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 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.

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.

Deletion/duplication analysis should be performed first for identification of the 200-kb minimally deleted region at chromosome band 1q21.1. Presence of this deletion is sufficient to verify the diagnosis of TAR syndrome in individuals with bilateral absence of the radius and presence of thumbs. However, lack of identification of this deletion is not sufficient to rule out the diagnosis. Sequence analysis of the coding and noncoding regions of RBM8A should follow if no deletion is identified, or to identify the second RBM8A mutation for confirmation of the diagnosis and/or genetic counseling purposes.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

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.

No phenotypes other than those discussed in this GeneReview are known to be associated with mutations in RBM8A.

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 individuals who have two disease-causing RBM8A mutations.

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.

Mode of Inheritance

Thrombocytopenia absent radius (TAR) syndrome is inherited in an autosomal recessive manner.

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 50%-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%-50% of probands [Klopocki et al 2007, Albers et al 2012].
• Recommendations for the evaluation of parents of a proband include radiographs of the limbs, as minor limb involvement in some has been reported and molecular genetic testing.

Sibs of a proband

The risk to the sibs of inheriting the 200-kb minimally deleted region at 1q21.1 and/or an RBM8A mutation depends on the genetic status of the parents.

• If both parents carry one allele, at conception each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• If only one parent is a carrier of a disease-causing mutation (and the other mutation is de novo), each sib has of an affected individual has a 50% chance of being an asymptomatic carrier, and a 50% chance of being unaffected and not a carrier.
• When both parents are carriers, once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband

• The offspring of an individual with TAR syndrome are obligate heterozygotes (carriers) for a disease-causing mutation in RBM8A.
• If an individual with TAR syndrome has children with a carrier of a disease-causing mutation in RBM8A, their offspring have a 50% chance of being affected and a 50% chance of being carriers. This may account for the reports of parent-to-child transmission [Ward et al 1986].

Other family members. The risk to other family members depends on the status of the proband's parents.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, 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 an RBM8A mutation, 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.

Prenatal Testing

Pregnancies known to be at increased risk for TAR syndrome (both parents are known carriers of a disease-causing mutation, one parent is a known carrier and the status of other parent is unknown, one parent has TAR syndrome, or one parent has a sib with TAR syndrome and their 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. When possible, the disease-causing mutations in the family should be identified before prenatal testing is performed.
  
  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.

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 two RBM8A mutations confirms the diagnosis of TAR syndrome [Houeijeh et al 2011].

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Molecular Genetic Pathogenesis

With one exception, all individuals with TAR syndrome are compound heterozygotes for an RBM8A null allele and a RBM8A hypomorphic allele [Albers et al 2012]. The null alleles are inactivated either by the minimal 200-kb deletion of 1q21.1 or by an intragenic inactivating mutation in RBM8A. The hypomorphic alleles are in noncoding regions of RBM8A; the mechanism by which they reduce RBM8A transcription and protein expression is unknown. The finding that individuals with TAR syndrome have significantly reduced amounts of the protein encoded by RBM8A, as compared to parents and controls, supports the assertion that RBM8A is the gene in which mutation is causative [Albers et al 2012].

Klopocki et al [2007] defined the minimal 200-kb deletion as a common defect in individuals with TAR syndrome and, because some unaffected parents were carriers, proposed that this deletion is necessary but not sufficient for a diagnosis of TAR syndrome. They hypothesized that one or more as-yet unidentified modifiers are thought to be necessary for the expression of the TAR syndrome phenotype. In a tour-de-force effort to identify the modifier, Albers et al [2012] performed exome sequencing of five affected individuals, which led to the identification of single nucleotide variants (SNV, sometimes referred to as SNP [single nucleotide polymorphisms]) in noncoding regions of RBM8A. Multiple lines of evidence support the role of the RBM8A noncoding SNVs as hypomorphic alleles, which in combination with an inactivating RBM8A allele (e.g., minimal 200-kb deletion, frameshift, or nonsense mutation) result in the TAR syndrome phenotype. Data presented by Albers et al [2012] define the cause of TAR syndrome as biallelic RBM8AI mutations that reduce but do not completely abolish RBM8A function.

Compound heterozygosity for a null allele and a hypomorphic allele of RBM8A may elucidate unexplained inheritance patterns previously reported in TAR syndrome.

• A paucity of affected sibs. Greenhalgh et al [2002] reported that 20% of sibs were similarly affected while an unpublished survey found that 6% of sibs were similarly affected. This may partially be explained by the 200-kb minimally deleted region of 1q21.1 occurring as a de novo event in a substantial proportion (25%-50%) of the cases [Albers et al 2012].
• Consanguinity of the parents of an affected child rarely reported. This phenomenon is now explicable, in that TAR syndrome is caused by compound heterozygosity for two different alterations, one inactivating and one hypomorphic.
• Apparent parent-to-child transmission reported. Given that the frequency of one of the hypomorphic alleles is approximately 3.5%, it would not be unusual for an individual with TAR syndrome to have a reproductive partner who is a carrier of a hypomorphic allele.
• Affected second- and third-degree relatives reported, with few or no manifestations in intervening relatives (see preceding bullet).

