Abstract
Introduction: Erdheim-Chester Disease (ECD) is a rare non-Langerhans histiocytic disorder with diverse clinical manifestations, ranging from indolent, localized presentation to life-threatening, multi-systemic disease. Delayed or erroneous diagnosis is common. Presence of classic radiographic finding along with foamy histiocytes that is positive for CD68 but negative for CD1a on histologic examination establishes the diagnosis. We report a second case of ECD from Ethiopia.
Case presentation: A 50-year old Ethiopian man presented with a 13-year history of bilateral lower leg bone pain, cold intolerance, somnolence, constipation, impotence, decreased libido, and secondary infertility. The diagnosis was suspected when skeletal X-ray revealed bilateral symmetric sclerosis of metadiaphysis of femur, tibia, and humerus. Demonstration of foamy histiocytes that were positive for CD68 but negative for CD1a on histologic examination with immunohistochemical staining confirmed the diagnosis. Evaluation for the extent of the disease revealed coated aorta sign, hairy kidney sign, and cystic lesion with ground glass opacity of lung, primary hypothyroidism, and hypergonadotropic hypogonadism.
Conclusion: Erdheim-Chester Disease is rare histiocytic neoplasm with wide range of clinical features which often delay the diagnosis. Clinician should be mindful of the various presentations and the classic radiographic and histologic features of ECD. This case highlight the significance of entertaining ECD in any patient presenting with lower leg bone pain and symmetric osteosclerosis of long bones of lower extremities to allow for early diagnosis and treatment.
Keywords: Erdheim-Chester Disease, Non-Langerhans cell histiocytosis, Osteosclerosis, Ethiopia, Case report
INTRODUCTION
Erdheim-Chester Disease (ECD) is a rare non-Langerhans histiocytic disorder with wide range of clinical manifestations. The exact incidence of ECD is unknown. However, around 1000 cases have been reported in the literature [1-2] and only one case has been reported from Ethiopia [3]. It primarily affects adult males in their fifth to seventh decade of life [4-5].
ECD is a clonal neoplastic disorder, marked by hyperactivating mutation of BRAF and/or other component of mitogen-activated protein kinase (MAPK) signaling pathways which results in clonal proliferation of myeloid progenitor cells and creates chronic uncontrolled inflammation which is primary mediator of organ dysfunction [6-8].
The clinical manifestations of ECD range from asymptomatic disease detected incidentally on imaging to life-threatening multi-systemic disease involving the bone, retroperitoneal organs, central nervous system, respiratory system, cardiovascular system, and skin [9-10]. A defining or pathognomonic feature of ECD is symmetric metadiaphyseal sclerosis of long bones on plain radiographs, PET-CT, or bone scintigraphy [11]. Peri-aortic soft tissue thickening (“coated aorta sign”) and perinephric tissue thickening (“hairy kidney sign”) are additional imaging findings suggestive of ECD [11]. The presence of lipid laden or foamy histiocytes surrounded by fibrosis that are reactive for CD68 but negative for CD1a on histologic examination confirms the diagnosis of ECD [12].
Diagnosis of ECD is usually difficult, due to its rarity and varied clinical features. It should be suspected in any patient presenting with lower leg bone pain and diffuse osteosclerosis of long bones of lower extremities. Diagnoses require the presence of characteristics histopathologic features in the proper clinical and radiologic contexts.
We report a second case of ECD from Ethiopia in a 50-year-old man presenting with chronic lower extremity pain and diffuse sclerotic lesions of long bone of legs. This case also emphasizes therapeutic challenges in resource-limited settings.
CASE HISTORY
A 50-year-old male driver from Ethiopia presented with a 13-year history of bilateral leg pain. The pain was dull aching, felt at distal part of the thigh and proximal part of lower leg bilaterally. It is worsened by movement and relieved by anti-pain. The pain is mild and intermittent at first but overtime it became severe and persistent disrupting his daily activities and lead to analgesic dependency. During this period he visited multiple health facilities, but received no definitive diagnosis and treatment. Associated to this he had history of cold intolerance, somnolence, poor concentration, excessive fatigue, and constipation. He also gave history of impotence and decreased libido. His past medical history includes childhood onset bilateral deafness treated with hearing aid device. He is married with two children, but unable to have additional child despite years of trying. Otherwise he denied any cough, shortness of breath, chest pain, palpitation, orthopnea, body swelling, headache, blurry vision, body weakness, dizziness, abnormal body movement, gait disturbance, polyuria and polydipsia, joint pain and swelling, skin rash, fever, night sweat, weight loss, and other systemic symptom. He did not smoke tobacco, use illicit drugs, or drink alcohol. He has no family history of hereditary skeletal disease or malignancy. No history of chronic illness like diabetes mellitus and hypertension.
On examination, his vital signs were with in normal range. There was slight tenderness on palpation of distal thigh and proximal tibia. The rest of physical examination was unremarkable.
METHODS
Investigation
Blood test revealed mild anemia (hemoglobin 12.4 g/dl), and raised erythrocyte sedimentation rate (ESR 62 mm/hr). Peripheral morphology reported normocytic normochromic anemia, adequate white blood cell and platelet count without blast or malignant cells. Otherwise serum electrolyte, renal function test, liver enzymes, serum albumin, and tumor markers were normal (Table 1).
Skeletal radiography of the femur showed bilateral symmetric distal metadiaphyseal bone expansion with diffuse medullary sclerosis with blurring of corticomedullary differentiation and associated cortical thickening (Figure 1A and B). Similar changes were identified on tibial and humeral X-ray, but skull, pelvic, and spinal x-ray were normal. Following a negative metabolic and hematologic work-up for such sclerotic bone lesions, diagnostic skeletal biopsy was obtained with a consideration of ECD.
Histopathologic examination of bone and fibro-adipose tissue demonstrated infiltration with foamy histiocytes admixed with scattered spindle cells, and occasional multi-nucleated giant cell (Touton cells) and surrounded by fibrosis along with focal cholesterol cleft of xanthogranulomatous reaction (Fig 2A-E). On immunohistochemical staining, the histiocytes were strongly reactive for CD68 and dimly reactive for S100 but negative for CD1a.
After confirming the diagnosis of ECD, several laboratory and imaging tests were done to determine the extent of the disease. Laboratory values were compatible with primary hypothyroidism (high sensitivity TSH 6.74 iu/ml, Free T4 4.94 ng/dl), hypergonadotropic hypogonadism (LH 22.9 miu/ml, FSH 6.52 miu/ml, free testosterone 3.39 n/ml) (Table 1).
Contrast enhanced chest CT detected mild soft tissue encasement of aortic arch and thoracic aorta (coated aorta sign) and randomly distributed multiple different size lung cysts with right lower lung zone ground glass opacity (Fig 3A-C). Abdominal CT scan revealed bilateral symmetrical peri-renal soft tissue infiltration and enhancement (hairy kidney sign) and mild soft tissue encasement of the abdominal aorta and the proximal bilateral common iliac arteries (Fig 4A-D). Thyroid and testicular ultrasound were none revealing. Echocardiography and electrocardiogram were unremarkable. Genetic test for BRAF mutation was not determined due to financial reason.