Down Syndrome, Transient Myeloproliferative Disorder, and InfantileLiver Fibrosis

Matthias Schwab, MD,1,3* Charlotte Niemeyer, MD,2 and Ulrich Schwarzer, MD3

Background. In neonates, Down syndromeis rarely accompanied by the leukemoid reac-tion called transient myeloproliferative disor-der. Procedures and Results. We present clini-cal and histopathologic data of another Downsyndrome neonate with transient myeloprolif-erative disorder and severe infantile liver fibro-sis. These findings in our patient are comparedin detail with the 20 cases published previ-ously. Similar clinical and laboratory findings

were present in all 21. Conclusions. Knowingthe cellular mechanism of hepatic fibrosis andits modulation by growth factors (e.g., platelet-derived growth factor), a pathogenetic link be-tween transient myeloproliferative disorder andthe development of liver fibrosis in Down syn-drome neonates seems probable. An associa-tion of this triad of findings no longer appears tobe accidental. Med. Pediatr. Oncol. 31:159–165, 1998. © 1998 Wiley-Liss, Inc.

Key words: Down syndrome; transient myeloproliferative disorder; infantile liverfibrosis; platelet-derived growth factor; megakaryocytes

INTRODUCTION

Numerous publications in recent years have accentu-ated the high interest in the pathogenesis of hematologi-cal disorders in Down syndrome [1,2]. The investigationsfocused in particular on the 10- to 20-fold risk of devel-oping acute leukemia when compared with the normalpopulation [3]. Furthermore, in the first year of life, chil-dren with Morbus Down may develop a transient leuke-moid reaction, also called transient abnormal myelopoi-esis, transient leukemia, or transient myeloproliferativedisorder (TMD) [4–7].

In this paper we present a Down syndrome neonatewith TMD who additionally exhibited infantile liver fi-brosis and compare this case with the few cases showingthe same triad that are mentioned in the current literature[8–19].

CASE REPORT

A male infant was born after 34 weeks of gestation toa healthy 28-year-old gravida 3 para 2 woman. After anuneventful pregnancy the child was delivered by caesar-ean section following a pathological cardiotocogram.The infant weighed 2620 g, the apgar score was 4, 9, 9 at2, 5 and 10 minutes and the pH of cord blood was 7.28.The child exhibited stigmata of Down syndrome in ad-dition to generalized edema, massive ascites, and hepa-tosplenomegaly. Peripheral blood cytogenetics showed47XY, trisomy 21. The initial complete blood countshowed a white blood count (WBC) corrected for eryth-roblast of 84 × 109/L, hemoglobin of 9.7 g/100 mL, anda platelet count of 430 × 109/L. The differential count

showed blasts of 55%, metamyelocytes 2%, bands 1%,segmented neutrophils 14%, eosinophils 2%, and lym-phocytes 26%. There were 26% nucleated red cells per100 leukocytes. The reticulocyte count was 19‰. Themorphology of the blast cells showed a large nucleuswith dense and homogeneous chromatin and one or morenucleoli (Fig. 1). The cytoplasm of the blast cells wasscanty, basophilic, and occasionally showed some cyto-plasmic blebs. Cytochemical staining with PAS andANAE revealed a mildly diffuse positive pattern. Peroxi-dase reaction and acid phosphatase staining were nega-tive. Analysis of cell surface markers by flow cytometrydemonstrated that the blasts in the peripheral blood ex-pressed CD41 (glycoprotein IIb/IIIa) with co-expressionof CD3, CD7, CD13, CD33, and CD34. Karyotyping ofperipheral blast cells by cytogenetic analysis of 35 meta-phases showed a karyotype of 47XY, +21 in all blastcells, but no other chromosome aberration. An ascitessmear taken on the third day of life showed some peri-toneal cover cells and a few macrophages whereas themajority of cells were lymphoid. Blasts, as seen in theperipheral blood, were absent. Immunophenotyping of

1Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology,Stuttgart, Germany2University Children’s Hospital, Albert-Ludwigs University, Freiburg,Germany3Children’s Hospital, Nu¨rnberg, Germany

*Correspondence to: Matthias Schwab, M.D., Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, D-70376 Stuttgart, Ger-many. E-mail: matthias.schwab@ikp-stuttgart.de

Received 31 October 1997; Accepted 26 March 1998

Medical and Pediatric Oncology 31:159–165 (1998)

© 1998 Wiley-Liss, Inc.

mononuclear ascitic cells was not performed. A bonemarrow aspirate obtained four weeks after birth showeda reduced number of cells without increase in blasts. Inaccordance with the clinical picture and the course ofdecreased WBC and the disappearance of blasts in pe-ripheral blood on day 26 after birth, TMD in the presenceof Down syndrome was diagnosed.

