Successful Haplo-hematopoietic Stem Cell Transplantation for Juvenile Myelomonocytic Leukemia in a Child with Underlying Thrombocytopenia-Absent Radius Syndrome: A Unique Case

Successful Haplo-hematopoietic Stem Cell Transplantation for Juvenile Myelomonocytic Leukemia in a Child with Underlying Thrombocytopenia-Absent Radius Syndrome: A Unique Case | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 9 May 2025 V1 Latest version Share on Successful Haplo-hematopoietic Stem Cell Transplantation for Juvenile Myelomonocytic Leukemia in a Child with Underlying Thrombocytopenia-Absent Radius Syndrome: A Unique Case Authors : Sondus Al Sharidah [email protected] , Ahmed Elhussien , Walid I. A. Soliman , and Nesma I. Ellithy Authors Info & Affiliations https://doi.org/10.22541/au.174679035.57948282/v1 Published Cancer Reports Version of record Peer review timeline 287 views 131 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background: Thrombocytopenia-absent radius (TAR) syndrome is a rare congenital disorder characterized by bilateral radial aplasia with preserved thumbs and early-onset thrombocytopenia. While hematologic and skeletal abnormalities are hallmarks of the condition, its association with hematologic malignancies is exceedingly rare, with only a few reported cases of leukemia. Juvenile myelomonocytic leukemia (JMML) is an uncommon pediatric myelodysplastic/myeloproliferative neoplasm frequently linked to RAS pathway mutations. The co-occurrence of JMML in a patient with TAR syndrome has not been previously documented. Case Presentation: We report the case of a male infant diagnosed with TAR syndrome based on clinical features and molecular confirmation of a homozygous RBM8A c.-21G>A mutation. The patient presented initially with persistent thrombocytopenia, skeletal deformities, and neonatal sepsis-like symptoms. At two years of age, he developed pancytopenia and progressive splenomegaly. Bone marrow examination and molecular studies confirmed JMML with a pathogenic NF1 mutation. He underwent successful haploidentical hematopoietic stem cell transplantation (HSCT) from a sibling donor, following a conditioning regimen of melphalan, treosulfan, cyclophosphamide, and anti-thymocyte globulin. The patient achieved full donor chimerism and hematologic remission with stable engraftment. Conclusion: This case represents, to our knowledge, one of the very few—if not the first—reported instances of successful HSCT for JMML in a patient with TAR syndrome. It underscores the importance of vigilant surveillance in TAR patients for potential malignant transformation and demonstrates the curative potential of HSCT in complex congenital and hematologic overlap syndromes. Introduction Thrombocytopenia-absent radius (TAR) syndrome is a rare congenital disorder characterized by the bilateral absence of the radii bones in the forearms with both thumbs present, and thrombocytopenia that usually develops within the first few weeks of life, with platelet counts below 50 × 10^9/L. Its worldwide prevalence is estimated to be 1 in 100,000 live births [1, 2]. Although TAR syndrome is known for its hematological and skeletal manifestations, its association with leukemia is exceedingly rare. There are only a few documented cases of leukemia in patients with TAR syndrome: four cases of acute myeloid leukemia (AML)—two in children [3, 4] and two in adults aged 42 and 47 years [5, 6]—and one pediatric case of acute lymphoblastic leukemia (ALL) [7]. Mortality from TAR, mainly due to hemorrhage, is generally limited to the first year of life, and survivors usually have a normal life expectancy [5]. However, children with TAR who developed leukemia have historically faced fatal outcomes [3, 4] or become severely thrombocytopenic even after achieving complete remission [7]. Here, we present an unusual case of a child with juvenile myelomonocytic leukemia (JMML) associated with TAR syndrome. Case Report A 33-day-old male infant was referred to our hospital with a provisional diagnosis of TAR syndrome for further investigation. He was born in 2022 and admitted to the NICU immediately after birth for respiratory distress, with chest X-ray findings consistent with transient tachypnea of the newborn. He was also diagnosed with neonatal sepsis, persistent thrombocytopenia, and leukocytosis. Empirical antibiotic therapy was initiated; however, blood cultures were negative. Over the following weeks, his clinical condition remained poor but stable. At presentation to our clinic, the patient was clinically stable and vital signs within normal limits. Physical examination revealed bilateral limb deformities and mild splenomegaly. Laboratory analysis showed a platelet count of 35 × 10^9/L (thrombocytopenia), which was managed with platelet transfusion. A limb X-ray confirmed the bilateral absence of the radii with the presence of both thumbs (Figure 1). Based on these findings, a molecular genetic panel was conducted. Next-generation sequencing (NGS) revealed a homozygous c.