Thrombocytopenia-Absent Radius Syndrome

A number sign (#) is used with this entry because in the vast majority of cases this phenotype is caused by compound heterozygosity for a rare null mutation involving the RBM8A gene (605313) on chromosome 1q12 on 1 allele (200-kb deletion involving at least 10 genes, frameshift, or premature termination), and 1 of 2 low-frequency noncoding single-nucleotide polymorphisms (SNPs) in RBM8A on the other.

Description

The thrombocytopenia-absent radius syndrome (TAR) is characterized by reduction in the number of platelets and absence of the radius; preservation of the thumb distinguishes TAR from other syndromes that combine blood abnormalities with absence of the radius, such as Fanconi anemia (see 227650). Individuals with TAR have low numbers of megakaryocytes, platelet precursor cells that reside in bone marrow, and frequently present with bleeding episodes in the first year of life that diminish in frequency and severity with age. The severity of skeletal anomalies varies from absence of radii to virtual absence of upper limbs, with or without lower limb defects such as malformations of the hip and knee (summary by Albers et al., 2012).

Clinical Features

Shaw and Oliver (1959) described sibs with absent radii and thrombocytopenia. They suggested that this disorder is distinct from Fanconi pancytopenic syndrome (227650) because there was no hypoplasia of the erythron and the blood disorder was evident in the first few months of life. The rare condition had been reported in sibs by Gross et al. (1956). In other reported cases congenital heart disease and renal malformations were found. Thrombocytopenia usually gives rise to symptoms early in life but is transient. Thus, the process is a more benign one than is Fanconi panmyelopathy, in which leukemia is a further complication. Other differences from Fanconi disease include the absence of particular change in the thumb, of pigmentary abnormalities, and of chromosomal breaks.

In a family studied at the Johns Hopkins Hospital, Hall et al. (1969), who gave the name and acronym to this syndrome, described 4 affected sisters. One with tetralogy of Fallot had died. The oldest was alive at age 27 and had 2 normal children. The occurrence of hypoplastic radius and hypoplastic thrombocytopenia with trisomy 18 (Rabinowitz et al., 1967) is of interest although a relationship to the mendelizing syndrome is doubtful.

Cow's milk intolerance is said to occur frequently in the TAR syndrome (Whitfield and Barr, 1976). Van Allen et al. (1982) showed that the radial artery is present (but with an abnormal course) in the TAR syndrome, suggesting that the radial aplasia is primary; in other forms of radial aplasia, abnormality of the blood supply appeared to be primary. Anyane-Yeboa et al. (1985) described an infant with the most severe expression in the limbs, tetraphocomelia, simulating thalidomide embryopathy. Pfeiffer and Haneke (1975) reported a similar case. The occurrence of cleft lip and palate in association with skeletal changes such as absent radius suggests Roberts syndrome (268300) or SC phocomelia (269000) rather than TAR syndrome. Clefting must be rare in TAR syndrome. Abnormalities in the legs are frequent (Ray et al., 1980; Schoenecker et al., 1984) and may be severe (e.g., Anyane-Yeboa et al., 1985).

Feingold et al. (1980) pointed out the occurrence of nonpitting dorsal pedal edema in the newborn period and excessive perspiration. The patient reported by van Haeringen et al. (1989) showed, in addition to absent radii and intermittent thrombocytopenia, cleft of the soft palate, subcricoid stenosis, duodenal atresia, and sensitivity to x-rays. In addition to reviewing the manifestations of this syndrome, Hall (1987) announced the organization of a parent support group called TARSA (Thrombocytopenia Absent Radius Syndrome Association).

Homans et al. (1988) found that megakaryocyte colony growth in vitro was virtually absent in optimally stimulated cultures of a patient's bone marrow progenitors, whereas erythroid and myeloid colony growth was preserved. Staining of the patient's bone marrow smears with antiserum against platelet membrane glycoproteins detected no immature, small megakaryocyte precursors. A high level of megakaryocyte colony stimulating activity, comparable to the levels present in sera from adults with aplastic anemia, was detected in the serum from the TAR infant. The elevated serum activity decreased by 6 months of age at which time partial platelet recovery had occurred.

Ashinoff and Geronemus (1990) described a patient with the TAR syndrome and a very large port-wine stain involving the right half of the face, scalp, neck, and chest. Flashlamp-pumped pulsed dye laser (PDL) was considered the treatment of choice for port-wine stains. However, they observed no beneficial effect after 3 treatments and postulated that severe thrombocytopenia prevented the formation of platelet thrombi, thus inhibiting the action of the PDL.

Among the children of second cousins of Mayan ancestry, Ceballos-Quintal et al. (1992) described a TAR-like syndrome. The sib described in detail had, in addition to the usual abnormalities of TAR syndrome, depressed nasal bridge, cataracts, glaucoma, megalocornea, and blue sclerae.

Greenhalgh et al. (2002) reported the results of a clinical study of 34 patients with TAR syndrome. All patients had documented thrombocytopenia and bilateral radial aplasia, 47% had lower limb anomalies, 47% intolerance to cow's milk, 23% renal anomalies, and 15% cardiac anomalies. Congenital anomalies also included facial capillary hemangiomata, intracranial vascular malformation, sensorineural hearing loss, and scoliosis.

Menghsol et al. (2003) reported a patient with TAR syndrome who also had coarctation of the aorta and axial rotation of the kidney. He died at approximately 3 weeks of age from cardiorespiratory arrest due to pneumonia and sepsis. Postmortem examination showed left ventricular hypertrophy and subendocardial fibrosis in addition to coarctation of the aorta. Other findings included adducted thumbs, radial aplasia, hypoplasia of the cerebellar vermis, and axial malrotation of the kidney, which is thought to result from abnormal migration during fetal development.

Skorka et al. (2005) reported a female infant with TAR syndrome and complete agenesis of the corpus callosum, hypoplasia of the cerebellum, and horseshoe kidney. She had cow's milk allergy, complex partial seizures with secondary generalization, and severe psychomotor retardation. She died at age 5 years of multiorgan failure following prolonged seizures. Skorka et al. (2005) concluded that cerebral dysgenesis is part of the TAR phenotype.

Inheritance

Parental consanguinity seems to be rarer than one might expect, and on segregation analysis based on the recessive hypothesis, Hall et al. (1969) found an excess of unaffected sibs. The possibility of multiple allelism was raised.

Teufel et al. (1983) gave what they claimed to be the first report of parental consanguinity. Ashinoff and Geronemus (1990) commented on the rarity of reported consanguinity.

Ward et al. (1986) reported the TAR syndrome in 2 sisters and in the daughter of one of them. The father of the affected child was said to be unrelated to the mother. Ward et al. (1986) pointed out other irregularities in the inheritance of this disorder. They suggested that 'counseling should include the possibility of recurrence risks as high as 50%.' This seems a frightening piece of information which is not justified on the basis of this single instance of parent-to-child transmission.

Schnur et al. (1987) described the TAR syndrome in a black male infant and his maternal uncle. The mother of the propositus was normal; a maternal aunt had mild radial hypoplasia, possibly representing partial expression of the syndrome. Schnur et al. (1987) found in the literature 2 other instances of aunt/nephew or uncle/niece affection. These findings, together with that of Ward et al. (1986) of parent-to-child transmission, may require an explanation.

The finding of Klopocki et al. (2007) (see CYTOGENETICS) that carriers of a 200-kb microdeletion (i.e., clinically inconspicuous parents and grandparents) are not affected implied that haploinsufficiency of the deleted region is not sufficient to cause TAR syndrome. They remarked that TAR syndrome does not appear to follow a standard autosomal dominant or complex pattern of inheritance. The possibility of genomic imprinting was excluded by the detection of maternal as well as paternal transmission of the deletion among the unaffected carrier parents. Klopocki et al. (2007) concluded that a model with one or more recessively acting modifiers, referred to as mTAR, appears likely, and proposed that TAR syndrome must be considered not a single-gene disease but a complex trait requiring at least 2 unlinked alleles--one rare, the other frequent--to manifest the phenotype.

Klopocki et al. (2007) found that the TAR microdeletion was inherited from 1 of the unaffected parents in most patients: from the mother in 12 and from the father in 5. In 1 family the deletion was demonstrated in both the affected mother and the affected fetus. The microdeletion arose de novo in 5. In the remaining patients the pattern of inheritance could not be investigated.

Diagnosis

Many skeletal dysplasias have been diagnosed prenatally after the birth of an affected sib. On the other hand, Donnenfeld et al. (1990) performed prenatal diagnosis in a primary (index) case of TAR syndrome. Ultrasound showed bilateral upper limb phocomelia and asymmetric lower limb reduction deficiencies, and cordocentesis showed thrombocytopenia and anemia.

Luthy et al. (1979) and Luthy et al. (1981) reported prenatal diagnosis of TAR by fetal radiography and ultrasound, respectively.

Cytogenetics

Klopocki et al. (2007) identified a common microdeletion (chr1: 144.1-144.3 Mb, NCBI36) in patients with TAR syndrome that encompasses 200 kb and 11 genes on chromosome 1q21.1.

Albers et al. (2012) gave the genomic coordinates of the minimally deleted region as chr1:145,399,075-145,594,214 (GRCh37).

Kaminsky et al. (2011) presented the largest copy number variant case-control study to that time, comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing on recurrent deletions and duplications involving 14 copy number variant regions. Compared with controls, 14 deletions and 7 duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic. The 1q21 deletion was identified in 17 cases and 1 control for a p value of 0.0026 and a frequency of 1 in 926 cases.

