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□ CASE REPORT □

Myelofibrosis Successfully Treated with Prednisolonein a Patient with Pachydermoperiostosis

Soranobu Ninomiya 1, Takeshi Hara 1, Hisashi Tsurumi 1, Nobuhiro Kanemura 1,

Senji Kasahara 1, Yoko Ogawa 2, Mariko Seishima 2,

Yoshinobu Hirose 3 and Hisataka Moriwaki 1

Abstract

Pachydermoperiostosis (PDP) is a rare disorder of bone and connective tissue growth. A 21-year-old man

was referred to our hospital with anemia. He showed characteristics of PDP. Bone marrow biopsy showed

myelofibrosis. Chromosomal abnormalities or JAK2 mutation were not found. Anemia gradually progressed,

and he became transfusion-dependent. Oral prednisolone was initiated; it gradually improved his anemia and

rendered the patient free of transfusion. However, other clinical symptoms such as clubbed fingers and skin

hypertrophy remained unimproved. In this case, the serum concentration of vascular endothelial growth factor

and transforming growth factor-β levels were increased. Further investigation will be necessary to establish

appropriate treatment strategies for this disease.

Key words: myelofibrosis, pachydermoperiostosis, prednisolone

(Intern Med 50: 2207-2211, 2011)(DOI: 10.2169/internalmedicine.50.5717)

Introduction

Pachydermoperiostosis (PDP) is a rare primary hy-

pertrophic osteoarthropathy appearing as a disorder of bone

and connective tissue growth. The disease is characterized

by the development of thickening of the fingers, cutis verti-

cis gyrata, digital clubbing, oily skin, periosteal reactions,

cortical thickening of the long bones and hypertrophic os-

teoarthropathy (1, 2). In particular, the presence of digital

clubbing, skin hypertrophy and radiographic periostosis are

the main diagnostic criteria for PDP (3). The disease is

markedly more prevalent in males, and is thought to repre-

sent an autosomal dominant trait with variable expression.

PDP symptoms also develop secondary to various acquired

diseases, particularly intrathoracic neoplasms (4). Cases of

myelofibrosis in association with PDP are rare in the litera-

ture, and the pathogenesis of PDP has not been clarified. We

report herein a case of myelofibrosis with PDP that was suc-

cessfully treated using prednisolone (PSL).

Case Report

A 21-year-old man was referred to our hospital with ane-

mia in August 2009. His birth had been uneventful and he

grew up healthy. Facial wrinkles had become prominent in

junior high school, with enlargement of the hands and feet

evident from 17 years old. He observed that his fingers and

toes gradually got thicker. College health checkups also

noted facial abnormalities and anemia. On physical exami-

nation, the patient seemed older than his actual age. His

height was 172 cm, and his weight was 65 kg. Cranial skin

was thickened and corrugated, and deep nasolabial folds

were apparent. He showed bilateral digital clubbing, and ele-

phant feet (Fig. 1). No joint pain was evident. Bone radiog-

raphy showed hypertrophic osteoarthropathy and cortical

thickening of the long bones (Fig. 2). No cardiorespiratory

or abdominal symptoms were present. Internal malignancy

was not found on computed tomography, endoscopy or

FDG-PET. Brain magnetic resonance imaging (MRI) re-

１The First Department of Internal Medicine, Gifu University Graduate School of Medicine, Japan, ２Department of Dermatology, Gifu University

Graduate School of Medicine, Japan and ３Department of Tumor Pathology, Gifu University Graduate School of Medicine, Japan

Received for publication April 26, 2011; Accepted for publication June 9, 2011

Correspondence to Dr. Hisashi Tsurumi, htsuru@gifu-u.ac.jp

Intern Med 50: 2207-2211, 2011 DOI: 10.2169/internalmedicine.50.5717

2208

Figure　1.　Clinical photographs of the patient. A) Cutis verticis gyrata, deep nasolabial folds and thickened facial skin. B) Digital clubbing, and C) elephant feet.

(A) (B) (C)

Figure　2.　Bone radiography and computed tomography. Thickening of the cortex in long bones and formation of new periosteal bone (arrow). Computed tomography revealed thickness of the cra-nial skin (arrow).

vealed no abnormalities. Table 1 summarizes the laboratory

findings at initial consultation. Leukocyte count was 3,950/

μL, hemoglobin level was 8.7 g/dL and platelet count was

11.5×104/μL. The serum concentration of ferritin was ele-

vated, but serum iron level was normal. Levels of growth

hormone and thyroid hormone were normal, ruling out ac-

romegaly and thyroid acropathy. No familial history of any

similar disorder was evident. Bone marrow aspiration

yielded dry taps and bone marrow biopsy showed hypocel-

lularity with fibrosis (Fig. 3A, 3B). No hepatomegaly or

splenomegaly was present. Chromosomal analysis showed

46,XY, with no JAK2 mutation. The diagnosis was myelofi-

brosis complicated with PDP.

Treatment with danazol had been initiated at another hos-

pital, but proved ineffective. He was not receiving any ther-

apy on presentation to our hospital, and anemia had gradu-

ally progressed to the point where the patient became

transfusion-dependent. Oral administration of PSL was

started at 30 mg/day in November 2009, resulting in a grad-

ual improvement in anemia. The patient was able to become

free of transfusion after PSL treatment (Fig. 4). In Septem-

ber 2010, bone marrow biopsy showed the recovery of he-

Intern Med 50: 2207-2211, 2011 DOI: 10.2169/internalmedicine.50.5717

2209

Figure　3.　Results of bone marrow biopsy. A) Bone marrow biopsy before treatment showed hypo-cellularity, increased fibroblasts and fibrosis (Hematoxylin and Eosin staining, ×200). B) Reticulin fibers were increased (silver stain, ×200). C) After PSL therapy, hematopoietic cells were increased and fibrosis was reduced.