-21G>A mutation in the RBM8A gene, consistent with TAR syndrome. Parental testing confirmed both parents were heterozygous carriers of the RBM8A mutation. Figure 1: X-ray film confirming absence of radius with the presence of normal digits including thumb and marked radial deviation of the wrist. A bone marrow aspirate was performed to investigate for malignancy, which showed 1% blast cells—below the threshold of leukemia diagnosis. Family history revealed a non-consanguineous marriage with no history of malignancy on either side, further reducing the likelihood of a hereditary leukemia predisposition. The patient continued regular follow-ups, frequently presenting with melena. Investigations confirmed hematochezia and persistent thrombocytopenia, necessitating ongoing platelet transfusions to maintain an average platelet count of 7-10 x 10 9 /L. In 2024, at the age of two years, he developed pancytopenia and progressive splenomegaly. A peripheral blood smear revealed 8% blast cells. Molecular studies identified a pathogenic NF1 gene mutation (c.2915T>C, p.L972P), in the absence of clinical features of neurofibromatosis. These findings were diagnostic of juvenile myelomonocytic leukemia (JMML) . Bone marrow biopsy revealed active myelopoiesis with an increased eosinophilic lineage, moderate erythropoiesis, absent megakaryopoiesis, and 7% blasts. Immunophenotyping indicated 5% myeloblasts expressing CD33, CD34, CD117, and HLA-DR. According to the WHO Classification of Haematolymphoid Tumours (5th edition) [8], the patient fulfilled the Genetic Criteria (Category 2) for JMML due to the presence of a somatic NF1 mutation. Coupled with the bilateral absence of radii with thrombocytopenia, a diagnosis JMML associated with TAR was confirmed. Hematopoietic stem cell transplantation (HSCT) was pursued. The patient’s sibling (brother) was identified as a suitable haploidentical donor with a 9/10 HLA match. The CD34⁺ cell dose, a protein marker on the surface of hematopoietic stem cells, was 7.2 × 10^6. The Pre-transplant conditioning regimen included melphalan, treosulfan, cyclophosphamide, and rabbit anti-thymocyte globulin (rATG). Graft-versus-host disease (GVHD) prophylaxis consisted of post-transplant cyclophosphamide, mycophenolate mofetil (MMF), and sirolimus. On day 13 post-transplant, the patient developed an acute skin rash associated with engraftment syndrome without infection. Neutrophil engraftment occurred on day +20, and platelet engraftment on day +37 post-transplant. The platelet count subsequently increased to 224 × 10⁹/L. Donor chimerism analysis demonstrated full donor engraftment in lymphoid, myeloid, and whole blood compartments, as shown in Table 1. Table 1: Post-transplant donor chimerism in patient Lymphocyte fraction (lymphoid chimera) 96.61 98.84 Myelocyte fraction (myeloid chimera) 97.97 99.53 Whole Blood 96.50 100 The patient’s post-transplant course was favorable. Frequent follow-ups and weekly monitoring demonstrated stable complete blood counts. A recent bone marrow aspirate showed a normocellular marrow with hematopoietic function Discussion TAR syndrome is caused by pathogenic variants in the RBM8A gene, which encodes RNA-binding motif protein 8A (also known as Y14). The identification of the c.-21G>A mutation in RBM8A , along with the clinical features observed in this case, confirms the diagnosis [9,10]. TAR syndrome typically results from compound heterozygosity involving a null allele (a deletion of RBM8A at chromosome 1q21.1) and a hypomorphic allele (a low-function variant), and follows an autosomal recessive inheritance pattern. The parents of affected individuals are usually heterozygous carriers for either of these pathogenic variants and asymptomatic [10]. Therefore, genetic testing of both the patient and the parents is essential for confirming the diagnosis and understanding the inheritance mechanism. Lesions in the RBM8A including microdeletion on chromosome 1 (1q21.1) and single nucleotide polymorphisms in coding or non-coding regions, result in decreased RBM8A expression. This leads to deficiency of the Y14 subunit of exon-junction complex, which is essential for RNA processing and regulation. [9]. Disruption of this pathway impairs the development of various tissues, including the hematopoietic and skeletal systems [11,12]. Albers et al. suggested the role of complex interactions between RNA-binding proteins (such as the translational repressor Evi-1) and binding sites created on mutated RBM8A in causing skeletal deformities [12]. In rodents, Evi-1 has been found to be transiently expressed in developing limb buds [13]. The thrombocytopenia seen in TAR is thought to result from defective thrombopoietin/c-Mpl receptor signaling, which impairs megakaryocyte differentiation [9]. To date, only three pediatric cases of leukemia associated with TAR syndrome have been reported. In 1993, Rock and Camitta described a case of ALL (FAB-L1) in a 5-year-old girl with TAR syndrome and cytogenetic abnormalities. Although she achieved complete remission with modified chemotherapy, she relapsed two years later and required additional therapy. She attained a second remission but remained severely thrombocytopenic (20–30 × 10⁹/L) [7]. Fadoo et al. reported a one-year-old boy with TAR and AML (M2), who died within a month of diagnosis before receiving chemotherapy [4]. Rao et al. described a fatal case of AML in a two-month-old infant with TAR syndrome [3]. These cases suggest that TAR patients may be predisposed to leukemia and may have poor outcomes. JMML is a rare and high-risk myelodysplastic/myeloproliferative disorder that typically occurs in infancy or early childhood. It is characterized by anemia, thrombocytopenia, leukocytosis, and