Clinical Reviews in Allergy & Immunology

, Volume 46, Issue 2, pp 112–119

Skin Manifestations of Primary Immune Deficiency



Cutaneous manifestations are common in primary immune deficiency diseases, affecting between 40 % and 70 % of patients with diagnosed primary immune deficiency. Skin infections characterize many primary immune deficiencies, but there are also frequent noninfectious cutaneous manifestations seen in many of these disorders, including eczematous lesions, erythroderma, cutaneous granulomas, dysplasia of skin, hair, and nails, autoimmune conditions, and frank vasculitis. For the patient with suspected primary immunodeficiency, much can be inferred by evaluating the presenting cutaneous findings, including various infectious susceptibilities, presence of atopy, and evidence of impaired or overactive inflammatory response. The skin manifestations of primary immune deficiency diseases are often early or heralding findings of the underlying immunologic disease. Therefore, awareness of associations between skin findings and immune deficiency may aide in the early detection and treatment of serious or life-threatening immunologic defects. This review summarizes the common skin manifestations of primary immune deficiency diseases and provides the reader with a differential diagnosis of primary immune defects to consider for the most common skin manifestations.


Immunologic deficiency syndromes Infectious skin diseases Chronic mucocutaneous candidiasis Erythroderma Chronic granulomatous disease Ectodermal dysplasia 


  1. 1.
    Al-Herz W, Bousfiha A, Casanova JL, Chapel H, Conley ME, Cunningham-Rundles C et al (2011) Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol 2:54PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Berron-Ruiz A, Berron-Perez R, Ruiz-Maldonado R (2000) Cutaneous markers of primary immunodeficiency diseases in children. Pediatr Dermatol 17:91–96PubMedCrossRefGoogle Scholar
  3. 3.
    Moin A, Farhoudi A, Moin M, Pourpak Z, Bazargan N (2006) Cutaneous manifestations of primary immunodeficiency diseases in children. Iran J Allergy Asthma Immunol 5:121–126PubMedGoogle Scholar
  4. 4.
    Al-Herz W, Nanda A (2011) Skin manifestations in primary immunodeficient children. Pediatr Dermatol 28:494–501PubMedCrossRefGoogle Scholar
  5. 5.
    Joshi AY, Iyer VN, Hagan JB, St Sauver JL, Boyce TG (2009) Incidence and temporal trends of primary immunodeficiency: a population-based cohort study. Mayo Clin Proc 84:16–22PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Stinchcombe J, Bossi G, Griffiths GM (2004) Linking albinism and immunity: the secrets of secretory lysosomes. Science 305:55–59PubMedCrossRefGoogle Scholar
  7. 7.
    Boxer LA, Newburger PE (2007) A molecular classification of congenital neutropenia syndromes. Pediatr Blood Cancer 49:609–614PubMedCrossRefGoogle Scholar
  8. 8.
    Fontana S, Parolini S, Vermi W, Booth S, Gallo F, Donini M et al (2006) Innate immunity defects in Hermansky-Pudlak type 2 syndrome. Blood 107:4857–4864PubMedCrossRefGoogle Scholar
  9. 9.
    Enders A, Zieger B, Schwarz K, Yoshimi A, Speckmann C, Knoepfle EM et al (2006) Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type II. Blood 108:81–87PubMedCrossRefGoogle Scholar
  10. 10.
    Spritz RA (1999) Multi-organellar disorders of pigmentation: tied up in traffic. Clin Genet 55:309–317PubMedCrossRefGoogle Scholar
  11. 11.
    Shaw TE, Currie GP, Koudelka CW, Simpson EL (2011) Eczema prevalence in the United States: data from the 2003 National Survey of Children’s Health. J Invest Dermatol 131:67–73PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Chu EY, Freeman AF, Jing H, Cowen EW, Davis J, Su HC et al (2012) Cutaneous manifestations of DOCK8 deficiency syndrome. Arch Dermatol 148:79–84PubMedCrossRefGoogle Scholar
  13. 13.
    Freeman AF, Holland SM (2009) Clinical manifestations, etiology, and pathogenesis of the hyper-IgE syndromes. Pediatr Res 65:32R–37RPubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA (1994) A multiinstitutional survey of the Wiskott-Aldrich syndrome. J Pediatr 125:876–885PubMedCrossRefGoogle Scholar
  15. 15.
    Powell BR, Buist NR, Stenzel P (1982) An X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy. J Pediatr 100:731–737PubMedCrossRefGoogle Scholar
  16. 16.
