Absent Radii Research Articles

Holt-Oram syndrome in an infant presenting with heart failure

Holt-Oram syndrome is an autosomal dominant condition characterized by morphological abnormalities of upper limbs and congenital cardiac defects. We report a case of 6-week-old infant with morphological alterations of upper limbs (absent radius and hypoplastic ulna) since birth and multiple congenital cardiac defects (atrial septal defects and ventricular septal defects), who presented with congestive cardiac failure. This case report illustrates that neonates with anomalies of thumb or upper limbs should be evaluated for possible congenital heart defects.

Acute myeloid leukemia in a patient with thrombocytopenia with absent radii: A case report and review of the literature

Thrombocytopenia with absent radii (TAR) syndrome is a rare congenital disorder characterized by low platelet counts of various severity, bilateral absent radii but thumbs are usually present. TAR syndrome is not generally associated with bone marrow failure or malignancy. Janus kinase-2, myeloproliferative leukemia protein, and calreticulin are not mutated in TAR patients. Only four cases of leukemia were reported in TAR patients in the literature: three acute myeloid leukemia (AML) and one acute lymphoblastic leukemia. Of the three cases of AML found in TAR patient, only one was reported in an adult. We report a case of myelodysplastic syndrome progressing to AML with calreticulin driver mutation in an adult male with TAR syndrome who was successfully treated with hematopoietic allogeneic stem cell transplantation.

Thrombocytopenia absent radii syndrome in a twenty five day old female neonate: a case report

<p class="abstract">Thrombocytopenia absent radii (TAR) is a rare genetic disorder associated with multiple additional anomalies. We report a case of a 25 day old female neonate with thrombocytopenia and bilateral absent radii with flexion of the elbow joint and radial deviation of the wrist joint. TAR, although rare are not uncommon. Thus, we have presented a 25 day old neonate with radiological features of absent radii and fluctuating platelet counts that subsequently showed thrombocytopenia that warranted the diagnosis of TAR syndrome in this case<span lang="EN-IN">. </span></p><p class="abstract"> </p>

The Study of relationship between fetal radius loss and chromosomal abnormality

Objective: To explore the relationship between fetal radius loss and chromosomal abnormalities. Methods: Collect data of 3 100 cases pregnant women who had been checked in the second hospital of Jilin University from 2012 to 2015.There were 8 cases of absent radius, except 1 case of fetal lost follow-up, the remaining 7 cases had complete ultrasound, chromosome examination and the result of induction.The relationship between fetal radius loss and chromosomal abnormalities were analysed. Results: There were 1 case of 21 trisomy syndrome, 1 case of trisomy 13 syndrome, 2 cases of trisomy 18, 2 cases of chromosome translocation, 1 case of normal chromosome result and 1 case was lost to follow-up of the 8 absent radius fetuses. Conclusion: Through a comparison between the chromosome and ultrasonic characteristics of fetuses who have absent radius, we had indicated the relationship of fetal radius deletion and chromosomal anomaly, improved the positive rate of chromosome invasion examination, and provided the reference for eugenics.

Otologic manifestations of Fanconi anemia and other inherited bone marrow failure syndromes.

The inherited bone marrow failure syndromes (IBMFSs) are diverse disorders with syndrome-specific features; their otologic and audiologic manifestations have not been well described. Our objective was to characterize these in patients with Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), and Shwachman-Diamond syndrome (SDS), and to determine the association between physical findings and hearing loss. Patients with an IBMFS underwent comprehensive clinical and laboratory evaluations and testing for syndrome-specific gene mutations. Hearing loss was measured by pure tone audiometry and otologic abnormalities by otomicroscopy. Patients included 33 with FA, 37 with DC, 32 with DBA, and nine with SDS. Hearing loss was most frequent in patients with FA (45%) and DBA (14%). The most common type of hearing loss in FA was conductive (65%). Absent or hypoplastic radius, noted in 21% of the patients with FA, was associated with hearing loss in all cases. Otomicroscopy was abnormal in 66% of patients with FA. Characteristic ear abnormalities included small tympanic membrane (66%), malformed malleus (57%), aberrant tympanic bony island (48%), narrow external auditory canal (EAC) (32%), and abnormal course of chorda tympani (34%). Ear malformations were almost always associated with hearing loss. Hearing loss was rare in patients with DC and SDS. FA is the major IBMFS with associated hearing loss, which is most commonly conductive. Radial hypoplasia or aplasia and characteristic congenital ear malformations are associated with hearing loss in patients with FA. Recognition of these syndrome-specific abnormalities should lead to earlier management of hearing loss.

