Thrombocytopenia With Absent Radii Research Articles

How to manage a congenital heart defect in a patient with thrombocytopenia-absent radius syndrome?

Ventricular septal defect (VSD) can be repaired using cardiopulmonary bypass, resulting in a favorable postoperative outcome with minimal bleeding. Thrombocytopenia-absent radius (TAR) syndrome is rare, occurring in approximately 0.42 out of 100,000 live births. This syndrome is characterized by hypo-megakaryocytic thrombocytopenia and bilateral absent radii. TAR syndrome can be life-threatening within the first 14 months of life due to severe bleeding. In this report, we present the case of a 4-month-old male patient diagnosed with both VSD and TAR syndrome. We describe the surgical management of the VSD as well as the perioperative treatment for hemorrhagic diathesis.

Analysis of clinical characteristics and molecular genetics in eighteen patients with 1q21.1 microdeletion syndrome

To explore the clinical characteristics of 1q21.1 microdeletion by using single nucleotide polymorphism microarrays (SNP array). Eighteen cases of 1q21.1 microdeletion syndrome diagnosed at the Longgang District Maternal and Child Health Care Hospital of Shenzhen City from June 2017 to December 2022 were selected as the study subjects. Clinical data of the patients were collected. Results of chromosomal karyotyping and SNP assay were retrospectively analyzed. Among the 18 cases with 1q21.1 microdeletions, 13 had a deletion between BP3 and BP4, 4 had a deletion between BP1/BP2 and BP4, whilst 1 had a proximal 1q21.1 deletion (between BP2 and BP3) involving the Thrombocytopenia-absent radius (TAR) region. The deletions had spanned from 360 kb to 3.9 Mb, which encompassed the GJA5, GJA8, CHD1L, RBM8AB and other morbid genes. In three families, the proband child has inherited the same 1q21.1 microdeletion from their parents, whose clinical phenotype was normal or slightly abnormal. The clinical phenotypes of 1q21.1 microdeletion had included cognitive or behavioral deficits in 9 cases (9/18, 50.0%), growth retardation in 8 cases (8/18, 44.4%), craniofacial deformities in 7 cases (7/18, 38.8%), cardiovascular malformations in 5 cases (5/18, 27.8%), and microcephaly in 3 cases (3/18, 16.7%). 1q21.1 microdeletion syndrome has incomplete penetrance and varied expression such as intellectual impairment, growth and development delay, and microcephaly, with a wide range of non-specific phenotypes.

Inherited bone marrow failure syndromes: phenotype as a tool for early diagnostic suspicion at a major reference center in Mexico.

Introduction: The inherited bone marrow failure syndromes (IBMFSs) are a group of rare disorders characterized by bone marrow failure (BMF), physical abnormalities, and an increased risk of neoplasia. The National Institute of Pediatrics (INP) is a major medical institution in Mexico, where patients with BMF receive a complete approach that includes paraclinical tests. Readily recognizable features, such as the hematological and distinctive physical phenotypes, identified by clinical dysmorphologists, remain crucial for the diagnosis and management of these patients, particularly in circumstances where next-generation sequencing (NGS) is not easily available. Here, we describe a group of Mexican patients with a high clinical suspicion of an IBMFS. Methods: We performed a systematic retrospective analysis of the medical records of patients who had a high IBMFS suspicion at our institution from January 2018 to July 2021. An initial assessment included first ruling out acquired causes of BMF by the Hematology Department and referral of the patient to the Department of Human Genetics for physical examination to search for specific phenotypes suggesting an IBMFS. Patients with high suspicion of having an IBMFS were classified into two main groups: 1) specific IBMFS, including dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), Shwachman-Diamond syndrome (SDS), thrombocytopenia with absent radii (TAR), and severe congenital neutropenia (SCN); 2) undefined IBMFS (UI). Results: We established a high suspicion of having an IBMFS in 48 patients. At initial evaluation, the most common hematologic features were bicytopenia (20%) and aplastic anemia (16%); three patients received hematopoietic stem cell transplantation. Among patients with a suspicion of an IBMFS, the most common physical abnormality was minor craniofacial features in 83% of patients and neurodevelopmental disorders in 52%. The specific suspicions that we built were DBA (31%), SDS (18%), DC (14%), TAR (4%), and SCN (4%), whereas 27% of cases remained as undefined IBMFS. SDS, TAR, and SCN were more commonly suspected at an earlier age (<1year), followed by DBA (2years) and DC (5years). Conclusions: Thorough examination of reported clinical data allowed us to highly suspect a specific IBMFS in approximately 70% of patients; however, an important number of patients remained with suspicion of an undefined IBMFS. Implementation of NGS and telomere length measurement are forthcoming measures to improve IBMFS diagnosis in Mexico.