Molecular Genetics

Given the unclear inheritance and frequently sporadic nature of TAR syndrome, Klopocki et al. (2007) searched for genomic aberrations in 30 patients with TAR syndrome and their families, using high-resolution microarray-based comparative genomic hybridization (rearray CGH). They identified a common 200-kb deletion on the long arm of chromosome 1 in all the affected individuals and in 25 (32%) of 78 unaffected family members. The results indicated that TAR syndrome is associated with a microdeletion on 1q21.1 that is necessary but not sufficient to cause the phenotype. They postulated that the phenotype develops only in the presence of an additional modifier (mTAR). The TAR deletion does not overlap with the deletion on 1q21.1 identified in another syndrome of mental retardation and congenital anomalies (see 612474).

Albers et al. (2012) reported that 51 of 55 cases of TAR syndrome had a 200-kb deletion on 1q21 while 2 had a truncation (605313.0004) or frameshift (605313.0003) (null) mutation in the RBM8A gene on 1 allele. Of these 53 cases, all had 1 of 2 low-frequency SNPs in regulatory regions of RBM8A on the other allele. The likelihood that this mode of inheritance happened by chance is less than 5 x 10(-228). Klopocki et al. (2007) had demonstrated that an inherited or de novo deletion on chromosome 1q21.1 is found in the majority of individuals with TAR syndrome, but the apparent autosomal recessive nature of this syndrome required the existence of an additional causative allele. To identify the additional causative allele, Albers et al. (2012) selected 5 individuals with TAR of European ancestry who had the 1q21.1 deletion and sequenced their exomes, but were unable to find TAR-associated coding mutations in any gene. However, 4 of the cases carried the minor allele of a low-frequency SNP in the 5-prime UTR of the RBM8A gene (rs139428292; 605313.0001), while the remaining case carried a previously unknown SNP in the first intron of the same gene (605313.0002). Genotyping by Sanger sequencing of another 48 cases of European ancestry identified the 2 SNPs in 35 and 11 samples, respectively. A mother of non-European ancestry with TAR and her fetus, aborted on the grounds of prenatal diagnosis of TAR, both did not carry the 5-prime UTR or the intronic SNP, and Albers et al. (2012) suggested that in this instance there was a different causative allele. In the 25 trios where the deletion in the child was not a de novo event, Albers et al. (2012) confirmed that the deletion and the newly identified SNPs were inherited from different parents. The minor allele frequency of the 5-prime UTR and intronic SNPs were 3.05% and 0.42%, respectively, in 7,504 healthy individuals of the Cambridge BioResource, and the deletion was absent from 5,919 shared healthy controls of the Wellcome Trust Case Control Consortium. There were 2 TAR cases who did not carry the 1q21.1 deletion but were found to carry the 5-prime UTR SNP. Albers et al. (2012) identified a 4-bp frameshift insertion at the start of the fourth exon (605313.0003) in the first case and established that the noncoding SNP and insertion were on different chromosomes; in the second case, they identified a nonsense mutation in the last exon of RBM8A (605313.0004). Both mutations were absent from 458 exome samples of the 1000 Genomes Project and 416 samples from the Cohorte Lausannoise. Albers et al. (2012) concluded that in the vast majority of cases, compound inheritance of a rare null allele (containing a deletion, frameshift mutation, or encoded premature stop codon) and 1 of 2 low-frequency noncoding SNPs in RBM8A causes TAR syndrome. Albers et al. (2012) showed that the 2 regulatory SNPs result in diminished RBM8A transcription in vitro and that expression of Y14 (a subunit of the exon junction complex (EJC) encoded by the RBM8A gene) is reduced in platelets from individuals with TAR. Albers et al. (2012) concluded that their data implicated Y14 insufficiency and, presumably, an EJC defect as the cause of TAR syndrome.

Exclusion Studies

Strippoli et al. (1998) screened the coding and promoter regions of the gene encoding the thrombopoietin receptor (TPOR; 159530) in 4 unrelated patients affected by TAR syndrome and found no mutations.

Animal Model

Klopocki et al. (2007) drew a parallel between a situation that may exist in the TAR syndrome and that demonstrated by the dactylaplasia mutation (Dac) in mice, the murine equivalent of human ectrodactyly. Affected patients and Dac mice have hypoplasia of the middle part of the distal limbs, a phenotype that is highly variable, ranging from syndactyly to monodactyly. Because Dac mice exhibit the ectrodactyly phenotype only on certain genetic backgrounds, Chai (1981) postulated that the manifestation of the mutant gene Dac is controlled by another locus, which was termed mDac. The mutation is expressed as an autosomal semidominant trait only if the mDac allele is homozygous. This hypothesis was verified by the identification of the Dac mutation (Sidow et al., 1999) and the mapping of mDac to the mouse chromosome 13 (Johnson et al., 1995).