Dilemma between knife and needle for acute abdominal pain in familial Mediterranean fever: Two case reports and literature review

Abstract

BACKGROUND

Acute abdominal pain in children often raises concern for surgical emergencies such as appendicitis. However, autoinflammatory disorders, including familial Mediterranean fever (FMF), may mimic acute abdomen, leading to diagnostic confusion and potentially unnecessary surgeries.

CASE SUMMARY

We present two contrasting pediatric cases, both of whom initially presented with acute right lower quadrant abdominal pain and tenderness. The first was a 5.5-year-old girl with fever who underwent appendectomy despite no sonographic evidence of appendicitis, yet her clinical score (Alvarado score) was highly suggestive of appendicitis. The second was a 5.5-year-old boy who was afebrile but had abdominal sonographic findings of a slightly inflamed appendix. He improved with conservative management and intravenous antibiotics. Upon second presentation, both were ultimately diagnosed with FMF.

CONCLUSION

FMF can mimic appendicitis in children; careful history, clinical suspicion, and judicious imaging help prevent unnecessary surgery during acute attacks.

Key Words: Abdominal ultrasonography; Acute abdomen; Acute appendicitis; Alvarado score; Familial Mediterranean fever; Peritonitis; Non-operative management; Case report

Core Tip: Children with familial Mediterranean fever (FMF) can present with acute abdominal attacks that resemble acute appendicitis. Diagnostic discrimination is challenging due to mimicry in clinical, laboratory, and even some radiological findings. We present two children with acute abdominal pain: One was managed surgically despite the lack of radiological evidence of appendicitis. By contrast, the other was managed conservatively despite radiological findings of a slightly inflamed appendix. Both were ultimately diagnosed with FMF. This highlights the importance of differentiating the causes of acute abdominal pain by maintaining a high index of suspicion for FMF, particularly in endemic areas of the Mediterranean basin.

INTRODUCTION

Familial Mediterranean fever (FMF) is a complex genetic and clinical autoinflammatory disorder characterized by self-limiting recurrent attacks of fever, serositis, arthritis, and erysipelas-like lesion. It has a high prevalence in the Mediterranean basin[1] and is caused by autosomal recessive mutations in the MEditerranean FeVer (MEFV) gene, which encodes the pyrin protein[2]. These mutations disrupt the ability of pyrin to regulate inflammation, leading to uncontrolled pyrin inflammasome activation, elevated interleukin-1β secretion, and autoinflammation[3]. Diagnosis is primarily clinical and may be supported by genetic testing; however, its absence does not preclude diagnosis[4].

Acute appendicitis is the most common indicator for emergency abdominal surgery. Early appendicitis may present atypically, and it is difficult to distinguish from a myriad of gastrointestinal, genitourinary, and gynecological conditions[5]. The diagnosis of acute appendicitis is a constellation of history, physical examination, coupled with laboratory investigations, and supplemented by selective focused imaging[6].

It is difficult to differentiate FMF attacks from acute appendicitis due to overlap in clinical presentation and laboratory findings, in addition to inconclusive radiological studies that expose FMF patients to unnecessary surgery[7]. The current report presents two children, exploring the dilemma in distinguishing the conditions.

CASE PRESENTATION

Chief complaints

Case 1: At first presentation, a 5.5-year-old girl presented with acute right lower quadrant abdominal pain, fever, and vomiting. At second presentation, she presented with acute lower abdominal pain and fever.

Case 2: At first presentation, a 5.5-year-old boy presented with acute abdominal pain, diarrhea, and vomiting, but no fever. At second presentation, he presented with acute abdominal pain and fever.

History of present illness

Case 1: At first presentation, the patient presented with a sudden onset and progressive course of abdominal pain for 1 day. These symptoms were followed by repeated vomiting and fever. There was loss of appetite. At the second presentation, 2 years later, the patient presented with sudden onset of acute lower abdominal pain and fever. This abdominal pain was sometimes accompanied by fever and occasionally by leg pain. There was no vomiting or diarrhea.

Case 2: At first presentation, the patient presented with a sudden onset of severe abdominal pain for 2 days with diarrhea and vomiting, but no fever. He sought medical advice and was treated for gastroenteritis; however, his symptoms did not improve, and his abdominal pain progressively worsened. At the second presentation 2 weeks later, he presented with generalized abdominal pain and fever, which partially improved with antipyretics. There was no vomiting or diarrhea.