At birth there were hypoalbuminemia and elevatedserum concentrations of LDH (4840 U/L), total and directbilirubin (10.3 and 4.1 mg/100 mL, resp.), and transam-inases (GOT 212 U/L, GPT 81 U/L, GGT 112 U/L). Onday 9 a hemorrhagic diathesis developed in the presenceof PTT 89 seconds, PT 35 seconds, fibrinogen 60 mg/100mL, antithrombin III 10%,a2-anti-plasmin 52%, andplasminogen 20%. Factor VII 34%, factor IX 21%, andfactor VIII 20% were significantly reduced. There wereno fibrin degradation products. Repeated substitution offresh frozen plasma resulted in improvement of the hem-orrhagic diathesis. In view of the increasing ascites andcontinuing deficiencies in the coagulation parameters, aliver biopsy was performed at the age of five weeks. Thehistological changes in the liver showed diffuse intralob-ular liver fibrosis. The hepatic architecture was destroyedwith surrounding proliferating ductular elements, andthere was a marked intrahepatic bile stasis with an insig-nificant inflammation reaction (Fig. 2 A,B). Hypoplasiaor aplasia of the bile duct was not evident. Moderate irondeposits in hepatocytes were noted. There was no evi-dence of primary inborn metabolic disease. Malforma-tions of the intra- or extrahepatic bile ducts or thrombosis

of the portal vein could be definitely ruled out by sonog-raphy. Additional anomalies, e.g., cardiovascular, werenot found. Repeated screening examinations disprovedthe presence of aminoacidopathies, particularly tyrosin-emia, perinatal hemochromatosis, anda1-antitrypsin de-ficiency. Prenatal infection with toxoplasmosis, rubella,CMV, herpes, syphilis, EBV, parvovirus B19, and HHV6was ruled out by serology. The patient died at the age of76 days; unfortunately, consent for autopsy was not ob-tained.

REVIEW OF THE LITERATURE

As in our case, an association between TMD andDown syndrome is complicated by the presence of liverfibrosis, described in the literature as perinatal liver dis-ease [15]. This disorder usually takes a lethal course andhas already been described in patients with Down syn-drome in the fifties and sixties of this century [8–11].Ruchelli et al. presented 18 infants (10 newborns, 8 pre-term infants) including 11 previously reported cases, af-flicted with Down syndrome and histologically verifiedsevere infantile liver fibrosis and compared these chil-dren with a control group of 7 patients with Down syn-drome without liver disease [15]. Eleven of these Downsyndrome neonates with hepatic fibrosis additionally ex-hibited TMD in the peripheral blood. Furthermore, Miyau-chi et al. described four autopsy cases of children withDown syndrome, TMD and the histopathologic findings

Fig. 1. Peripheral blood cells of our patient at birth. The blasts show a large nucleus with dense and homogeneous chromatin; the cytoplasmis scanty with some cytoplasmatic blebs. May-Gru¨nwald-Giemsa stain.

160 Schwab et al.

of hepatic fibrosis [16]. Becroft described two cases offetal megakaryotic dyshemopoiesis in Down syndromethat simultaneously exhibited distinct visceral fibrosiswhich had commenced in utero [17]. Although the fetalhematological abnormalities were not typical of TMD(low WBC counts), we added these two case reports toour list since the blast cells showed megakaryocytic dif-

ferentiation in addition to positive immunohistochemis-try for megakaryocytic markers. Recently, Yagihashi etal. [18] reported two necropsy cases of infants withDown syndrome and TMD accompanied by characteris-tic hepatic sinusoidal fibrosis, and Zambrano et al. [19] afurther Down syndrome neonate with diffuse intralobularliver fibrosis diagnosed by biopsy. Table I shows the

Fig. 2. Histology of the liver biopsy of our patient performed at the age of five weeks showed (A) disarrangement and disassembly of hepaticcell cords with diffuse periportal fibrosis (Gomori’s stain; original magnification ×190). A typical field of the liver histology (B) showing ahydropic cell with fine granules as a mark of cholestasis in the right central area (hematoxylin and eosin stain; original magnification ×480).

