Clinical Diagnosis

The diagnosis of thrombocytopenia absent radius (TAR) syndrome is established by the combination of:

• Bilateral absence of the radii with the presence of both thumbs. In addition, upper limb manifestations may include ulnar and/or humeral anomalies. Lower limb anomalies may include hip and/or patellar dislocation and anomalies of one or more of the long bones.

• Thrombocytopenia. Thrombocytopenia is present in almost all, although it is generally transient. Onset ranges from before birth to adulthood, but in most it is manifest during the first weeks of life.

Testing

Platelet counts are determined as part of a complete blood count (CBC). Individuals with TAR syndrome usually have platelet counts below 50 platelets/nL. Normal range is 150-400 platelets/nL.

Molecular Genetic Testing

Locus/gene. Individuals with TAR syndrome have a minimally deleted region of 200 kb at chromosome band 1q21.1, which is distinct from the region involved in the 1q21.1 deletion/duplication syndrome (see Molecular Genetics) [Klopocki et al 2007, Mefford et al 2008]. Deletion of this segment is necessary but not sufficient to cause the phenotype. Identification of the 200-kb minimally deleted region at chromosome band 1q21.1 is sufficient to confirm the diagnosis of TAR syndrome in individuals with bilateral absence of the radius and presence of thumbs.

One or more as-yet unidentified modifiers are thought to be necessary for the expression of the TAR syndrome phenotype [Klopocki et al 2007]. One possible function of this modifier is downregulation of relevant genes in the 1q21.1 region [Guastadisegni et al 2011].

Table 1. Summary of Molecular Genetic Testing Used in TAR Syndrome

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Locus	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
200-kb minimally deleted region at 1q21.1 2	Deletion / duplication analysis 3, 4	Deletion	100%	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a deletion at this locus

2. See Molecular Genetics for molecular description of the region.

3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment. See array CGH.

4. Because the deletion often extends beyond the 200-kb minimally deleted region [Klopocki et al 2007], a test that can approximate the extent of the deletion is optimal.

Testing Strategy

To confirm/establish the diagnosis in a proband. The diagnosis is suspected on clinical grounds, initially based on bilateral absence of the radius and presence of thumbs. Newborns should be evaluated for thrombocytopenia; if platelet count is normal, it should be repeated whenever evidence of increased bleeding tendency (bruising, petechiae) occurs.

Identification of the 200-kb minimally deleted region at chromosome band 1q21.1 is sufficient to verify the diagnosis of TAR syndrome in individuals with bilateral absence of the radius and presence of thumbs.

Carrier testing for at-risk relatives. Because the 200-kb minimally deleted region at 1q21.1 is necessary but not sufficient to cause the TAR syndrome phenotype, at-risk relatives may be found to carry this deletion. Molecular genetic testing will identify those unaffected family members who have the 200-kb minimal deletion and therefore are at increased risk of having a child with TAR syndrome.

Prenatal diagnosis may be possible for pregnancies known to be at increased risk and for pregnancies in which radial anomalies are identified on routine ultrasound examination.

• In a pregnancy known to be at increased risk for TAR syndrome, the finding of the 200-kb minimally deleted region at 1q21.1 should be correlated with ultrasound findings.

• In a pregnancy not known to be at increased risk for TAR syndrome in which radial anomalies are identified on a routine ultrasound evaluation, the detection of the 200-kb minimally deleted region at 1q21.1 verifies the diagnosis of TAR syndrome.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with the 200-kb minimally deleted region at 1q21.1. Recurrent deletion or duplication of nearby DNA segments at 1q21.1 gives rise to the variable phenotypes associated with 1q21.1 deletion/duplication [Brunetti-Pierri et al 2008, Mefford et al 2008] (see 1q21.1 Microdeletion). Occasionally, these rearrangements may extend into the 200-kb minimally deleted TAR locus. See Molecular Genetics.

