Thrombocytopenia Absent Radius Syndrome

Clinical characteristics.

Thrombocytopenia absent radius (TAR) syndrome is characterized by bilateral absence of the radii with the presence of both thumbs, and thrombocytopenia that is generally transient. Thrombocytopenia may be congenital or may develop within the first few weeks to months of life; in general, thrombocytopenic episodes decrease with age. Cow's milk allergy is common and can be associated with exacerbation of thrombocytopenia. Other anomalies of the skeleton (upper and lower limbs, ribs, and vertebrae), heart, and genitourinary system (renal anomalies and agenesis of uterus, cervix, and upper part of the vagina) can occur.

Diagnosis/testing.

The diagnosis of TAR syndrome is established in a proband with bilateral absent radii, present thumbs, and thrombocytopenia. Identification of a heterozygous null allele (most often a minimally deleted 200-kb region at chromosome band 1q21.1) in trans with a heterozygous RBM8A hypomorphic allele on molecular genetic testing confirms the diagnosis.

Management.

Treatment of manifestations: Orthopedic intervention as needed to maximize limb function. Platelet transfusion for thrombocytopenia as needed; to reduce the risks of alloimmunization and infection, avoid platelet transfusion in older individuals whose platelet counts exceed a particular threshold (10 platelets/nL). Standard treatments for cardiac and genitourinary anomalies. Avoidance of cow's milk to reduce the severity of gastroenteritis and to avoid exacerbations of thrombocytopenia. Central venous catheter as an alternative to repeated venipuncture.

Surveillance: Platelet count when evidence of increased bleeding tendency (bruising, petechiae) occurs. Assess for gastrointestinal manifestations in children, which may indicate cow's milk allergy, at each visit. Serum electrolytes, blood urea nitrogen, and creatinine to assess kidney function per nephrologist.

Agents/circumstances to avoid: Avoid cow's milk to reduce the severity of gastroenteritis and associated thrombocytopenia (in older children). Platelet function is somewhat impaired, suggesting that drugs such as nonsteroidal anti-inflammatory drugs or aspirin should be avoided or used with caution.

Genetic counseling.

TAR syndrome is caused by compound heterozygosity for a null allele and an RBM8A hypomorphic allele and is inherited in an autosomal recessive manner. However, because null alleles are rare (and often occur de novo in the proband) and RBM8A hypomorphic alleles are common, inheritance of TAR syndrome is associated with several features unusual in autosomal recessive disorders: a paucity of affected sibs, apparent parent-to-child transmission, and affected second- and third-degree relatives. The risk to sibs of a proband varies depending on the genetic status of the parents; for example:

• If one parent is known to be heterozygous for a null allele and the other parent is heterozygous for an RBM8A hypomorphic allele, each sib of an affected individual has at conception a 25% chance of being affected.
• If one parent is known to be heterozygous for a null allele and the other parent has biallelic RBM8A hypomorphic alleles, each sib of an affected individual has at conception a 50% chance of being affected.
• If one parent is known to be heterozygous for an RBM8A hypomorphic allele and the other parent has two normal RBM8A alleles, each sib of an affected individual has at conception a 50% chance of being an asymptomatic carrier of an RBM8A hypomorphic allele and a 50% chance of being unaffected and not a carrier.

Individuals who are heterozygotes (carriers) for one TAR syndrome-related pathogenic variant (either an RBM8A hypomorphic allele or a null allele) are asymptomatic; individuals with biallelic RBM8A hypomorphic alleles are asymptomatic. Once the causative null allele and RBM8A hypomorphic allele have been identified in an affected family member, carrier testing for at-risk relatives as well as prenatal and preimplantation genetic testing are possible.