Down Syndrome, TMD, and Infantile Liver Fibrosis 161

TABLE I. Summary of Clinical, Laboratory, and Histological Characteristics of Published Cases With Down Syndrome, TMD, and Liver Fibrosis*

CaseNo.[Ref.]a Sex

Gestationalage

(weeks)

Peripheral blood

Chromosomeb

Symptoms ofliver disease/hepatomegaly

Liver

Fibrosis inother organs

Additionalanomalies

Age atdeath(days)

WBC(×109/L)

Blast(%) Fibrosis EMH MEGS

Irondeposits

Bilestasis

1[13] M 35 leukemoidreaction

ND 46XY/47XY,+21 at birth/No Yes ‘‘marked’’ Yes Yes ND ND No 4

2[13] F 37 200 62 47XX,+21 at birth/Yes Yes ‘‘moderate’’ Yes Yes ND No VSD 343[15] F ‘‘term’’ 100 21 47XX,+21 at birth/No Yes ‘‘moderate’’ Yes Yes ND pancreas Hypertrophic

cardiomyopathy35

4[15] F ‘‘term’’ leukemoidreaction

ND 47XX,+21 at birth/Yes Yes ‘‘marked’’ Yes Yes ND bone marrow AV-canal 28

5[13] F 37 160 ND 47XX,+21 at birth/Yes Yes ‘‘moderate’’ Yes Yes ND No AV-canal,duodenal atresia

42

6[14] F 36 200 68 47XX,+21 at birth/yes Yes ‘‘scattered’’ Yes ND Yes pancreas ASD, PDA 287[10] F ‘‘term’’ 230 80 47XX,+21 at birth/Yes Yes ‘‘present’’ ND ND Yes pancreas PDA,

imperforate anus,M. Hirschsprung

35

8[11] F ‘‘term’’ 141 18 47XX,+21 at birth/Yes Yes ‘‘massive’’ ND ND Yes No ASD, PDA,COARCT

5

9[12] F ‘‘term’’ 130c 93 47XX,+21 at day 6/Yes Yes ND ND ND ND No ASD, VSD 7710[8] M ‘‘preterm’’ 261 58 NA at birth/Yes Yes ‘‘myeloid

infiltrate’’No No Yes pancreas visceral leukemic

infiltrates37

11[9] M ‘‘term’’ 72.5 61 NA at day 3/ND Yes ND ND ND ND ND ASD, VSD 4612[16] F 35 128 85 NA at birth/Yes Yes ‘‘extensive’’ Yes Yes Yes No ASD, VSD 213[16] M 38 69.8 75 NA at birth/Yes Yes ‘‘extensive’’ Yes No Yes No No 1014[16] M 39 289 91 47XY,+21 at day 7/Yes Yes No Yes Yes Yes No No 4115[16] F 34 16.5 15 NA at day 13/Yes Yes ‘‘extensive’’ Yes Yes Yes No ASD, PDA 6616[17] F 31 4.9d 0.47 ×

109/Ld47XX,+21 prenatal/Yes Yes Yes Yes No ND pancreas ASD 30 min

17[17] M 35 stillborn 14e 20e 47XY,+21 prenatal/Yes Yes No No No ND pancreas ASD,duodenal atresia

IUFD

18[18] F 38 128.8 50 NA at birth/Yes Yes ‘‘smallnumbers’’

Yes ND Yes pancreas,bone marrow

No 53

19[18] F 38 89 27 47XX,+21 at birth/Yes Yes ‘‘diffuse’’ Yes ND Yes pancreas,bone marrow

No 23

20[19] F ‘‘term’’ 41.5 22 47XX,+21 at birth/Yes Yes ‘‘extensive’’ Yes ND Yes ND No 6021f M 34 84 55 47XY,+21 at birth/Yes Yes No No Yes Yes ND No 76

*WBC, white blood count; EMH, extramedullary hematopoiesis; MEGS, megakaryocytes; ND, not described; NA, not available; VSD, ventricular septal defect; ASD, atrial septal defect;AV-canal, arterioventricular canal; PDA, patent ductus arteriosus; COARCT, coarctation of the aorta; IUFD, intrauterine fetal death.aReference of the paper in which the case has been initially reported.bIf karyotype was not available, patients were described as ‘‘mongoloid’’ on physical examination by the investigators.cIncrease of WBC to 470 × 109/L with 99% blast cells.dWBC in fetal blood (30 weeks of gestation), absolute blast count in cord blood (31 weeks of gestation).eWBC and blasts in fetal blood (31 weeks of gestation).fOwn case report.

clinical, laboratory, and histological characteristics ofpublished cases—including our case—with the triadDown syndrome, TMD and liver fibrosis.

