Diagnosis Of A Mysterious Case Of Proprotein Convertase (Pc1/3) Deficiency In A Patient With Malabsorptive Diarrhea With Next Generation Sequencing

R761H (compound heterozygous state, 57%), K695R (heterozygous state, 21%), E148Q (heterozygous state,10%), R202Q (heterozygous state, 3%) and R202Q + M694V mutations (3%).GI motility was assessed in the asymptomatic phase by functional ultrasonography (changes of gastric antral areas and gallbladder volumes; 5.0 MHz ClarUs©, Telemed device) and H2-breath test (orocecal transit time by Lactofan®, FAN-GmbH, DE and Italchimici, Italy).Measurements were taken at 5-15 min intervals in the fasting state and during 270 min postprandially after a 200ml liquid meal formula (Nutridrink®, Nutricia added with 10g lactulose).A group of 142 age-sex-BMI-matched healthy subjects served as control (M:F=67:75, age 38±1 yrs).Results.Acute attacks (1 day mean duration), had a frequency of <1 (48%), 2 (22%) and ≥3 (13%) episodes/mo.Symptoms included abdominal pain and fever (44%), joint pain (22%), fever alone (9%), fatigue (4%), erysipelas-like erythema (4%) or none (17%).Although the mean age at symptom onset was 19.2±8.4 yrs, FMF was only diagnosed after 15.4±9.7 yrs.Compared to control, FMF patients had comparable fasting antral areas (3.3±0.2 vs. 3.2±0.1 cm2), but increased max postprandial area (14.1±0.4 vs. 11.6±0.2cm2, P<0.000001), residual postprandial area (4.3±0.2 vs. 3.5±0.1 cm2, P<0.001) and longer half emptying time (43.2±1.2 vs. 26.6±0.5 min, P<0.000001).Gallbladder vol. in FMF and control was comparable during fasting (19.8±2.1 vs. 22.4±0.5 ml) and postprandially (residual 5.4±0.4 vs. 5.5±0.2ml), with a trend of increased percent residual volume (28.9±1.6 FMF vs. 24.8±0.7 % in controls, P=0.059).Gallbladder emptying time was comparable in FMF and control (23.2±1.7 FMF vs. 21.0±0.5 min).OCTT was longer in FMF (132.3±10.5 vs. 99.5±1.6 min, P<0.000001).All FMF patients responded to colchicine therapy 1 mg/day p.o. Conclusions.In a novel cluster of FMF patients, the final diagnosis of FMF is consistently delayed.Patients with FMF exhibit impaired motorfunction in the GI tract but not in the gallbladder.Our study of GI motility provides additional clues on the natural history of this rare disorder before and after therapy.