Clinical Heterogeneity in RUNX1-Associated Familial Myelodysplastic Syndrome - Report of Two Novel Pedigrees with Childhoodleukemia
Authors: Ripperger Tim , Burkhardt Birgit , Hauck Fabian , Albert Michael H. , Thomay Kathrin , Wlodarski Marcin , Yoshimi Ayami , Göhring Gudrun , Schlegelberger Brigitte , Niemeyer Charlotte M , Steinemann Doris 
Published: October 2019

Abstract
RUNX1-associated familial leukemia is a rare hematologic malignancy. It is inherited in an autosomal dominant manner and mainly causes myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Since constitutional mutations in RUNX1 can lead to thrombocytopenia or dysfunctional platelets, the disease is termed familial platelet disorder with associated myeloid malignancies (FPDMM, MIM 601399). Here, we report two novel families with early onset MDS illustrating the variability of the disorder.
The index patient (P1) of family 1 (Fig. 1A) was known to have asymptomatic thrombocytopenia (90 G/l) since his neonatal period. Platelet assays revealed impaired in vitro aggregation. Asymptomatic thrombocytopenia was also known in his younger sister, his mother and his maternal grandfather. A maternal uncle had died from leukemia at age 4. While P1 was treated with antibiotics for a middle ear infection, he developed petechiae and hematoma. He was found to have a platelet count of 11 G/l with a normal white blood count (WBC), hemoglobin concentration (Hb) and MCV. Bone marrow investigations led to the diagnosis of MDS with excess blasts (MDS-EB) with normal karyotype. Sequencing of RUNX1 identified a heterozygous truncating RUNX1 mutation in P1 that was also present in his mother: c.90_117dup; p.(Leu40AlafsX80). P1 underwent hematopoietic stem cell transplantation (HSCT) from a matched unrelated donor (MUD) following a preparative regimen consisting of busulfan, cyclophosphamide and melphalan (BuCyMel). He is alive and well 4 years post HSCT. Two years after his diagnosis, a 17-year-old maternal uncle of P1 (P2) was also diagnosed with MDS-EB with normal karyotype. Successively, the disorder progressed to AML and karyotyping showed a clonal derivative chromosome 7 due to an unbalanced translocation der(7)t(2;7)(p12;q21), and later on, a clonal evolution with trisomy 12. RUNX1 sequencing indicated that P2 also carries the familial RUNX1 mutation. Finally, the causative RUNX1 mutation was also identified in the younger sister and two further maternal uncles, all showing mild, asymptomatic thrombocytopenia without evidence of malignant transformation.
In the second family (Fig. 1B), the male index patient (P3) had congenital, asymptomatic thrombocytopenia with subsequent platelet counts of 60-80 G/l. At age 3.5, platelet count declined over several months reaching values of 3-20 G/l. WBC, Hb and MCV were normal. The patient had recurrent nose bleeds and prolonged bleeding after cuts and blood drawing. Diagnostic bone marrow examination showed MDS-EB with normal karyotype. Since, thrombocytopenia was also known in P3's mother, RUNX1 was sequenced and showed a typical heterozygous truncating mutation in P3 and his mother: c.415C>T; p.(Arg139X). The mutation was absent in P3's brother. At age 16, a maternal aunt of P3 had died due to a cervical cancer. Her DNA was not available for testing. P3 received a MUD HSCT following a BuCyMel preparative regimen and is alive and well 2 years post HSCT.
These two new pedigrees with germline RUNX1 mutation emphasize a few interesting points. For both index patients the history of familial thrombocytopenia had been known since birth, but genetic work-up was only initiated after the platelet count had rapidly decreased and bleeding had become obvious. At the time of genetic confirmation, MDS-EB had to be diagnosed despite normal values and blood morphology for white cells and red cells. Thus, decreasing platelet counts in patients with known RUNX1 germline mutations or long-standing thrombocytopenias of unknown cause should result in prompt bone marrow examination, even in the absence of other signs or symptoms suspicious of hematopoietic neoplasia. Furthermore, the platelet count might be a suitable screening instrument in surveillance of patients known to carry germline RUNX1 mutations. Although both index patients had been successfully transplanted following a standard myeloablative regimen, earlier diagnosis of MDS might have saved toxicity and late effects. With our current knowledge of myeloid neoplasms with germline predisposition and pre-existing platelet disorders, children with thrombocytopenia and a family history should have complete genetic work-up for currently known alterations. Consensus guidelines need to be developed by specialists in hematology/oncology, coagulation, general pediatrics and human genetics.
Figure 1 Pedigrees Figure 1. Pedigrees

Disclosures
No relevant conflicts of interest to declare.