Thrombocytopenia and Predisposition to Acute Myeloid Leukemia due to Mosaic Ring 21 with Loss of RUNX1: Cytogenetic and Molecular Characterization

Abstract

Familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML) has been well documented in the literature and is a new entity within the latest revised edition of the WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues (OMIM). The disorder arises due to mutations within the RUNX1 gene in chromosome 21; mutations within the Runt-binding domain are the most commonly encountered anomalies that cause decreased platelet count and function. Rare cases of haploinsufficiency have also been shown to cause this disorder. Here, we describe a 12-year-old female with mosaicism for a ring chromosome 21 and monosomy 21 who was born with thrombocytopenia which is now explained by loss of the RUNX1 gene resulting in FPD/AML. We also comment on the structure of the ring and the mechanism of its formation.

Next Generation Cytogenetics in Myeloid Hematological Neoplasms: Detection of CNVs and Translocations

“…RUNX1 was also the gene that presented CNV losses more frequently (4/22), followed by IKZF1 (3/22). RUNX1 intragenic deletions as well as point mutations have been described as the cause of familial platelet disorders with propensity to acute myeloid leukemia [39,40], suggesting that loss of RUNX1 function could be involved in myeloid transformation. Deletions of IKZF1 are frequent and they are classified as a poor prognosis marker in ALL [41]; however, it is described as a rare alteration in MN and within a 7p deletion landscape [42].…”

The past, present, and future for constitutional ring chromosomes: A report of the international consortium for human ring chromosomes

“… 109 , 110 Patients of RC 11 associated with Wilms tumor, RC 13 with retinoblastoma, RC 17 with neurofibromatosis, RC 21 with acute myeloid leukemia, and RC 22 with neurofibromatosis, meningiomas, and vestibular schwannoma have been reported. 85 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 Dynamic mosaicism and dysfunction of harbored tumor suppressor genes in these constitutional RCs mediated the predisposition to cancer. 119 Cancer surveillance should be considered for patients carrying these RCs.…”

“… 85 21 RUNX1 acute myeloid leukemia Burillo-Sanz et al., 113 Vormittag-Nocito et al. 114 22 NF2 neurofibromatosis type II, meningiomas, schwannoma, Tommerup et al., 115 Petrella et al., 116 Denayer et al. 117 …”