Myopathy in thrombocytopenia-absent radius (TAR) syndrome

Myopathy in thrombocytopenia-absent radius (TAR) syndrome

PP-07 TAR Syndrome case report

PP-07 TAR Syndrome case report

Determination of Carrier Frequency of Actionable Pathogenic Variants in Autosomal Recessive Genetic Diseases in the Turkish Cypriot Population.

Whole-exome DNA sequencing is a rich source of clinically useful information for specialists, patients, and their families, as well as elucidating the genetic basis of monogenic and complex diseases in clinical diagnosis. However, interpreting and reporting variants encompassing exome and genome sequence analysis outcome data are one of the greatest challenges of the genomic era. In this study, we aimed to investigate the frequency and allele frequency spectrum of single nucleotide variants accepted as recessive disease carrier status in Turkish Cypriot exomes. The same sequencing platform and data processing line were used for the analysis of data from 100 Turkish Cypriot whole-exome sequence analysis. Identified variants were classified according to ACMG guidelines, and pathogenic variants were confirmed in other databases such as ClinVar, HGMD, Varsome, etc. Pathogenic variants were detected in 68 genes out of 100 whole-exome sequence data. The carriage rate was the highest in the CYP21A2 gene, causing 21-hydroxylase deficiency (14.70%), 11.76% in the HBB gene causing β-thalassemia, 10.29% in the BTD gene causing biotinidase deficiency, 8.82% in the CFTR gene causing cystic fibrosis, 8.82% in the RBM8A gene causing thrombocytopenia-absent radius syndrome, which is an ultra-rare disease, and 5.88% in the GAA gene causing glycogen storage disease II. The carriage of pathogenic variants in other genes causing the disease (GJB2, PAH, GALC, CYP11B2, COL4A3, HBA1, etc.) was determined as less than 5.00%. Also, the identified variations in the mentioned gene within the examined population were reported. The most prevalent mutation in North Cyprus was a missense variant (c.1360 C>T, p.Pro454Ser) detected in the CYP21A2 gene (rs6445), and the most frequently seen variant in the HBB gene was c.93-21G>A (rs35004220). We investigated reported pathogenic variants by estimating the lower and upper limits of carrier and population frequencies for autosomal recessive diseases, for which exome sequencing may reveal additional medically relevant information. Determining the lower and upper limits of these frequencies will shed light on preventive medicine practices and governmental actions.

SAT080 Partnering With Medical Genetics To Provide Molecular Diagnosis In Atypical Diabetes