Reconstruction for elbow instability caused by congenital aplasia of the ulnar coronoid process—a case report

A 13-year-old girl presented at our tertiary referral center with bilateral posterior radial head dislocation and aplasia of the ulnar coronoid process (Figure 1). She was pain-free, had a 30-degree lack of elbow extension, limited forearm pronation and supination (80–20 degrees on the right side, 80–0 degrees on the left side), but no signs of elbow instability. After several years without any relevant restrictions during her daily life activities, she returned to our outpatient clinic at the age of 17 with increasing pain on both sides and distinct radiological signs of posterior humeroulnar dislocation due to aplasia of the ulnar coronoid process (Figure 2). A review of the literature did not yield any information about that specific deformity or any possible treatment options. We decided to reconstruct the right elbow via an anteromedial approach, using a tricortical iliac crest bone graft as a coronoid equivalent and artificial bony restraint to the elbow joint.

Understanding thrombocytopenia: physiological role of microRNA in survival of neonatal megakaryocytes.

Neonates are predisposed to developing thrombocytopenia and neonates are affected by megakaryocytic disorders such as thrombocytopenia with absent radius syndrome and transient myeloproliferative disorder. Small double stranded non-coding microRNAs (miRNAs) have been shown to crucially involve in the regulation of stem-cell differentiation in normal as well as malignant haematopoiesis. The regulatory mechanism in developmental megakaryocytopoiesis and role of miRNAs in biological differences between adult and neonatal megakaryopoiesis is unknown. Here in we compared miR-99a levels in megakaryocytes (MKs) derived from cord blood (CB) and peripheral blood using qRT-PCR. CTDSPL is predicted as potential target of miR-99a and was confirmed by western blot. CTDSPL is shown to involve in regulation of cell growth and differentiation and exhibits tumor suppressor activity. We believe that miR-99a regulates CTDSPL, which induces the G1/S transition by increasing Cyclin expression and play a significant role in proliferation of CB-MKs.

Horseshoe Lung Associated With Holt-Oram Syndrome.

Horseshoe Lung Associated With Holt-Oram Syndrome.

2082715 TACRD and VACTERL associations in a fetus: case report and review of the literature

2082715 TACRD and VACTERL associations in a fetus: case report and review of the literature

Radial Ray Defect

A 24 days old male neonate presented to the University of Gondar Hospital with deformity at the right wrist joint since birth. Physical findings were deformity of the wrist joint with lateral deviation of fingers and absent thumb. Plain radiographs of the wrist joint showed absent radius and bones of the thumb which suggest the diagnosis of radial ray defect. Radial ray defect is a rare congenital defect that may be isolated or associated with other anomalies. This is a rare case of radial ray defect which has no association with other anomalies.

Typical and Atypical Associated Findings in a Group of 346 Patients with Mayer-Rokitansky-Kuester-Hauser Syndrome