monocytosis. The disease is driven by hypersensitive myeloid progenitor cells and frequently involves somatic or germline mutations in RAS pathway genes such as NF1 , PTPN11 , KRAS , NRAS , and CBL [8,14,15]. Symptoms of JMML—such as respiratory distress, hepatosplenomegaly, pallor, fever, and rash—can overlap with those of neonatal sepsis, particularly in early-onset cases [14,15]. In our patient, JMML was initially mimicked by sepsis and respiratory distress, but was later confirmed via molecular studies showing an NF1 mutation and by bone marrow and immunophenotypic findings. Given the similarity in presentation, it is essential to rule out infections before confirming a diagnosis of JMML [14]. The association between TAR syndrome and leukemia may be due to shared or overlapping genetic factors or pathways involved in both conditions. Jameson-Lee et al. in their case report and review, proposed that downregulation of Y14, a component of the spliceosome complex, may disrupt RNA processing in a manner that promotes leukemogenesis [5]. Since mutations in spliceosome-related genes have been implicated in de novo AML, impaired RBM8A function could contribute to leukemia transformation in TAR patients. Two adult cases of leukemia associated with TAR syndrome have also been documented. Go et al. reported a 42-year-old woman with AML and TAR syndrome who achieved remission following intensive chemotherapy [6] —a treatment approach not feasible in infants. Jameson-Lee et al. described a 47-year-old man with TAR syndrome and myelodysplastic syndrome progressing to AML, who was successfully treated with hematopoietic stem cell transplantation (HSCT) [5]. These cases underscore the potential role of HSCT in achieving remission in TAR-associated hematologic malignancies. In JMML, conventional chemotherapy is often ineffective, with reported mortality rates exceeding 90% due to chemotherapy resistance and treatment-related toxicity in young children. HSCT remains the only curative option, with survival rates improving to approximately 50% in recent years [15,16]. Our patient underwent haploidentical HSCT using a sibling donor and achieved full donor chimerism, normalization of blood counts, and resolution of clinical symptoms. To our knowledge, this is one of the very few —if not the first —reported cases of successful HSCT for JMML in a patient with TAR syndrome. Conclusion The rare association between TAR syndrome and JMML, combined with emerging reports of leukemia in patients with TAR, highlights a potentially underrecognized predisposition to hematologic malignancies in this population. Given the diagnostic challenges and historically poor outcomes associated with this dual pathology, vigilant clinical surveillance and early molecular evaluation are essential. Furthermore, this case emphasizes the feasibility and therapeutic potential of hematopoietic stem cell transplantation (HSCT) in achieving remission, even in the context of complex congenital syndromes. To our knowledge, this is one of the very few—if not the first—reported cases of successful HSCT for JMML in a patient with TAR syndrome, underscoring the need for further research into shared pathogenic mechanisms and long-term treatment outcomes. Acknowledgments Informed Consent Written informed consent was obtained from legal guardians for the publication of any potentially identifiable images or data included in this article. Author Contributions Dr. Sondus Al Sharidah: Conceptualization, investigation, formal analysis, supervision, writing- review and editing. Dr. Ahmed Elhussien: Methodology, writing -original draft. Dr. Walid I. A. Soliman: Data curation. Dr. Nesma I. Ellithy: Data curation. All authors approved the final version of this article for the submission. Medical Writing Support Medical Writing support was provided by Al Essa Medical and Scientific Group. Conflict of Interest Statement The authors declare no conflicts of interest related to this case report. Funding The publication of this article is supported by NBK Children Specialized Hospital, Kuwait. R eferences 1. Greenhalgh KL, Howell RT, Bottani A, Ancliff PJ, Brunner HG, Verschuuren-Bemelmans CC, Vernon E, Brown KW, Newbury-Ecob RA: Thrombocytopenia-absent radius syndrome: a clinical genetic study . J Med Genet 2002, 39 (12):876-881.2. Roberts I, Stanworth S, Murray NA: Thrombocytopenia in the neonate . Blood Rev 2008, 22 (4):173-186.3. Rao VS, Shenoi UD, Krishnamurthy PN: Acute myeloid leukemia in TAR syndrome . Indian J Pediatr 1997, 64 (4):563-565.4. 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Information & Authors Information Version history V1 Version 1 09 May 2025 Peer review timeline Published Cancer Reports Version of Record 2 Apr 2026 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords congenital thrombocytopeni hematopoietic stem cell transplantation juvenile myelomonocytic leukemia nf1 mutation pediatric leukemia tar syndrome Authors Affiliations Sondus Al Sharidah [email protected] National Bank of Kuwait Specialized Hospital for Children View all articles by this author Ahmed Elhussien National Bank of Kuwait Specialized Hospital for Children View all articles by this author Walid I. A. Soliman National Bank of Kuwait Specialized Hospital for Children View all articles by this author Nesma I. 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