Suggestive Findings

Thrombocytopenia absent radius (TAR) syndrome should be suspected in individuals with:

• Bilateral absence of the radii with the presence of both thumbs
• Thrombocytopenia, usually <50 platelets/nL (normal range: 150-400 platelets/nL)

Establishing the Diagnosis

The diagnosis of TAR syndrome is established in a proband with Suggestive Findings and a null heterozygous variant (most often a 500-kb deletion or 200-kb deletion including RBM8A at chromosome band 1q21.1) in trans with a heterozygous RBM8A hypomorphic allele identified by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with radial ray defects are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Thrombocytopenia absent radius (TAR) syndrome is characterized by bilateral absence of the radii with the presence of both thumbs and thrombocytopenia that is generally transient. Additional manifestations can include cow's milk allergy and anomalies of the lower limbs, ribs, vertebrae, heart, and genitourinary system. To date, more than 150 individuals have been reported with a TAR-related RBM8A variant [Klopocki et al 2007, Giordano et al 2011, Houeijeh et al 2011, Albers et al 2012, Bottillo et al 2013, Papoulidis et al 2014, Yassaee et al 2014, Kumar et al 2015, Tassano et al 2015, Nicchia et al 2016, Diep & Arcasoy 2017, Manukjan et al 2017, Brodie et al 2019, Boussion et al 2020, Miertuš et al 2020, Travessa et al 2020, Beauvais et al 2021, da Rocha et al 2021, Ding et al 2021, Morgan et al 2021, Espinoza et al 2022, Farlett et al 2022]. The following description of the phenotypic features associated with TAR syndrome is based on these reports.

Limb anomalies can affect both upper and lower limbs; upper limb involvement tends to be more severe than lower limb involvement. Individuals with TAR syndrome almost always have bilateral absence or hypoplasia of the radius. The thumbs are always present and are of near-normal size but somewhat wider and flatter than usual. Thumbs 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].

The upper limbs may also 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 indiviuals 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 tetraphocomelia.

Thrombocytopenia may be congenital or may develop within the first few weeks to months of life. In most individuals, platelet counts remain low during the first two years of life; they then increase but do not reach the lower reference value [Fiedler et al 2012, Manukjan et al 2017].

Cow's milk allergy is common, and can be associated with exacerbation of thrombocytopenia, either by direct immunoglobulin E (IgE) immune-mediated mechanism or secondary to increased gastrointestinal bleeding caused by loss of coagulation proteins [Farlett et al 2022].

Cardiac anomalies usually include septal defects (e.g., atrial septal defect, ventricular septal defect, patent foramen ovale) rather than complex cardiac malformations [Hedberg & Lipton 1988, Greenhalgh et al 2002]. One individual with tetralogy of Fallot has been reported [Kumar et al 2015].

Gastrointestinal involvement includes cow's milk allergy or intolerance and an increased susceptibility to gastroenteritis [Greenhalgh et al 2002]. Both tend to improve with age. These findings may be underreported since many fetuses and adults with TAR syndrome are described in the literature. Cow's milk intolerance may present with poor weight gain, failure to thrive, vomiting, or diarrhea, requiring non-cow's milk formulas. Unrelated to cow's milk intolerance, an increased susceptibility to gastroenteritis and dehydration requiring intravenous fluids has been reported in 30% of individuals [Greenhalgh et al 2002].

Genitourinary anomalies include mostly congenital anomalies of the kidney and urinary tract (CAKUT), such as kidney agenesis or malrotation, horseshoe kidney, hydronephrosis, and pyelectasis. Rarely, Mayer-Rokitansky-Kuster-Hauser syndrome (agenesis of uterus, cervix, and upper part of the vagina) has been reported [Griesinger et al 2005, Klopocki et al 2007, Ahmad & Pope 2008].

Other hematologic features have been rarely reported. During the first year of life some children develop anemia that cannot be fully attributed to increased bleeding as a result of thrombocytopenia. Some individuals become severely anemic, requiring red blood cell transfusions (particularly those with RBM8A variant c.-21G>A) [Manukjan et al 2017].