Abstract Disclosure: M.C. Foss de Freitas: Advisory Board Member; Self; PTC Therapeutics. C. Chase: None. M. Henry: None. A. Neidert: None. G. Narla: Advisory Board Member; Self; HERA Biolabs. Consulting Fee; Self; RAPPTA Therapeutics. Owner/Co-Owner; Self; RAPPTA Therapeutics. W. Uhlmann: None. K. Lee: None. E.A. Oral: Consulting Fee; Self; Regeneron Pharmaceuticals, Aegerion Pharmaceuticals, Ionis Pharmaceuticals Inc., Third Rock Ventures, Rejuvenate Inc. Grant Recipient; Self; Regeneron Pharmaceuticals, Aegerion Pharmaceuticals, Ionis Pharmaceuticals Inc., Novo Nordisk, Fractyl Laboratories, Rhythm Pharmaceuticals, GID Dynamics. Other; Self; Aegerion Pharmaceuticals. Uncovering genetic alterations causing rare and atypical phenotypes related to diabetes mellitus is becoming increasingly possible with next-generation sequencing. Our Atypical Diabetes Program formed a partnership with the Division of Genetic Medicine, creating a specialized Atypical Diabetes Genetics Clinic to provide genetic counseling and clinical diagnostic testing to patients with rare forms of diabetes and other metabolic diseases. Between 10/2019 and 07/2022, 82 patients were seen (42±12 years old; 76.3% female). Indications for referral varied: 32 (39.0%) were referred for suspected monogenic obesity, 31 (37.8%) for familial partial lipodystrophy (FPLD), 10 (12.2%) for MODY, 7 (8.5%) for familial dyslipidemia (FD), 4 (4.9%) for acquired partial lipodystrophy (APL), and 14 (17.1%) for other indications including concern for acquired generalized or partial lipodystrophy, adrenomyeloneuropathy, Alport syndrome, GIST, hemochromatosis, hypothyroidism and hypogonadism, immune dysregulation, laminopathy, multisystem health problems/congenital anomalies, Prader-Willi syndrome, renal glycosuria, and TAR syndrome. Fourteen (17.1%) patients were referred for multiple indications. Results from 64 patients who underwent genetic testing revealed 4 positive molecular findings (all in patients with lipodystrophy), confirming a pathogenic LMNA variant detected on research testing in one and revealing previously unknown molecular etiologies in three (a previously described likely pathogenic LMNA variant, a novel likely pathogenic PPARG variant, and a previously described homozygous pathogenic MFN2 variant). Clinical management was altered, aiming for a more personalized approach in patients with these new findings, and two are participating in clinical trials for their condition. Cascade testing for family members is now being pursued. Sixteen patients had variants of uncertain significance (VUS); in one of these cases, in silico prediction suggesting that the detected SH2B variant could be pathogenic has enabled enrollment in a Phase 2 study with setmelanotide. For other identified VUS, we are undertaking functional and biological studies using our novel translational platform, which was established to contribute evidence for possible variant reclassification. Deeper sequencing strategies are being considered for patients with negative results, with most of our patients participating in an NIH funded network study for Rare and Atypical Diabetes (RADIANT). In our early experience, partnering with a medical genetics team to provide molecular testing for rare forms of diabetes and other metabolic conditions can lead to precise molecular diagnosis and set the stage for deeper testing and improved clinical care while driving novel discovery work. Presentation: Saturday, June 17, 2023

PP-07 TAR Syndrome case report

PP-07 TAR Syndrome case report

Prenatal phenotypes and pregnancy outcomes of fetuses with recurrent 1q21.1 microdeletions and microduplications.

Chromosomal 1q21.1 deletions and duplications are genomic disorders that are usually diagnosed postnatally. However, the genotype-phenotype correlations of 1q21.1 copy number variants (CNVs) during the prenatal period are still not clear. This study aimed to provide a systematic summary of prenatal phenotypes for such genomic disorders. In total, 26 prenatal amniotic fluid samples diagnosed with 1q21.1 microdeletions/microduplications were obtained from pregnant women who opted for invasive prenatal testing. Karyotypic analysis and chromosomal microarray analysis (CMA) were performed for all cases simultaneously. The pregnancy outcomes and health conditions after birth in all cases were followed up. Meanwhile, prenatal cases with 1q21.1 microdeletions or microduplications in the literature were retrospectively collected. In total, 11 pregnancies (11/8,252, 0.13%) with 1q21.1 microdeletions and 15 (15/8,252, 0.18%) with 1q21.1 microduplications were identified. Among these 1q21.1 CNVs, 4 cases covered the thrombocytopenia-absent radius (TAR) region, 16 cases covered the 1q21.1 recurrent microdeletion/microduplication region, and 6 cases covered all regions mentioned above. The prenatal abnormal ultrasound findings were recorded in four participants with 1q21.1 deletions and seven participants with 1q21.1 duplications. Finally, three cases with 1q21.1 deletions and five with 1q21.1 duplications terminated their pregnancies. In the prenatal setting, 1q21.1 microdeletions were associated with increased nuchal translucency (NT), anomalies of the urinary system, and cardiovascular abnormalities, while 1q21.1 microduplications were correlated with cardiovascular malformations, nasal bone dysplasia, and increased NT. In addition, cerebral ventriculomegaly might be correlated with 1q21.1 microduplications. Considering the variable expressivity and incomplete penetrance of 1q21.1 CNVs, long-term follow-up after birth should be carried out in these cases.

Thrombocytopenia Absent Radius (TAR)-Syndrome: From Current Genetics to Patient Self-Empowerment.