Natural History

Individuals with thrombocytopenia absent radius (TAR) syndrome almost always have bilateral absence of the radius. The thumbs are always present. Thumbs in TAR syndrome are of near normal size, but are somewhat wider and flatter than usual. They are also held in flexion against the palm, and tend to have limited function, particularly in terms of grasp and pinch activities [Goldfarb et al 2007].

Thrombocytopenia may be congenital or develop within the first few weeks to months of life. In one review, it was noted that thrombocytopenia developed during the first week of life in only 59% [Hedberg & Lipton 1988]. In general, thrombocytopenic episodes decrease with age, with most children with TAR syndrome having normal platelet counts by school age. However, cow’s milk allergy is common, and can be associated with exacerbation of thrombocytopenia.

In addition, some individuals with TAR syndrome have been reported to have leukemoid reactions, with white blood cell counts exceeding 35,000 cells/mm³. These leukemoid reactions are generally transient [Klopocki et al 2007].

Cognitive development is usually normal in individuals with TAR syndrome.

Most have height on or below the 50th centile.

Other anomalies can also occur, and affect the skeletal, cardiac, gastrointestinal, and genitourinary systems.

Limb anomalies can affect both upper and lower limbs, although upper limb involvement tends to be more severe than lower limb involvement. The upper limbs may have hypoplasia or absence of the ulnae, humeri, and shoulder girdles. Fingers may show syndactyly, and fifth finger clinodactyly is common. Lower limbs are affected in almost half of those with TAR syndrome; hip dislocation, coxa valga, femoral and/or tibial torsion, genu varum, and absence of the patella are common findings. The most severe limb involvement is of tetraphocomelia.

Other skeletal manifestations, including rib and cervical vertebral anomalies (e.g., cervical rib, fused cervical spine), tend to be relatively rare.

Cardiac anomalies affect 15%-22% [Hedberg & Lipton 1988, Greenhalgh et al 2002] and usually include septal defects rather than complex cardiac malformations.

Gastrointestinal involvement includes cow’s milk allergy and gastroenteritis. Both tend to improve with age.

Genitourinary anomalies include renal anomalies (both structural and functional) and in rare cases, Mayer-Rokitansky-Kuster-Hauser syndrome (agenesis of uterus, cervix, and upper part of the vagina) [Griesinger et al 2005, Ahmad & Pope 2008].

Genotype-Phenotype Correlations

No genotype-phenotype correlations are known.

Penetrance

Penetrance appears to be complete in those with the clinical diagnosis, in that individuals with radial involvement always have thrombocytopenia, and vice versa. However, in rare instances, an individual with TAR syndrome has unilateral radial aplasia with lesser involvement of the contralateral arm. In order for an individual to be affected, both the 200-kb minimally deleted region and an as-yet-unidentified modifier are hypothesized to be necessary for expression of the syndrome.

Prevalence

The prevalence of TAR syndrome is estimated at 1:200,000-1:100,000.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with thrombocytopenia absent radius (TAR) syndrome, the following evaluations are recommended:

• Platelet count, if initial diagnosis is based on radial aplasia with presence of thumbs

• Orthopedic evaluation of both upper and lower limbs

• Echocardiography to assess for cardiac anomalies

• Evaluation of renal structure and function

• Genetics consultation

Treatment of Manifestations

The treatment of thrombocytopenia is platelet support. Bone marrow transplantation is generally not indicated, given the transient nature of the thrombocytopenia.

Orthopedic intervention is indicated to maximize function of limbs, with such intervention including prostheses, orthoses, adaptive devices, and surgery [McLaurin et al 1999].

Prevention of Primary Manifestations

Avoidance of cow’s milk lessens the severity of gastroenteritis and thrombocytopenia (in older children).

Prevention of Secondary Complications

Frequent transfusion with platelets can lead to alloimmunization and increased risk of infection. It is therefore recommended that platelet transfusion in older individuals not be done until platelet counts fall below a particular threshold (10/nL). Note: The threshold for platelet transfusion in newborns is unknown.

Surveillance

Platelet count is indicated whenever evidence of increased bleeding tendency (bruising, petechiae) occurs.