(A)

(C)

(B)

Table　1.　Laboratory Data

Peripheral blood Blood Chemistry Coagulation WBC 3,950 /μL TP 7.6 g/dL PT (INR) 1.24

Basophil 0.3 % Alb 3.9 g/dL APTT 30.4 secEosinophil 1.0 % Na 137 mEq/L Fiblinogen 288 mg/dLNeutrophil 52.1 % K 3.7 mEq/L FDP 2.2 μg/mLLymphocyte 42.5 % Cl 107 mEq/L D-dimer 0.6 μg/mLMonocyte 4.1 % BUN 5.8 mg/dL

RBC 326 × 104 /μL Cr 0.6 mg/dL SerologyHemoglobin 8.7 g/dL T.Bil 0.7 mg/dL CRP 0.9 mg/dLHematocrit 28.5 % ALP 187 IU/L IgG 1,996 mg/dLMCV 87.4 fL AST 9 IU/L IgA 107 mg/dLMHC 26.7 pg ALT 8 IU/L IgM 56 mg/dLMCHC 30.5 % LDH 135 IU/L HBsAg (-)Platelet 11.5 × 104 /μL GTP 6 U/L HCVAb (-)

Ca 8.5 mg/dLP 3.1 mg/dL GH 0.6 ng/mLUA 6.2 mg/dL IGF-1 102 ng/mL

Bone marrow aspiration TCHO 135 mg/dL EPO 1230 mU/mLDry tap TG 45 mg/dL

HbA1c 5.2 % UrinalysisFe 69.0 μg/dL pH 5.0Ferritin 325 ng/mL Sugar (-)

Protein (-) Blood (-)

Bilirubin (-)

matopoiesis efficacy and improvement of fibrosis (Fig. 3C).

However, other clinical symptoms such as clubbed fingers

and skin hypertrophy remained unimproved.

Discussion

This patient displayed the characteristic features of PDP,

such as digital clubbing and radiographic periostosis. In this

Intern Med 50: 2207-2211, 2011 DOI: 10.2169/internalmedicine.50.5717

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Figure　4.　Clinical course. The patient became transfusion-dependent. Oral administration of PSL was started at 30 mg/day in November 2009, resulting in a gradual improvement in anemia. The pa-tient was able to discontinue transfusions. Other clinical symptoms such as clubbed fingers and skin hypertrophy remained unimproved.

Hemoglobin

Leukocyto

Platelet

30mg 25mg 20mg 17.5mg 20mg 17.5mg

: Red Blood Cell infusion

20102009

Prednisolone

case, anemia was attributable to myelofibrosis. PDP compli-

cated by myelofibrosis has been reported in only a few

cases (5-7). Myelofibrosis is one of the primary forms of

chronic myeloproliferative disorder, characterized by eryth-

roblastic anemia, hepatosplenomegaly from extramedullary

hematopoiesis, and dysplastic megakaryocytic hyperplasia

associated with bone marrow fibrosis. The JAK2 V617F mu-

tation is present in more than 90% of patients with poly-

cythemia vera and in 40-60% of patients with idiopathic

myelofibrosis (8). In this case, the bone marrow was hypo-

cellular with a decreased number of megakaryocytes, and no

JAK2 mutation or chromosomal abnormalities were found.

High levels of circulating CD34+ cells and JAK2 mutations

might allow differentiation of myelofibrosis with myeloid

metaplasia from other myeloproliferative disorders, includ-

ing secondary myelofibrosis (9). However, the JAK2 V617F

mutation has been detected in patients with polycythemia

vera, essential thrombocythemia, and idiopathic myelofibro-

sis (10). In any case, the JAK2V617F mutation was not evi-

dent in this patient, so myelofibrosis in this case might have

been secondary to PDP.

Cytokines such as vascular endothelial growth factor

(VEGF), transforming growth factor (TGF)-β, hepatocyte

growth factor, and platelet-derived growth factor are sus-

pected to influence the pathogenesis of PDP and myelofi-

brosis (11). Modifications to vessels in PDP are reportedly

associated with diffuse endothelial hyperplasia showing acti-

vated endothelial cells, thickening of the basal membrane,

and sclerosis with packing of collagen fibers (12). In the

present case, levels of VEGF and TGF-β were increased to

641 pg/mL (normal, <38.3 pg/mL); and 13.6 ng/mL (nor-

mal, 0.89-1.80 ng/mL), respectively. For patients with pri-

mary myelofibrosis, anabolic steroids are used as a treat-

ment for anemia (13). Indeed, the present patient was in-

itially treated using danazol, although the treatment proved

ineffective. In juvenile osteopetrosis, effective treatment of

anemia or skeletal complications using PSL has been re-

ported (14, 15). In another case report, typical doses of PSL

were not effective, and steroid pulse therapy improved ane-

mia caused by myelofibrosis with PDP (5). In the present

case, we selected PSL (0.5 mg/kg/day) as treatment in our

hospital. This dose of PSL proved effective against anemia

in the present case, and the patient was able to discontinue

transfusions. Bone marrow biopsy showed improvement of

fibrosis. However, serum concentrations of VEGF and TGF-

β were not decreased. This result might suggest that these

cytokines were not essential for myelofibrosis and another

cytokine caused myelofibrosis in this case, indicating the

complexity of the mechanisms underlying PDP. Indeed,

other symptoms such as clubbed fingers or skin hypertrophy

remained unimproved with oral administration of PSL.

Myelofibrosis might be one of the important complications

among patients with PDF. Adequate treatment strategies

need to be established for PDP, and further investigation of

the mechanisms underlying PDP with myelofibrosis are nec-

essary.

The authors state that they have no Conflict of Interest (COI).

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