History of past illness

Case 1: At first presentation, the patient’s history was unremarkable. At the second presentation, she had recurrent abdominal pain, sometimes associated with fever and occasionally with leg pain.

Case 2: The child had a history of recurrent severe leg pain with fever for the preceding 2 months. The pain was limited to the knee joint with limitation of movement but no joint swelling. The joint pain was temporarily relieved by analgesics for nearly 1 hour, then it recurred. Tests revealed elevated anti-streptolysin-O titers [(ASOT) = 900 IU/mL; normal ≤ 400 IU/mL], normal erythrocyte sedimentation rate [erythrocyte sedimentation rate (ESR) = 14/28 mm/hour; 1^st/2^nd hour; normal = 15/30], and microcytic hypochromic anemia [hemoglobin = 11 g/dL (normal = 11.5-13.5 g/dL); mean corpuscular volume = 56 fL (normal = 80-96 fL)]. He was prescribed an injection of long-acting penicillin every 2 weeks for presumed rheumatic arthritis with no satisfactory improvement except for partial relief of leg pain with analgesics. The diagnosis of rheumatic arthritis was later reconsidered and ruled out.

Personal and family history

Case 1: The patient is the offspring of a consanguineous couple and has two siblings (one male and one female). No similar conditions have been reported in the family.

Case 2: The patient is the offspring of a non-consanguineous couple and has one sister. No similar conditions have been reported in the family.

Physical examination

Case 1: At the initial presentation, the patient appeared ill, with a flexed posture while walking. She was febrile (38.2°C) and had right lower quadrant abdominal pain with tenderness. At the second presentation, she was again febrile, with lower abdominal pain and tenderness. No other significant abnormalities were detected. The recurrent episodes of abdominal pain associated with fever, and occasionally with leg pain, raised suspicion for FMF.

Case 2: At the initial presentation, the patient appeared ill but was afebrile. Abdominal pain was localized to the right lower quadrant with rebound tenderness, while the remainder of the clinical examination was unremarkable. At the second presentation, he had generalized abdominal pain accompanied by fever and continued to experience leg pain. The recurrence of abdominal pain, presence of fever, and recurrent leg pain raised suspicion for FMF.

Laboratory examinations

Case 1: At the initial presentation, the complete blood count (CBC) showed leukocytosis (14.3 × 10⁹/L) with neutrophilia (77%) and the C-reactive protein (CRP) level was 24 mg/L. At the second presentation, serum amyloid A (SAA) was elevated at 108 mg/L, ASOT was 540 IU/mL, and CRP was 20 mg/L.

Case 2: At the initial presentation, the CBC showed leukocytosis (13.0 × 10⁹/L) with neutrophilia (88%) and the ASOT remained elevated at 840 IU/mL. At the second presentation, SAA was 200 mg/L, ASOT was 600 IU/mL, and CRP was 91.9 mg/L. Polymerase chain reaction (PCR) analysis of the MEFV gene revealed a compound heterozygous mutation (M680I/E148Q).

Imaging examinations

Case 1: At the initial presentation, abdominal ultrasound revealed an inflamed small bowel and right colon with multiple mesenteric lymphadenitis but no evidence of appendicitis. At the second presentation, abdominal ultrasound showed mesenteric lymphadenitis and mild splenomegaly.

Case 2: At the initial presentation, abdominal ultrasound revealed inflammation of the right colon and terminal ileum with hypoechoic wall thickening and a slightly inflamed appendix. Ultrasound was repeated each day for 3 consecutive days and showed a gradual improvement of the inflamed appendix and intestine. At the second presentation, the abdominal ultrasound was normal. Echocardiography was normal.

MULTIDISCIPLINARY EXPERT CONSULTATION

Case 1

At the initial presentation, the patient was referred for pediatric surgical consultation. Appendicitis was ruled out, and symptomatic treatment was prescribed, with a recommendation to repeat the abdominal ultrasound the following day. On reassessment, the fever had partially subsided with antipyretics, while the abdominal pain became generalized, with persistent right lower quadrant tenderness. Ultrasonography demonstrated findings unchanged from the previous examination. At the parents’ request, a second pediatric surgical opinion was obtained, and appendectomy was recommended based on a significant Alvarado clinical score, which suggests surgery for scores ≥ 7 points[8]. The patient’s score was 7 (Table 1).

Table 1 Alvarado score of case 1.

