Cryopyrin-associated periodic syndrome differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2]

Overview

Cryopyrin-associated periodic syndrome must be differentiated from other diseases that cause fever, fatigue, weight loss, arthralgia, myalgia, rash and soft tissue swelling.

Differential diagnosis

• Cryopyrin-associated periodic syndrome (CAPS) should be differentiated from other autoinflammatory disorders presenting with fever, fatigue, weight loss, arthralgia, myalgia, rash and soft tissue swelling. The differentials include the following:

Category of Disease	Diseases	Signs and symptoms														Laboratory findings
		Inheritance pattern	Fever duration	Frequency of attacks	Abdominal pain	Arthralgia/Arthritis	Chest pain	Skin rash	Myalgia/Body pain	Diarrhea/Vomiting	Neurologic manifestations	Conjunctivitis	Aphthous stomatitis	Lymphadenopathy	Splenomegaly	Complete blood count (CBC)	C- reactive protein (CRP)
																		Erythrocyte sedimentation rate (ESR)	Other findings	Genetic analysis
Autoinflammatory diseases	Familial mediterranean fever	Autosomal recessive/dominant	12-72 h	Weekly or 3-4 times/year	+	+	+	erysipelas-like erythema	+	+	Headache	-/+	-/+	-/+	+	Leukocytosis	↑	↑	High risk for amyloidosis	Mutation in MEFV gene
	Hyper IgD with recurrent fever	Autosomal recessive	3-7 days	Every 2-12 weeks	+	+	+	Diffuse maculopapular rash Polymorphous rash	+	+	Headache	-	+/-	+/-	+/-	Leukocytosis	↑	↑	Elevated srum level of IgD & IgA Chronic mevalonic aciduria	Mutation in MVK gene
	TNF receptor-associated periodic syndrome	Autosomal dominant	3-4 weeks	Variable	+	+	-	Migrating rash with deep pain under the areas with the rash Severe pain follows the rash path in a centrifugal pattern	-	-	Headache	+	-	+/-	+	Leukocytosis	↑	↑	Periorbital edema	Mutation in TNFRSF1A gene
	Muckle-Wells Syndrome	Autosomal dominant	2-3 days	More common during cold seasons	+	+	-	Urticaria-like rash	+	+	Headache	+	+	-	-	Leukocytosis	↑	↑	Cold-triggered attacks	Mutation in NLRP3 gene
	Familial cold urticaria	Autosomal dominant	12-24 hours, or longer	Common in cold seasons	-	+	-	Urticaria-like rash	-	-	Headache Mild hearing loss	+	+/-	-	-	Leukocytosis	↑	↑	Cold-triggered attacks	Mutation in NLRP3 gene
	Neonatal onset multisystem inflammatory disease	Autosomal dominant	Continuous	Common in cold seasons	+		+	Urticaria-like rash	+	+	Headache Aseptic meningitis Papilledema Seizure sensorineural hearing loss	+	+/-	Generalized lymphadenopathy	+	Leukocytosis	↑	↑	Intellectual disability Elevated levels of Immunoglobulins Cold-triggered attacks	Mutation in NLRP3 gene
	PSTPIP1-associated Arthritis, pyoderma gangrenosum and acne (PAPA)	Autosomal dominant	Variable	Variable	+/-	Destructive arthritis	+/-	Pyoderma gangrenosum ulcerative lesions Severe cystic acne	+/-	+/-	-	-	-	-	-	Leukocytosis	↑	↑	High neutrophilic content of synovial fluid Negative cultures of bone and skin	Mutation in PSTPIP1 gene
	Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA)	Unkown	3-6 days	Every 21-28 days	+	+	-	-	+	+	-	-	+	Cervical lymphadenopathy	-	Leukocytosis	↑	↑	Culture negative exudative pharyngitis is a classic finding	Unknown
	Blau syndrome	Autosomal dominant	Intermittent or persistent daily fever	Variable	+/-	+	+/-	scaly plaques Non-caseating granulomatous dermatitis in Biopsy	+	+/-	Cranial neuropathies Visual problems in 80% Peripheral neuropathies	-	+	+/-	+	Leukocytosis	↑	↑	Ophthalmologic manifestations are common	Mutation in NOD2 gene

• Neonatal onset multi-system inflammatory disease (NOMID) causes a destructive arthropathy and bone disease which must be differentiated from other disorders affecting the joints such as :
  • Juvenile Rheumatoid Arthritis (JRA)
  • Chronic Recurrent Multifocal Osteomyelitis (CRMO)
  • Rickets
• Table below differentiates the aforementioned conditions:

