Thrombocytopenia Absent Radius Syndrome
Summary
Clinical characteristics.
Thrombocytopenia absent radius (TAR) syndrome is characterized by bilateral absence of the radii with the presence of both thumbs and thrombocytopenia (<50 platelets/nL) 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: Platelet transfusion for thrombocytopenia as needed; central venous catheter as an alternative to repeated venipuncture; orthopedic intervention as needed to maximize function of limbs.
Prevention of primary manifestations: Avoidance of cow’s milk to reduce the severity of gastroenteritis and to avoid exacerbations of thrombocytopenia.
Prevention of secondary complications: To reduce the risks of alloimmunization and infection, avoid platelet transfusion in older individuals whose platelet counts exceed a particular threshold (10/nL).
Surveillance: Platelet count whenever evidence of increased bleeding tendency (bruising, petechiae) occurs.
Genetic counseling.
TAR syndrome is inherited in an autosomal recessive manner and results from compound heterozygosity of RBM8A pathogenic variants. Affected individuals have one R8BM8A null allele, typically a 200-kb minimally deleted region at chromosome band 1q21.1, and one R8BM8A hypomorphic allele. About 50%-75% of probands have inherited the deletion (null allele) from an unaffected parent; the deletion occurs de novo in about 25%-50% of probands. If both parents carry one variant 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 pathogenic variant (and the other variant/deletion is de novo), each sib of an affected individual has a 50% chance of being an asymptomatic carrier, and a 50% chance of being unaffected and not a carrier. Prenatal diagnosis for pregnancies at increased risk for TAR syndrome is possible using (a) molecular genetic testing if the genetic alterations are identified in the family and/or (b) ultrasound examination to evaluate the limbs.
Diagnosis
Suggestive Findings
Thrombocytopenia absent radius (TAR) syndrome should be suspected in individuals with absent radii and presence of thumbs in combination with thrombocytopenia.
Establishing the Diagnosis
The diagnosis of TAR syndrome is established in a proband with both of the following features:
- Bilateral absence of the radii with the presence of both thumbs
- Thrombocytopenia; usually <50 platelets/nL (normal range: 150-400 platelets/nL)
The diagnosis is confirmed by identification of a null heterozygous allele (most often a minimally deleted 200-kb region at chromosome band 1q21.1, but can be a heterozygous RBM8A pathogenic variant detected by molecular genetic testing) in trans with a heterozygous RBM8A hypomorphic allele that can be identified by molecular genetic testing (see Table 1).
Molecular Genetic Testing
Single-gene testing. Gene-targeted deletion/duplication analysis of RBM8A is performed first, followed by sequence analysis of RBM8A if no deletion is found. Although the diagnosis of TAR syndrome can be established by identification of a heterozygous minimally deleted 200-kb region at chromosome band 1q21.1, sequence analysis of RBM8A can be done subsequently in individuals with the deletion to confirm the presence of a second pathogenic variant (hypomorphic allele) and allow family studies. Homozygous RBM8A null alleles (e.g., deletions) are thought to be lethal (see Abnormal Gene Product).
A multigene panel that includes RBM8A and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if single-gene testing (and/or use of a multigene panel that includes RBM8A) fails to confirm a diagnosis in an individual with features of TAR syndrome. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Thrombocytopenia Absent Radius Syndrome
| Gene 1 | Test Method | Proportion of Probands with Pathogenic Variant(s) 2 Detectable by This Method |
|---|---|---|
| RBM8A | Gene-targeted deletion/duplication analysis 3 | 95% 4 |
| Sequence analysis 5 | ~95% 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 4.
Both a 200-kb and a more common 500-kb TAR syndrome-associated deletion have been described. 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.
- 5.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 6.
Sequence analysis requires inclusion of 5' UTR and intronic gene regions. A heterozygous RBM8A hypomorphic allele was identified in 51/53 affected individuals with the 200-kb deletion. Biallelic RBM8A pathogenic variants (1 null allele and 1 hypomorphic allele) were identified in two individuals who (out of the 55 individuals included in the study) did not have the 200-kb deletion. Two individuals (an affected mother and daughter) had a deletion identified, but did not have a hypomorphic allele identified [Albers et al 2012].
Clinical Characteristics
Clinical Description
Limb anomalies can affect both upper and lower limbs, although upper limb involvement tends to be more severe than lower limb involvement. Individuals with thrombocytopenia absent radius (TAR) syndrome almost always have bilateral absence of the radius. The thumbs are always present. The thumbs in individuals with 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].
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 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 tetraphocomelia.
Thrombocytopenia may be congenital or may 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.
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 rarely, Mayer-Rokitansky-Kuster-Hauser syndrome (agenesis of uterus, cervix, and upper part of the vagina) [Griesinger et al 2005, Ahmad & Pope 2008].
Leukemoid reactions have been reported in some individuals with TAR syndrome, 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.
