Affected individuals had multiple comorbid
symptoms, including those often considered ‘functional’ in nature
because of the lack of pathological findings. Gastrointestinal dys-
motility was common, most often manifesting as irritable bowel
syndrome (IBS), defined by Rome III criteria (49%) or symptoms
of chronic gastroesophageal reflux (65%), with both present at a
prevalence approximately three- to fivefold greater than that in the
general population12,13. Connective tissue abnormalities were also
common; the overall prevalence of joint hypermobility (Beighton ≥
4, ages 12–76 years) was 28% (approximately twice the prevalence
for the general population14), while congenital skeletal abnormali-
ties (26%) and retained primary dentition (21%) were also frequently
identified. These findings were associated with chronic arthralgia
(45%) and headache or body pain (47%). Complaints suggestive of
autonomic dysfunction, including postural orthostatic tachycardia
syndrome (POTS), were common.
Forty-six percent of individuals
had elevated composite autonomic symptom scores by validated
measure (COMPASS 31), of whom 11 (34% of those with elevated
scores) were validated by tilt-table testing (Supplementary Fig. 2a).
Additional symptoms included recurrent cutaneous flushing and
pruritus (51%), which in some cases associated with urticaria,
concomitant with complaints of sleep disruption (39%). Systemic
reaction to stinging insects (for example, Hymenoptera), an occur-
rence known to be associated with elevated basal serum tryptase
levels15, was increased by two- to threefold (16%) over the frequency
of such reactions in the general population16 (Table 1).