Absent Radii Syndrome Research Articles

Thrombocytopenia and absent radii (TAR) syndrome associated with bilateral congenital cataract: a case report

IntroductionThrombocytopenia with absent radii is a rare congenital defect with hypomegakaryocytic thrombocytopenia and bilateral radial aplasia that may have additional anomalies. We report the case of a girl baby with thrombocytopenia and absent radii syndrome and bilateral congenital cataract. This anomaly has not been previously reported in the children of a non- consanguineous marriage.Case presentationThis case report describes a two-day-old girl baby of Arab origin with thrombocytopenia and absent radii syndrome and bilateral congenital cataract.ConclusionsThis report describes a finding of bilateral congenital cataract associated with thrombocytopenia and absent radii syndrome that has been reported only once before in the literature. This case report highlights a new ocular manifestation in one of the bone marrow failure syndromes.

Deficiency of the Y14 protein is a critical factor underlying the etiology of thrombocytopenia with absent radii syndrome

Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndromeAlbers CA et al. (2012)Nature Genetics 44(4): 435–439.

Two patterns of thrombopoietin signaling suggest no coupling between platelet production and thrombopoietin reactivity in thrombocytopenia-absent radii syndrome

Thrombocytopenia with absent radii syndrome is defined by bilateral radius aplasia and thrombocytopenia. Due to impaired thrombopoietin signaling there are only few bone marrow megakaryocytes and these are immature; the resulting platelet production defect improves somewhat over time. A microdeletion on chromosome 1q21 is present in all patients but is not sufficient to form thrombocytopenia with absent radii syndrome. We aimed to refine the signaling defect in this syndrome. We report an extended study of 23 pediatric and adult patients suffering from thrombocytopenia with absent radii syndrome in order to scrutinize thrombopoietin signal transduction by immunoblotting and gel electrophoretic shift assays. In addition, platelet immunotyping and reactivity were analyzed by flow cytometry. Results were correlated with clinical data including age and platelet counts. Two distinct signaling patterns were identified. Juvenile patients showed abrogated thrombopoietin signaling (pattern #1), which is restored in adults (pattern #2). Phosphorylated Jak2 was indicative of activation of STAT1, 3 and 5, Tyk2, ERK, and Akt, showing its pivotal role in distinct thrombopoietin-dependent pathways. Jak2 cDNA was not mutated and the thrombopoietin receptor was present on platelets. All platelets of patients expressed normal levels of CD41/61, CD49b, and CD49f receptors, while CD42a/b and CD29 were slightly reduced and the fibronectin receptor CD49e markedly reduced. Lysosomal granule release in response to thrombin receptor activating peptide was diminished. We show a combined defect of platelet production and function in thrombocytopenia with absent radii syndrome. The rise in platelets that most patients have during the first years of life preceded the restored thrombopoietin signaling detected at a much later age, implying that these events are uncoupled and that an unknown factor mediates the improvement of platelet production.

Inherited Hematologic and Oncologic Syndromes

Inherited Hematologic and Oncologic Syndromes

Exacerbation of thrombocytopenia in a pregnant woman with thrombocytopenia–absent radius syndrome

degreeof dysfunction [4]. It is uncertainwhethermisoprostol is removed via dialysis [4]. Thus, its use for medical abortion in women with renal disease has been a point of contention, with most obstetricians opting against use. However, in the present cases, misoprostol was used to achieve abortion in consenting women with impaired renal function, with no adverse effects. Larger studies are required to determine the optimum doses at different degrees of renal impairment.

Developmental differences in megakaryocytopoiesis are associated with up-regulated TPO signaling through mTOR and elevated GATA-1 levels in neonatal megakaryocytes

