CHICAGO — Many genetically based periodic fever syndromes have skin signs that may help identify the syndromes on the rare occasions when they occur, Dr. Kathryn M. Edwards said at the annual meeting of the Society for Pediatric Dermatology.
Although these syndromes, called familial periodic fever syndromes, are rare, knowing something about them will “allow you to think more about how we control fever and inflammatory processes in children,” noted Dr. Edwards, professor of pediatrics at Vanderbilt University, Nashville, Tenn.
“Periodic fever is a very specific diagnosis,” said Dr. Edwards, an expert vaccinologist who has conducted research for the National Institutes of Health. Periodic fevers are fevers that recur at intervals lasting from a few days to a few weeks separated by totally symptom-free intervals.
A periodic fever syndrome is a form of autoinflammatory disorder. “Generally periodic fevers that have been present for more than 2 years are never associated with infection or malignancy,” she explained.
In one study, 29 children with periodic fevers tended to be younger at the onset of the fever (often less than 1 year of age), had a longer duration of symptoms before they were referred for further evaluation, and had higher maximum fever temperatures, compared with 11 children with daily fevers (J. Pediatr. 1996;129:419–23).
About a quarter of the periodic fever patients had a nonspecific rash, but so did the children with daily fevers. Comorbid rash and fever isn't enough to diagnose a familial periodic fever syndrome. But pharyngitis and oral ulcers or adenopathy were seen much more often in patients with periodic fever during their intervals of fever than in those with daily fevers.
The familial syndromes are characterized by identified genetic defects that inhibit the body's ability to control inflammation, and genetic testing is needed to confirm a diagnosis of these syndromes.
There are distinct patterns of ancestry for familial periodic fever syndromes and the genes have been circulating for generations, said Dr. Edwards. “The familial febrile syndromes are not easy to diagnose, and if you have a patient who you suspect has one of these syndromes, please contact the NIH for genotyping,” she said.
Following are the familial periodic fever syndromes she described:
▸ Familial Mediterranean Fever (FMF). FMF is linked to a recessive gene known as MEFV. Many patients experience secondary amyloidosis, in which a protein buildup in various organs and tissues can impede their functions. FMF is common in Jewish families of Spanish, Portuguese, or Middle Eastern descent, but it is rare in Jewish families of European descent, Dr. Edwards noted.
Clinical features include serositis and scrotal swelling, and the periodic attacks of fever often begin in childhood. The most common dermatologic manifestation is a distinctive erysipeloid rash on the lower extremities that occurs in about 15% of children with this syndrome. Studies have shown that about half of these patients also report arthritis in one ankle, knee, or hip. The fever attacks in FMF patients occur at regular intervals, and they usually respond to treatment within 12–72 hours. Colchicine treatment has been shown to be effective in preventing the fever episodes (and the subsequent rash), although not in treating the acute attacks of fever once they occur.
“If you treat people with FMF regularly with colchicine they don't get attacks of fever and they don't get amyloidosis, so it is important that FMF is diagnosed,” Dr. Edwards said.
▸ Hyperimmunoglobulinemia D Syndrome (HIDS). HIDS has an early onset (the median age of onset is 6 months), and recurrent attacks of fever persist throughout the patient's life. Febrile attacks usually last for 3–7 days at irregular intervals ranging from 4 to 8 weeks. Clinical features include cervical adenitis, vomiting, and diarrhea. A patient with HIDS may present to a dermatologist with a maculopapular rash, with petechiae and purpura that appear during a febrile attack. Generalized lymphadenopathy and rash are very common in these patients.
Distinctive laboratory features include an elevated IgD (greater than 14.3 mg/dL), but this elevation is not present in all HIDS patients. The gene for HIDS has been mapped to chromosome 12 and at least 8 different mutations or deletions have been seen, but the syndrome is most likely to occur in people with Dutch or French ancestry, Dr. Edwards said.
▸ Tumor Necrosis Factor-Receptor Associated Periodic Syndrome (TRAPS). Children with TRAPS may have a lifelong history of febrile episodes that last 2–3 weeks at a time, but the febrile episodes only occur 2–3 times per year.
Conjunctivitis and raised red lesions distinguish TRAPS from other familial periodic fever syndromes. One study of 25 TRAPS patients showed that 21 (84%) had erythematous patches, including both wavy and circular lesions (N. Engl. J. Med. 2001;345:1748–57). Other clinical features of TRAPS include myalgia, arthralgia, and abdominal pain.