Study ObjectiveThe Mayer-Rokitansky-Kuester-Hauser (MRKH) syndrome is characterized by vaginal and uterine aplasia in a 46,XX individual. Multiple abnormalities may be associated with MRKH syndrome, and it appears to overlap other syndromes. The aim of this study was to describe the spectrum of associated malformations and syndromes as well as abnormal karyotypic findings in a large cohort of 346 patients. Design, Setting, and ParticipantsThe study is a retrospective analysis of 346 MRKH patients treated in the University Hospital in Tuebingen between 1998 and 2013. Main Outcome MeasuresThe dataset was screened for typical associated malformations as well as atypical malformations and abnormal karyotypes. A complete review of the literature was included. ResultsAmong our cohort of 346 patients, we found that 53.2% had MRKH type 1, 41.3% had MRKH type 2, and 5.5% had MURCS syndrome. The group with associated malformations included 57.6% renal, 44.4% skeletal, and 30.8% other malformations. Additionally, we found 2 cases of absent radius syndrome, 3 cases of anal atresia, and 1 patient with oculodentodigital dysplasia, and other atypical malformations. Abnormal karyotypes were found in 5 cases, and 39 siblings and 11 parents had known malformations. ConclusionsThis study supports the hypothesis that the syndrome has a multifactorial pathogenesis. With the high numbers of associated malformations reported in this study, patients with MRKH syndrome should be regarded as having a complex syndrome. Molecular–genetic analyses in larger numbers of children after surrogacy, twin pregnancies, and familial cases may make it possible to obtain further information about the etiology of the syndrome.

CORR Insights ®: Are copy number variants associated with adolescent idiopathic scoliosis?

A dolescent idiopathic scoliosis (AIS) is a genetically heterogeneous complex condition that affects approximately 3% of the population. Although genome-wide association studies have pointed us towards candidate loci for genetic causes of this condition, it is evident that these loci do not constitute the majority of AIS heritability. Since copy number variation has been associated with the presence of birth defects, neuropsychiatric disabilities, congenital heart disease, and skeletal disorders such as clubfoot, Buchan et al. theorized that rare copy number variants contribute to the pathogenesis of scoliosis. In their study, Buchan et al. identified clinically significant copy number variation with a size of 125kb or greater having at least 50 markers using the Affymetrix Genome wide SNP array 6.0 in nine of 143 (6.3%) patients with AIS. These included proximal duplications of 1q21.1 (Thrombocytopenia Absent Radius syndrome region); 2q13, 15q11.2, and 16p11.2 deletions. Trisomy X was identified in two of 114 (1.8%) females with AIS. The 1q21.1 variant appeared to have reduced penetrance. These rare and novel copy number variations were observed with a greater frequency in the AIS population compared to a control population derived from 1079 individuals of European-American ancestry, which included individuals with bipolar disorder and idiopathic clubfoot. It is noteworthy that three of the observed copy number variations are associated with bone phenotypes including 1q21.1 (radial abnormalities), 15q11.2 duplications (hemivertebrae), and Trisomy X (scoliosis).

A rare case of Goldenhar syndrome with radial aplasia

Goldenhar syndrome (GS) is a well-recognised condition characterised by variable degree of uni- or bilateral involvement of craniofacial structures involving first and second branchial arches manifesting ocular and auricular anomalies and also vertebral defect. This syndrome presents at birth and its exact aetiology is still unknown. The affections of the neural crest cells may have some role in the multiple malformations of the GS. We present a teenaged female case who attended the Orthopaedic Outpatient Department to receive handicapped certificate in Bankura Sammilani Medical College and Hospital. She had multiple skeletal abnormalities, which included hemifacial microsomia, vertebral malformations in the form of scoliosis, distorted pelvis, but the most striking feature was the absence of thumb and aplasia of radius of left side. She did not suffer from any ocular or auricular abnormalities, neither from any cardiological, urogenital or gastroenteric ones. Radial defects associated with GS might represent a subset within this spectrum. Our case probably belongs to this subset, therefore is a very rare one.