    Marrella V, Maina V, Villa A (2011) Omenn syndrome does not live by V(D)J recombination alone. Curr Opin Allergy Clin Immunol 11:525–531PubMedCrossRefGoogle Scholar
  17. 17.
    Chavanas S, Bodemer C, Rochat A, Hamel-Teillac D, Ali M, Irvine AD et al (2000) Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nat Genet 25:141–142PubMedCrossRefGoogle Scholar
  18. 18.
    Renner ED, Hartl D, Rylaarsdam S, Young ML, Monaco-Shawver L, Kleiner G et al (2009) Comel-Netherton syndrome defined as primary immunodeficiency. J Allergy Clin Immunol 124:536–543PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Sehgal VN, Srivastava G, Sardana K (2004) Erythroderma/exfoliative dermatitis: a synopsis. Int J Dermatol 43:39–47PubMedCrossRefGoogle Scholar
  20. 20.
    Al-Dhalimi MA (2007) Neonatal and infantile erythroderma: a clinical and follow-up study of 42 cases. J Dermatol 34:302–307PubMedCrossRefGoogle Scholar
  21. 21.
    Hoeger PH, Harper JI (1998) Neonatal erythroderma: differential diagnosis and management of the “red baby”. Arch Dis Child 79:186–191PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Traupe H (1989) The Comèl–Netherton syndrome. The Ichthyoses: Springer Berlin, Heidelberg, pp 168–178Google Scholar
  23. 23.
    de Saint-Basile G, Le Deist F, de Villartay JP, Cerf-Bensussan N, Journet O, Brousse N et al (1991) Restricted heterogeneity of T lymphocytes in combined immunodeficiency with hypereosinophilia (Omenn’s syndrome). J Clin Invest 87:1352–1359PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Le Deist F, Raffoux C, Griscelli C, Fischer A (1987) Graft vs graft reaction resulting in the elimination of maternal cells in a SCID patient with maternofetal GVHd after an HLA identical bone marrow transplantation. J Immunol 138:423–427PubMedGoogle Scholar
  25. 25.
    Anderson KC, Weinstein HJ (1990) Transfusion-associated graft-versus-host disease. N Engl J Med 323:315–321PubMedCrossRefGoogle Scholar
  26. 26.
    Wen L, Atkinson JP, Giclas PC (2004) Clinical and laboratory evaluation of complement deficiency. J Allergy Clin Immunol 113:585–593, quiz 594PubMedCrossRefGoogle Scholar
  27. 27.
    Arunachalam M, Sanzo M, Lotti T, Colucci R, Berti S, Moretti S (2010) Common variable immunodeficiency in vitiligo. G Ital Dermatol Venereol 145:783–788PubMedGoogle Scholar
  28. 28.
    Spickett G, Prentice AG, Wallington T, Webster AD, Chapel H (1991) Alopecia totalis and vitiligo in common variable immunodeficiency. Postgrad Med J 67:291–294PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Koskinen S (1996) Long-term follow-up of health in blood donors with primary selective IgA deficiency. J Clin Immunol 16:165–170PubMedCrossRefGoogle Scholar
  30. 30.
    Ahonen P, Myllarniemi S, Sipila I, Perheentupa J (1990) Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med 322:1829–1836PubMedCrossRefGoogle Scholar
  31. 31.
    Dupuis-Girod S, Medioni J, Haddad E, Quartier P, Cavazzana-Calvo M, Le Deist F et al (2003) Autoimmunity in Wiskott-Aldrich syndrome: risk factors, clinical features, and outcome in a single-center cohort of 55 patients. Pediatrics 111:e622–e627PubMedCrossRefGoogle Scholar
  32. 32.
    Catucci M, Castiello MC, Pala F, Bosticardo M, Villa A (2012) Autoimmunity in wiskott-Aldrich syndrome: an unsolved enigma. Front Immunol 3:209PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Dohil M, Prendiville JS, Crawford RI, Speert DP (1997) Cutaneous manifestations of chronic granulomatous disease. A report of four cases and review of the literature. J Am Acad Dermatol 36:899–907PubMedCrossRefGoogle Scholar
  34. 34.
    Cunningham-Rundles C, Bodian C (1999) Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol 92:34–48PubMedCrossRefGoogle Scholar
  35. 35.
    Fasano MB, Sullivan KE, Sarpong SB, Wood RA, Jones SM, Johns CJ et al (1996) Sarcoidosis and common variable immunodeficiency. Report of 8 cases and review of the literature. Medicine (Baltimore) 75:251–261CrossRefGoogle Scholar
  36. 36.
