Journal of the New Zealand Medical Association, 23-April-2004, Vol 117 No 1192
Case of myelofibrosis with hypertrophic osteoarthropathy: the role of platelet-derived growth factor in pathogenesis
Binu John, Heraganahally Subhash, and Kurien Thomas
Hypertrophic osteoarthropathy (HOA) is a condition characterised by clubbing of digits—with periostitis, plus articular and periarticular pain. We report a patient with hypertrophic osteoarthropathy, who presented with severe anaemia, and was found to also have myelofibrosis (agnogenic myeloid metaplasia). This extremely rare association is particularly significant since it lends credence to the theory implicating platelet-derived growth factor (PDGF) in the pathogenesis of both of these conditions (myelofibrosis and hypertrophic osteoarthropathy).
A 27-year-old man presented with history of breathlessness (on exertion) and fatigue of 2 years’ duration. There had been gradual painless enlargement of both hands and feet (of 3 years’ duration) with mild pain and swelling involving ankles, wrist, and knee joints. There was no history of cough with expectoration, haemoptysis, wheeze, abdominal pain, alteration in bowel habits, melaena or bloody diarrhoea. He had no history of fever, palpitations, or cardiac disease. There was no family history of similar illness.
On examination, he had a pulse rate of 80/min and a blood pressure of 120/80 mmHg. He had pallor with marked clubbing. There was swelling of distal extremities; both hands and feet were grossly enlarged. Feet appeared ‘elephant like’ (Figure 1). There was no icterus, lymphadenopathy, or pedal oedema. Chest was clear. The liver was palpable 2 cm below the costal margin. Spleen was not palpable. There was no free fluid. Examination of the cardiovascular system was normal.
There was no evidence of effusion of any joint and no evidence of acromegaly such as prognathism, coarse facial features, change in voice, or proximal myopathy. Investigations showed haemoglobin 4.7 grams/dL, with a reticulocyte count of 4.6%. Blood picture revealed ovalocytes and teardrop cells. The total leucocyte count was 3100/cu mm, with the differential count showing 68% polymorphs, 16% lymphocytes, and 16% eosinophils. The platelet count was 182,000/cu mm. The mean corpuscular volume was 73, and erythrocyte sedimentation rate (ESR) 87mm/hr. Serum calcium, phosphate, alkaline phosphatase, liver function tests, growth hormone level, and thyroid function tests were normal.
Radiograph of the chest was normal. The forearms showed linear periosteal reaction involving radius and ulna bilaterally (Figure 2), and the lower limbs showed periosteal thickening of bilateral tibia and fibula and distal soft tissue enlargement (Figure 3). Ultrasonography of the abdomen revealed hepatosplenomegaly. Attempted bone marrow aspiration revealed a dry tap. Cellular imprints of the bone marrow trephine biopsy fragment revealed normoblastic erythroid maturation, diffuse lymphocytosis, and increased osteoblastic activity. The bone marrow trephine biopsy was consistent with the cellular phase of myelofibrosis.
Figure 1. Photograph of both lower limbs of a 27-year-old man showing marked enlargement of both legs with swelling of both ankle joints and clubbing of toes
This patient presented with hepatosplenomegaly, peripheral cytopaenias, teardrop poikilocytosis, and marrow fibrosis suggestive of myelofibrosis (AMM). The other disorders that may lead to this clinical picture (including infections such as tuberculosis—and metabolic disorders such as renal osteodystrophy, hypoparathyroidism, and hyperparathyroidism) were ruled out in our patient.
He also had features of hypertrophic osteoarthropathy (HOA), a clinical syndrome characterised by marked clubbing of the digits; specifically, enormous hands and feet, arthralgia, and periosteal overgrowth. There were no cutaneous manifestations of primary hypertrophic osteoarthropathy (pachydermoperiostosis), such as furrowed forehead, broad nose, prominent nasolabial folds, and thickened eyelids. There were no clinical or laboratory evidence of other conditions that are commonly associated with secondary hypertrophic osteoarthropathy—such as suppurative lung disease, pulmonary neoplasm, inflammatory bowel disease, colonic neoplasm, congenital cyanotic heart disease, infective endocarditis, or thyrotoxicosis.
Multiple mediators (including PDGF, prostaglandins, ferritin, bradykinin, and oestrogen) have been implicated as causes of clubbing or hypertrophic osteoarthropathy.1 The most popular theory is that megakaryocytes or large fragments of megakaryocytes in the systemic circulation, preferentially lodge in the tips of the digits, because of the prevailing patterns of blood flow. Once stuck there, the cells release PDGF and other substances that increase endothelial permeability and activate fibroblasts and other connective tissue cells.1 The exact aetiology of myelofibrosis is not clear, but one of the most widely accepted theories is that it results from the liberation of excessive amounts of growth factors (including PDGF, transforming growth factor-β [TGF-β], and epidermal growth factor [EGF], which are each contained within platelet and megakaryocyte α-granules). These can lead to marrow fibroblast expansion and collagen synthesis. The PDGF content of platelets from AMM patients is known to be decreased, indicating a release or leakage of such growth factors.2
There are only three other case reports describing the association of myelofibrosis and hypertrophic osteoarthropathy.3–5 In one of these reports, the authors demonstrated a high proliferative potential of bone marrow derived fibroblasts in vitro as well as an increased expression of PDGF-BB binding sites.3 Thus, the concurrent occurrence of these two uncommon conditions may be a pointer to the role of PDGF in the pathogenesis of these conditions.
Author information: Binu V. John, Consultant, Department of Medicine - Unit 2, Christian Medical College and Hospital, Vellore, Tamilnadu, India; Heraganahally S. Subhash, Medical Practitioner, Modbury Public Hospital, Modbury, SA, Australia; Kurien Thomas, Professor and Head, Department of Medicine - Unit 2, Christian Medical College and Hospital, Vellore, Tamilnadu, India.
Correspondence: Binu V. John, Department of Medicine - Unit 2, Christian Medical College and Hospital, Vellore, Tamilnadu, 632004, India. Fax: +91 416 2232035; email: email@example.com
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