Genetics of Neonatal Autoimmune and Autoinflammatory Diseases


Genetic predisposition has been widely studied in autoimmune and autoinflammatory diseases and has been found to play a significant role in pathogenesis, although the environment, including dietary habits, chemicals and hygienic conditions have been postulated to influence expression of these diseases as well. The autoimmune diseases most prevalent in the newborn include neonatal lupus and neonatal antiphospholipid antibody syndrome. The diseases are characterised by maternal antibodies to SS‐A (Ro) and SS‐B (La). The genetics underlying these diseases have been found to involve both HLA and non‐HLA associations. The neonatal autoinflammatory diseases include the cryopyrin‐associated periodic syndromes (CAPS), of which familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS) and neonatal onset multisystem inflammatory diseases (NOMID) are the three distinct phenotypes resulting from mutations in the CIAS 1 gene (NLRP3 gene). The gene mutation in CAPS are gain‐of‐function mutation of the NLRP3 gene coding for cryopyrin, resulting in dysfunctional inflammasomes. A defect in the inflammasome leads to overproduction of interleukin‐1, resulting in inflammatory symptoms seen in CAPS. Understanding the genetics responsible for neonatal lupus, neonatal antiphospholipid antibody syndrome and CAPS may drive future research into an elucidation of complex pathophysiologic mechanisms of these diseases and perhaps ultimately lead to better treatment modalities.

Key Concepts:

  • Diseases that involve immune dysfunction in the neonate include neonatal autoimmune and autoinflammatory conditions, along with the more well‐defined immunodeficiency syndromes.

  • The genetics of neonatal autoimmunity and neonatal autoinflammatory syndromes are very different.

  • In addition to a genetic component, the pathogenesis of these two groups of diseases may also involve an epigenetic and environmental component.

  • The presence of a common genetic defect may result in different clinical phenotypes, as illustrated by the three CAPS syndromes.

  • Treatment of these diseases is dependent on an increased knowledge of the pathogenesis of these diseases.

  • Genetic counselling is an important component of the management of these diseases.

Keywords: autoimmune disease; autoinflammatory disease; neonatal lupus; neonatal antiphospholipid syndrome; Cryopyrin‐associated periodic syndromes (CAPS); familial cold autoinflammatory syndrome (FCAS); Muckle–Wells syndrome (MWS); neonatal onset multisystem inflammatory disease (NOMID); NLRP3; CIAS 1

Figure 1.

Spectrum of cryopyrin‐associated periodic syndromes.

Figure 2.

Structure of the NLRP3 gene.



Aganna E, Martinon F, Hawkins PN et al. (2002) Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis. Arthritis and Rheumatism 46(9): 2445–2452.

Agostini L, Martinon F, Burns K et al. (2004) NALP3 forms an IL‐1beta‐processing inflammasome with increased activity in Muckle–Wells autoinflammatory disorder. Immunity 20(3): 319–325.

Aksentijevich I, Nowak M, Mallah M et al. (2002) De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal‐onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin‐associated autoinflammatory diseases. Arthritis and Rheumatism 46(12): 3340–3348.

Alessandri C, Conti F, Pendolino M, Mancini R and Valesini G (2011) New autoantigens in the antiphospholipid syndrome. Autoimmunity Reviews 10(10): 609–616.

Aróstegui JI, Lopez Saldaña MD, Pascal M et al. (2010) A somatic NLRP3 mutation as a cause of a sporadic case of chronic infantile neurologic, cutaneous, articular syndrome/neonatal‐onset multisystem inflammatory disease: novel evidence of the role of low‐level mosaicism as the pathophysiologic mechanism underlying mendelian inherited diseases. Arthritis and Rheumatism 62(4): 1158–1166.

Buyon JP, Rupel A and Clancy RM (2003) Neonatal lupus syndromes. Current Opinion In Rheumatology 15(5): 535–541.

Clancy RM, Backer CB, Yin X et al. (2003) Cytokine polymorphisms and histologic expression in autopsy studies: contribution of TNF‐alpha and TGF‐beta 1 to the pathogenesis of autoimmune‐associated congenital heart block. Journal of Immunology 171(6): 3253–3261.