    Warnatz K, Denz A, Drager R, Braun M, Groth C, Wolff-Vorbeck G et al (2002) Severe deficiency of switched memory B cells (CD27(+)IgM(−)IgD(−)) in subgroups of patients with common variable immunodeficiency: a new approach to classify a heterogeneous disease. Blood 99:1544–1551PubMedCrossRefGoogle Scholar
  37. 37.
    Piqueras B, Lavenu-Bombled C, Galicier L, Bergeron-van der Cruyssen F, Mouthon L, Chevret S et al (2003) Common variable immunodeficiency patient classification based on impaired B cell memory differentiation correlates with clinical aspects. J Clin Immunol 23:385–400PubMedCrossRefGoogle Scholar
  38. 38.
    Sanchez-Ramon S, Radigan L, Yu JE, Bard S, Cunningham-Rundles C (2008) Memory B cells in common variable immunodeficiency: clinical associations and sex differences. Clin Immunol 128:314–321PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Collins SM, Dominguez M, Ilmarinen T, Costigan C, Irvine AD (2006) Dermatological manifestations of autoimmune polyendo-crinopathy–candidiasis–ectodermal dystrophy syndrome. Br J Dermatol 154:1088–1093PubMedCrossRefGoogle Scholar
  40. 40.
    Hanson EP, Monaco-Shawver L, Solt LA, Madge LA, Banerjee PP, May MJ et al (2008) Hypomorphic nuclear factor-kappaB essential modulator mutation database and reconstitution system identifies phenotypic and immunologic diversity. J Allergy Clin Immunol 122(1169–1177):e1116Google Scholar
  41. 41.
    Courtois G, Smahi A, Reichenbach J, Doffinger R, Cancrini C, Bonnet M et al (2003) A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. J Clin Invest 112:1108–1115PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Notarangelo LD, Roifman CM, Giliani S (2008) Cartilage-hair hypoplasia: molecular basis and heterogeneity of the immunological phenotype. Curr Opin Allergy Clin Immunol 8:534–539PubMedCrossRefGoogle Scholar
  43. 43.
    Savage SA, Bertuch AA (2010) The genetics and clinical manifestations of telomere biology disorders. Genet Med 12:753–764PubMedCrossRefGoogle Scholar
  44. 44.
    Dokal I (2011) Dyskeratosis congenita. Hematol Am Soc Hematol Educ Program 2011:480–486CrossRefGoogle Scholar
  45. 45.
    Knight SW, Heiss NS, Vulliamy TJ, Aalfs CM, McMahon C, Richmond P et al (1999) Unexplained aplastic anaemia, immunodeficiency, and cerebellar hypoplasia (Hoyeraal-Hreidarsson syndrome) due to mutations in the dyskeratosis congenita gene, DKC1. Br J Haematol 107:335–339PubMedCrossRefGoogle Scholar
  46. 46.
    Toomes C, James J, Wood AJ, Wu CL, McCormick D, Lench N et al (1999) Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis. Nat Genet 23:421–424PubMedCrossRefGoogle Scholar
  47. 47.
    Winkelstein JA, Marino MC, Johnston RB Jr, Boyle J, Curnutte J, Gallin JI et al (2000) Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore) 79:155–169CrossRefGoogle Scholar
  48. 48.
    Windhorst DB, Good RA (1971) Dermatologic manifestations of fatal granulomatous disease of childhood. Arch Dermatol 103:351–357PubMedCrossRefGoogle Scholar
  49. 49.
    Nord KM, Pappert AS, Grossman ME (2011) Pyoderma gangrenosum-like lesions in leukocyte adhesion deficiency I treated with intravenous immunoglobulin. Pediatr Dermatol 28:156–161PubMedCrossRefGoogle Scholar
  50. 50.
    Hinze CH, Lucky AW, Bove KE, Marsh RA, Bleesing JH, Passo MH (2010) Leukocyte adhesion deficiency type 1 presenting with recurrent pyoderma gangrenosum and flaccid scarring. Pediatr Dermatol 27:500–503PubMedCrossRefGoogle Scholar
  51. 51.
    Paller AS, Nanda V, Spates C, O’Gorman M (1994) Leukocyte adhesion deficiency: recurrent childhood skin infections. J Am Acad Dermatol 31:316–319PubMedCrossRefGoogle Scholar
  52. 52.
