Table 1.

Characteristics of the 15 patients who were clinically diagnosed with PFS and who tested positive with PFS genetic screening

Case	Clinical Presentation	Genetics	Takeaway	Clinical Diagnosis	Genetic Diagnosis	Therapeutic intervention
1	Severe Crohn’s disease associated with fevers, fistula, polyarthralgias, subcutaneous nodules, bilateral knee effusions, and GI bleeding; other symptoms include Raynaud’s disease, cold-induced urticaria	heterozygous NOD2; (c.3017dupC)	heterozygous NOD2 mutation seen with Crohn’s disease	Crohn’s disease	heterozygous NOD mutation	Failed tx: mercaptopurine, mesalamine, plaquenil, pentasa, methotrexate, metronidazole, steroids Current tx: sulfasalazine, certolizumab pegol
2	Periodic fevers every two to five weeks with joint, abdominal, and chest pain	heterozygous E148Q, P369S, R408Q mutations	Three independent mutations at the MEFV gene conferring FMF symptoms	FMF	compound heterozygous FMF	Self-resolves
3	Periodic fevers with bilateral neck pain followed by abdominal pain and migraines; past medical history includes common variable immune deficiency	Heterozygous A-G 694 MEFV	heterozygous mutation at MEFV gene conferring phenotypic expression of FMF symptoms	FMF	heterozygous FMF	Failed tx: none Current tx: colchicine
4	Past medical history includes FMF; episodic, self-resolving abdominal pain with recurrent respiratory tract illnesses	heterozygous E148Q	heterozygous mutation at MEFV gene conferring phenotypic expression of FMF symptoms	FMF	heterozygous FMF	Failed tx: none Current tx: colchicine
5	Recurrent episodes of cold-induced urticaria with arthralgias, edema, tenderness, and fever	heterozygous 1591T MEFV	heterozygous mutation at MEFV expressing atypical FMF presentation	FMF	heterozygous FMF	Failed tx: methotrexate Current tx: colchicine, canakinumab
6	Recurrent fever, arthralgias, abdominal pain, and pretibial erysipelas rash triggered by stress, cold, exertion, and cessation of colchicine	heterozygous M694V and M694I	Two heterozygous MEFV mutations seen with FMF symptoms	FMF	compound heterozygous FMF	Failed tx: none Current tx: partial response to colchicine
7	Recurrent fevers, GI bleeding, skin manifestations, frequent bronchitis, history of cognitive deficits, behavioral changes and motor disturbances	heterozygous TRNT1	heterozygous mutation at TRNT1 gene conferring FMF symptoms	FMF	heterozygous SIFD	Failed tx: anakinra, Previous successful tx: IVIg Current tx: partial response to colchicine
8	Recurrent fever since age 2 with elevated inflammatory markers. Late abdominal and joint pain. Neg anti-nuclear antibodies, normal anti-neutrophil cytoplasmic antibody and proteinase 3. Development of Crohn’s disease	heterozygous M694V exon 10	FMF in heterozygote	FMF	heterozygous FMF	Current tx: infliximab, colchicine, azathioprine
9	Periodic fevers every two to four weeks with irritability, insomnia, nausea, vomiting, anorexia, and articular complaints	heterozygous NOD2 (c 2017C→T)	heterozygous NOD2 mutation seen with fever of unknown origin	FUO	heterozygous NOD mutation	Current tx: steroids
10	Periodic fevers every 28 days with accompanying downward progressing pustular, erythematous rash starting on abdomen; severe arthralgias on hands and feet; other symptoms include abdominal pain, oral ulcers, lower extremity weakness, and dysuria	heterozygous V3771 MVK	heterozygous mutation at MVK gene conferring expression of HIDS	HIDS	heterozygous HIDS	Failed tx: anakinra Current tx: None
11	Flares with urticaria, abdominal pain, and fever; intact audiology exam	heterozygous V200M CIAS1 and heterozygous E148Q MEFV	Two independent heterozygous mutations at CIAS1 and MEFV genes presents with hybrid MWS symptoms	Muckle-Wells syndrome	compound heterozygous	Current tx: canakinumab
12	Recurrent fevers associated with sinus congestion and multiple sclerosis flares; history of photosensitive rash, childhood hive episodes, and progressive deafness	heterozygous c2407C>A NOD2	heterozygous NOD2 mutation usually with Crohn’s disease or Blau syndrome presenting as Muckle-Wells syndrome	Muckle-Wells syndrome	heterozygous NOD mutation	Failed tx: hydoxyurea Current tx: ruxolitinib for essential thrombocytosis
13	Episodic fevers responsive to steroids with elevated inflammatory markers lasting one to six weeks associated with night sweats, shoulder, back, and hand pain without edema and occasional non-pruritic erythematous macular rash on hands, conjunctivitis, and glossitis; episodes evolved to include headaches, twice daily fevers, arthralgias and myalgias, macular rash on hands and feet, and pharyngitis	heterozygous LPIN2	heterozygous LPIN2 mutation confers symptoms consistent with Still’s disease	Still’s disease	Majeed syndrome	Current tx: colchicine; steroids
14	Genetic, but not tissue transglutaminase positive celiac disease; no fever, abdominal pain or conjunctivitis	heterozygous R121Q in TNFRSF1A	heterozygous TNFRSF1A mutation with unusual presentation of TRAPS	TRAPS	TRAPS	Current tx: none
15	Episodic flares lasting three to five days including numbness, paresthesias, and weakness in extremities, constipation, oral ulcers, low grade fever, chest, joint, abdominal, and back pains. Development of SLE	heterozygous R121Q in TNFRSF1A	heterozygous R92 conferring unusual presentation of TRAPS	TRAPS	TRAPS	Failed tx: methotrexate, adalimumab, anakinra, infliximab, hydroxychloroquine, colchicine, tocilizumab Current tx: golimumab

GI: gastrointestinal, FMF: familial Mediterranean fever, IVIg: intravenous immunoglobulin, NOD2: nucleotide-binding oligomerization domain-containing protein 2, MEFV: familial Mediterranean fever gene, MVK: mevalonate kinase, HIDS: hyper IgD syndrome, TRAPS: tumor necrosis factor receptor associated periodic syndrome, FUO: fever of unknown origin, SIFD: sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay