A 9-year-old Middle Eastern boy developed abdominal pain and diarrhea for 7 days before presenting to an external clinic. Stool analysis identified Entamoeba histolytica cysts, leading to a 10-day metronidazole course (25 mg/kg/d). The family first noted abdominal distention on day 3 of therapy. Despite full antimicrobial compliance, distention progressed over the next 3 weeks alongside worsening malaise and anorexia. The patient is referred to our hospital 1 month after initial symptoms onset. There is no history of travel, sick contact, or animal exposure. Family history is significant for Crohn’s disease (CD) in 2 paternal uncles, diagnosed in adolescence, but negative for recurrent fevers, autoimmune disorders, or consanguinity. On physical examination, the patient appears pale and lethargic, with dry mucous membranes and mild periorbital shadows. Vital signs reveal tachycardia (110 beats per minute), normotension (blood pressure, 110/70 mm Hg), and an afebrile status (36. 8 °C 98. 2 °F). Abdominal inspection demonstrates marked, symmetric distention with taut, glistening skin. Palpation elicits diffuse tenderness without guarding or rebound, and percussion confirms shifting dullness. A fluid wave is elicited too, consistent with significant ascites. There is no evidence of hepatosplenomegaly. Bowel sounds are normoactive, and no abdominal masses or lymphadenopathy are detected. Examination of the skin reveals no rash, erythema, or ecchymoses, and joints are without swelling, warmth, or limited range of motion. The remainder of the physical examination is unremarkable. Abdominal ultrasonography confirms large-volume ascites (2. 3 L) with no other abnormal findings. The child is admitted for further workup and management. Initial evaluation reveals neutrophilic predominance (78%) on complete blood count (CBC), elevated inflammatory markers (erythrocyte sedimentation rate, 49 mm/h; C-reactive protein CRP, 34 mg/L), hypoalbuminemia (3. 0 g/dL), and increased fecal calprotectin (877 μg/g). Renal function tests, electrolytes, and liver enzymes are unremarkable. Ascitic fluid analysis confirms exudative ascites (serum-ascites albumin gradient SAAG, 0. 5 g/dL; protein, 4. 5 g/dL). See Table 1 for initial laboratory investigation results. The Gram stain of ascitic fluid demonstrates gram-positive cocci. These are subsequently identified as coagulase-negative staphylococci, a finding that is most likely indicative of contamination. Further evaluation includes autoimmune serology, which shows negative results for antinuclear antibodies (ANAs, C; p. Val726Ala), diagnostic of FMF. 9, 10 Colchicine (0. 5 mg twice per day) was started immediately upon genetic confirmation. Prednisone was tapered and stopped uneventfully. FMF is an autosomal recessive autoinflammatory disorder caused by pathogenic variants in the MEFV gene, which encodes pyrin, a critical regulator of inflammasome activity. 7, 8 The homozygous MEFV c. 2177T>C (p. Val726Ala) mutation identified in this case disrupts pyrin’s ability to suppress interleukin-1β (IL-1β) release, leading to uncontrolled neutrophilic inflammation and recurrent serositis. 8, 11 FMF typically manifests as recurrent fever (85% of cases), acute serositis (92%), and self-limited arthritis (40%). Chronic ascites, observed in our case, represents an atypical manifestation of FMF, documented in rare case reports and linked to persistent IL-1β–mediated neutrophilic inflammation of peritoneal membranes. 12, 13Elevated fecal calprotectin in the patient initially pointed toward inflammatory bowel disease (IBD). However, increased fecal calprotectin is nonspecific for IBD, as levels >200 μg/g occur in bacterial gastroenteritis (eg, Salmonella), enteropathy induced by nonsteroidal anti-inflammatory drugs, and systemic inflammatory disorders such as FMF. 14 Studies demonstrate that fecal calprotectin levels in FMF patients (median, 192 μg/g) can approach those seen in mild IBD, likely due to subclinical intestinal inflammation secondary to peritoneal and mesenteric serositis rather than mucosal ulceration. 14 This distinction is critical, as colonoscopy in our case revealed no granulomas, crypt architectural distortion, or other hallmarks of IBD, despite the significantly elevated calprotectin level. The discordance between serosal inflammation (driving calprotectin elevation) and mucosal integrity (preserved on endoscopy) underscores the necessity of integrating genetic testing with clinical and endoscopic findings to differentiate FMF from IBD. 9, 14A homozygous splicing variant in IRF5 (NM₀32643. 4: c. -13 + 3G>T) was detected as an incidental finding on WES, and is known to be associated with increased risk for systemic lupus erythematosus (SLE), although the child has not developed any symptoms related to the condition. 15 While homozygous IRF5 variants amplify SLE susceptibility compared with heterozygous states (odds ratio, 2. 5–3. 0 vs 1. 5–1. 8), meta-analyses show homozygous rs2004640-T/T genotypes confer 1. 8- to 2. 2-fold increased risk vs wild type. Epidemiological studies demonstrate SLE patients have 1. 6 to 3. 2 times higher FMF prevalence vs general populations, with shared IL-1β/IFN-α pathway interactions mediated through IRF5’s dual role in inflammasome priming and interferon signaling. 15 The patient exhibited no SLE-related manifestations. Biannual monitoring for proteinuria, CBC abnormalities, and ANA/double-stranded DNA (anti-dsDNA) is advised, while anti-Smith antibody screening lacks evidence in asymptomatic carriers. The patient will be monitored during regular follow-up visits, but our primary focus remains FMF management. At 2-year follow-up, the child remains asymptomatic on daily colchicine (1 mg), with normal inflammatory marker levels, and no ascites recurrence on serial ultrasonography. Growth parameters and renal function remain within normal limits, and annual serum amyloid A (SAA) monitoring shows no evidence of amyloidosis. SAA should be monitored every 3 months during colchicine dose escalation in active FMF to assess subclinical inflammation and amyloidosis risk. Annual monitoring is adequate for patients who remain stable. 8, 16 Persistent SAA elevation (>10 mg/L) drives AA amyloid deposition, particularly in high-risk genotypes. 11, 16 Our patient’s favorable renal and inflammatory outcomes align with cohort studies demonstrating that colchicine initiation within 12 months of symptom onset reduces amyloidosis incidence by 94% to 97% (vs late/no treatment) while achieving complete attack control in 85% to 90% of compliant patients. 7, 8, 16 This protective effect correlates with maintaining SAA levels <10 mg/L, which stabilizes renal function in 92% of early-treated cases. Chronic ascites, even in the absence of fever, warrants consideration of FMF, especially in populations or regions with a high prevalence of the disease. Elevated fecal calprotectin in FMF mirrors IBD but reflects serosal, not mucosal, inflammation. Endoscopy remains the diagnostic procedure to avoid misdiagnosis. In complex cases such as FMF with atypical presentations, WES can provide definitive molecular diagnosis to confirm clinical suspicion and guide long-term management. Early colchicine initiation is associated with prevention of amyloidosis and achievement of disease remission in most patients with FMF.
Hassoun et al. (Wed,) studied this question.