    Buckley RH (2001) The hyper-IgE syndrome. Clin Rev Allergy Immunol 20:139–154PubMedCrossRefGoogle Scholar
  53. 53.
    Renner ED, Puck JM, Holland SM, Schmitt M, Weiss M, Frosch M et al (2004) Autosomal recessive hyperimmunoglobulin E syndrome: a distinct disease entity. J Pediatr 144:93–99PubMedCrossRefGoogle Scholar
  54. 54.
    Reichenbach J, Rosenzweig S, Doffinger R, Dupuis S, Holland SM, Casanova JL (2001) Mycobacterial diseases in primary immunodeficiencies. Curr Opin Allergy Clin Immunol 1:503–511PubMedCrossRefGoogle Scholar
  55. 55.
    Antaya RJ, Gardner ES, Bettencourt MS, Daines M, Denise Y, Uthaisangsook S et al (2001) Cutaneous complications of BCG vaccination in infants with immune disorders: two cases and a review of the literature. Pediatr Dermatol 18:205–209PubMedCrossRefGoogle Scholar
  56. 56.
    Holland SM (2010) Chronic granulomatous disease. Clin Rev Allergy Immunol 38:3–10PubMedCrossRefGoogle Scholar
  57. 57.
    Engelhardt KR, Grimbacher B (2012) Mendelian traits causing susceptibility to mucocutaneous fungal infections in human subjects. J Allergy Clin Immunol 129:294–305, quiz 306–297PubMedCrossRefGoogle Scholar
  58. 58.
    Al Khatib S, Keles S, Garcia-Lloret M, Karakoc-Aydiner E, Reisli I, Artac H et al (2009) Defects along the T(H)17 differentiation pathway underlie genetically distinct forms of the hyper IgE syndrome. J Allergy Clin Immunol 124:342–348, 348 e341-345PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Puel A, Cypowyj S, Marodi L, Abel L, Picard C, Casanova JL (2012) Inborn errors of human IL-17 immunity underlie chronic mucocutaneous candidiasis. Curr Opin Allergy Clin Immunol 12:616–622PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Ferwerda B, Ferwerda G, Plantinga TS, Willment JA, van Spriel AB, Venselaar H et al (2009) Human dectin-1 deficiency and mucocutaneous fungal infections. N Engl J Med 361:1760–1767PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Liu L, Okada S, Kong XF, Kreins AY, Cypowyj S, Abhyankar A et al (2011) Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med 208:1635–1648PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    van de Veerdonk FL, Plantinga TS, Hoischen A, Smeekens SP, Joosten LA, Gilissen C et al (2011) STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N Engl J Med 365:54–61PubMedCrossRefGoogle Scholar
  63. 63.
    Drewniak AA, Gazendam RP, Tool AT, van Houdt M, Jansen MH, van Hamme JL et al (2013) Invasive fungal infection and impaired neutrophil killing in human CARD9 deficiency. Blood 121:2385-2392Google Scholar
  64. 64.
    Glocker EO, Hennigs A, Nabavi M, Schaffer AA, Woellner C, Salzer U et al (2009) A homozygous CARD9 mutation in a family with susceptibility to fungal infections. N Engl J Med 361:1727–1735PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Puel A, Doffinger R, Natividad A, Chrabieh M, Barcenas-Morales G, Picard C et al (2010) Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J Exp Med 207:291–297PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Chatzipanagiotou S, Takou K, Perogamvros A (1998) Cutaneous purulent aspergillosis in a young man with chronic granulomatous disease. Mycoses 41:379–382PubMedCrossRefGoogle Scholar
  67. 67.
    Zhang Q, Davis JC, Lamborn IT, Freeman AF, Jing H, Favreau AJ et al (2009) Combined immunodeficiency associated with DOCK8 mutations. N Engl J Med 361:2046–2055PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Ramoz N, Rueda LA, Bouadjar B, Montoya LS, Orth G, Favre M (2002) Mutations in two adjacent novel genes are associated with epidermodysplasia verruciformis. Nat Genet 32:579–581PubMedCrossRefGoogle Scholar
  69. 69.
    Hernandez PA, Gorlin RJ, Lukens JN, Taniuchi S, Bohinjec J, Francois F et al (2003) Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Nat Genet 34:70–74PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Division of Allergy, Immunology and Pediatric Rheumatology, Department of Pediatrics, Women and Children’s Hospital of Buffalo, SUNY Buffalo, School of Medicine and Biomedical SciencesBuffaloUSA

Personalised recommendations