Perinatal Visceral Fibrosis Accompanying the Megakaryoblastic Leukemoid Reaction of Down Syndrome

Abstract

Two infants with Down syndrome, one 4 weeks old and the other stillborn, at necropsy showed hepatic and pancreatic fibrosis, which was very severe in the liver of the liveborn infant and in the pancreas of the stillbirth. The liveborn infant had typical hematological features of the transient congenital leukemoid reaction of Down syndrome, and the identification of a megakaryoblastic component was consistent with recent opinion that this is a spontaneously-remitting congenital megakaryoblastic leukemia. The hydropic stillborn infant had intense extramedullary megakaryocytosis. The visceral fibrosis may have had a pathogenesis similar to that postulated for the myelofibrosis of megakaryoblastic leukemia in older children.

A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): Children's Oncology Group (COG) study POG-9481

“…43 However, most newborns with DS never develop TL. Of those who do, our study indicates that about 60% will experience a spontaneous and continuous remission, about 20% will experience early death [20] 48XXϩ21cϩ21 [11]; 47XYϩ21c [9] 2-AMKL 47XYϩ21cdel(16)(q21) [4]; 47XYϩ21c [16] 47XYϩ21c [12] 3-AMKL 48XYϩ21cϩ11 [4]; 47XYϩ21c [16] 48XYϩ21cϩ11 [8] 4-AMKL 47XYϩ21c [26]; 45-46XYϩ21c [4] (random loss) 48XYϩ21cϩ8…”

“…5-ALL 47XXϩ21c [20] 47XXϩ21c [20] 6-AMKL 47XYqs,del(13)(q13q31)ϩ21 [20]/46XYqs [3] 47XYqs,ϩ21del(13)(q13q31), add (17) 7-AMKL* 47XYϩ21c [20] 47XYϩ21c,isochrome 7(q10) [12] 8-AMKL 47XYϩ21c [20] 49XYϩ21cϩ21ϩ8 [9]/47XYϩ21c [11] 9-AMKL 46XYder(14;21)(q10:q10)cϩ21c [5] 46XY der(14;21)(q10:q10)cϩ21c [5]/46XYder(7)t(1;17)(q21;q36),der(14;21)(q10;q10)cϩ21c [5] ALL indicates B-precursor acute lymphoblastic leukemia. *The one patient who died despite intensive therapy.…”

“…In some cases, however, the disease is severe and potentially lethal, manifesting as hydrops fetalis, multiple effusions, and liver or multiorgan system failure. [7][8][9][10][11][12][13][14][15][16][17] Most of the natural history and biology of TL has been gleaned from sporadic case reports or retrospective reviews of medical or pathologic records. 4,5,15,17 Frequently TL disappears during the first 3 months of life, but after a period of normal marrow morphology and peripheral blood count recovery a significant percentage of patients develop acute leukemia (most commonly AMKL) within the first 4 years of life.…”

Unique Myeloid Leukemias in Young Children with Down Syndrome: Cell Origin, Association with Hematopoietic Microenvironment and Leukemogenesis

“…4a, b), autopsy cases of patients with TL have demonstrated that these patients often exhibit unusual diffuse sinusoidal liver fibrosis (Fig. 4c, d), but not myelofibrosis (Becroft & Zwi, 1990;Ruchelli et al, 1991;Miyauchi et al, 1992;Yagihashi et al, 1995;Schwab et al, 1998;Shiozawa et al, 2004). It has been shown that leukemic blasts in AMKL produce cytokines, including platelet-derived growth factor (PDGF), platelet factor 4 and transforming growth factor β (TGFβ) that stimulate fibroblasts in the bone marrow causing myelofibrosis (Breton-Gorius et al, 1982;Roberts et al, 1986;Sunami et al, 1987;Terui et al, 1990).…”

Proinflammatory Cytokinemia Associated with Transient Myeloproliferative Disorder in Down Syndrome

“…infantile cases, as well as stillborns with evidence of TMD [7][8][9][10][11][12]. Indeed, TMD may originate during intrauterine life, since several cases have been diagnosed on the basis of hydrops fetalis as early as the 27th week of gestation [13,14]. As is true for its course, the pathophysiologic mechanisms resulting in occurrence of TMD remain obscure.…”