Oncology-BMT, University of British Columbia, Canada
Coauthor(s): Michelle P Wong, MD, Staff Physician, Department of Hematopathology, University of British Columbia Faculty of Medicine, Canada; Suzan Williams, MD, MSc, FRCPC, Staff Physician, Division of Hematology, The Hospital for Sick Children, Canada
Contributor Information and Disclosures

Updated: Sep 17, 2009

Introduction

Background

Thrombocytopenia-absent radius (TAR) syndrome is a rare condition in which thrombocytopenia is associated with bilateral radial aplasia. TAR syndrome was first described in 1951. An autosomal recessive inheritance pattern was proposed because TAR affected more than one member of some families. In 1969, TAR was defined as a syndrome and further classified as the association of hypomegakaryocytic thrombocytopenia and absent radii. The expression varies and includes abnormalities in the GI, skeletal, hematologic, and cardiac systems.

Pathophysiology

Some have proposed that the association of seemingly disparate skeletal and hematologic abnormalities is related to the simultaneous development of the heart, the radii, and the megakaryocytes at 6-8 weeks' gestation. The similarity of TAR syndrome to congenital rubella suggests intrauterine injury when the involved systems develop, but a common etiologic agent has not been identified. As an alternative, the contiguous gene model is based on the premise that phenotypic findings are related when genes responsible for each defect are geographically related in a chromosome. This mechanism, if true, is independent of the anatomic association and the degree of involvement in either system.

The exact pathophysiology of the thrombocytopenia is still unclear. The platelet abnormality reflects platelet hypoproduction, for which numerous explanatory theories have been proposed. One suggestion is that a failure in production of humoral or cellular stimulators of megakaryocytopoiesis (eg, thrombopoietin) is responsible for inhibiting platelet production. However, studies by Ballmaier and colleagues and Sekine and associates showed comparable or increased levels of thrombopoietin in patients with TAR compared with healthy control subjects.^1,2 These findings suggest that the thrombocytopenia is due to a lack of response to thrombopoietin, especially given the observation of normal thrombopoietin receptor expression on megakaryocytes. Letestu and colleagues suggested that the defect was a blockage in cell differentiation at an early stage.³

Other theories for platelet hypoproduction include an abnormal response to stimulators of megakaryocytopoiesis involving an abnormal signal-transduction pathway, decreased numbers and sizes of megakaryocytic progenitor cells,² abnormal progenitor cells with a maturational defect or receptor defect, and the presence of humoral or cellular inhibitors of megakaryocytopoiesis.

No causative mutation has been identified despite investigations of the c-mpl gene in patients with TAR.⁴ Another proposed candidate gene is a HOX gene. The HOX family of genes plays a major role in embryogenesis and cell differentiation, including differentiation of hematopoietic cell lines. However, Fleischman and colleagues did not detect mutations in the coding sequence of HOX genes known to affect radial development.⁵ An interstitial microdeletion of chromosome 1q was identified in 30 patients with TAR syndrome.⁶ All patients and 75% of unaffected parents in this cohort had the microdeletion, suggesting co-inheritance of an additional modifier gene for disease expression. The observation that platelet counts improve during infancy and that they may even normalize with age has led to the suggestion that abnormal genes may be developmentally regulated.

TAR syndrome is generally considered an autosomal recessive disease. Some have suggested that the inheritance pattern may be autosomal dominant with variable penetrance. Urban and associates postulated that, given the phenotypic overlap between Roberts syndrome and TAR syndrome, allelic heterogeneity might cause both. In this postulate, TAR syndrome is the compound heterozygous form, with a mild and a severe mutation, whereas Roberts syndrome is the homozygous form with the severe mutation. However, genetic heterogeneity and environmental factors cannot be completely ruled out.

Frequency

United States

TAR syndrome rarely occurs in the United States.

International

The frequency of TAR syndrome is 0.42 case per 100,000 live births in Spain.

Mortality/Morbidity

The major cause of mortality in TAR syndrome is hemorrhage. The incidence of hemorrhage is limited to the first 14 months of life. In a study by Hedberg and associates, 18 of 20 deaths in 76 patients were due to hemorrhagic events; most of patients who died had platelet counts <10 X 10⁹/L.⁷

Bleeding and hemorrhage can also result in clinically significant morbidity, especially intracranial hemorrhage. Hand and upper-extremity function is usually good if radial aplasia is the only skeletal abnormality. However, patients require plastic surgery, occupational therapy, and physiotherapy.

Race

No ethnic or racial predilection is reported.

Sex

The male-to-female ratio is 1:1. Greenhalgh and associates reported an excess of females (27:7),⁸ as did Hall and colleagues (26:14).⁹

Age

TAR syndrome is congenital, and patients usually present with symptomatic thrombocytopenia in the first week of life.