AbstractMultiple observations support the existence of developmental differences in megakaryocytopoiesis. We have previously shown that neonatal megakaryocyte (MK) progenitors are hyperproliferative and give rise to MKs smaller and of lower ploidy than adult MKs. Based on these characteristics, neonatal MKs have been considered immature. The molecular mechanisms underlying these differences are unclear, but contribute to the pathogenesis of disorders of neonatal megakaryocytopoiesis. In the present study, we demonstrate that low-ploidy neonatal MKs, contrary to traditional belief, are more mature than adult low-ploidy MKs. These mature MKs are generated at a 10-fold higher rate than adult MKs, and result from a developmental uncoupling of proliferation, polyploidization, and terminal differentiation. This pattern is associated with up-regulated thrombopoietin (TPO) signaling through mammalian target of rapamycin (mTOR) and elevated levels of full-length GATA-1 and its targets. Blocking of mTOR with rapamycin suppressed the maturation of neonatal MKs without affecting ploidy, in contrast to the synchronous inhibition of polyploidization and cytoplasmic maturation in adult MKs. We propose that these mechanisms allow fetuses/neonates to populate their rapidly expanding bone marrow and intravascular spaces while maintaining normal platelet counts, but also set the stage for disorders restricted to fetal/neonatal MK progenitors, including the Down syndrome–transient myeloproliferative disorder and the thrombocytopenia absent radius syndrome.

Radioulnar Synostosis and Its Hematology and Genetic Associations

AbstractAbstract 2521Defects in the radial ray are associated with hematological problems such as thrombocytopenia and bone marrow failure, i.e. Thrombocytopenia Absent Radius Syndrome and Fanconi Anemia. Congenital radioulnar synostosis (RUS), a rare developmental anomaly involving fusion of the bones of the forearms, has been recognized in the orthopedic literature since the mid-1800s. The bony union of the radius and ulna prevents normal supination of the affected forearm, yet the condition is painless and compatible with a normal functional existence without the need for surgery. RUS occurs more frequently in males, and is bilateral in about fifty percent of cases. In utero, growth patterning of the limbs along the various axes requires products of the Homeobox (Hox) genes, which are members of a highly conserved set of transcription gene factors that are expressed very early in embryonic development. In addition to limb patterning, studies regarding homeobox genes have suggested that they are involved in hematopoiesis, including self-renewal, proliferation, differentiation, and leukemogensis. In the year 2000, Thompson and Nguyen published a report in Nature Genetics that identified an unusual association of amegakaryocytic thrombocytopenia and radioulnar synostosis in two unrelated, non-consanguineous families; sequencing of these families found a point mutation of exon 2 of HoxA11. Several other studies have confirmed the association of bone marrow failure or thrombocytopenia and RUS, although a number of patients have not tested positive for the HoxA11 mutation. The aims of our IRB approved project are to create a registry of patients and their family members with congenital RUS with or without hematological problems; compile their medical histories, clinical phenotypes, and results of complete blood counts; archive blood samples; and perform genomic testing for HoxA11 and other DNA screening. We began recruiting subjects at New York Presbyterian Hospital Department of Hematology/Oncology in August of 2009. Through radiology screening, chart review, and referrals from our collaborating pediatric orthopedists, we have identified eight source patients with RUS. All except one patient have hematological manifestations; three have subtle symptoms of easy bruising and recurrent epistaxis, one had thrombocytopenia with reduced megakaryoctyes, one has intermittent thrombocytopenia and leucopenia of undetermined etiology, one had pancytopenia/bone marrow failure in infancy and is status post bone marrow transplant (s/p BMT), and one had acute lymphoblastic leukemia/lymphoma in young adulthood and is also s/p BMT. The eighth patient was recently adopted from an orphanage in a foreign country, and his past and family histories are unknown. Other related anomalies or syndromes found in the primary subjects or family members are clinodactyly of the 5th finger, Angelman Syndrome, Autism Spectrum Disorders, Pulmonary Hypertension (PHTN), Polycystic Kidney Disease (PCKD), and possible Poland Syndrome. We have also compiled family pedigrees and collected blood from immediate family members, some of whom also have RUS and hematological manifestatations [Figure 1]. Five of the eight families are of Mediterranean (mostly Italian) ancestry, suggesting a possible founder effect to the mutation versus geographic bias of the New York metropolitan area. One family of Italian descent had consanguinity of the subject's maternal grandparents. We are in the process of sequencing HoxA11 for the subjects and their families. Subject #1 previously tested normal for the HoxA11 gene. If samples are determined to be normal for HoxA11, genome wide SNP analysis for further homozygosity and/or linkage mapping will be pursued. We hope to increase awareness of the linked clinical entities of RUS, thrombocytopenia, bone marrow failure, and possible malignant transformation at the level of the general pediatrician, orthopedists, and hematologists. Additionally, besides HoxA11, we hope to discover other candidate genes or molecular mechanisms within related Hox genes that may influence the development of forearm morphogenesis, thrombopoiesis, and leukemogenesis. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Clavicular pseudoarthrosis, anomalous coronary artery and extra crease of the fifth finger-previously unreported features in individuals with class II 1q21.1 microdeletions