Growth. Most have height on or below the 50th centile.
Other skeletal manifestations, including rib and cervical vertebral anomalies (e.g., cervical rib, fused cervical vertebrae), tend to be relatively rare.
Genotype-Phenotype Correlations
No genotype-phenotype correlations are known.
Penetrance
Penetrance appears to be complete in individuals who have biallelic RBM8A pathogenic variants.
Prevalence
The prevalence of TAR syndrome is estimated at 1:200,000-1:100,000.
Differential Diagnosis
The following conditions, which include radial aplasia as a component manifestation, can show some overlap with TAR syndrome:
- Holt-Oram syndrome, an autosomal dominant disorder resulting from pathogenic variants in TBX5, is characterized by (1) upper-extremity malformations involving radial, thenar, or carpal bones; a personal and/or family history of congenital heart malformation, most commonly ostium secundum atrial septal defect (ASD) and ventricular septal defect (VSD), especially those occurring in the muscular trabeculated septum; and/or cardiac conduction disease. The thumb is often absent or hypoplastic in this condition.
- Roberts syndrome, an autosomal recessive disorder resulting from pathogenic variants in ESCO2, is characterized by mild to severe prenatal growth retardation, microcephaly, cleft lip and/or palate, and limb malformations (including bilateral symmetric tetraphocomelia or hypomelia caused by mesomelic shortening). Other limb malformations include oligodactyly with thumb aplasia or hypoplasia, syndactyly, clinodactyly, and elbow and knee flexion contractures. Additional craniofacial abnormalities include downslanting palpebral fissures, widely spaced eyes, exophthalmos resulting from shallow orbits, corneal clouding, hypoplastic nasal alae, beaked nose, malar hypoplasia, ear malformations, and micrognathia. Intellectual disability is reported in the majority of affected individuals.
- Fanconi anemia (FA) is characterized by bone marrow failure, an increased risk of malignancy, and specific physical features including: short stature, abnormal skin pigmentation, and malformations of the thumbs and forearms. Additional anomalies of the skeletal system, eyes, ears, heart, gastrointestinal system, kidneys and genitourinary tract, and central nervous system can also occur. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. FA can be inherited in an autosomal recessive manner (>15 genes reported), an autosomal dominant manner (RAD51-related FA), or an X-linked manner (FANCB-related FA).
- Thalidomide embryopathy occurs secondarily to maternal ingestion of thalidomide. Affected children can have a pattern of limb, cardiac, craniofacial, and genitourinary anomalies.
- VACTERL association is an acronym that stands for the cardinal manifestations of vertebral, anal, cardiac, tracheo-esophageal fistula, renal anomalies, and limb anomalies. The limb anomalies tend to affect the thumb and radius, although the thumb is often absent in this condition. Thrombocytopenia does not occur as a manifestation of VACTERL.
- Duane-radial ray syndrome (Okihiro syndrome, acro-renal-ocular syndrome) is characterized by the combination of Duane anomaly (inability to abduct the eye) and radial anomalies of varying severity, ranging from thenar hypoplasia to radial aplasia. In addition, renal and skeletal anomalies and hearing loss and/or ear anomalies often occur. See SALL4-Related Disorders.
- Townes-Brocks syndrome, an autosomal dominant disorder resulting from pathogenic variants in SALL1, is characterized by the triad of imperforate anus, dysplastic ears, and thumb malformations (triphalangeal thumbs, duplication of the thumb, and rarely thumb hypoplasia). Hematologic abnormalities do not occur in Townes-Brocks syndrome.
- Rapadilino syndrome is an acronym of sorts for the cardinal manifestations of radial defects, absent/hypoplastic patellae (and high/cleft palate), diarrhea (and joint dislocations), little size, and a long/slender nose (and normal intelligence). The radial defects include absent or hypoplastic radii and absent or hypoplastic thumbs (thus distinguishing it from TAR syndrome). See Baller-Gerold Syndrome and Rothmund-Thomson Syndrome.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with thrombocytopenia absent radius (TAR) syndrome, the following evaluations are recommended:
- Platelet count if this has not been completed
- Orthopedic evaluation of both upper and lower limbs
- Echocardiography to assess for cardiac anomalies
- Evaluation of renal structure and function
- Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
The treatment for thrombocytopenia is platelet transfusion as needed. Bone marrow transplantation is generally not indicated, given the transient nature of the thrombocytopenia.
The use of central venous catheters as an alternative to venipuncture has been suggested to reduce the pain associated with repeated procedures [Coccia et al 2012].
Orthopedic intervention is indicated to maximize function of limbs, with such intervention including prostheses, orthoses, adaptive devices, and surgery [McLaurin et al 1999, Al Kaissi et al 2015].
Prevention of Primary Manifestations
Avoidance of cow's milk lessens the severity of gastroenteritis and reduces exacerbations of 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 ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu 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.