Feature	Points	Patient score
		Yes/no	Points
Signs
Tenderness in the right lower quadrant	2	Yes	2
Elevated temperature	1	Yes	1
Rebound tenderness	1	No	0
Symptoms	1
Anorexia	1	Yes	1
Nausea/vomiting	1	Yes	1
Migration of pain	1	No	0
Laboratory values
Leukocytosis (> 10000/mm³)	2	Yes	2
Shift to the left (> 75% neutrophils)	1	No	0
Total points	10		7

Score 1-4: Discharge; score 5-6: Observe; score 7-10: Surgery.

Case 2

The patient was referred for pediatric surgical consultation, and conservative management with parenteral antibiotics was initiated, with follow-up planned for the following day. Abdominal ultrasonography was performed over 3 consecutive days and demonstrated gradual improvement in the inflamed intestine and appendix. The patient’s symptoms resolved within 4 days.

FINAL DIAGNOSIS

Both patients were diagnosed with FMF.

TREATMENT

Case 1

At the initial presentation, the patient had an appendectomy. At the second presentation, she received 0.03 mg/kg/day colchicine.

Case 2

At the initial presentation, the patient received intravenous antibiotics and antipyretics for radiologic appendicitis and was already receiving long-acting penicillin. At the second presentation, colchicine was initiated at a dose of 0.03 mg/kg/day. In the absence of migratory arthritis, with normal echocardiographic findings, and given the lack of a sustained clinical response to penicillin therapy, the diagnosis of rheumatic arthritis was reconsidered and ultimately ruled out. Long-acting penicillin was subsequently discontinued due to the absence of a clear indication. Recurrent leg pain was managed symptomatically until the diagnosis of FMF was established.

OUTCOME AND FOLLOW-UP

Case 1

After 3 months, the attacks had completely resolved, and the SAA level returned to normal (6.2 mg/L).

Case 2

At 3-week follow-up, the patient showed marked clinical improvement, accompanied by a decline in inflammatory markers. SAA was 16.1 mg/L, CRP was 3 mg/L, and ASOT was 300 IU/mL.

DISCUSSION

FMF is characterized by recurrent episodes of polyserositis, with attacks typically manifesting as fever, peritonitis, and arthritis. FMF-related peritonitis is a well-recognized source of diagnostic confusion, as it frequently mimics an acute surgical abdomen, particularly acute appendicitis. Given that acute appendicitis is the leading cause of emergency abdominal surgery, surgical interventions are frequently performed in patients experiencing FMF-related abdominal attacks[9]. Masri et al[10] reported that 1 in 2600 Arab children have FMF, with a gene frequency of 1 in 50. The most common variants detected are M694V and V726A, followed by E148Q and M694I[11]. This high regional prevalence carries considerable risk of exposing a large population of FMF patients to unnecessary surgery.

In addition to its clinical overlap, the laboratory findings of FMF pose further challenges[12]. Patients display high levels of inflammatory reactants, including CRP, ESR, and SAA, accompanied by leukocytosis and neutrophilia. Importantly, although the disease name is termed “familial Mediterranean fever”, some patients may not experience fever[13].

These diagnostic challenges are clearly illustrated in the first case. The main presentation was that of peritonitis with an inflamed small bowel and right colon, without ultrasonographic evidence of appendicitis. Abdominal ultrasound is a useful and safe diagnostic tool for acute appendicitis; however, it is not 100% accurate. The reported sensitivity and specificity vary considerably (44%-100% and 47%-99% respectively), largely reflecting operator expertise[14]. Consequently, reliance on ultrasonography alone may be insufficient in equivocal cases.

To address these limitations, clinical scoring systems combined with ultrasound have improved the diagnosis of acute appendicitis. The Alvarado score can help in excluding or suggesting acute appendicitis[15]. In case 1, persistent localized tenderness, fever, and a high Alvarado score (7/10 points) prompted surgical intervention despite inconclusive ultrasonography.

Alvarado score has been validated in children with acute appendicitis. A meta-analysis reported lower values of 76.0% sensitivity and 71.0% specificity and concluded that the Alvarado score can be an auxiliary tool for diagnosing acute appendicitis in children, but that relying on the Alvarado score alone is not recommended for the diagnosis of acute appendicitis[16]. In addition, Rafiei Tabatabaei et al[17] reported that the Alvarado score does not provide adequate positive predictive value in the pediatric population for clinical practice as a safe way for determining whether surgery is necessary.