Submicroscopic deletions of two adjacent regions within chromosomal band 1q21.1 were recently associated with two distinct phenotypes: A deleted region of 200–500 kb was found in individuals with Thrombocytopenia Absent Radius syndrome (TAR). Deletion in another region of about 1.25 Mb that is located just telomeric of the TAR region, referred to as distal 1q21.1 region, was found to be associated with a phenotype of cognitive impairment, congenital heart defects and other variable manifestations. A significant proportion of individuals with either of the two deletions did not have phenotypic abnormalities. More than 40 individuals with distal 1q21.1 deletions have been reported to-date. A proportion of them (9 reported individuals) had larger (>2 Mb) deletions involving both the TAR and the distal 1q21.1 regions, referred to as class II deletions. We describe here four additional individuals from two families with such class II deletions, who presented with previously unreported manifestations: clavicular pseudoarthrosis and anomalous origin of the coronary artery in the proband of the first family; an extra transverse crease of the fifth finger, segregating in two of the three deletion carriers in the second family. Previously reported features, associated with such microdeletions – absolute or relative microcephaly, cognitive impairment and short stature, were variably observed in the reported individuals. This report expands the phenotypic spectrum associated with class II 1q21.1 deletions, and demonstrates striking phenotypic variability even within the same family.

Thrombocytopenia Absent Radius Syndrome: Presence of Brachiocarpalis Muscle and Its Importance

Common clinical manifestations associated with thrombocytopenia absent radius (TAR) syndrome have been reported in the literature since its initial description in 1959. The purpose of this study was to report a clinical observation and describe the anatomic location of this brachiocarpalis muscle. The radiographs of 20 patients (39 extremities) with TAR syndrome were reviewed and are the focus of this report. The presence or absence of an abnormal muscle crossing both the humero-ulnar and ulno-carpal joint, and its anatomic origin and insertion, were documented by radiographs, surgery, or both. A total of 12 patients underwent surgery on 19 extremities. Furthermore, we compared the radiographs of these 20 patients (39 extremities) with the radiographs of 20 arbitrarily selected patients with non-TAR type IV radial dysplasia, which were part of our database. An abnormal brachiocarpalis muscle was noted radiographically in all 39 of the extremities and was observed surgically in all 19 patients who underwent surgery. It was absent in all 40 extremities of the non-TAR type IV radial dysplasia patients. One TAR patient had only unilateral radial dysplasia. This anomalous muscle has an abnormally high origin on the anterolateral aspect of the proximal humerus, and an insertion into the radial side of the carpus. As such, it has a deforming force at both the wrist and the elbow. We report the consistent finding of a brachiocarpalis muscle in patients with TAR syndrome. Because of its location, the presence of this muscle may influence the surgical treatment of these patients. Diagnostic IV.

Congenital FX deficiency combined with other clotting defects or with other abnormalities: a critical evaluation of the literature

The presence of more than one congenital clotting defect in a given patient is a rare event but not an exceptional one. Combined defects of factor X (FX) are very rare because congenital isolated FX deficiency is by itself very rare. A perusal of personal files and of the literature has yielded 12 families with FX deficiency in which an association with another clotting factor deficiency was found. The associated defects were factor VII (FVII) or factor VIII (FVIII) or factor XII (FXII) deficiency. By far the most frequently associated was with FVII. Two forms of this association were found. In the first form there is casual association of both FVII and FX deficiency in the proband with independent recessive segregation of the two defects in other family members. The second form is because of abnormalities in chromosome 13 (deletions, translocations and so on) involving both FX and FVII genes. These genes are known to be very close and located on the long arm of chromosome 13 at about 13q34. In this form the hereditary pattern is autosomal dominant. Isolated FX deficiency and, more frequently, combined FX + FVII deficiency appear also associated with coagulation-unrelated abnormalities (carotid body tumours, mitral valve prolapse, atrial septal defect, ventricular septal defect, thrombocytopenia absent radius (TAR) syndrome, mental retardation, microcephaly and cleft palate). Diagnosis of a combined clotting defect could be difficult on the basis of global tests. For example, both isolated FX deficiency and combined FX + FVII deficiency yield a prolongation of basal PTT and PT. Only specific assays could allow one to reach the correct diagnosis. In cases of casual association with other defects, it is also important to study family members, as the two defects should segregate independently.