Disease name	Age of onset	Signs/Symptoms	X-ray findings	MRI findings
NOMID/CINCA	Early infancy	Parietal and frontal bossing Joint pain Knee valgus or varus Limb length differences Saddleback nose Contractures Urticaria-like rash Fever Chronic aseptic meningitis	Physis is the epicenter Early radiograph: enlargement of the unossified physis, resulting in a mass-like lesion Late radiograph: stippled ossification/calcification causing deformed adjacent epiphysis Possible involvement of multiple joints simultaneously or at different times	Enlarged, heterogenous physis with hypointense calcifications on T1 & T2 weighted images Heterogenous enhancement at the physis in post-gadolinium images Presence of popliteal lymph node Absence of bony erosion
Juvenile Rheumatoid Arthritis (JRA)	Younger than 16 years old	Fever Arthritis Rash Lymphadenopathy Hepatosplenomegaly	Involvement of the articular surface of the joints Initially, soft tissue swelling and enlarged epiphyseal enlargement due to hyperemia As the disease progresses, joint space narrowing and bony erosion are the dominant features	First, joint effusion, cartilage thinning and loss Later, joint erosion and evidence of secondary osteoarthritis Potential complications such as avascular necrosis
Chronic Recurrent Multifocal Osteomyelitis (CRMO)	Childhood and adolescence	Episodes of pain and joint swelling Fever may be present or not may occur as part of a syndrome or alone	Multiple symmetrical metaphyseal lesions Lesions ranges between purely osteolytic, osteolytic with a sclerotic rim, mixed lytic and sclerotic, and purely sclerotic	Early phases: marrow edema with hypointense appearance on T1-weighted images Hyperintense on T2-weighted images Synovial thickening Joint effusion Destruction of joint cartilage Subchondral bone
Rickets	Childhood (depends on the severity of deficiency)	Delay in fontanel closure Parietal and frontal bossing Rachitic rosary Harrison sulcus (or groove) Widening of the wrist Bowing of the distal radius and ulna Progressive lateral bowing of long bones	Widening, cupping and fraying of the metaphysis Irregular and widened epiphyseal plate Periosteal reaction	High signal intensity of unossified cartilage in the physis of the primary and secondary ossification centers No mass lesion or ossification in the physis

• Familial cold autoinflammtory syndrome must be differentiated from other diseases that cause urticaria, and rash, such as:
  • Cold Contact Urticaria
  • Schnitzler Syndrome
  • Deficiency in Interleukin-1 Receptor Antagonist
  • Systemic-Onset Juvenile Idiopathic Arthritis
  • Adult-Onset Still’s Disease
• Table below differentiates the aforementioned conditions:

Disease name	Age of onset	Signs/Symptoms	Diagnostic feature(s)	Other features
Cold Contact Urticaria	Early adulthood	Urticarial skin eruption after exposure to cold Urticaria and/or angioedema affects areas only in contact with cold Systemic symptoms may be present in case of extensive skin involvement (even anaphylaxis)	Ice cube test is positive	The wheal appears within 5 minutes of cold contact
Familial Cold Autoinflammatory Syndrome	Infancy, but may be delayed until adulthood	Non-pruritic urticarial rash Fever Headache Fatigue Conjunctivitis	Ice cube test is negative	Cold-induced rash Skin biopsy shows increased neutrophils at the eccrine coils
Schnitzler Syndrome	Middle age	Chronic urticarial rash Fever Arthralgia Bone pain	Monoclonal gammopathy	Rash is the presenting sign Neutrophillic infiltrate in dermis Dermographism
Deficiency in Interleukin-1 Receptor Antagonist	Infancy	Pustular rash Bone pain Swollen joints Aphthous ulcers	Occurs due to mutation in IL1RN gene Pustular rash similar to pustular psoriasis	Epidermal neutrophilic pustules at hair follicles Pathergy Hyperkeratosis and acanthosis High neutrophil infiltrate of the dermis
Systemic-Onset Juvenile Idiopathic Arthritis	2-16 years of age	High fever Arthralgia Generalized lymphadenopathy Splenomegaly	Evanescent rash Bright salmon-pink Morbilliform, macular rash Rash presents with onset of fever	May cause amyloidosis
Adult-Onset Still’s Disease	16-35 years May affect all ages	High spiking fever Joint pain Skin rash Lymphadenopathy Splenomegaly	Evanescent salmon-colored bumpy rash Pruritic rash on the proximal limbs and trunk	More commonly seen among women May cause destructive arthritis