Chilblains as a Diagnostic Sign of Aicardi-Goutières Syndrome

Abstract

Aicardi-Goutières syndrome (AGS) is a genetically heterogeneous disorder showing variability in age of onset and clinical features. Chilblain lesions have been described in AGS patients and recent papers have discussed the clinical, molecular and cutaneous histopathological overlap with chilblain lupus. Here we report on 2 unrelated children with AGS and chilblain lesions, whose clinical histories and examination findings well illustrate the wide phenotypic variability that can be seen in this pleiotropic disorder. Although both patients show remarkable similarity in the histopathology of their associated skin lesions, with thrombi formation, fat necrosis and hyalinization of the subcutaneous tissue, we note that the histopathology reported in other AGS cases with chilblains does not necessarily demonstrate this same uniformity. Our findings highlight the significant role of the characteristic chilblain skin lesions in the diagnosis of AGS, and variability in the associated histopathology which may relate to the stage and severity of the disease.

Aicardi-Goutières syndrome - intracranial calcification - glaucoma - interferon alpha - chilblains - histopathology - systemic lupus erythematosus

References

• 1 Aicardi J, Goutierés F. A progressive familial encephalopathy in infancy, with calcification of the basal ganglia, and chronic cerebrospinal fluid lymphocytosis.  Ann Neurol. 1984;  15 49-54
• 2 Baltaci M, Fritsch P. Histologic features of cutaneous lupus erythematosus.  Autoimmunity Rev.. 2009;  8 467-473
• 3 Barth PG, Walter A, van Gelderen I. Aicardi-Goutières syndrome: a genetic microangiopathy?.  Acta Neuropathol (Berl). 1999;  98 212-216
• 4 Crow YJ, Massey RF, Innes JR. et al . Congenital glaucoma and brain stem atrophy as features of Aicardi-Goutières syndrome.  Am J Med Genet. 2004;  129 303-307
• 5 Crow YJ, Hayward BE, Parmar R. et al . Mutations in the gene encoding the 3′–5′ DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus.  Nat Genet. 2006;  38 917-920
• 6 Crow YJ, Leitch A, Hayward BE. et al . Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection.  Nat Genet. 2006;  38 910-916
• 7 Crowson AN, Magro CM. Idiopathic perniosis and its mimics: a clinical and histological study of 38 cases.  Hum Pathol. 1997;  28 478-484
• 8 Dale RC, Tang SP, Heckmatt JZ. et al . Familial systemic lupus erythematosus and congenital infection-like syndrome.  Neuropediatrics. 2000;  31 155-158
• 9 Dale RC, Gornall H, Singh-Grewal D. et al . Familial Aicardi-Goutières syndrome due to SAMHD1 mutations is associated with chronic arthropathy and contractures.  Am J Med Genet Part A. 2010;  152A 938-942
• 10 Fernandez D, Arichi T, Chakrapani A. et al . Aicardi-Goutières syndrome and biotinidase deficiency − are they related?.  J Inherit Metab Dis. 2005;  28 (S 01) 252
• 11 Günther C, Meurer M, Stein A. et al . Familial chilblain lupus – a monogenic form of cutaneous lupus erythematosus due to a heterozygous mutation in TREX1.  Dermatology. 2009;  219 162-166
• 12 Hirschmann JV, Raugi GJ. Blue (or purple) toe syndrome.  J Am Acad Dermatol. 2009;  60 1-20
• 13 Juern A, Robbins A, Galbraith S. et al . Aicardi-Goutières syndrome: cutaneous, laboratory, and radiologic findings: a case report.  Pediatr Dermatol. 2010;  27 82-85
• 14 Kolivras A, Aeby A, Crow YJ. et al . Cutaneous histopathological findings of Aicardi-Goutières syndrome, overlap with chilblain lupus.  J Cutan Pathol. 2008;  35 774-778
• 15 Lanzi G, Fazzi E, D’Arrigo S. Aicardi-Goutières syndrome: a description of 21 new cases and a comparison with literature.  Eur J Paediatr Neurol. 2002;  6 (Suppl. A) A9-A22
• 16 Lebon P, Meritet JF, Krivine A. et al . Interferon and Aicardi-Goutières syndrome.  Eur J Paediatr Neurol. 2002;  6 (Suppl. A) A47-A53
• 17 Lee-Kirsch MA, Gong M, Chowdhury D. et al . Mutations in the gene encoding the 3′–5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus.  Nat Genet. 2007;  39 1065-1067
• 18 McEntagart M, Kamel H, Lebon P. et al . Aicardi-Goutières syndrome: an expanding phenotype.  Neuropediatrics. 1998;  29 163-167
• 19 Prendiville JS, Crow YJ. Blue (or purple) toes: Chilblains or chilblain lupus-like lesions are a manifestation of Aicardi-Goutières syndrome and familial chilblain lupus.  J Am Acad Dermatol. 2009;  61 727-728
• 20 Ramantani G, Kohlhase J, Hertzberg C. et al . Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Goutières syndrome.  Arthritis & Rheumatism. 2010 Jan 29;  [Epub ahead of print]
• 21 Rasmussen M, Skullerud K, Bakke SJ. et al . Cerebral thrombotic microangiopathy and antiphospholipid antibodies in Aicardi-Goutières syndrome – report of 2 sisters.  Neuropediatrics. 2005;  36 40-44
• 22 Rice G, Patrick T, Parmar R. et al . Clinical and molecular phenotype of Aicardi-Goutières syndrome.  Am J Hum Genet. 2007;  81 713-725
• 23 Rice G, Newman WG, Dean J. et al . Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutières syndrome.  Am J Hum Genet. 2007;  80 811-815
• 24 Rice GI, Bond J, Asipu A. et al . Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response.  Nat Genet. 2009;  41 829-832
• 25 Stephenson JBP, Tolmie J, Heckmatt J. et al . Aicardi-Goutières syndrome: Autoimmune clues to diagnosis and pathogenesis, and link to microcephaly intracranial calcification syndrome.  Dev Med Child Neurol. 1997;  39 (S 77) 15
• 26 Stephenson JB. Aicardi-Goutières syndrome. Observations of the Glasgow school.  Eur J Paediatr Neurol. 2002;  6 (Suppl. A) A67-A70
• 27 Stephenson JBP. Aicardi-Goutières syndrome (AGS).  Eur J Paediat Neurol. 2008;  12 355-358
• 28 Tolmie JL, Shillito P, Hughes-Benzie R. et al . The Aicardi-Goutières syndrome (familial, early onset encephalopathy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis).  J Med Genet. 1995;  32 881
• 29 Viguier M, Pinquier L, Cavelier-Balloy B. et al . Clinical and histopathologic features and immunologic variables in patients with severe chilblains. A study of the relationship to lupus erythematosus.  Medicine. 2001;  80 180-188

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