Recombinant activated factor VII for hemostatic cover of orthopedic interventions in a girl with thrombocytopenia with absent radii syndrome

Over the past 10 years recombinant activated factor VIIa (rFVIIa) has been successfully used for treatment and prophylaxis of bleeding in patients with platelet defects, including thrombocytopenia and congenital and acquired platelet function abnormalities. Most reported data concern patients with Glanzmann's thrombasthenia and the information available is still limited, especially for surgery. We report on a 15-year-old girl with thrombocytopenia ( approximately 60,000/microl) and platelet dysfunction (bleeding time 30 min, absent platelet aggregation and ATP secretion in response to collagen), related to thrombocytopenia with absent radii syndrome, undergoing two surgical interventions on the upper limbs due to forearm deformities, with prolonged postoperative revisions. In both surgeries rFVIIa was successfully employed as a bolus administration (80 microg/kg every 4 h during the first day, then every 6 h over the following 5 and 3 days, respectively; tranexamic acid was associated from the second day, administered for 2 weeks), avoiding the need for blood products. This report highlights rFVIIa as an attractive, alternative approach to secure hemostasis in patients with platelet defects; on the other hand, the heterogeneity of reported rFVIIa treatment regimens and, in particular, the lack of definite and easily available parameters (or assays) for monitoring rFVIIa efficacy and safety are the main open issues in this setting.

A rare association of crossed fused renal ectopia

BackgroundThrombocytopenia and absent radius syndrome (TAR) is a rare genetic disorder. It is an autosomal recessive disorder characterised by radial aplasia and thrombocytopenia that may have additional anomalies. We report a case of TAR syndrome with crossed fused renal ectopia. This anomaly has not been previously reported in association with TAR syndrome.Case presentationA 24 years old female with Thrombocytopenia and absent radius syndrome admitted with pelvic fracture was investigated for recurrent urinary tract infections. Abdominal ultrasonography could not visualise the kidney on right side. Further extensive investigations in the form of intravenous urography (IVU), Magnetic resonance imaging (MRI) and renal isotope scans revealed a crossed fused renal ectopia.ConclusionThis report describes the new finding of a crossed fused renal ectopia associated with TAR syndrome that has not been reported before in the literature. Ectopic kidneys have increased susceptibility to develop complications like urinary infections, urolithiasis, and abdominal mass. There is a reported case of TAR syndrome with renal anomaly that developed Wilm's tumor. Finding of crossed fused renal ectopia warrants complete urologic investigation to rule out surgically correctable pathology in the urinary tract.

Complex Inheritance Pattern Resembling Autosomal Recessive Inheritance Involving a Microdeletion in Thrombocytopenia–Absent Radius Syndrome

Thrombocytopenia-absent radius (TAR) syndrome is characterized by hypomegakaryocytic thrombocytopenia and bilateral radial aplasia in the presence of both thumbs. Other frequent associations are congenital heart disease and a high incidence of cow's milk intolerance. Evidence for autosomal recessive inheritance comes from families with several affected individuals born to unaffected parents, but several other observations argue for a more complex pattern of inheritance. In this study, we describe a common interstitial microdeletion of 200 kb on chromosome 1q21.1 in all 30 investigated patients with TAR syndrome, detected by microarray-based comparative genomic hybridization. Analysis of the parents revealed that this deletion occurred de novo in 25% of affected individuals. Intriguingly, inheritance of the deletion along the maternal line as well as the paternal line was observed. The absence of this deletion in a cohort of control individuals argues for a specific role played by the microdeletion in the pathogenesis of TAR syndrome. We hypothesize that TAR syndrome is associated with a deletion on chromosome 1q21.1 but that the phenotype develops only in the presence of an additional as-yet-unknown modifier (mTAR).