Clancy RM, Marion MC, Kaufman KM et al. (2010) Identification of candidate loci at 6p21 and 21q22 in a genome‐wide association study of cardiac manifestations of neonatal lupus. Arthritis and Rheumatism 62(11): 3415–3424.

Cohen SB, Goldenberg M, Rabinovici J et al. (2000) Anti‐cardiolipin antibodies in fetal blood and amniotic fluid derived from patients with the anti‐phospholipid syndrome. Human Reproduction 15(5): 1170–1172.

Cuisset L, Drenth JP, Berthelot JM et al. (1999) Genetic linkage of the Muckle–Wells syndrome to chromosome 1q44. American Journal of Human Genetics 65(4): 1054–1059.

Dhimolea E (2011) Interleukin‐1beta inhibitors for the treatment of cryopyrin‐associated periodic syndrome. Application of Clinical Genetics 4: 21–27.

Garcia S and Campos‐de‐Carvalho AC (2000) Neonatal lupus syndrome: the heart as a target of the immune system. Anais da Academia Brasileira de Ciências 72(1): 83–89.

Hoffman HM, Wright FA, Broide DH, Wanderer AA and Kolodner RD (2000) Identification of a locus on chromosome 1q44 for familial cold urticaria. American Journal of Human Genetics 66(5): 1693–1698.

Hoffman HM, Mueller JL, Broide DH, Wanderer AA and Kolodner RD (2001a) Mutation of a new gene encoding a putative pyrin‐like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome. Nature Genetics 29(3): 301–305.

Hoffman HM, Wanderer AA and Broide DH (2001b) Familial cold autoinflammatory syndrome: phenotype and genotype of an autosomal dominant periodic fever. Journal of Allergy and Clinical Immunology 108(4): 615–620.

Izmirly PM, Llanos C, Lee LA et al. (2010) Cutaneous manifestations of neonatal lupus and risk of subsequent congenital heart block. Arthritis and Rheumatism 62(4): 1153–1157.

Jéru I, Marlin S, Le Borgne G et al. (2010) Functional consequences of a germline mutation in the leucine‐rich repeat domain of NLRP3 identified in an atypical autoinflammatory disorder. Arthritis and Rheumatism 62(4): 1176–1185.

Jesus AA, Silva CA, Segundo GR et al. (2008) Phenotype‐genotype analysis of cryopyrin‐associated periodic syndromes (CAPS): description of a rare non‐exon 3 and a novel CIAS1 missense mutation. Journal Of Clinical Immunology 28(2): 134–138.

Kobayashi R, Mii S, Nakano T, Harada H and Eto H (2009) Neonatal lupus erythematosus in Japan: a review of the literature. Autoimmunity Reviews 8(6): 462–466.

Kraus DM, Elliott GS, Chute H et al. (2006) CSMD1 is a novel multiple domain complement‐regulatory protein highly expressed in the central nervous system and epithelial tissues. Journal of Immunology 176(7): 4419–4430.

Lee LA, Lillis PJ, Fritz KA et al. (1983) Neonatal lupus syndrome in successive pregnancies. Journal of the American Academy of Dermatology 9(3): 401–406.

Llanos C, Izmirly PM, Katholi M et al. (2009) Recurrence rates of cardiac manifestations associated with neonatal lupus and maternal/fetal risk factors. Arthritis and Rheumatism 60(10): 3091–3097.

Matsubayashi T, Sugiura H, Arai T, Oh‐Ishi T and Inamo Y (2006) Anakinra therapy for CINCA syndrome with a novel mutation in exon 4 of the CIAS1 gene. Acta Paediatrica 95(2): 246–249.

McCuistion CC and Schoch EP Jr (1954) Possible discoid lupus erythematosus in newborn infant; report of a case with subsequent development of acute systemic lupus erythematosus in mother. AMA Archives of Dermatology and Syphilology 70(6): 782–785.

Montpetit ML, Stocker PJ, Schwetz TA et al. (2009) Regulated and aberrant glycosylation modulate cardiac electrical signaling. Proceedings of the National Academy of Science of the USA 106(38): 16517–16522.

