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A Boy with Fever and Whorl Keratopathy To the Editor: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) and Fabry disease are both uncommon genetic disorders characterized by multisystem involvement (Table 1). We describe for the first time a patient with the coexistence of these 2 conditions.
A 9-year-old boy presented to our rheumatology clinic for evaluation for recurrent febrile episodes. About every 8 weeks he developed fever (up to 105°F), arthralgias, myalgias, headache, abdominal pain, nausea, vomiting, cough, and hyperparesthesias affecting the extremities. The year prior to his evaluation at our clinic he also developed decreased visual acuity and arthralgias and myalgias that were not associated with febrile episodes. Physical examination was remarkable for eyelid swelling, thinning of the subcutaneous tissue of the extremities, and presence of angiokeratomas. Ophthalmologic examination revealed subepithelial, anterior stromal whorl-like deposits, a characteristic infiltrate seen in Fabry disease. The finding of a reduced a-galactosidase A level measured in both plasma (0.3 U/ml; reference range 6.20–18.6 U/ml) and in leukocytes (0.4 U/mg; reference range 12.8–74.1 U/mg) along with identification of a missense mutation in the patient's a-galactosidase gene confirmed the presence of Fabry disease. An additional diagnosis of TRAPS was made after sequence analysis of the tumor necrosis factor receptor superfamily 1A (TNFRSF1A) gene was performed. This revealed a heterozygous missense mutation in exon 4. This mutation, referred to as R92Q, is associated with TRAPS1. Our patient's mother was a heterozygote carrier for the same Fabry mutation, but she did not have the R92Q mutation. His father and brother were both asymptomatic and positive for the R92Q mutation. His 8-year-old brother also had the Fabry gene mutation. Fabry disease is a rare X-linked recessive lysosomal storage disorder caused by a-galactosidase A (a-Gal A) deficiency, which results in the multisystemic deposition of globotriaosylceramide within susceptible cells, tissues, and organs, leading to early death2. In classic disease the metabolic abnormality manifests usually by 10 years of age and is characterized by severe acroparesthesias, angiokeratomas, corneal opacities, and hypohidrosis. Abdominal pain is common and occurs after meals. Significant airflow obstruction and fever is also frequent in these patients2. Atypical male variants, because of low residual a-Gal A levels, have an attenuated form of the disease and present usually after age 40 years with mild proteinuria and/or cardiac manifestations of the disease3. The majority of female carriers will be asymptomatic or have mild disease manifestations such as corneal dystrophy, angiokeratomas, hypohidrosis, and infrequent attack of acroparesthesias3. Enzyme replacement therapy (ERT), which has been shown to clear globotriaosylceramide from the kidneys, heart, and skin, is now the standard of care in the treatment of symptomatic Fabry disease3,4. The autosomal dominant disease TRAPS is characterized by episodes of fever, myalgia, arthralgia or arthritis, rash, abdominal pain, pleuritis, periorbital edema, and conjunctivitis lasting for at least 5 days. Mutations of the TNFRSF1A receptor gene on chromosome 12 have been recognized as the cause of TRAPS5. The disease mechanism is commonly attributed to impaired TNFRSF1A receptor shedding after engagement and signaling by TNF-a, which leads to a decreased amount of receptor available to bind soluble TNF-a and repress inflammation5. Receptor shedding is normal with the R92Q mutation, which suggests that defective receptor shedding does not account for the entire disease mechanism5. Nonsteroidal antiinflammatory drugs and glucocorticoids relieve acute attacks but in most patients do not alter frequency of episodes5. Etanercept, an anti-TNF medication, decreases the frequency of attacks and improves disease activity, allowing corticosteroid reduction6. It was interesting that there was no family history of a similar febrile illness despite family members who carried the R92Q mutation, particularly in the brother who had both the TRAPS and Fabry mutations. This R92Q mutation has been documented in 1% of Northern European subjects who were asymptomatic and is thought to have low penetrance7. The mother did have a history of acroparesthesias likely secondary to mild Fabry disease. Our patient was prescribed a trial of colchicine to treat the TRAPS, but this was discontinued because of lack of benefit. He began treatment for Fabry disease with ERT and has gone 9 months without a recurrent febrile/pain episode, his longest symptom-free period to date. The severity and early onset of symptoms in our patient may reflect an interaction between the 2 genetic disorders, potentially worsening the clinical phenotype. In patients with a diagnosis of TRAPS who have atypical symptoms, further investigation to evaluate for the presence of other concomitant conditions should be performed. A missed diagnosis of Fabry disease without the opportunity for treatment could have had tragic consequences for this patient. CHRISTINE HALLIGAN, MD, Division of Rheumatology; BRYCE A. HEESE, MD, Department of Medical Genetics, Mayo Clinic, Rochester, Minnesota; GRANT MELLOR, MD, Ottumwa Pediatrics, Ottumwa, Iowa; VIRGINIA V. MICHELS, MD, Department of Medical Genetics; ANN REED, MD, Division of Rheumatology, Mayo Clinic, 200 First Street, Rochester, Minnesota 55905, USA. Address reprint requests to Dr. Reed. E-mail: reed.ann@mayo.edu REFERENCES 1. Sarrauste de Menthiere C, Terriere S, Pugnere D, Ruiz M, Demaille J, Touitou I. INFEVERS: the Registry for FMF and hereditary inflammatory disorders mutations. Nucl Acids Res 2003;31:282-5. 2. Mehta A. New developments in the management of Anderson-Fabry disease. QJM 2002;95:647-53. 3. Desnick RJ, Brady R, Barranger J, et al. Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med 2003;138:338-46. 4. Eng CM, Guffon N, Wilcox WR, et al. International Collaborative Fabry Disease Study Group. Safety and efficacy of recombinant human alpha-galactosidase A -- replacement therapy in Fabry's disease. New Engl J Med 2001;345:9-16. 5. Hull KM, Drewe E, Aksentijevich I, et al. The TNF receptor-associated periodic syndrome (TRAPS): emerging concepts of an autoinflammatory disorder. Medicine 2002;81:349-68. 6. Drewe E, McDermott EM, Powell PT, Isaacs JD, Powell RJ. Prospective study of anti-tumour necrosis factor receptor superfamily 1B fusion protein, and case study of anti-tumour necrosis factor receptor superfamily 1A fusion protein, in tumour necrosis factor receptor associated periodic syndrome (TRAPS): clinical and laboratory findings in a series of seven patients. Rheumatology Oxford 2003;42:235-9. 7. Aksentijevich I, Galon J, Soares M, et al. The tumor-necrosis-factor receptor-associated periodic syndrome: new mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies, and evidence for further genetic heterogeneity of periodic fevers. Am J Hum Genet 2001;69:301-14. |
