Detrimental variants in MPIG6B in two children with myelofibrosis: Does immune dysregulation contribute to myelofibrosis?

Abstract

is a rare disorder in children. It mostly occurs secondary to disorders such as malignancy, vitamin D deficiency, autoimmunity, and infections. 1,2 Primary MF has been reported in a limited number of children. [3][4][5] Germline mutations in genes such as MPL, VPS45, and RBSN are associated with primary MF. 6-8 A recent report described an Arab family with MF associated with a homozygous mutation in MPIG6B (also known as G6B or C6orf25). 9Another report described four unrelated Arab families with homozygous loss-of-function variants in MPIG6B associated with childhood MF. 10 MPIG6B is located in the class III region of the major histocompatibility complex and encodes G6B protein that interacts with protein tyrosine phosphatases Shp1 and Shp2. 11,12 G6B is primarily expressed in platelets. [13][14][15] G6B knockout mice had low platelet count, increased platelet volume, and platelet dysfunction. 10,16 We report two unrelated patients who presented during infancy with anemia, thrombocytopenia, and focal MF and had homozygous mutations in MPIG6B. The first case is a 10-year-old female who presented at 7 months of age with epistaxis and had thrombocytopenia and anemia. Her parents are first cousins. Physical examination was unremarkable. Blood smear showed some giant platelets and anisopoikilocytosis with teardrop cells, schistocytes, elliptocytes, and spherocytes. Bone marrow (BM) at age 1 year was hypercellular with megakaryocyte clusters, as shown in Figure S1. BM was infiltrated with large cells with vesicular nuclei and prominent nucleoli and was surrounded by a mixture of small lymphocytes and eosinophils.The large cells were positive for CD10, CD20, CD45, and CD79a and negative for CD3, CD7, CD15, CD30, CD34, CD56, CD57, pan CK, desmin, and synaptophysin. The background cells were positive for CD15, CD45, MPO and negative for other markers. There was a mild increase in reticulin fibers. Follow-up BM studies showed subsequent fading of lymphocytic infiltration, dysplastic megakaryocytes, a slight reduction in erythropoiesis, and a marked increase in MF with no myelodysplasia (Figure S1). Cytogenetic analysis was normal.Chromosomal fragility test, vitamin D, vitamin B12, and folate levels were normal. The patient required intermittent platelet transfusion.There was no major bleeding. The spleen progressively increased in size with an increase in platelet transfusion requirements. Splenectomy led to transient improvement in platelet counts. Whole exome sequencing (WES) revealed a homozygous loss-of-function mutation in MPIG6B: c.523C>T (p.Arg175Ter). Recently, the patient started to

ASXL2 mutated myelodysplastic syndrome in a novel germline G6b variant

“…Congenital mega-thrombocytopenia with germline G6b mutation is a rare autosomal recessive disease. Only 19 persons from 9 affected families are reported including 17 of Arab descent [ 2 , 3 , 6 ], 1 of European descent [5] and 1 of Chinese descent [4] . All affected persons were from consanguineous families.…”

“…Most affected persons have macro-thrombocytopenia and focal myelofibrosis with variable degrees of anemia, leukocytosis and splenomegaly and a mild to moderate bleeding diathesis. Splenomegaly and bone marrow fibrosis may worsen over time and contribute to worsening anemia [ 5 , 6 ]. The main clinical manifestations at onset in our patients were splenomegaly and thrombocytopenia, and bone marrow biopsy revealed grade-2 reticulin fibrosis, which is consistent with the typical clinical features of the disease with germline G6b mutation.…”

“…The types of G6b variants that have been reported include c.61_61+1dup, c.147insT, c.149dup, c.324C > A, c.392delC, c.469 G > A , and c.523C > T [2] , [3] , [4] , [5] , [6] . We identified a novel G6b truncation mutation (c.420T > A , p. Tyr140 ∗) in a Chinese family.…”

“…Common treatment options for disease with germline G6b mutation include RBC-transfusions, corticosteroids, intravenous immunoglobulin, splenectomy and a hematopoietic cell transplant [ 3 , 5 , 6 ]. Corticosteroids and splenectomy are transiently effective in some cases, and transplants can cure occasional patients [ 3 , 5 , 6 ].…”

“…More than a dozen of germline genes predisposing to MNs are described. Germline loss-of-function (LOF) mutations in G6b ( G6b-B, C6orf25 or MPIG6B ) are associated with congenital macro-thrombocytopenia with focal myelofibrosis, a rare autosomal recessive disease [2] , [3] , [4] , [5] , [6] . However, it is unclear whether germline G6b variants increase the risk of developing a MN.…”