Paro‐Panjan D, Kitanovski L and Avcin T (2007) Neonatal antiphospholipid syndrome associated with heterozygous methylentetrahydrofolate reductase C677T and prothrombin G20210A gene mutations. Rheumatology (Oxford) 46(4): 720–721.

Ramos PS, Marion MC, Langefeld CD et al. (2012) Brief report: enrichment of associations in genes with fibrosis, apoptosis, and innate immunity functions with cardiac manifestations of neonatal lupus. Arthritis and Rheumatism 64(12): 4060–4065.

Ross RS and Borg TK (2001) Integrins and the myocardium. Circulation Research 88(11): 1112–1119.

Saito M, Fujisawa A, Nishikomori R et al. (2005) Somatic mosaicism of CIAS1 in a patient with chronic infantile neurologic, cutaneous, articular syndrome. Arthritis and Rheumatism 52(11): 3579–3585.

Sammaritano LR, Ng S, Sobel R et al. (1997) Anticardiolipin IgG subclasses: association of IgG2 with arterial and/or venous thrombosis. Arthritis and Rheumatism 40(11): 1998–2006.

Saxena A, McDonnell E, Ramos PS et al. (2012) Preferential transmission of genetic risk variants of candidate loci at 6p21 from asymptomatic grandparents to mothers of children with neonatal lupus. Arthritis and Rheumatism 64(3): 931–939.

Shahian M, Khosravi A and Anbardar MH (2011) Early cholestasis in neonatal lupus erythematosus. Annals of Saudi Medicine 31(1): 80–82.

Sirén MK, Julkunen H, Kaaja R, Kurki P and Koskimies S (1999a) Role of HLA in congenital heart block: susceptibility alleles in mothers. Lupus 8(1): 52–59.

Sirén MK, Julkunen H, Kaaja R, Ekblad H and Koskimies S (1999b) Role of HLA in congenital heart block: susceptibility alleles in children. Lupus 8(1): 60–67.

Soares Rolim AM, Castro M and Santiago MB (2006) Neonatal antiphospholipid syndrome. Lupus 15(5): 301–303.

Stokkers PC, Reitsma PH, Tytgat GN and van Deventer SJ (1999) HLA‐DR and ‐DQ phenotypes in inflammatory bowel disease: a meta‐analysis. Gut 45(3): 395–401.

Strandberg LS, Ambrosi A, Jagodic M et al. (2010) Maternal MHC regulates generation of pathogenic antibodies and fetal MHC‐encoded genes determine susceptibility in congenital heart block. Journal of Immunology 185(6): 3574–3582.

Tincani A, Rebaioli CB, Andreoli L, Lojacono A and Motta M (2009) Neonatal effects of maternal antiphospholipid syndrome. Current Rheumatology Reports 11(1): 70–76.

Wahren‐Herlenius M and Sonesson SE (2006) Specificity and effector mechanisms of autoantibodies in congenital heart block. Current Opinion in Immunology 18(6): 690–696.

Further Reading

Chang C (2013) The pathogenesis of neonatal autoimmune and autoinflammatory diseases: a comprehensive review. Journal of Autoimmunity 41: 100–110.

Federici S and Gattorno M (2014) A practical approach to the diagnosis of autoinflammatory diseases in childhood. Best Practice & Research Clinical Rheumatology 28(2): 263–276.

Lindrop R, Arentz G, Thurgood LA et al. (2012) Pathogenicity and proteomic signatures of autoantibodies to Ro and La. Immunology and Cell Biology 90(3): 304–309.

Rioux JD and Abbas AK (2005) Paths to understanding the genetic basis of autoimmune disease. Nature 435: 584–589.

Stojanov S and Kastner DL (2005) Familial autoinflammatory diseases: genetics, pathogenesis and treatment. Current Opinion in Rheumatology 17(5): 586–599.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Bachove, Inessa, and Chang, Christopher(Sep 2014) Genetics of Neonatal Autoimmune and Autoinflammatory Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025735]