Leukemoid reactions have been reported in some individuals with TAR syndrome, with white blood cell counts exceeding 35,000 cells/mm³. Leukemoid reactions are generally transient [Klopocki et al 2007]. However, several individuals with acute myeloid leukemia [Rao et al 1997, Fadoo & Naqvi 2002, Go & Johnston 2003, Jameson-Lee et al 2018, Boussion et al 2020] or acute lymphoblastic leukemia [Camitta & Rock 1993] have been reported.

Cognitive development is usually normal in individuals with TAR syndrome.

Growth. Most have height at or below the 50th centile.

Other skeletal manifestations such as rib and vertebral anomalies (e.g., cervical rib, fused cervical vertebrae, vertebral segmentation defects) are relatively rare.

Langerhans cell histiocytosis has been rarely reported in individuals with TAR syndrome [Giordano et al 2011, Manukjan et al 2017, Hipólito et al 2019, Boussion et al 2020].

Genotype-Phenotype Correlations

Individuals with TAR syndrome have one null allele in trans with a hypomorphic allele. The hypomorphic allele is usually located in the 5' UTR, intron 1, or 3' UTR.

Only limited genotype-phenotype correlations have been described:

• The c.-21G>A hypomorphic allele has been associated with lower platelet counts and hemoglobin values below the lower reference value; the low hemoglobin levels could not be fully attributed to increased bleeding as a result of thrombocytopenia [Manukjan et al 2017].
• Individuals with intronic hypomorphic allele c.67+32G>C had higher platelet counts, even during the first months of life, which eventually reached the reference range. Individuals with the c.67+32G>C allele also had normal hemoglobin levels.

Penetrance

Penetrance appears to be complete in individuals who have biallelic RBM8A pathogenic variants (a heterozygous null allele in trans with a hypomorphic allele).

Prevalence

The prevalence of TAR syndrome is estimated at 1:100,000 to 1:200,000, but it is likely more frequent in populations of African descent, due to a recurrent RBM8A hypomorphic allele (c.Ter6C>G) with a minor allele frequency of 14.8% in the African population.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with TAR syndrome, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Agents/Circumstances to Avoid

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

Platelet function is somewhat impaired, suggesting that drugs such as nonsteroidal anti-inflammatory drugs including aspirin should be avoided or used with caution.

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 [Diep & Arcasoy 2017]. Almost all develop thrombocytopenia during pregnancy. Corticosteroids can be considered to treat a superimposed immune component, but platelet transfusions may be required prior to surgery or to treat bleeding. In one pregnant woman with TAR syndrome, exacerbation of her thrombocytopenia preceded the development of preeclampsia [Wax et al 2009].

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 ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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 caused by compound heterozygosity for a null allele (most often a 500-kb deletion or 200-kb deletion including RBM8A at chromosome band 1q21.1) and a heterozygous RBM8A hypomorphic allele and is inherited in an autosomal recessive manner. However, because null alleles are rare and RBM8A hypomorphic alleles are common, inheritance of TAR syndrome is associated with several features unusual in autosomal recessive disorders:

• 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. The smaller-than-expected percentage of affected sibs 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 individuals [Albers et al 2012].
• Apparent parent-to-child transmission reported. Given that the frequency of the RBM8A hypomorphic alleles can be as high as 3% to 14.8%, an individual with TAR syndrome may have a reproductive partner who is a carrier of an RBM8A hypomorphic allele.
• Affected second- and third-degree relatives reported (with few or no manifestations in intervening relatives; see preceding bullet).

