Objective: Several monogenic causes of familial myelodysplastic syndrome (MDS) have recently been identified. Genetic studies disclosed heterozygous missense mutations in SAMD9L, a tumor suppressor gene located on chromosome arm 7q. Consistent with a gain-of-function effect, ectopic expression of the 2 identified SAMD9L mutants decreased cell proliferation relative to wild-type protein.
Case report: A one month old girl was referred to our hospital with bruising. She was followed-up at a local hospital with thrombocytopenia for three weeks. She had normal physical examination findings except petechiaes on her extremities, trunk, and face. There was no bleeding diathesis and consanginous marriage in her family history. Complete blood count showed hemoglobin of 7.2g/dL, reticulocyte of 2.4%, leukocyte count of 3.1×109/L, absolute neutrophil count of 0.3×109/L, platelet count of 2×109/L. Coagulation tests, liver and kidney functions were normal. Her viral serologies were negative for EBV, CMV, rubella, hepatitis and parovirus B19. However, vitamin B12 level was below normal limits, then cyanocobalamin treatment was started. Her mother's serum vitamin B12 level was normal. Immune thrombocytopenia was considered and intravenous immunoglobulin (IVIG) was given to her, and platelets raised to 87×109/L, thereafter decreased to 14×109/L within a few days. Bone marrow aspiration showed hypocellularity with dysplastic changes in myeloid lineage. Karyotype analysis revealed 46,XX der(20), and negative for monosomy 7. Her neurologic examination was normal except bulging of anterior fontanel, cranial ultrasonography was performed and it showed triventricular hydrocephalus and left cerebellar hypoplasia. A ventrculo-peritoneal shunt was inserted to her. She had cellular and humoral immunodeficiency with decreased peripheral blood B and natural killer (NK) cell numbers (C19+20 cell number of 1%) and low immunoglobulin levels. On the follow-up, she received monthly IVIG prophlylaxis and platelet transfusions as needed. Genetic analysis disclosed that a heterozygous missense variant in SAMD9L (c.2627T>C). Bone marrow aspiration was planned to done in every 3 months on the follow-up. Platelet count and hemoglobin levels gradually increased over the time, but monosomy 7 was positive at the age of 2 in the 52% of the cells. She underwent hematopoietic stem cell transplantation (HSCT) from a matched unrelated donor with myeloablative conditioning regimen.
Methodology: We herein report a girl presenting with pancytopenia and immunodeficiency which was revealed SAMD9L mutation.
Results: SAMD9L, the gene is located in a region of chromosome 7 that is commonly deleted in myeloid malignancies. In mice, Samd9l deficiency causes development of MDS with age, suggesting that SAMD9L is a tumor suppressor. Heterozygous SAMD9L missense mutations may cause of familial MDS like Ataxia-pancytopenia syndrome which is associated with neurological findings (ataxia and nystagmus), cytopenias and predisposition to myeloid leukemia involving −7/del(7q). In addition, SAMD9L may regulate differentiation of diverse immune cell lineages like B and NK cells, however cellular basis of neurological manifestations in the carriers remains unclear.
Conclusion: In conclusion, SAMD9L mutation screening should be considered in all pediatric patients with MDS, AML, or JMML with chromosome 7 aberrations, even in the absence of neurological symptoms or a family history of myeloid malignancies.
