Tumor Necrosis Factor Receptor–associated Periodic Syndrome as a Cause of Recurrent Abdominal Pain in Identical Twins and Description of a Novel Mutation of the TNFRSF1A Gene

Tumor necrosis factor (TNF) receptor–associated periodic syndrome (TRAPS; Online Mendelian Inheritance in Man no. 142680) is an autoinflammatory disease caused by mutations in the gene TNFRSF1A, which encodes the TNF receptor superfamily 1A (TNFRSF1A), on the short arm of chromosome 12 (1,2). It was first described in a large Irish family but has since been reported in many ethnic groups (1,2). It is the most common autosomal dominant periodic fever syndrome. TRAPS is characterized by fever at irregular intervals with abdominal pain, localized myalgia, pleurisy, rashes, conjunctivitis, and periorbital edema. Symptoms can last days to weeks (1,2). Diagnosis is made by genetic sequencing of the TNFRSF1A gene, of which there are many known mutations. TRAPS is treated with anti-inflammatory medications, anti-TNF therapy, or interleukin-1 antagonists (1,3,4). We report the case of a novel mutation of the TNFRSF1A gene in identical twin brothers with varying clinical manifestations of TRAPS. An 11-year-old boy was referred to our pediatric gastroenterology clinic. He reported a history of recurrent abdominal pain, difficulty passing stool, and fevers up to 104°F lasting 1 to 3 weeks. These episodes occurred 3 to 5 times per year, starting around the age of 4. He also reported anorexia with weight loss (about 10 lb per episode in the last year, which was regained after each episode), night sweats, myalgias, arthralgias, and occasional pleuritic chest pain during these episodes, but denied any rashes, conjunctivitis, or periorbital edema. Interestingly, he had an identical twin brother with similar symptoms that started around the same age; however, his occurrences were much less frequent, less severe, and associated with less weight loss (about 5 lb per episode). Further family history demonstrated a similar clinical history in their father, grandfather, and paternal uncle, with no known renal or heart failure. On review of their father's medical record, he had multiple diagnoses of “gastroenteritis” as well. The patients’ father stated that he is of Irish, Dutch, English, Scotch, French, and German ancestry; however, the family has been in the United States for several generations. Physical examination when the twins were asymptomatic was largely unremarkable except for mild tenderness to palpation of the right lower abdomen of the index twin. Neither had periorbital swelling, serositis on musculoskeletal examination, or rashes. When visually comparing the twins, both were 60 inches tall, but the index patient appeared slightly more gaunt and had dark circles under his eyes, and weighed 90 lb (brother weighed 95 lb). Initial laboratory studies showed a normocytic anemia, thrombocytosis and elevated inflammatory markers and normal metabolic, ANA, immunoglobulin D, and complement studies. The less symptomatic twin's laboratory studies were completely normal (Table 1).TABLE 1: Baseline laboratory studies of the patient and his identical twinComputed tomography revealed scattered subcentimeter mesenteric lymph nodes but was otherwise normal. Upper and lower endoscopies were normal, as were biopsies. Celiac testing was negative. The patient was referred to the allergy and immunology division, where clinical and family history were concerning for a periodic fever syndrome. DNA sequencing of TNFRSF1A exons 2–5 was performed at GeneDx, showing substitution of exon 3, resulting in replacement of a cysteine codon with a tyrosine codon at amino acid position 102, denoted c.305 G>A at the cDNA level or p.Cyst102Tyr (C102Y) at the protein level. Although this specific mutation has never been published, missense mutations at the same amino acid positions have been previously published in association with TRAPS, C102R, and C102W (5). His twin brother and father were tested and found to have the same mutation. Due to the frequency and severity of his symptoms, patient started taking etanercept 50-mg autoinjector (1.2 mg/kg) weekly, which resulted in normalizing of his anemia and inflammatory markers. Parents were reluctant to use etanercept weekly, so we reduced his treatment to every 2 weeks. This kept him in symptomatic remission for the next year but caused increase of his inflammatory markers (Table 2).TABLE 2: Patient's laboratory studies before and after treatment with etanerceptDue to the patient's father and brother having milder and less frequent symptoms with normal baseline labs, we decided to treat them with corticosteroids as needed. During a 2-year period, the twin brother only required 1 burst of prednisone for 5 days. DISCUSSION We report 2 identical twins with TRAPS with a novel mutation of the TNFRSF1A gene. Our index patient has a classic presentation of TRAPS. It is notable that his twin brother has a much milder phenotype despite identical genotype and similar environmental factors, including diet and exposures (they were both homeschooled). Interestingly, the patients’ mother noted that the twin with the milder phenotype had an easygoing nature, whereas the index patient was always more anxious and stressed. Although the exact pathogenesis of TRAPS is not entirely clear (6), there are theories that there is impaired shedding or trafficking of the TNF receptor from the cell surface resulting in prolonged inflammation (6,7). Newer studies suggest that other cytokines may be involved, with some patients having increased NFκB activation (6). There is still much to be learned about disease-modifying factors, as seen in our 2 patients who have the same genetic makeup, and whether psychological stressors may play a significant role in the process. An article by Pelagatti et al (8) assessed health-related quality of life questionnaires on their pediatric patients with periodic fever syndromes. They found a correlation between their emotional and psychosocial domains and disease activity. It is not possible to assume causality, whether their disease activity affects their emotional and psychosocial well-being or if their inherent nature can modulate their disease. Although this case report is a limited observation, it is interesting to note their similarities and differences within the context of identical genetics and largely similar environment and exposures. As always, the question remains whether the psychosocial drives the disease or if it is the other way around. Epigenetics changes can be considered as a possible disease-modifying factor as well in any heritable disease. There are >80 mutations of TNFRSF1A associated with TRAPS (5). We present a new mutation at an amino acid position that has previously been associated with it. Our patient was successfully treated with low-dose etanercept, and less-affected family members responded to short courses of corticosteroids. Although amyloidosis, which affects about 10% of patients with TRAPS (1,7), is the main complication that determines prognosis and mortality, this patient's family does not have any known history of early renal or heart failure or any family members with early deaths. CONCLUSIONS In conclusion, we report a novel mutation of the TNFRSF1A gene in identical twins presenting with differing manifestations and response to etanercept. Our report expands on the spectrum of TRAPS, whether this exhibits varying penetrance within the same genotype, epigenetics changes, psychosocial factors, or other disease-modifying factors that may affect the phenotype. Finally, periodic fever syndromes should be considered in the differential diagnosis of any patient with the common pediatric complaints of recurrent fevers and abdominal pain.