Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disorder; it is characterized by self-limited episodes of fever, polyserositis and elevated inflammatory markers.
While symptoms are nonspecific, FMF should be suspected in patients with recurrent febrile episodes accompanied by peritonitis, pleuritis, pericarditis and elevated C-reactive protein, especially among people of Ashkenazi Jewish descent and other at-risk ethnic groups.
Treatment with colchicine prevents clinical flares and the amyloidosis and renal failure that can be associated with the disease.
Delayed diagnosis can have grave consequences for patients, including unnecessary surgeries and associated complications.
In 2015, a 28-year-old woman of Ashkenazi Jewish descent presented to the medical genetics clinic with concerns about flexible joints, easy bruising, stretchable skin, chronic back pain and mild scoliosis since childhood. Differential diagnoses included connective tissue disorders such as Ehlers–Danlos (EDS), Marfan and Loeys–Dietz syndromes. She had an elevated Beighton score (6/9), reflecting joint hypermobility, and none of the features consistent with Marfan syndrome or Loeys–Dietz syndrome. Her echocardiogram was normal and her family history was unremarkable. A 13-gene panel was negative for EDS, and she was given a clinical diagnosis of hypermobile EDS.
Over the next 5 years, the patient developed recurrent episodes of fever, elevated C-reactive protein (CRP), abdominal pain and other symptoms (Table 1). Although most episodes lasted 1–3 days, the patient often noted recurrence or worsening of symptoms after interventions, such as fever or abdominal pain after various surgeries.
Chronology of events for a 28-year-old woman with familial Mediterranean fever
In 2016, the patient had an ovarian cystectomy for suspected ovarian torsion (no torsion found), an appendectomy for suspected appendicitis (no appendicitis found) and an endoscopic retrograde cholangiopancreatography with stent placement for presumed chronic pancreatitis. In 2017, she received diagnoses of cholecystitis, chronic pancreatitis and malnutrition, which led to a cholecystectomy and central line placement for total parenteral nutrition. She also had chest pain and shortness of breath with pleural effusions; presumed volvulus, which led to emergency laparotomy, with no evidence of volvulus intraoperatively; and thrombophlebitis of the internal jugular vein. Intermittent abdominal pain, distension and nausea were attributed to colonic dysmotility related to hypermobile EDS. She had serious malnutrition, and her body mass index dropped from 20.3 to 15.8, which led to placement of a gastrojejunostomy tube to support enteral feeds and avoid complications associated with prolonged total parenteral nutrition.
The patient’s clinical status deteriorated through 2018, with flares of abdominal pain, constipation and feeding intolerance, which continued to be attributed to colonic dysmotility secondary to hypermobile EDS. Gram-negative enteric bacteria were identified on blood cultures twice, and were attributed to the impact of her EDS on the integrity of the bowel wall leading to bacterial translocation. Total colectomy and ileostomy were performed, followed by prolonged recovery, with recurrent fevers, elevated CRP and abdominal pain. After a period of stability, reversal of her ileostomy with J-pouch formation was complicated by postoperative abdominal pain, fever and elevated CRP. In 2019, she had episodes of left lower quadrant pain and tenesmus, diagnosed as pouchitis and managed with antibiotics. In 2020, the patient had episodes of pelvic pain and fever lasting 2–3 days, elevated inflammatory markers, pericardial effusion, hepatosplenomegaly and blood cultures positive for Escherichia coli. She was given a diagnosis of urosepsis and prescribed antibiotics.
In 2020 the patient sought a genetics reassessment. No clinical diagnosis was made; however, it was thought that her history could not be explained by hypermobile EDS. A geneticist ordered whole exome sequencing, which found compound heterozygous pathogenic DNA variants in the MEFV gene, namely c.2084A>G (p.Lys695Arg) and c.2177T>C (p.Val726Ala), consistent with familial Mediterranean fever (FMF).
The patient was referred to a rheumatologist and started on colchicine 0.6 mg once a day. During the 2 years since she started taking colchicine, she has had 2 mild, self-resolving flares of FMF that did not require hospital admission or intervention. She has returned to her baseline strength and nutritional status, and has stopped all other medications. She has no evidence of renal amyloidosis; her serum creatinine (71 mmol/L) and urea (4.4 mmol/L) are within normal ranges, and she has no protein in her urine.