VACTERL association with hydrocephalus in a fetus conceived by in vitro fertilization and embryo transfer

ObjectiveWe present a case of VACTERL association with hydrocephalus (VACTERL-H) in a fetus conceived by in vitro fertilization (IVF) and embryo transfer (ET) and review the literature. Case reportA 35-year-old woman presented with multiple fetal anomalies at 22 weeks of gestation. She and her husband were non-consanguineous and there was no family history of congenital malformations. This was her second pregnancy conceived via IVF-ET. Two embryos had been implanted and only one survived. She underwent chorionic villus sampling at 17 weeks of gestation because of oligohydramnios and advanced maternal age. Cytogenetic analysis revealed a karyotype of 46,XY, and array comparative genomic hybridization analysis revealed no genomic imbalance. Prenatal ultrasound at 21 weeks of gestation revealed a singleton with fetal biometry equivalent to 18 weeks, ventriculomegaly, a small cerebellum, and a ventricular septal defect. Level II ultrasound showed a single umbilical artery, scoliosis, a right club hand, radial aplasia, and renal agenesis. The parents elected to terminate the pregnancy at 22 weeks of gestation, and a fetus was delivered with bilateral arthrogryposis, right radial aplasia, a club hand and thumb aplasia, hypoplasia of the left thumb, scoliosis, and an imperforate anus. The clinical findings were consistent with the diagnosis of VACTERL-H. Molecular analysis of PTEN, FANCB, and HOXD13 genes revealed no mutation. ConclusionPrenatal diagnosis of radial ray defects in fetuses conceived by assisted reproductive technology should include a differential diagnosis of VACTERL association with anorectal malformation. VACTERL-H may occur in pregnancy after IVF-ET.

A HoxD11 Homeobox Gene Mutation Associated With Congenital Absent Radius But Without The Thrombocytopenia Of The TAR Syndrome Or a HoxA11 Mutation

HoxA11 and HoxD11 are homeobox genes critical for normal development of the forearm and thus are potential candidate genes for involvement in the pathogenesis of the thrombocytopenia/absent radius (TAR) syndrome. However, we previously reported an absence of coding sequence mutations in either HoxA11 or HoxD11 in a series of 10 unrelated TAR syndrome patients (Fleischman RA et al., Br J Haematol., 116:367-75, 2002). Despite this negative finding, interest in the potential role of homeobox genes in the TAR syndrome has been supported by a report of a HoxA11 mutation occurring in two kindreds with amegakaryocytic thrombocytopenia and radio-ulnar synostosis, a less pronounced more proximal pattern of radial malformation (Thompson AA and Nguyen LT. Nat Genet., 26:397-8, 2000). Unlike HoxA11, however, no mutations in the human HoxD11 gene have been described thus far that would help elucidate the potential role of this paralogous gene in megakaryopoiesis or the TAR syndrome. We now describe a novel mutation in human HoxD11 that results in a polyalanine sequence expansion, (GCG)6→ (GCG)8, and report that this mutation is associated with a unilateral absent radius in the affected propositus. A familial syndrome is suggested in this kindred, moreover, by the prior observation of a bilateral absent radius in a deceased maternal aunt. This mutation was not present in more than 100 unrelated normal subjects or 8 other unrelated individuals with sporadic absence of the radius. Two other living maternal relatives also carried the mutation but did not exhibit any radial defects, a finding consistent with autosomal dominance with incomplete penetrance, an inheritance pattern reported for short polyalanine expansion mutations in the related homeobox gene HoxD13 which cause synpolydactyly. In contrast to the reported HoxA11 mutation, however, neither the propositus nor the mutation carriers of this HoxD11 mutation exhibited thrombocytopenia or any other cytopenias or congenital defect. The results suggest that at least one class of mutation in human HoxD11 may be sufficient to cause an absent radius syndrome but unlike the reported HoxA11 mutation, does not adversely affect megakaryopoiesis. The findings further suggest that additional studies of the TAR syndrome may be necessary to exclude as yet undetected non-coding mutations in promoter or enhancer sequences that alter the expression of HoxA11, HoxD11 or other homeobox genes critical for radial development and/or megakaryopoiesis. This work was supported by a VA Merit Award. Disclosures: No relevant conflicts of interest to declare.