Agents/Circumstances to Avoid

Avoid cow’s milk to reduce the severity of gastroenteritis and associated thrombocytopenia (in older children).

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Fewer than ten pregnancies have been reported in women with TAR syndrome. Almost all develop thrombocytopenia during pregnancy. In one, corticosteroids appeared to be fairly successful in treating the thrombocytopenia [Bot-Robin et al 2011]. In one pregnant woman with TAR syndrome, exacerbation of her thrombocytopenia preceded the development of preeclampsia.

Other considerations during pregnancy include potential difficulties with administration of regional anesthetics, given potential difficulties with vascular access, and difficulties accessing the airway for general anesthesia [Wax et al 2009].

Therapies Under Investigation

Search Clinical Trials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Registries

Contact information for voluntary patient registries is provided by GeneReviews staff.

NCI Inherited Bone Marrow Failure Syndromes (IBMFS) Cohort Registry
Phone: 800-518-8474
Email: lisaleathwood@westat.com
Web: www.marrowfailure.cancer.gov

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Thrombocytopenia absent radius (TAR) syndrome was initially thought to be inherited in an autosomal recessive manner; however, evidence suggests otherwise:

• There is a paucity of affected siblings (one unpublished survey found that 6% of siblings were similarly affected).

• Consanguinity of the parents of an affected child is rarely reported.

• Apparent parent-to-child transmission has been reported.

• Affected second- and third-degree relatives have been reported, with few or no manifestations in intervening relatives.

Therefore, the mode of inheritance of TAR syndrome is unknown.

Deletion of the described 200-kb region at 1q21.1 is necessary but not sufficient to cause the phenotype.

Risk to Family Members

Parents of a proband

• Parents of individuals with TAR syndrome are typically unaffected. However, parent-to-child transmission [Ward et al 1986] and the presence of affected individuals in multiple generations have been reported [Schnur et al 1987].

• Approximately 75% of probands have inherited the 200-kb minimally deleted region at 1q21.1 from an unaffected parent. The deletion occurs de novo in about 25% of probands [Klopocki et al 2007].

• Recommendations for the evaluation of parents of a proband include:

  • Radiographs of the limbs, as minor limb involvement in some has been reported.

  • Deletion analysis looking for the 200-kb minimally deleted region at 1q21.1, particularly if the minor limb involvement noted above is found.

Sibs of a proband

• Sibs of a proband are at increased risk of also having TAR syndrome, although the recurrence risk appears to be less than 25%.

• The risk to the sibs of inheriting the 200-kb minimally deleted region at 1q21.1 depends on the genetic status of the parent. If a parent has the deletion, the risk to each sib of inheriting it is 50%. However, the presence of the deletion alone is not sufficient to cause TAR.

Offspring of a proband

• Offspring of a proband are at increased risk of also having TAR syndrome. Although reports of parent-to-child transmission have been published, no empiric risk figures are available.

• The risk to each child of an individual with TAR syndrome of inheriting the 200-kb minimally deleted region at 1q21.1 is 50%. However, the presence of the deletion alone is not sufficient to cause TAR syndrome.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent has the 200-kb minimally deleted region at 1q21.1, his or her family members may also be at risk of having it. However, presence of the deletion alone is not sufficient to cause TAR syndrome.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers of the 200-kb minimally deleted region at 1q21.1, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Pregnancies known to be at increased risk for TAR syndrome (parent with TAR syndrome, parent with the 200-kb TAR-specific deletion of 1q21.1, or a sib of an individual with TAR syndrome whose parental genetic status is unknown)

• Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk for TAR syndrome is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. Confirmation of deletion of the 200-kb TAR-specific region of 1q21.1 in an affected family member and a parent is needed for accurate interpretation of prenatal testing results. Because the deletion is necessary but not sufficient for the diagnosis of TAR syndrome, molecular genetic testing in at-risk pregnancies should be coupled with ultrasound evaluation of fetal limbs and heart.
  
  Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

• Fetal ultrasound examination. Ultrasound evaluation of fetal limbs and heart can be used either alone or in conjunction with molecular genetic testing for the deletion of the 200-kb TAR-specific region of 1q21.1.

Pregnancies not known to be at increased risk for TAR syndrome

• Fetal ultrasound examination. In a pregnancy not known to be at increased risk for TAR syndrome in which radial anomalies are identified on a routine ultrasound evaluation, the fetus with TAR syndrome may be misdiagnosed as having Holt-Oram, Roberts, or other syndromes. The detection of the 200-kb minimally deleted region at 1q21.1 confirms the diagnosis of TAR syndrome [Houeijeh et al 2011].

Preimplantation genetic diagnosis (PGD) of deletion of the 200-kb TAR-specific region of 1q21.1 may be available for families in which this deletion has been identified. However, because the deletion is necessary but not sufficient for the diagnosis of TAR syndrome, PGD is not currently available for TAR syndrome.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

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3. Brunetti-Pierri N, Berg JS, Scaglia F, Belmont J, Bacino CA, Sahoo T, Lalani SR, Graham B, Lee B, Shinawi M, Shen J, Kang SH, Pursley A, Lotze T, Kennedy G, Lansky-Shafer S, Weaver C, Roeder ER, Grebe TA, Arnold GL, Hutchison T, Reimschisel T, Amato S, Geragthy MT, Innis JW, Obersztyn E, Nowakowska B, Rosengren SS, Bader PI, Grange DK, Naqvi S, Garnica AD, Bernes SM, Fong CT, Summers A, Walters WD, Lupski JR, Stankiewicz P, Cheung SW, Patel A. Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nat Genet. 2008;40:1466–71. [PMC free article: PMC2680128] [PubMed: 19029900]
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6. Griesinger G, Dafopoulos K, Schultze-Mosgau A, Schroder A, Felberbaum R, Diedrich K. Mayer-Rokitansky-Kuster-Hauser syndrome associated with thrombocytopenia-absent radius syndrome. Fertil Steril. 2005;83:452–4. [PubMed: 15705390]
7. Guastadisegni MC, Roberto R, L'Abbate A, Palumbo O, Carella M, Giordani L, Cecinati V, Giordano P, Storlazzi CT. Thrombocytopenia-absent-radius syndrome in a child showing a larger 1q21.1 deletion than the one in his healthy mother, and a significant downregulation of the commonly deleted genes. Eur J Med Genet. 2011;204:512–5.
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9. Houeijeh A, Andrieux J, Saugier-Veber P, David A, Goldenberg A, Bonneau D, Fouassier M, Journel H, Martinovic J, Escande F, Devisme L, Bisiaux S, Chaffiotte C, Maux M, Kerckaert JP, Holder-Espinasse M, Mouvrier-Hanu S. Thrombocytopenia-absent radius (TAR) syndrome: a clinical genetic series of 14 further cases. Impact of the associated 1q21.1 deletion on the genetic counseling. Eur J Med Genet. 2011;54:e471–77. [PubMed: 21635976]
10. Klopocki E, Schulze H, Strauss G, Ott CE, Hall J, Trotier F, Fleischhauer S, Greenhalgh L, Newbury-Ecob RA, Neumann LM, Habenicht R, König R, Seemanova E, Megarbane A, Ropers HH, Ullmann R, Horn D, Mundlos S. Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome. Am J Hum Genet. 2007;80:232–40. [PMC free article: PMC1785342] [PubMed: 17236129]
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Suggested Reading

1. Geddis AE. Congenital amegakaryocytic thrombocytopenia and thrombocytopenia with absent radii. Hematol Oncol Clin North Am. 2009;23:321–31. [PMC free article: PMC2757092] [PubMed: 19327586]
2. Rivers A, Slayton WB. Congenital cytopenias and bone marrow failure syndromes. Semin Perinatol. 2009;33:20–8. [PubMed: 19167578]

Revision History

• 2 February 2012 (me) Comprehensive update posted live

• 8 December 2009 (me) Review posted live

• 26 August 2009 (hvt) Original submission