M is a 4-year-old child with a profile of perinatal stroke detected at 6 months after preferential use of his left side. Further investigation revealed Factor V Leiden mutation and he was left with a diagnosis of mild cerebral palsy with right-sided hemiplegia as a result of the stroke. Starting at age 1 year, he would have fevers like clockwork every month, sometimes associated with tonsillitis, ear infections or oral ulcers. His temperature would be elevated for an average of 5 days, starting as low-grade fever but reaching up to 106°F on days 3-4 before subsiding. His parents tried anti-pyretics such as Tylenol and Advil without much improvement.
Laboratory investigations for these fevers were normal, except for elevated ESR and CRP. He was often put on antibiotics based on physical examination findings through the family physician’s office and on a few occasions, swabs were Group A Streptococcus positive. Despite clearing these infections, he continued to have cyclic fevers at fixed intervals. An MRI scan unrelated to the periodic fevers showed a periventricular venous infarct on the right side of the corticospinal tracts, explaining the hemiparesis.
Further questioning on family history revealed nothing much. M is of Irish and Italian descent and is the eldest child of healthy parents. The pregnancy was uneventful and he was born normally. He began missing motor and speech developmental milestones around age 3 months. He sees a neurologist, hematologist, physiotherapist, occupational therapist and a number of community organizations for children with chronic diseases.
The fevers led to a referral to a rheumatologist, who recommended trying steroids. A single dose of oral steroids seemed to eliminate the fevers each time. At the age of 3 years, he had a tonsillectomy for obstructive sleep apnea that resulted in one fever afterwards but thereafter obliterated them for good.
M has a 2-year-old brother who started having periodic fevers a year ago with similar associated symptoms but the family has not yet given him steroids.
What did M have?
M’s case is a textbook definition of periodic fever with apthous stomatitis, pharyngitis and adenitis (PFAPA). This is one of many syndromes of cyclical fevers that occur predictably at fixed time intervals. The best-known periodic fever syndromes are Familial Mediterranean Fevers (FMF) and cyclic neutropenia. All of these illnesses are genetically mediated and hereditary, except perhaps PFAPA, which is of unknown etiology.
These fevers generally don’t leave any long-term sequelae. In the short-term, however, they can place a lot of strain on caregivers, because of their chronic nature.
In PFAPA, fevers typically start in those younger than 5 years, are associated with oral ulcers, pharyngitis and lymphadenopathy. The only laboratory findings are elevated ESR and CRP, unless there’s an underlying infectious etiology (which should naturally be investigated first in a febrile patient). In PFAPA, the fevers are usually eliminated each time with a single dose of oral steroids but return in the next cycle. Tonsillectomy and cimetidine therapy have been associated with permanent cures of the fevers in some studies.
The etiology for PFAPA is not known and the diagnosis at present is a clinical one. Research into the other cyclical fever syndromes has always shown associated genetic defects. Other types of cyclical fevers differ in their associated symptoms, characteristic ages of onset, cycle lengths, fever duration, laboratory findings and treatment responses. But there’s one thing they have in common: it can be years before a child gets diagnosed with a cyclical fever syndrome because so little is known about them!
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