Pathologic Findings

In summary, the histological liver changes of the 21reported cases resembled diffuse lobular or intralobularfibrosis surrounded by proliferating ductular or pseudo-ductular elements, and prominent fibrous obliteration ofthe central veins. A pattern of sinusoidal fibrosis and avarying degree of giant cell transformation of the re-sidual hepatocytes were observed. In addition, parenchy-mal iron deposits could be verified in 9 of these cases,signifying a mild or moderate hemosiderosis mainly inhepatocytes. Investigations by Ruchelli et al. also dem-onstrated increased extrahepatic iron deposits in the pan-creas, the thyroid gland and the heart in some cases [15].Furthermore, in 14 of the 21 reported cases verificationof a large number of megakaryocytes in the liver wasparticularly remarkable, with maturing cells of all threelineages also being observed. In some cases this wasconfirmed by immunohistochemical staining for each ofthe lineage-specific markers [15,16]. Slight or diffusefibrotic changes were also partly demonstrated in otherorgans, e.g., the pancreas (8 cases), accompanied bymegakaryocytic infiltrates in only two cases (cases No. 6and 19). Intrahepatic bile stasis was present in 12 caseswith this triad without abnormalities of the portal andextrahepatic bile ducts.

The control group of Down syndrome neonates with-out liver disease described by Ruchelli et al. showed noliver fibrosis, no megakaryocytes in the liver (except forone preterm infant), and in no case similar extrahepaticiron deposits.

DISCUSSIONTransient Myeloproliferative Disorder

After Schunk et al. reported for the first time in 1954on congenital leukemia in cases of Down syndrome, laterinvestigations proved that the majority of Down syn-drome neonates with leukemoid reaction can be assignedto the group of TMD cases [5,20]. Relating TMD tocongenital leukemia in the form of acute megakaryoblas-tic leukemia FAB M7 (AMKL) that is also frequentlymanifested by Down syndrome neonates [21,22] is notadmissible initially. Nevertheless, the course of the leu-kemoid reaction shows some characteristic symptomsspecific for TMD: (a) the leukocytes count decreases postpartum within a few weeks or months without any anti-leukemic therapy while the patient recovers satisfactorily[1,23]; (b) the number of blasts in bone marrow is lowcompared with the count in peripheral blood [24]; (c) incontrast to the picture of congenital leukemia, the blastsshow the karyotype of trisomy 21 without other clonal

chromosomal abnormalities [25–27]; (d) extramedullaryhematopoiesis of all three maturing cell lineages can bedemonstrated in the peripheral hematopoietic tissues[10,28]; (e) in vitro the stem cell cultures show normalgrowth in colonies, maturing into granulocytes [29]; (f)the proliferating blast cells show phenotypes of mega-karyocytic lineage [16,27,29].

Considering the 21 cases presently known, the asso-ciation between Down syndrome, TMD, and infantileliver fibrosis no longer appears to be accidental. In thiscontext, our opinion is that verification of the presence ofmegakaryocytes in the liver tissue of many patientsmight be regarded as an important factor.

Platelet-derived Growth Factor and Myelofibrosis

Castro-Malaspina et al. showed a fibroblast-stimulating effect of platelet-derived growth factor(PDGF) causing distinct proliferation of human bonemarrow fibroblasts combined with increased collagensynthesis and resulting in myelofibrosis [30]. Since plate-lets are fragments of megakaryocyte cytoplasm and havea rudimentary biosynthetic apparatus PDGF is synthe-sized by megakaryocytes and stored in granules [31–33].An increased incidence of AMKL quite frequently fol-lowed by acute myelofibrosis is well documented forMorbus Down patients [21,22,34]. Sunami et al. [35]succeeded in proving the presence of the mRNA of thec-sis oncogene, which encodes the B-chain of PDGF[36], in all megakaryoblastic leukemia cells of a 10-month-old boy with AMKL and Down syndrome. Thisproved the capability of megakaryoblastic leukemia cellsto produce PDGF with associated myelofibrotic activity,which was also demonstrated for transforming growthfactor b (TGFb) possibly implicating myelofibrosis inpatients with AMKL [37,38]. In addition, recombinantPDGF significantly enhances murine and human mega-karyocyte colony formation in a dose-dependent mannerin vitro indicating that PDGF is a positive regulator ofmegakaryocytopoiesis [39]. Investigations by Yumura-Yagi et al. showed blasts of TMD and AMKL to origi-nate from very immature cells and to represent a mixedphenotype [40]. Blasts of Morbus Down patients withTMD or AMKL develop either from cells of the mega-karyocytic lineage or from a myeloid progenitor with thecapacity for megakaryocytic differentiation [27], and apredominance of megakaryocyte and erythroid surfacemarkers can be proved in blasts of TMD patients both inperipheral blood and in bone marrow [27,29,41].