Literature Cited

1. Ahmad R, Pope S. Association of Mayer-Rokitansky-Küster-Hauser syndrome with Thrombocytopenia Absent Radii syndrome: a rare presentation. Eur J Obstet Gynecol Reprod Biol. 2008;139:257–8. [PubMed: 17537565]
2. Albers CA, Paul DS, Schulze H, Freson K, Stephens JC, Smethurst PA, Jolley JD, Cvejic A, Kostadima M, Bertone P, Breuning MH, Debili N, Deloukas P, Favier R, Fiedler J, Hobbs CM, Huang N, Hurles ME, Kiddle G, Krapels I, Nurden P, Ruivenkamp CA, Sambrook JG, Smith K, Stemple DL, Strauss G, Thys C, van Geet C, Newbury-Ecob R, Ouwehand WH, Ghevaert C. (2012) Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome. Nat Genet. 44:435-9, S1-2. [PMC free article: PMC3428915] [PubMed: 22366785]
3. Bot-Robin V, Vaast P, Deruelle P. Exacerbation of thrombocytopenia in a pregnant woman with thrombocytopenia-absent radius syndrome. Int J Gynaecol Obstet. 2011;114:77–8. [PubMed: 21530967]
4. 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]
5. Goldfarb CA, Wustrack R, Pratt JA, Mender A, Manske PR. Thumb function and appearance in thrombocytopenia: absent radius syndrome. J Hand Surg Am. 2007;32:157–61. [PubMed: 17275588]
6. Greenhalgh KL, Howell RT, Bottani A, Ancliff PJ, Brunner HG, Verschuuren-Bemelmans CC, Vernon E, Brown KW, Newbury-Ecob RA. Thrombocytopenia-absent radius syndrome: a clinical genetic study. J Med Genet. 2002;39:876–81. [PMC free article: PMC1757221] [PubMed: 12471199]
7. 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]
8. 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. [PubMed: 22201559]
9. Hedberg VA, Lipton JM. Thrombocytopenia with absent radii. A review of 100 cases. Am J Pediatr Hematol Oncol. 1988;10:51–64. [PubMed: 3056062]
10. 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]
11. 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]
12. McLaurin TM, Bukrey CD, Lovett RJ, Mochel DM. Management of thrombocytopenia-absent radius (TAR) syndrome. J Pediatr Orthop. 1999;19:289–96. [PubMed: 10344309]
13. Mefford HC, Sharp AJ, Baker C, Itsara A, Jiang Z, Buysse K, Huang S, Maloney VK, Crolla JA, Baralle D, Collins A, Mercer C, Norga K, de Ravel T, Devriendt K, Bongers EM, de Leeuw N, Reardon W, Gimelli S, Bena F, Hennekam RC, Male A, Gaunt L, Clayton-Smith J, Simonic I, Park SM, Mehta SG, Nik-Zainal S, Woods CG, Firth HV, Parkin G, Fichera M, Reitano S, Lo Giudice M, Li KE, Casuga I, Broomer A, Conrad B, Schwerzmann M, Räber L, Gallati S, Striano P, Coppola A, Tolmie JL, Tobias ES, Lilley C, Armengol L, Spysschaert Y, Verloo P, De Coene A, Goossens L, Mortier G, Speleman F, van Binsbergen E, Nelen MR, Hochstenbach R, Poot M, Gallagher L, Gill M, McClellan J, King MC, Regan R, Skinner C, Stevenson RE, Antonarakis SE, Chen C, Estivill X, Menten B, Gimelli G, Gribble S, Schwartz S, Sutcliffe JS, Walsh T, Knight SJ, Sebat J, Romano C, Schwartz CE, Veltman JA, de Vries BB, Vermeesch JR, Barber JC, Willatt L, Tassabehji M, Eichler EE. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med. 2008;359:1685–99. [PMC free article: PMC2703742] [PubMed: 18784092]
14. Schnur R, Eunpu D, Zackai E. Thrombocytopenia with absent radius in a boy and his uncle. Am J Med Genet. 1987;28:117–23. [PubMed: 3314504]
15. Ward R, Bixler D, Provisor A, Bader P. Parent to child transmission of the thrombocytopenia absent radius (TAR) syndrome. Am J Med Genet Suppl. 1986;2:207–14. [PubMed: 3146292]
16. Wax JR, Crabtree C, Blackstone J, Pinette MG, Cartin A. Maternal thrombocytopenia-absent radius syndrome complicated by severe pre-eclampsia. J Matern Fetal Neonatal Med. 2009;22:175–7. [PubMed: 19253167]

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

• 28 June 2012 (cd) Revision: Albers et al [2012] documents a role for RBM8A mutations in TAR syndrome; testing for RBM8A mutations available clinically
• 2 February 2012 (me) Comprehensive update posted live
• 8 December 2009 (me) Review posted live
• 26 August 2009 (hvt) Original submission