Thumb Function and Appearance in Thrombocytopenia: Absent Radius Syndrome

To evaluate thumb function and appearance in patients with thrombocytopenia absent radius (TAR) syndrome. The size and shape of the 14 thumbs in 7 patients with TAR syndrome were quantified and compared with age-matched normals. Function was assessed using a series of standardized tasks. The thumb length averaged 73% relative to the length of the index finger proximal phalanx (normal, 70%) and 36% relative to the length of the entire index finger (normal, 32%). The thumb/index nail width and girth ratios measured 138% and 101%, respectively (normal, 133% and 105%, respectively). The relative thumb/index thumbnail width-to-girth ratio was 1.36, which was significantly greater than the normal average of 1.27, suggesting the TAR thumbs are relatively wide and flat compared with normal thumbs. The thumb interphalangeal joint was held in a neutral posture and did not show active motion in any patient; the metacarpophalangeal joint was held in a position of flexion and had an average of 32 degrees of extension lag. Patients had difficulty with all activities tested, especially grasping large objects. The thumb in TAR syndrome patients is of relatively normal size and shape; however, the thumb is held in a position of metacarpophalangeal flexion in most patients and function is impaired.

Insufficiency fracture of the ilium associated with thrombocytopenia and absent radius (TAR) syndrome

Insufficiency fracture of the ilium associated with thrombocytopenia and absent radius (TAR) syndrome

Radial Longitudinal Deficiency: The Incidence of Associated Medical and Musculoskeletal Conditions

Radial longitudinal deficiency (RLD) is associated with certain syndromes and medical and musculoskeletal conditions. The purpose of this investigation was to evaluate the incidence of these conditions with RLD. A comprehensive chart review identified patients with RLD and a complete medical record. These charts were evaluated for the presence of associated medical and musculoskeletal conditions and biographic information on gestation, delivery, and family history. A total of 164 patients with 245 affected extremities were identified; 138 patients had radius abnormalities and 26 patients had isolated thumb hypoplasia. Twenty-five patients had thrombocytopenia absent radius syndrome; 22 patients had vertebral, anal, cardiac, tracheoesophageal, renal, and limb abnormalities association; 7 patients had Holt-Oram syndrome; and 1 patient had Fanconi anemia. There were 32 patients with cardiac abnormalities and 60 patients with spinal or lower-extremity musculoskeletal abnormalities. The percentage of patients with associated abnormalities increased with an increasing severity of RLD. One hundred two of the 138 patients with types I through V RLD had associated medical or musculoskeletal abnormalities. In contrast, only 9 of 26 patients with an isolated thumb hypoplasia (type 0 RLD) had associated abnormalities. The high incidence of associated medical and musculoskeletal abnormalities in patients with RLD emphasizes the importance of a complete assessment including a complete musculoskeletal examination, cardiac auscultation, complete blood count, echocardiogram, renal ultrasound, and spinal radiographs. Although approximately one third of patients in this investigation had a syndrome commonly associated with RLD, most patients with RLD types I through V had an additional medical or musculoskeletal anomaly. Patients with type 0 RLD were less likely to have comorbidities.

Mullerian Agenesis and Thrombocytopenia Absent Radius Syndrome: A Case Report and Review of Syndromes Associated With Mullerian Agenesis

Mullerian agenesis, commonly referred to as Mayer-Rokitansky-Kuster-Hauser syndrome (MRKHS), is a congenital defect that is most commonly associated with renal and spinal malformations. It is very rare for Mullerian agenesis to be accompanied by malformations of the extremities. In this report, we describe a 22-year-old woman with Mullerian agenesis and thrombocytopenia absent radius syndrome (TARS). We also review rare syndromes associated with Mullerian anomalies, including Mullerian hypoplasia/aplasia-renal agenesis-cervicothoracic somite dysplasia (MURCS), Roberts syndrome, Bardet-Biedl syndrome (BBS), McKusick-Kaufman syndrome (MKS), Wolf-Hirschhorn syndrome, and others. The pathogenesis of these complex malformation syndromes is not well understood as a result of their sporadic occurrence. However, some of these syndromes do follow a pattern of inheritance, suggesting that they could provide insights into our understanding of their origins. Obstetricians & Gynecologists, Family Physicians After completion of this article, the reader should be able to review the rare congenital defects associated with Mullerian agenesis, to determine the genetic etiologies of the associated syndromes with Mullerian agenesis, and to discuss information for parental counseling related to inheritance patterns and growth and development of the affected child.