Risk to Family Members

Parents of a proband

• The parents of an individual with TAR syndrome are typically unaffected. One parent is presumed to be a carrier of an RBM8A hypomorphic allele; the other parent may or may not be a carrier of a null allele.
• Rarely, one parent of an individual with TAR syndrome is a carrier of an RBM8A hypomorphic allele and the other parent is affected with TAR syndrome. Apparent parent-to-child transmission [Ward et al 1986, Klopocki et al 2007, Boussion et al 2020] and the presence of affected individuals in multiple generations have been reported [Schnur et al 1987].
• Approximately 50%-75% of individuals with TAR syndrome 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].
• Molecular genetic testing for the TAR syndrome-related pathogenic variants identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk assessment.
• Individuals who are heterozygotes (carriers) for one TAR-syndrome related pathogenic variant (either an RBM8A hypomorphic allele or a null allele) are asymptomatic. Individuals with biallelic (homozygous or compound heterozygous) RBM8A hypomorphic alleles are asymptomatic. (Biallelic null alleles have never been reported and are thought to be lethal.)

Sibs of a proband

• If one parent is known to be heterozygous for a null allele and the other parent is heterozygous for an RBM8A hypomorphic allele, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
• If one parent is known to be heterozygous for a null allele and the other parent has biallelic RBM8A hypomorphic alleles, each sib of an affected individual has at conception a 50% chance of being affected and a 50% chance of being an asymptomatic carrier of an RBM8A hypomorphic allele.
• If one parent is known to be heterozygous for an RBM8A hypomorphic allele and the other parent has two normal RBM8A alleles (i.e., the other parent is not a carrier), each sib of an affected individual has at conception a 50% chance of being an asymptomatic carrier of an RBM8A hypomorphic allele and a 50% chance of being unaffected and not a carrier.
• Individuals who are heterozygotes (carriers) for one TAR-syndrome related pathogenic variant (either an RBM8A hypomorphic allele or a null allele) are asymptomatic. Individuals with biallelic (homozygous or compound heterozygous) RBM8A hypomorphic alleles are asymptomatic. (Biallelic null alleles have never been reported and are thought to be lethal.)

Offspring of a proband

• An individual with TAR syndrome will transmit either a null allele or an RBM8A hypomorphic allele to all offspring.
• If the reproductive partner of an individual with TAR syndrome is a carrier of a heterozygous RBM8A hypomorphic allele, offspring have a 25% chance of inheriting a null allele and an RBM8A hypomorphic allele and being affected.
• If the reproductive partner of an individual with TAR syndrome has biallelic (homozygous or compound heterozygous) RBM8A hypomorphic alleles, offspring have a 50% chance of inheriting a null allele and an RBM8A hypomorphic allele and being affected.

Other family members. The risk to other family members depends on the status of the proband's parents. If the parent of a proband is a carrier of a TAR syndrome-related pathogenic variant, each sib of that parent is at increased risk of being a carrier of the pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the TAR syndrome-related pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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 a TAR syndrome-related pathogenic variant, or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the causative null allele and RBM8A hypomorphic allele have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

For pregnancies known to be at increased risk for TAR syndrome – that is, either (a) both parents are known carriers of a TAR syndrome-related pathogenic variant (one parent is a carrier of a null allele and one parent is carrier of an RBM8A hypomorphic allele); or (b) one parent is a known carrier and the status of the other parent is unknown; or (c) one parent has TAR syndrome; or (d) one parent with unknown genetic status has a sib with TAR syndrome:

• Molecular genetic testing. If the pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
• Fetal ultrasound examination. Ultrasound evaluation of fetal limbs and heart can be used either alone or in conjunction with molecular genetic testing.

For 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 and in which radial anomalies are identified on routine ultrasound evaluation, the fetus with TAR syndrome may be misdiagnosed as having Holt-Oram, Roberts, or other syndromes. The detection of a heterozygous 200-kb minimally deleted region at 1q21.1 [Houeijeh et al 2011] or other heterozygous null alleles in trans with an RBM8A hypomorphic allele confirms the diagnosis of TAR syndrome in a fetus with typical radial anomalies.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

RBM8A encodes RNA-binding protein 8A (RBM8A; also known as Y14), a protein found predominantly in the nucleus, although it is also present in the cytoplasm. RBM8A has a conserved RNA-binding motif and is preferentially associated with mRNAs produced by splicing, including both nuclear mRNAs and newly exported cytoplasmic mRNAs. It is thought that the protein remains associated with spliced mRNAs as a tag to indicate where introns were present, thus coupling pre- and post-mRNA splicing events. RBM8A is involved with mRNA and snRNA biogenesis, based on its role as a component of the exon junction complex (EJC). RBM8A also plays a role in genomic stability; its knockdown delays the recruitment of DNA damage repair factors to damage sites and compromises the efficiency of DNA end joining [Chuang et al 2019].

