A 42-year-old man of Armenian descent was admitted to the internal medicine service complaining of intermittent fever and night sweats for one month. The fevers continued for >36 hours, peaked at 40 C, and were associated with diffuse myalgias, rigors, and diaphoresis. He also reported drenching night sweats and a 20 lb. weight loss over the previous month. He does not smoke and drinks alcohol sparingly. His past medical history and family history were unremarkable. His review of systems was otherwise unremarkable. He is married with two children and works at a petroleum tank farm with exposure to benzenes and industrial solvents. His physical exam upon admission was significant for fever of 39.1 C, marked diaphoresis, tenderness to palpation in the lower extremities bilaterally, blanching maculopapular rash on the legs bilaterally and left forearm, and subcentimeter mobile, nontender inguinal lymph nodes bilaterally. Myalgias and fevers continued throughout the hospital stay. His myalgias were only moderately relieved by the aggressive use of opiates and NSAIDs. The patient continued to complain of the same symptoms throughout his hospital stay during which he was evaluated for fever of unknown origin.
Laboratory evaluation was significant for ESR 66 mm/hr, C-reactive protein 10.79 mg/L, creatinine kinase 34 U/L, and lactate dehydrogenase 117 U/L. His complete blood count, liver, kidney and thyroid function tests were all within normal limits, as were his serum electrolytes, iron studies, uric acid, amylase, proteins, and immunoglobulins. Serial blood, urine, and sputum cultures, including mycobacterium, were negative. Serologic testing was negative for HIV, EBV, CMV, HBV, HCV, and Syphilis. A PPD was also negative. His EKG, chest X-ray, and abdominal sonography were normal. Testing for the following autoimmune factors was negative: ANA, anti-dsDNA, RF, anti-smith, anti-RNP, anti-SSA, anti-SSB, and CCP.
A malignancy work-up included bone marrow examination. Core biopsy, aspirate, flow cytometry, molecular pathology, immunohistochemistry, and cultures (for tuberculosis, bacteria, and fungi) were all unrevealing. Flow cytometry of peripheral blood was normal, no atypical cells were identified by peripheral smear, and there was no M-spike detected in serum or urine. Whole body PET/CT scan showed hypermetabolic retroperitoneal enlarged lymph nodes in the left paraaortic region at the level of the renal vessels (largest 1.7 x 2.5 cm) and minimally active lymph nodes in the following regions: right axillary region (1.8 cm), right lower paratracheal region (1.5 cm), right upper lung (8 mm), retrocaval, common iliac, internal iliac and obturator regions bilaterally and left external iliac (all subcentimeter), and the inguinal region bilaterally (largest 1.2 cm).
CT-guided aspiration biopsy of the retroperitoneal periaortic lymph node (Figure 1) showed atypical lymphoid proliferation of small lymphocytes, which were polyclonal by flow cytometric analysis. Surgical consultation was requested for an excisional biopsy of the periaortic lymph node; however, this was deferred due to unacceptable risk related to anatomical location of the node.
The patient was given the presumptive diagnosis of a low-grade lymphoproliferative disorder and in addition to careful expectant management, an empiric trial of prednisone was started despite the risk of losing diagnostic lymph node architecture. The patient was discharged and had outpatient follow-up one week later. Over the next several weeks, the patient noted a subjective improvement in his symptoms. However, attempts to taper the prednisone dose resulted in a relapse of fevers and myalgias.
Although very atypical in presentation, the diagnosis of familial Mediterranean fever was considered given the robust response to steroids and his Armenian descent. Genetic studies were performed and an empiric trial of colchicine 0.6 mg daily was also initiated. The patient reported a near immediate relief of symptoms and was then able to be tapered off of prednisone completely. One month later, the MEFV genetic results were returned, which confirmed the diagnosis. His genetic tests were significant for a complex heterozygous genotype with the three mutations: E148Q, P369S, and A744S. The patient's mother was also genotyped to determine allelic distribution and risk of inheritance. The patient's mother's test was significant for heterozygosity at the A744S locus. The patient's father was not willing to undergo genetic counseling or testing but denies any symptoms that might be attributed to FMF. Thus, the father's presumed haplotype E148Q/P369S is likely not sufficient to produce any symptoms or clinical phenotype.
Three months later, a follow-up PET scan was performed to evaluate the patient's previously identified lymphadenopathy (Figure 2). The study revealed near resolution previous paraaortic lymph node and resolved axillary and pelvic lymphadenopathy. However, new extensive hypermetabolic mediastinal and hilar lymphadenopathy were identified, revealing new right upper paratracheal node (1.7 cm), enlarging right lower paratracheal node (1.6 cm), subcarinal node (2.7 cm), and bilateral hypermetabolic hilar lymphadenopathy. At this point, several core needle biopsies of the subcarinal and peritracheal lymph nodes were performed under CT-guidance. Pathologic examination showed nonspecific reactive heterogeneous population of lymphocytes and was negative for granulomatous and amyloidal disease. Molecular pathology, immunohistochemistry, and flow cytometry were unremarkable.
Despite these findings, the patient continued to do well and remained symptom-free on colchicine.