P14.02: First‐trimester diagnosis of thrombocytopenia‐absent radius (TAR) syndrome in a triplet pregnancy after assisted reproduction techniques

Thrombocytopenia absent radius (TAR) syndrome is an autosomal recessive disorder involving bilateral radial aplasia and hypomegakaryocytic thrombocytopenia. The presence of the thumbs usually exclude other forms of radial aplasia. Clubfoot deformities may be associated and the ulna and humerus may be also absent. This condition is not always fatal, but presents severe morbidity and a high mortality rate, usually secondary to hemorrhage early in infancy. Prenatal diagnosis of TAR syndrome has been occasionally reported, mostly in the second half of pregnancy and in cases with a prior affected child. To the best of our knowledge, we present the first case of first-trimester detection of TAR syndrome in a fetus from a triplet pregnancy achieved by assisted reproduction techniques. A 36-year-old nulliparous woman conceived a trichorionic triamnotic pregnancy after in vitro fertilization with ovum donation. We performed a first-trimester Down syndrome screening at 12 weeks of pregnancy. The ultrasound examination showed bilateral absent radius associated with bilateral ulna hypoplasia and clubhands in triplet I. The diagnosis was confirmed two weeks later, being both thumbs present in the affected fetus. No other abnormal findings were detected in that fetus or in the other two. After discussing the different options, the couple opted for selective termination of the affected fetus which was carried out at 17 weeks. A cesarean section was performed at 32 + 6 weeks due to severe cholestasis and intrauterine growth retardation. An X-ray film confirmed the bilateral radial agenesis with presence of thumbs in the reduced fetus. The mother and the remaining twins recovered uneventfully.

Acute myelogenous leukemia in an adult with thrombocytopenia with absent radii syndrome

Acute myelogenous leukemia with t(8;21)(q22;q22) developed in a 42-yr-old woman having thrombocytopenia with absent radii syndrome (TARS). Standard induction and postremission therapies were safely administered. With each successive chemotherapy, the onset of platelet recovery was not delayed, but peak platelet counts were persistently suppressed. Nine months after achieving complete hematologic and cytogenetic remission, she remains severely thrombocytopenic (platelet count 6-12 x 109/L). She is, however, asymptomatic and transfusion independent. Of interest is the transient normalization of platelet count (rebound relative thrombocytosis). Our report and review of the literature suggests that TARS, contrary to previous belief, may be associated with increased risk of acute leukemia.

Absence of mutations in the HoxA10, HoxA11 and HoxD11 nucleotide coding sequences in thrombocytopenia with absent radius syndrome.

Recent studies have suggested the HoxA10, HoxA11 and HoxD11 homeobox genes as candidate loci for the thrombocytopenia with absent radius (TAR) syndrome. For example, targeted disruptions of these Hox genes result in abnormal development of the mouse radius, while overexpression of HoxA10 stimulates mouse megakaryocyte (MK) development in vitro. To examine the expression of Hox genes in human MK cells, we utilized reverse transcription polymerase chain reaction with degenerate oligonucleotides to study megakaryocytic cell lines (MEG-01, DAMI), and primary human MK purified from adult and cord blood. Using this approach, 13 out of 40 clones isolated from cell lines, 10 out of 21 from cord MK, and 11 out of 21 from adult MK were identified as HoxA10, while HoxA11 and HoxD11 sequences were not detected. The normal genomic sequences for the human HoxA10, -A11, and -D11 genes were then determined and sequenced in 10 unrelated individuals with TAR syndrome. In all patients the derived amino acid sequence for the three Hox genes was identical to normal controls. Southern blotting did not reveal genomic rearrangements or deletions at these loci, and in two patients intact HoxA10 transcripts were detected by amplification in myeloid cells. Although these studies cannot completely exclude the possibility that the TAR syndrome results from non-coding mutations that affect the level of Hox gene expression in megakaryocytes, mutations in the coding sequence of the Hox genes known to affect radial development are not a common cause of TAR syndrome.