Hepatic Fibrosis

Recent studies on hepatic fibrogenesis and its modu-lation by growth factors indicate the importance of lipo-cytes as a predominant source of extracellular matrix,with the activation and regulation of extracellular matrixproduction being influenced by growth factors [42,43].

Down Syndrome, TMD, and Infantile Liver Fibrosis 163

Together with other potent inducers such as TGFb,PDGF acts as a substantial activator of lipocytes andlipocyte proliferation with subsequent fibrogenesis[44,45]. Accordingly, the assumption of a theoreticalpathogenetic link between perinatal liver fibrosis andTMD, for the first time postulated by Becroft and Zwi[14], later by Ruchelli et al. [15] and Miyauchi et al. [16],appears to be conclusive. The hypothesis of Miyauchi etal. that the lower ratio of blasts in bone marrow com-pared to that in the peripheral blood of TMD patientsforms substantial proof of a primarily fetal liver origin ofthe abnormal blasts, which might explain the absence ofmyelofibrosis in these cases [16].

Additionally, in 14 of the 21 reported cases mega-karyocytes were detected in the liver specimens and onlyin 3 cases—including our case—were megakaryocytesdefinitely not found (cases No. 10, 17, and 21); six in-vestigators did not describe liver histology in more detail.Any form of biliary atresia (intra- or extrahepatic), whichhas been described in association with Down syndrome,could in all cases be ruled out as a congenital cause ofliver fibrosis. In our case, for example, malformations ofthe bile ducts were not revealed by sonography and liverbiopsy. In contrast to the symptoms of a neonatal hepa-titis syndrome (‘‘giant cell hepatitis’’), multinucleate gi-ant hepatocytes were absent in the cases published. Viralhepatitis can be ruled out since virus titers were absent, ifdetermined (see our case report), and liver histology wasnot typical (nonzonal distribution of fibrosis along thevascular bed). Metabolic disorders such asa1-antitrypsindeficiency, hereditary tyrosinemia, perinatal hemosider-osis, etc., could be further ruled out by negative meta-bolic screening (when performed) and uncharacteristicliver histology.

In accordance with the liver histology of our case, allcases are so far similar not only in their histopathologicalpattern but also in the clinical symptoms at the time ofovert liver disease. The intrahepatic bile stasis in the 12cases can be explained as a ‘‘blocked’’ outflow of bile inthe hepatic lobules or at the junction between the intra-lobular and interlobular bile ducts. Although Down syn-drome is characterized by a multitude of further disordersof various organs and systems, additional anomalies werenot uniformly demonstrable in the described cases (TableI). Therefore a further association of these malformationswith the triad Down syndrome, TMD, and liver fibrosisis unlikely.

It seems to be of interest that to our knowledge, he-patic involvement with secondary liver fibrosis was ob-served only in one infant with AMKL and major myelo-fibrosis but without Down syndrome [46] and that, on theother hand, only three cases with diffuse or slight my-elofibrotic changes have been described in patients withDown syndrome, TMD, and hepatic fibrosis [15,18]. Itremains unclear why the majority of Down syndrome

neonates with TMD do not develop liver fibrosis. Thus itis most likely that in addition to PDGF, further pathoge-netic factors can be postulated for the extramedullary—primarily hepatic—fibrosis.

CONCLUSIONS

It is quite reasonable to assume participation of theliver in substantially more Down syndrome neonateswith TMD aside from extramedullary hematopoiesismanifested by a minor rise in the transaminases only. Ina presentation of 7 cases with Down syndrome and TMD,5 of these children exhibited elevated transaminase levelswithout hepatic failure [47]. Miyauchi et al. publishedthe laboratory data of four additional non-autopsy casesof Down syndrome and TMD combined with indicationsof hepatic dysfunction [16]. Two of these patients died,but no autopsy was performed. In order to obtain moreprecise information about the pathogenesis of this triad itis most important to recognize this constellation of symp-toms very early if symptoms of hepatomegaly and/orelevated liver enzymes and TMD are manifest in Downsyndrome neonates. In this context, great importanceshould be attached to the detection of cytokines (e.g.,PDGF or TGFb), including an early liver biopsy.

ACKNOWLEDGMENTS

We thank Prof. Dr. H. Lo¨ffler, Kiel, and Prof. Dr. O.Klinge, Kassel, Germany, for taking pictures of periph-eral blood cells and for the histopathology of liver speci-mens.

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