Clinical

History

• Episodes of thrombocytopenia begin in the neonatal period in patients with thrombocytopenia-absent radius (TAR) syndrome.
  • About 50% of affected infants are symptomatic in the first week of life, and 90% are symptomatic by the age of 4 months.
  • Thrombocytopenia can fluctuate over time. Therefore, if TAR syndrome is strongly suspected on the basis of one normal platelet count, repeating the blood work is recommended.
  • Thrombocytopenic episodes are most frequent during the first 2 years of life, when they increase the mortality rate secondary to intracranial hemorrhage.
  • With increasing age, the recurrence of thrombocytopenic episodes decreases. Thrombocytopenia can improve to a near-normal state.
  • Nonspecific stress, infection, and diet (eg, allergy to cow's milk) may precipitate episodes.
  • Symptoms include purpura, petechiae, epistaxis, melena, hemoptysis, hematuria, hematemesis, and, rarely, intracranial hemorrhage.
• Symptomatic cow's-milk allergy is associated with 47% of all cases of TAR syndrome, and patients may present as vomiting, bloody diarrhea, and failure to thrive.
• Mental retardation is associated with about 7% of all cases of TAR syndrome.
  • The association of TAR with mental retardation is presumed to be secondary to complications from intracranial hemorrhage precipitated by thrombocytopenia.
  • Symptoms of acute intracranial hemorrhage in an infant are associated with poor feeding, lethargy, irritability, and fluctuating levels of consciousness.
  • Structural causes that predispose the patient to mental retardation and other neuropsychiatric disorders (psychosis) have been suggested.¹⁰
  • Hypoplasia of the cerebellar vermis and corpus callosum has been reported in this syndrome.¹¹

Physical

• Upper-extremity abnormalities range from isolated absent radii to phocomelia. Abnormalities include the following:
  • Bilateral radial aplasia
  • Radial club hand
  • Hypoplastic carpals and phalanges
  • Hypoplastic ulnae, humeri, and shoulder girdles
  • Syndactyly and clinodactyly of fingers and toes
  • Selective hypoplasia of middle phalanx, fifth digit
  • Altered palmar contours
• Greenhalgh and colleagues examined 34 patients with TAR syndrome.⁸ Their findings demonstrated how the length of the upper limb can affect the patient's functional ability. They divided upper-limb defects into 3 categories of severity, as follows:
  • The first group (71%) had mild defects consisting of radial aplasia with various degrees of ulnar and humeral hypoplasia. The patients also had normal shoulder girth and, hence, near-normal upper-body strength, but splints were still useful for periods of prolonged activity of the upper limbs.
  • The second group (18%) had increased degrees of limb shortening, humeral hypoplasia, and underdevelopment of the shoulder girth with decreased upper-body strength. Splints were also useful in this group.
  • The last group was the most affected, with severe ulnar and humeral shortening and phocomelia.
• Lower-extremity anomalies occur in 46% of patients and vary from clinically undetectable changes to phocomelia. These anomalies are usually less severe than those of the upper limbs. Abnormalities include the following:
  • Hip dislocation
  • Femoral torsion
  • Tibial torsion
  • Valgus and varus foot deformities
  • Deformity of the knee (eg, absence of the patella, patellar dislocation)
  • Absent tibiofibular joint
  • Abnormal toe placement
  • Fifth toe overlapping the fourth
• Cardiac anomalies occur in 15-33% of patients and include the following:
  • Tetralogy of Fallot
  • Atrial septal defect
  • Ventricular septal defect (VSD)
• Facial anomalies (which occur in 53% of patients) include the following:
  • Micrognathia (3-30% of patients)
  • Tall, broad forehead
  • Facial hemangiomas
  • Hypertelorism
  • Low, posteriorly rotated ears
• Other abnormalities are numerous and include the following:
  • Asymmetric first rib
  • Cervical rib, cervical spina bifida, fused cervical spine, and nuchal folds
  • Meckel diverticulum
  • Uterine anomalies
  • Dorsal pedal edema
  • Hyperhidrosis
  • Short stature (95% of patients at or below the 50th percentile)
  • Skeletal malformations
  • Renal anomalies (23% of patients), eg, duplex ureter, mild renal pelvis dilatation, horseshoe kidneys
  • Intracranial vascular malformation
  • Sensorineural loss
  • Cleft palate
  • Scoliosis
  • GI anomalies (eg, esophageal atresia, tracheoesophageal fistula, anal atresia)
  • Annular pancreas
• Only patients with TAR syndrome consistently have bilateral absence of the radii with the presence of thumbs and 4 digits. In distinguishing TAR from other syndromes involving skeletal abnormalities of the upper extremities, the following features may be of assistance:
  • Patients with TAR syndrome always have thumbs, but thumbs may be hypoplastic or absent in patients with Fanconi anemia. Fanconi anemia is also associated with chromosomal abnormalities, a rare onset of thrombocytopenia before age 1 year, and pancytopenia in children aged 5-10 years. A reliable diagnostic test is a chromosomal breakage study.
  • Thumb abnormalities include absent, hypoplastic, and triphalangeal thumbs in Holt-Oram syndrome, and blood counts are normal. The patient often has a family history of heart and limb defects due to the autosomal dominant pattern of inheritance.
  • Thrombocytopenia is not often observed in Roberts syndrome (Roberts-SC phocomelia). Most patients with this syndrome have microcephaly and mental retardation.
  • Radial hypoplasia is found in patients with Aase syndrome, but the thumb is triphalangeal. Hypoplastic anemia is the usual presentation, similar to that of Blackfan-Diamond syndrome. Thrombocytopenia is not a feature.

Causes

• Causes of TAR syndrome are not fully elucidated. See Pathophysiology.

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