Molecular Characterization Of a Patient With Thrombocytopenia-Absent Radii (TAR) Syndrome and Diffuse Langerhans Cell Histiocytosis (LCH): Novel Genetic Findings

TAR is a rare bone marrow failure syndrome comprised of thrombocytopenia and a spectrum of bony abnormalities, the most common being bilateral radial aplasia in the presence of thumbs. Recent research has implicated alterations in the RBM8A gene in the pathogenesis of this disorder. Diffuse LCH is a neoplasm of mature Langerhans cells, a subset of dendritic cells, that has now been demonstrated to be clonal in nature. The co-occurrence of these two rare disorders has only been reported twice (Ingram, BMT 2006; Guastadisegni EJMG 2012). We report the third case of a patient with TAR and LCH and present the molecular and genetic characterization of this patient. A 52 year woman with TAR presented with abdominal mass, splenomegaly and left axillary adenopathy. CT scan showed a right pelvic mass measuring 11.5 x 8.6 cm, retroperitoneal lymphadenopathy, enlarged spleen and patchy areas of radiolucency throughout the spine, pelvis and left femoral head. Excisional biopsy of the left axillary lymph node revealed complete effacement of the normal lymph node architecture by an atypical proliferation of Langerhans cell histiocytes. Bone marrow involvement was documented as well. On immunohistochemistry, these cells were positive for CD1a (membrane staining) and S-100 (nuclear and cytoplasmic staining). As part of the diagnostic evaluation, CGH microarray (Signature Genomics) was performed. A diagnosis of diffuse LCH was made. She was treated with vinblastine and prednisone for a year and remains in complete remission from her disease 14 months later. Genomic DNA was extracted from peripheral blood (normal mononuclear cells) and paraffin-embedded tumor tissue, with written informed consent following the approval of the Institutional Review Board of Thomas Jefferson University. The CGH result on the patient's uninvolved tissue as well as the tumor sample showed a hemizygous deletion of 1q21.1 encompassing the RBM8A gene, consistent with recent TAR literature (Albers, Nat Genet 2012). Sequence analysis of the other RBM8A allele revealed minor allele A at SNP rs139428292 at position chr1:145,507,646 (hg19) in the 5'UTR of RBM8A and nt G at chr1:145,507,777 in the first intron (int1 +44). The coding sequence was normal. Minor allele A at the 5'UTR SNP has been associated with TAR syndrome, along with minor allele C at intronic SNP (rs 201779890, int1 +32) which was major allele G in our patient. However, nt G at intron 1 +44 is a novel variant that has not been reported before in dbSNP137, HapMap or 1000 Genomes (UCSC Genome Browser, August 1, 2013). The CGH result on the patient's tumor sample showed a 1.82 Kb deletion within the MAF gene. We identified in normal and tumor DNA one intact MAF gene and one deleted of all of the coding sequences of MAF isoform 1 (alternatively, complete deletion of exon 1 of MAF isoform 2). In addition, a copy loss in the 14q32.2 region was found in the tumor sample but not in the uninvolved tissue. This region contains the BCL11b gene. Finally, we identified a tumor-specific missense mutation (GTG to GAG) resulting in a change in amino acid from valine to glutamine at codon 600. This is the BRAF V600E mutation previously described in LCH and other malignancies.In summary, we report the third ever reported case of the co-occurrence of two rare disorders, TAR and LCH, in a single patient and identify novel molecular changes. We have found the patient to have the recently reported RBM8A genetic alterations of TAR (microdeletion of 1q21 for one allele, minor 5'UTR SNP on the other allele), plus a novel RBM8A intronic SNP. We found a somatic MAF deletion in our patient, possibly a predisposing factor towards LCH. In addition, BRAF V600E mutation is a tumor-specific mutation in our patient. Whether BRAF inhibitors will be of therapeutic benefit in primary or relapsed LCH is currently unknown. Future research is needed to elucidate the function, if any, of the novel RBM8A SNP, the mechanism(s) by which the identified SNPs lead to reduced Y14 levels, and the potential contribution of Y14 deficiency in tumorigenesis.The authors wish to acknowledge the invaluable role of Dr. Elena Gitelson in the care of this patient. Disclosures:No relevant conflicts of interest to declare.