Thrombocytopenia absent radius (TAR) syndrome is the result of loss of function of RBM8A, reducing the expression of RBM8A below a critical threshold [Albers et al 2012]. Experiments in model animal systems indicate that a complete deficiency of RBM8A (homozygosity for two null alleles) is lethal.

The consequences of insufficiency on the functioning of the EJC and its repercussions on cellular metabolism are not fully understood. Although the EJC appears to act ubiquitously, the reason why some tissues are consistently and severely affected by downregulation of RBM8A while other organs are spared is unknown. It has been shown, for example, that hypomorphic alleles lead to a loss of expression in osteoblastic and megakaryocytic cells in vitro, but not in human vascular cells [Albers et al 2012].

Several authors have studied the mechanism of thrombocytopenia in TAR syndrome by studying the thrombopoietin receptor (TPO) signaling pathway. In TAR syndrome, thrombocytopenia is characterized by a very low rate of megakaryocytic precursors within the bone marrow. While the TPO signaling pathway plays a major role in the control of megakaryocyte differentiation, to date no association between it and TAR syndrome has been demonstrated [Ballmaier et al 1997, Ballmaier et al 1998, Fiedler et al 2012].

Mechanism of disease causation. Loss of function

RBM8A-specific laboratory technical considerations. A closely related pseudogene, RBM8B, has been described [Faurholm et al 2001].

Notable RBM8A variants. The minimally deleted segment is a 200-kb region at 1q21.1 encompassing RBM8A as well as at least 12 known genes [Klopocki et al 2007]. However, the most frequently observed deleted allele (28/30 individuals with TAR syndrome) is a 500-kb deletion extending toward the telomere that spans an additional five genes [Klopocki et al 2007]. Both the 200-kb and 500-kb TAR syndrome-associated deletions are typically distinct and separate from the region of the 1q21.1 deletion/duplication syndrome (see Genetically Related Disorders). Larger rearrangements involving these regions have been reported [Brunetti-Pierri et al 2008, Mefford et al 2008]. An atypical TAR syndrome region deletion has also been described [Brunetti-Pierri et al 2008].

Author Notes

Prof Florence Petit (rf.ellil-uhc@titep.ecnerolf) is actively involved in clinical research regarding individuals with limb malformations and especially thrombocytopenia in thrombocytopenia absent radius (TAR) syndrome. Her group would be happy to communicate with persons who have any questions regarding diagnosis of TAR syndrome or other considerations.

Prof Petit is also interested in hearing from clinicians treating families affected by TAR syndrome in whom no causative variants have been identified through molecular genetic testing.

Contact Prof Petit to inquire about review of RBM8A variants of uncertain significance.

Acknowledgments

We acknowledge all clinicians and researchers, patients, and families who contributed to a better description and understanding of TAR syndrome.

Author History

Simon Boussion, MD (2022-present)

Florence Petit, MD, PhD (2022-present)

Helga V Toriello, PhD; Michigan State University (2009-2022)

Revision History

• 2 November 2023 (aa) Revision: clarification of disease mechanism (loss of function) in Molecular Pathogenesis
• 25 August 2022 (sw) Comprehensive update posted live
• 8 December 2016 (sw) Comprehensive update posted live
• 29 May 2014 (me) Comprehensive update posted live
• 2 February 2012 (me) Comprehensive update posted live
• 8 December 2009 (me) Review posted live
• 26 August 2009 (hvt) Original submission

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