Thrombocytopenia absent radius (TAR) syndrome is a rare form of hereditary thrombocytopenia associated with a bilateral radial aplasia. TAR syndrome is genetically defined by the combination of a microdeletion on chromosome 1 which includes the gene RBM8A, and a single nucleotide polymorphism (SNP) in the second RBM8A allele. While most patients with TAR syndrome harbor a SNP in either the 5' UTR region or in intron 1 of RBM8A, further SNPs associated with TAR syndrome are still being identified. Here, we report on the current understanding of the genetic basis, diagnosis, and therapy of TAR syndrome and discuss patient self-empowerment by enabling networking and exchange between affected individuals and families.

TAR syndrome

TAR syndrome

Nuclear speckleopathies: developmental disorders caused by variants in genes encoding nuclear speckle proteins.

Nuclear speckles are small, membrane-less organelles that reside within the nucleus. Nuclear speckles serve as a regulatory hub coordinating complex RNA metabolism steps including gene transcription, pre-mRNA splicing, RNA modifications, and mRNA nuclear export. Reflecting the importance of proper nuclear speckle function in regulating normal human development, an increasing number of genetic disorders have been found to result from mutations in the genes encoding nuclear speckle proteins. To denote this growing class of genetic disorders, we propose "nuclear speckleopathies". Notably, developmental disabilities are commonly seen in individuals with nuclear speckleopathies, suggesting the particular importance of nuclear speckles in ensuring normal neurocognitive development. In this review article, a general overview of nuclear speckle function, and the current knowledge of the mechanisms underlying some nuclear speckleopathies, such as ZTTK syndrome, NKAP-related syndrome, TARP syndrome, and TAR syndrome, are discussed. These nuclear speckleopathies represent valuable models to understand the basic function of nuclear speckles and how its functional defects result in human developmental disorders.

P625: Diagnosis of thrombocytopenia absent radius (TAR) syndrome after abnormal first trimester ultrasound: A case report

P625: Diagnosis of thrombocytopenia absent radius (TAR) syndrome after abnormal first trimester ultrasound: A case report

Two-stage treatment of extremity deformities associated with thrombocytopenia-absent radius syndrome.

The aim of this study was to evaluate the results of 2-stage treatment of upper and lower extremity deformities in patients with thrombocytopenia absent radius syndrome. Four patients (3 female, 1 male) with a mean age of 1.8 years (range 1-4) were included in the study. The patients were followed up for an average of 5.5 years. All 4 patients had bilateral radial longitudinal deficiency, whereas only 2 patients had bilateral fixed knee contractures. A 2-stage surgical procedure was implemented. The surgical procedure performed for radial longitudinal deficiency consisted of distraction with an Ilizarov frame in the first stage, followed by centralization performed in the second stage. Knee contractures were first treated using an Ilizarov frame, followed by a hamstring tendon transfer in the second procedure. Radiological evaluation of the radial longitudinal deficiency was done by measuring hand-forearm angle, hand-forearm position, and ulnar bowing preoperatively and at postoperative follow-ups. Knee contracture was evaluated by measuring the angle preoperatively and at postoperative follow-ups. The mean hand-forearm angle values of patients at preoperative assessment, early postoperative period, and at the last follow-ups were 82.60, 5,80, and 11.10, respectively (P < .001). The hand-forearm position values were -14.25 mm, +11, and +7.1 mm, respectively (P < .001). The ulnar bowing values were 7.3°, 4.5°, and 2.9°, respectively (P < .001). Recurrence of the radial longitudinal deficiency deformity requiring surgery occurred in 1 patient. In the other 3 patients, some deformity recurred but did not require surgical intervention. In addition, 1 patient with knee flexion contracture had a recurrence of the contracture that did not require surgical intervention. There was no circulatory disorder or skin necrosis in the lower or upper extremities of the patients. This study has shown us that two-stage treatment is a reliable method for lower and upper extremity deformities accompanying thrombocytopenia absent radius syndrome. However, recurrence is still a major problem. Level IV, Therapeutic Study.

Severe Extremity Anomaly and Neurodevelopmental Retardation in an Infant with TAR Syndrome and Differential Diagnosis in Radial Defects

Severe Extremity Anomaly and Neurodevelopmental Retardation in an Infant with TAR Syndrome and Differential Diagnosis in Radial Defects

Prenatal Diagnosis and Management of Thrombocytopenia-Absent Radius Syndrome.