Holt–Oram syndrome with aortopulmonary window – a rare association

A 4-month-old male infant presented with recurrent cough for 2 months. He had a shortened right upper limb with absent right thumb and continuous murmur in the left parasternal area. The X-ray showed an absent radius and the first metacarpal and phalyngeal bones on the right side. Echocardiogram revealed aortopulmonary window and small secundum atrial septal defect. Aortopulmonary window was successfully treated by device closure. Holt-Oram syndrome with aortopulmonary window is an extremely rare association.

Mirror Hand Deformity: A Report of Two Cases.

Mirror hand (ulnar dimelia) is an extremely rare congenital deformity in the upper extremity; only approximately seventy cases have been reported in the literature1,2 since the anomaly was first described in 1587 by Rueff3. The typical deformity consists of an absent radius, a duplication of the ulna, and polydactyly4,5. The elbow is generally stiff in extension, and the wrist is hyperflexed. The shoulder can be affected with instability and underdeveloped musculature1,6. The main functional problems that need to be resolved are the stiff elbow and the polydactylous hand. A resection of the olecranon process of one of the ulnae (usually the lateral “radial” one) is advised in order for the elbow7 to have improved flexion and pronation and supination. Early arthrolysis of the elbow joint has also been described8. For pollicization, the most normal finger is chosen to create a thumb9, and extensor tendons from the removed digits can be transferred to strengthen the new thumb7. We describe two patients who presented with mirror hand deformity. The patients and their parents were informed that data concerning their cases would be submitted for publication, and they provided consent. Case 1. A two-month-old girl presented with unilateral abnormalities to the left upper extremity (Fig. 1-A). There had been no perinatal medical problems, and the family history was negative for congenital anomalies. There was good movement in the shoulder. The elbow was extended with no sign of active flexion. The wrist was hyperflexed and could be passively extended to 0°. The hand had seven triphalangeal fingers. The most radial finger (number 1) did not show any sign of movement and was unstable. The other six fingers were active, but finger number 3 …

Thrombocytopenia and Absent Radii (TAR) Syndrome in Non Identical Twins

This is a case report of female non identical twins with bilateral absent radii and severe thrombocytopenia. Genetic studies confirmed 1q21.1 deletion. A review of literature showed TAR syndrome in 2 pairs of identical twins (reported in 1986) and one pair of non identical twins (reported in 1979). DOI: http://dx.doi.org/10.3126/jnps.v33i2.8378 J Nepal Paediatr Soc. 2013; 33(2):150-151

Prenatal diagnosis and post-mortem examination in a fetus with thrombocytopenia-absent radius (TAR) syndrome due to compound heterozygosity for a 1q21.1 microdeletion and a RBM8A hypomorphic allele: a case report

BackgroundThrombocytopenia–absent radius syndrome is a rare autosomal recessive disorder characterized by megakaryocytic thrombocytopenia and longitudinal limb deficiencies mostly affecting the radial ray. Most patients are compound heterozygotes for a 200 kb interstitial microdeletion in 1q21.1 and a hypomorphic allele in RBM8A, mapping in the deleted segment. At the moment, the complete molecular characterization of thrombocytopenia–absent radius syndrome is limited to a handful of patients mostly ascertained in the pediatric ageCase presentationWe report on a fetus with bilateral upper limb deficiency found at standard prenatal ultrasound examination. The fetus had bilateral radial agenesis and humeral hypo/aplasia with intact thumbs, micrognathia and urinary anomalies, indicating thrombocytopenia–absent radius syndrome. Molecular studies demonstrated compound heterozygosity for the 1q21.1 microdeletion and the RBM8A rs139428292 variant at the hemizygous state, inherited from the mother and father, respectivelyConclusionThe molecular information allowed prenatal diagnosis in the following pregnancy resulting in the birth of a healthy carrier female. A review was carried out with the attempt to the trace the fetal ultrasound presentation of thrombocytopenia–absent radius syndrome and discussing opportunities for second-tier molecular studies within a multidisciplinary setting.