Moreover, Awayshih et al[18] reported that the Alvarado score was positive in non-acute appendicitis conditions. Several score components, such as fever, nausea, vomiting, right lower quadrant tenderness, leukocytosis, and neutrophilia, are also common in other conditions that mimic acute appendicitis, such as gastroenteritis, intussusception, and ovarian disorders. Similarly, autoinflammatory conditions such as FMF may predispose to a false-positive Alvarado score in the setting of abdominal attacks.

The timing of presentation represents another critical factor contributing to misdiagnosis. Although peritonitis is one of the presentations of FMF, it is hard to diagnose at the first attack, as recurrence of self-limiting attacks is a cornerstone for FMF diagnosis. Accordingly, FMF was not initially suspected in the first patient until she presented 2 years later with recurrent abdominal pain associated with fever and leg pain.

When diagnostic uncertainty persists, further imaging may be warranted. In cases where clinical suspicion for acute appendicitis remains high despite inconclusive ultrasonographic findings, abdominal computed tomography (CT), particularly contrast-enhanced CT, can provide valuable additional diagnostic information. CT has superior sensitivity and specificity compared with ultrasound in differentiating appendicitis and other abdominopelvic causes of acute abdomen[19]. Contrast-enhanced CT can show isolated peri-appendicitis. Peri-appendicitis without appendiceal inflammation is defined as serosal inflammation of the appendix without involvement of the muscular or mucosal layers and has emerged as an FMF-specific entity[20]. In the first case, CT was not performed. This may represent an overlooked point of presurgical evaluation and a missed opportunity for more comprehensive preoperative assessment.

Even after surgical intervention, diagnostic ambiguity may persist. Following appendectomy, recurrence of abdominal pain in the first patient was initially attributed to post-appendectomy syndrome after excluding other causes for her abdominal pain. This entity encompasses persistent or recurrent right lower abdominal pain after appendectomy and may result from preoperative misdiagnosis or postoperative complications such as adhesions, operative scar tenderness, or stump appendicitis. Other possibilities may be related to missed Meckel’s diverticula, urological pathology, or inflammatory condition[21]. In retrospect, it is now evident that the patient’s recurrent symptoms were attributable to FMF attacks rather than surgical sequelae.

Genetic evaluation did not provide diagnostic clarity in this case. The first patient tested negative for MEFV mutation, which did not rule out FMF. Although FMF was originally defined as an autosomal recessive disorder, approximately 25% of patients with FMF carry only one MEFV gene mutation[22], and 10%-20% carry no mutations in MEFV[23]. Studies in the Egyptian pediatric population of 1387 FMF children have demonstrated high rates (57%) of PCR negativity[24], reinforcing the primacy of clinical diagnostic criteria[25].

The ambiguity in differentiating FMF attacks from acute appendicitis is illustrated by the fact that FMF patients were previously offered elective laparoscopic appendectomy[26]. The rationale was to avoid future appendicitis being assigned to FMF attacks, delayed diagnosis of appendicitis, and to prevent perforation. The strategy was later abandoned, primarily due to the risk that surgery may induce an FMF attack from intra-abdominal adhesions[7].

The second patient followed a different yet equally instructive diagnostic course. In this patient, recurrent arthralgia, pallor, and markedly elevated ASOT led to an initial diagnosis of rheumatic arthritis and treatment with long-acting penicillin. Although ASOT significantly increases in rheumatic fever, high levels have also been reported in 50%-60% of FMF patients with no evidence of streptococcal infection up to 4 months prior to ASOT testing[27]. The consequent presentation with acute abdomen, combined with a history of leg pain, ultimately prompted reconsideration of the diagnosis and raised the suspicion of FMF. After careful cardiac evaluation, long-acting penicillin was discontinued.

The presence of microcytic hypochromic anemia in the second patient may reflect chronic inflammation, iron deficiency, or a combination of both. Anemia is commonly reported in a significant proportion (26.6%) of pediatric FMF cases and warrants appropriate evaluation and correction[28,29].

From a management perspective, the second case was treated conservatively without surgical intervention. Although operative management of acute appendicitis is the standard-of-care, accumulating evidence supports non-operative management in selected cases of uncomplicated appendicitis[30]. In this instance, mild appendiceal inflammation, clinical stability, absence of systemic toxicity, and documented improvement on serial ultrasonography supported conservative treatment. This decision was consistent with current evidence indicating that non-operative treatment of uncomplicated appendicitis in children is safe and feasible[31].