Prenatal Diagnosis and Management of Thrombocytopenia-Absent Radius Syndrome.

Congenital Disorders of the Pediatric Thumb.

Surgical timing for pediatric trigger thumb treatment is controversial for numerous reasons including the potential for spontaneous resolution, the possibility of bilateral involvement, and anesthesia concerns regarding the developing brain. Hence, a reasonable approach is to delay the surgical procedure until the patient is ≥3 years of age. Preaxial polydactyly is usually unilateral and sporadic, with the most common reconstruction method consisting of excision of the diminutive thumb with preservation and soft-tissue reconstruction of the dominant thumb. The surgical procedure is typically performed around the patient age of 1 year to decrease the risks of anesthesia but allow reconstruction prior to the development of a tip-to-tip pinch. Triphalangeal thumb and thumb hypoplasia are often found in the setting of systemic anomalies such as Holt-Oram syndrome, thrombocytopenia absent radius syndrome, Fanconi anemia, VACTERL (vertebral anomalies, anal atresia, cardiac anomalies, tracheoesophageal fistula, renal defects, and limb anomalies), and/or Blackfan-Diamond anemia. As such, patients should receive adequate workup for these entities. A surgical procedure should be performed only once patients have been medically cleared. The status of the carpometacarpal joint in thumb hypoplasia determines whether reconstruction with first web space deepening, collateral ligament stabilization, and opponensplasty compared with index pollicization is performed.

Multiple Genitorurinary Abnormalities and Ectopic Kidney in a Patient with Thrombocytopenia with Absent Radii (TAR) Syndrome: a Case Report and Literature Review

Multiple Genitorurinary Abnormalities and Ectopic Kidney in a Patient with Thrombocytopenia with Absent Radii (TAR) Syndrome: a Case Report and Literature Review

The Y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia

SummaryThrombocytopenia-absent radius (TAR) syndrome is caused by RBM8A insufficiency. We generated megakaryocyte-specific Rbm8a knockout (Rbm8aKOMK) mice that exhibited marked thrombocytopenia, internal hemorrhage, and splenomegaly, providing evidence that genetic deficiency of Rbm8a causes a disorder of platelet production. Rbm8aKOMK mice accumulated low-ploidy immature megakaryocytes in the bone marrow and exhibited defective platelet activation and aggregation. Accordingly, depletion of Y14 (RBM8A) in human erythroleukemia (HEL) cells compromised phorbol-ester-induced polyploidization. Notably, Y14/RBM8A deficiency induced both p53 and p21 in megakaryocytes and HEL cells. Treatment with a p53 inhibitor restored ex vivo differentiation of Rbm8aKOMK megakaryocytes and unexpectedly activated Y14 expression in HEL cells. Trp53 knockout partially restored megakaryocyte differentiation by reversing cell-cycle arrest and increased platelet counts of Rbm8aKOMK, indicating that excess p53 in part accounts for thrombocytopenia in TAR syndrome. This study provides evidence for the role of the Y14-p53 circuit in platelet production and a potential therapeutic strategy.

Congenital limb deficiency: Genetic investigation of 44 individuals presenting mainly longitudinal defects in isolated or syndromic forms.

Congenital limb deficiency (CLD), one of the most common congenital anomalies, is characterized by hypoplasia/aplasia of one or more limb bones and can be isolated or syndromic. The etiology in CLD is heterogeneous, including environmental and genetic factors. A fraction remains with no etiological factor identified. We report the study of 44 Brazilian individuals presenting isolated or syndromic CLD, mainly with longitudinal defects. Genetic investigation included particularly next-generation sequencing (NGS) and/or chromosomal microarray. The overall diagnostic yield was 45.7%, ranging from 60.9% in the syndromic to 16.7% in the non-syndromic group. In TAR syndrome, a common variant in 3´UTR of RBM8A, in trans with 1q21.1 microdeletion, was detected, corroborating the importance of this recently reported variant in individuals of African ancestry. NGS established a diagnosis in three individuals in syndromes recently reported or still under delineation (an acrofacial dysostosis, Coats plus and Verheij syndromes), suggesting a broader phenotypic spectrum in these disorders. Although a low rate of molecular detection in non-syndromic forms was observed, it is still possible that variants in non-coding regions and small CNVs, not detected by the techniques applied in this study, could play a role in the etiology of CLD.