Discussion
Familial Mediterranean fever is the most common monogenic autoinflammatory disorder; it is characterized by self-limited episodes of fever, polyserositis and elevated inflammatory markers.1–4 The condition is associated with gain-of-function sequence variations in the MEFV gene that encodes for the pyrin protein, and results in uncontrolled production of interleukin-1β and an exaggerated inflammatory response.1,2,4 The disease manifests as recurrent bouts of fever, abdominal pain and chest pain that start abruptly and peak soon after onset, last for 1–4 days and then resolve spontaneously. Patients typically have no symptoms between attacks.2 Familial Mediterranean fever should be considered for patients who have undergone laparotomy or laparoscopy with no pathology identified. Stress, cold exposure, fat-rich meals, infections, vigorous exercise, surgery and the menstrual cycle may all provoke an attack. Familial Mediterranean fever may present uncommonly as erysipelas-like erythema, aseptic meningitis, recurrent urticaria or vasculitis.3
Laboratory abnormalities during attacks are nonspecific and include elevated systemic markers of inflammation, leukocytosis with neutrophilia, and elevated erythrocyte sedimentation rate, CRP and fibrinogen. Serum amyloid A protein is also elevated during attacks, but is not routinely measured unless a diagnosis of FMF is suspected.3 One of the long-term complications of untreated disease is amyloidosis of the kidneys, which has been reported to be present in about 12% of patients with FMF; it can have severe complications, including renal failure. 1,2 Amyloidosis may also develop in the spleen, liver, gastrointestinal tract, thyroid and testes. Small bowel obstruction may develop because of recurrent peritonitis and adhesion formation. Before colchicine was used in the treatment of FMF, infertility was common and was thought to be caused by obstruction of fallopian tubes in females and testicular amyloidosis in males.2,3
Familial Mediterranean fever is common in people of Ashkenazi Jewish descent, with a substantial gene carrier rate (about 1:7.8).5 The prevalence is about 1 in 500 to 1 in 1000 among people of other at-risk ethnic descents, including those of Turkish, Armenian, Arabic, non-Ashkenazi Jewish, North African, Italian, Greek, Chinese and Japanese ancestry. Known risk factors include family history of FMF, present in 30%–50% of people with the condition, and belonging to an at-risk ethnic group.6 More than 95% of genetic carriers are asymptomatic; however, some individuals with a single mutation may manifest symptoms and may benefit from treatment with colchicine.1
Our patient’s many episodes of fever and abdominal pain led to different diagnoses, invasive procedures and complications. Intraoperative findings and postoperative pathology reports were often inconsistent with the initial diagnosis of hypermobile EDS, and hospital admissions were prolonged owing to postoperative flares of pain, fever and elevated CRP. Over the course of her illness, treating clinicians appeared not to have considered FMF.
Hypermobile EDS is the mildest subtype of EDS, with no life-threatening complications, although patients with hypermobile EDS can have various types of gastroesophageal dysmotility such as esophageal dysmotility, gastroparesis, small bowel or colon altered transit time or global dysmotility.7 However, unlike the vascular EDS subtype, hypermobile EDS does not cause bowel wall fragility or rupture. Genes for hypermobile EDS have not yet been identified. Vascular EDS and other EDS subtypes were highly unlikely in this patient, given her negative results from genetic testing. Hypermobile EDS would not explain this patient’s symptoms, except perhaps colonic dysmotility.7
After the patient developed new symptoms in 2015, genetics specialists were not consulted again until the patient requested a follow-up in 2020. She qualified for whole genome sequencing based on the Ministry of Health of Ontario’s testing criteria of severe functional impairment, multisystem involvement and progressive clinical course. When FMF or another periodic fever syndrome is suspected, a gene panel for periodic fever syndromes can identify pathogenic DNA variants. When variants of unknown clinical importance or single pathogenic DNA variants are found, a diagnosis can still be made based on clinical findings, with the help of diagnostic criteria such as the Eurofever-PRINTO classification criteria.1,8 Whole genome sequencing can be useful in patients with severe multisystem involvement, even in the absence of a clear diagnosis. A patient may also have more than 1 genetic disorder, as in our patient with FMF and hypermobile EDS.
Most patients with FMF are symptomatic by age 20 years.4 In hindsight, the patient had fevers with severe abdominal pain a few times a year, starting in early childhood. Familial Mediterranean fever should be considered in a differential for recurrent fevers, peritonitis and elevated CRP (Table 2).
Differential diagnosis for patients with periodic fevers and elevated inflammatory markers
Treatment with colchicine is effective, preventing FMF flares in more than 60% of patients and reducing the number of attacks in a further 20%–30% of patients. Colchicine can also prevent deposition of amyloid fibrils and subsequent renal failure.2–4,7,9 Anti–interleukin-1 biological therapy can be used in patients unresponsive to colchicine.2–4
The symptoms of FMF can mimic other conditions and, unfortunately, patients with FMF often experience years of misdiagnosis, unnecessary surgeries and prolonged hospital admissions. 4,6,10 Delays in diagnosis likely occur because of the lack of specificity in symptoms, and the relapsing and remitting pattern of disease. Furthermore, clinicians may not consider the disease in at-risk ethnic populations.4
The section Cases presents brief case reports that convey clear, practical lessons. Preference is given to common presentations of important rare conditions, and important unusual presentations of common problems. Articles start with a case presentation (500 words maximum), and a discussion of the underlying condition follows (1000 words maximum). Visual elements (e.g., tables of the differential diagnosis, clinical features or diagnostic approach) are encouraged. Consent from patients for publication of their story is a necessity. See information for authors at www.cmaj.ca.
Footnotes
Competing interests: None declared.
This article has been peer reviewed.
The authors have obtained patient consent.
Contributors: All of the authors contributed to the conception and design of the article. Kayla Richard and Sara Glazer drafted the first version of the manuscript and have contributed equally. All of the authors revised the manuscript critically for important intellectual content, gave final approval of the version to be published and agreed to be accountable for all aspects of the work.
This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is noncommercial (i.e., research or educational use), and no modifications or adaptations are made. See: https://creativecommons.org/licenses/by-nc-nd/4.0/
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