Diamond EF. J Pediatr 1959;54:341-7 The mystery of widespread occurrence of streptococcal pharyngitis and yet relatively uncommon and unpredictable occurrence of rheumatic fever has intrigued the medical community for a century. Observant clinicians wondered whether gross physical characteristics might distinguish a rheumatic constitution—much as the prematurely gray, blue-eyed Nordic type is known to have a proclivity for pernicious anemia. By the 1950s, numerous authors had reported a preponderance of certain physical characteristics in children with rheumatic fever, spurring Diamond to formally evaluate a roster of Chicago children with rheumatic fever (sample size, 76-204, depending on factor studied). He sought a simple preponderance of certain features and used a formalized control group for assessing other characteristics. Unlike previously reported associations, Diamond found no preponderance in rheumatic children of race, hair or eye color, asthenic or pyknic body build, skin pallor, blood type, or salivary non-secretion of ABO substance (ie, probable secretion of Lewis substance). Diamond found a single significant constitutional factor—hyperextensibility of metacarpophalangeal joints—significantly more frequently in active and inactive rheumatic groups compared with control subjects. Diamond speculated that this finding may be an expression of an underlying biochemical abnormality of connective tissue. In The Journal in 2002, Barron et al (J Pediatr 2002;141:421-5) reported a case-control study performed in children referred to Johns Hopkins Hospital for chronic fatigue and found hyperextensibility of joints 3.5 times more frequently in these patients than in control children referred to the hospital's dermatology clinic. One wonders whether this finding in patients with chronic fatigue and rheumatic fever is merely deconditioning or whether it belies an underlying genetic disorder. Recent geographically confined outbreaks of rheumatic fever and use of modern molecular microbiology have focused attention on rheumatogenic strains of group A streptococcus. Family size, however, also has been a risk factor for rheumatic fever. It seems that the duration of the unsolved mystery alone and evidence from several corners suggest that there is room to consider relevant contributions to rheumatogenicity from the microbe, the host, and the environment.