When less is more: primary immunodeficiency with an autoinflammatory kick.

[sneddon syndrome]

Next -generation sequencing is revolutionizing the molecular taxonomy of human disease . Recent studies of patients with unexplained autoinflammatory disorders reveal germline genetic mutations that target important regulators of innate immunity .Whole-exome analyses of previously undiagnosed patients have catalyzed the recognition of two new disease genes . First , a phenotypic spectrum , including livedo racemosa , fever with early -onset stroke , polyarteritis nodosa , and Sneddon syndrome , is caused by loss -of-function mutations in cat eye syndrome chromosome region , candidate 1 (CECR 1 ), encoding adenosine deaminase 2 . Adenosine deaminase 2 is a secreted protein expressed primarily in myeloid cells , and a regulator of macrophage differentiation and endothelial development . Disease-associated mutations impair anti-inflammatory M 2 macrophage differentiation . Second , patients presenting with cold-induced urticaria , granulomatous rash , autoantibodies , and common variable immunodeficiency , or with blistering skin lesions , bronchiolitis , enterocolitis , ocular inflammation , and mild immunodeficiency harbor distinct mutations in phospholipase Cγ 2 , encoding a signaling molecule expressed in natural killer cells , mast cells , and B lymphocytes . These mutations inhibit the function of a phospholipase Cγ 2 autoinhibitory domain , causing increased or constitutive signaling .These findings underscore the power of next -generation sequencing , demonstrating how the primary deficiency of key molecular regulators or even regulatory motifs may lead to autoinflammation , and suggesting a possible role for cat eye syndrome chromosome region , candidate 1 and phospholipase Cγ 2 in common diseases .

Diseases
Validation

Diseases presenting "fever" symptom

22q11.2 deletion syndrome

acute rheumatic fever

alexander disease

allergic bronchopulmonary aspergillosis

canavan disease

carcinoma of the gallbladder

child syndrome

congenital toxoplasmosis

cushing syndrome

cystinuria

dracunculiasis

erdheim-chester disease

esophageal adenocarcinoma

esophageal carcinoma

familial mediterranean fever

focal myositis

hodgkin lymphoma, classical

lamellar ichthyosis

legionellosis

locked-in syndrome

malignant atrophic papulosis

neonatal adrenoleukodystrophy

neuralgic amyotrophy

oculocutaneous albinism

papillon-lefèvre syndrome

pyomyositis

pyruvate dehydrogenase deficiency

scrub typhus

severe combined immunodeficiency

sneddon syndrome

systemic capillary leak syndrome

triple a syndrome

typhoid

waldenström macroglobulinemia

wolf-hirschhorn syndrome

This symptom has already been validated