Genotype-phenotype correlations provide further insight into disease heterogeneity. The compound heterozygous M680I/E148Q genotype identified in the second patient has been associated with variable clinical expression, with abdominal pain and arthralgia being prominent features[32]. M680I is considered a pathogenic mutation linked to a severe form of the disease[33], while E148Q is associated with a milder form of the disease[34] and may modulate disease expression when combined with another pathogenic allele[35]. Yildirim et al[36] reported that patients with the M680I/E148Q genotype present with prominent abdominal pain (in 83.7% and 78.4% respectively) and arthralgia (in 78.4% and 48.2 respectively) when compared to other patients.

Other studies revealed that the M694V mutation is associated with more frequent and severe attacks, prominent abdominal serositis, and a higher risk of amyloidosis, while mutations such as M680I and V726A are associated with intermediate disease severity[37]. Contrarily, Albayrak et al[38] reported that patients without the M694V/M694V genotype (86%) had a higher frequency of abdominal attacks than did those with such genotype (67%) (P < 0.05).

Reports on the genotype/phenotype correlation are not consistent, implying that FMF severity is influenced not only by MEFV mutations but also by additional genetic modifiers, epigenetic mechanisms, and environmental factors, which together shape individual disease expression.

Symptoms and severity can vary among affected individuals with the same MEFV variant, even among members of the same family[39]. Based on twin studies, the relative contribution of MEFV, non-MEFV genetic factors, and environmental factors on phenotypic variation is estimated at a ratio of 6:1.5:1, respectively[40]. The known MEFV independent genetic modifiers are polymorphisms of interleukin-1β and alpha/alpha genotype for SAA protein 1 gene, which increases the risk of developing renal amyloidosis. Moreover, epigenetics, such as microRNAs and DNA methylation, may contribute to phenotypic variation.

The influence of specific environmental factors on the FMF phenotype has not been defined, but country of residence is repeatedly reported as an independent modifier, with Turkey, Armenia, and the Middle East increasing the risk of severe disease and renal amyloidosis[41]. Emerging evidence suggests that dietary patterns may influence FMF disease severity. Greater consumption of pro-inflammatory foods such as processed foods, diets high in omega-6 fatty acids, and foods rich in advanced glycation and lipoxidation end-products is associated with increased attack severity, whereas diets rich in fruits, vegetables, fiber, omega-3 fatty acids, and antioxidant- and flavonoid-containing foods improved symptom management and quality of life[2].

There is an urgent need to develop more specific diagnostic approaches to discriminate acute appendicitis and FMF abdominal attacks. The use of new genetic biomarkers to diagnose pediatric appendicitis[42] and the novel inflammatory biomarkers of FMF in conjunction with SAA, should be evaluated in the future to improve the discriminative ability in such situation[43,44]. This approach would help early diagnosis and appropriate therapeutic intervention without delay.

In the current report, both cases were treated with colchicine, and both showed a favorable clinical and laboratory response. CRP and SAA are key inflammatory markers in FMF. SAA is particularly valuable for monitoring disease activity and amyloidosis risk[44]. Updated 2025 European League Against Rheumatism guidelines recommend a level of SAA below 10 mg/L as a treat-to-target laboratory reference. If SAA remained elevated in-between attacks in a treatment-compliant patient, a dose escalation is then indicated[12].

Lifelong colchicine therapy is the cornerstone of management. It suppresses the inflammatory process, normalizes acute phase reactants, and protects from amyloidosis. Colchicine is generally safe. Side effects include gastric upset, bone marrow suppression, and hepatitis. Accordingly, pre-treatment and follow-up monitoring of CBC, kidney, and liver function are essential. Microalbuminuria, as evaluated by urinary albumin/creatinine ratio, is an indicator for early kidney affection that points to interference and modulating therapy to protect against the occurrence of amyloidosis[12].

CONCLUSION

In conclusion, in FMFendemic regions, clinicians must maintain a high index of suspicion for FMF in children presenting with acute abdomen. These cases underscore the substantial risk of misdiagnosis when FMF mimics appendicitis. Careful integration of clinical history, laboratory findings, imaging results, and clinical scoring systems is essential to avoid unnecessary surgical intervention. Early recognition of FMF and timely initiation of colchicine therapy are fundamental to improving long-term outcomes and preventing disease-related complications.