• Clinical science

Congenital immunodeficiency disorders


Congenital immunodeficiency disorders are characterized by a deficiency, absence, or defect in one or more of the main components of the immune system. These disorders are genetically determined and typically manifest during infancy and childhood as frequent, chronic, or opportunistic infections. Classification is based on the main component of the immune system that is deficient, absent, or defective. The diagnosis is confirmed with tests such as differential WBC count, absolute lymphocyte count, quantitative immunoglobulin (Ig) measurements, and antibody titers. Treatment usually consists of prophylactic antibiotics to manage and prevent infections. The prognosis in primary immunodeficiency disorders is variable and depends on the specific disorder.

Congenital B-cell immunodeficiencies

B-cell defects (humoral immunity deficiencies) account for 50–60% of all primary immunodeficiencies.

Bruton agammaglobulinemia (X-linked agammaglobulinemia)

Live vaccines (e.g., MMR) are contraindicated in patients with Bruton agammaglobulinemia.

Selective IgA deficiency (SIgAD)

  • Definition: the most common primary immunodeficiency with near or total absence of serum and secretory IgA
  • Epidemiology: approx. 1/220 to 1/1000
  • Etiology: unknown
  • Clinical features
    • Often asymptomatic
    • May manifest with sinusitis or respiratory infections (S. pneumoniae, H. influenzae), chronic diarrhea (Giardia), steatorrhea
    • Associated with gluten-sensitive enteropathy, inflammatory bowel disease
  • Diagnosis: serum IgA level < 7 mg/dL, with normalIgG and IgM levels
  • Treatment

To prevent transfusion reactions, IgA deficient patients must be given washed blood products without IgA or obtain blood from an IgA-deficient donor.

Common variable immunodeficiency (CVID)


Congenital T-cell immunodeficiencies

T cell defects (cellular immunity deficiencies) are responsible for 5–10% of primary immunodeficiencies.

DiGeorge syndrome (22q11.2 deletion syndrome)

Autosomal dominant hyperimmunoglobulin E syndrome (Job syndrome)

  • Definition: : defect in neutrophil chemotaxis
  • Etiology: STAT3 mutation → decreased Th17 cells → defect in neutrophil/macrophage recruitment
  • Clinical features
    • FATED:
      • Facies coarse
      • Abscesses (recurrent bacterial infections)
      • Retained primary Teeth
      • Hyper-IgE (Eosinophilia)
      • Dermatologic (severe eczema)
  • Diagnosis
  • Treatment
    • Antibiotic treatment and prophylaxis
    • IV immunoglobulin therapy

IL-12 receptor deficiency

  • Definition: impaired Th response due to IL-12 receptors
  • Etiology: autosomal recessive
  • Pathophysiology: : Normally, antigen-presenting macrophages release IL-12, which triggers T-helper cells to transform to T1 type. T1-helper cells then release IFN-γ to activate macrophages. If IL-12 receptors are defective, macrophages cannot be activated by IFN-γ to trigger cytotoxicity in cells infected with intracellular pathogens such as mycobacteria and salmonella
  • Clinical features
    • Age at onset varies depending on the age at exposure to causative pathogens (on average 1–3 years of age).
    • Features of disseminated disease, especially tuberculosis (e.g., following administration of BCG vaccine)
    • Fungal infections
  • Diagnosis: IFN-γ
  • Treatment: antibiotic and IFN-γ therapy

Chronic mucocutaneous candidiasis

IPEX syndrome (Immune dysregulation, polyendocrinopathy, enteropathy, X-linked)


Congenital mixed immunodeficiencies

Severe combined immunodeficiency (SCID, bubble boy disease, Glanzmann–Riniker syndrome, alymphocytosis)

Wiskott-Aldrich syndrome

WIPE → Wiskott-Aldrich, Infections, Purpura, Eczema

Hyper-IgM syndrome

Ataxia telangiectasia


Congenital neutrophil and phagocyte disorders

Phagocytic defects are characterized by impaired ability of phagocytic cells (e.g., monocytes, macrophages, granulocytes such as neutrophils and eosinophils) to kill pathogens and account for 10–15% of primary immunodeficiencies.

Chronic granulomatous disease (CGD)

Leukocyte adhesion deficiency type 1

Chédiak-Higashi syndrome

Myeloperoxidase deficiency

  • Definition: deficiency or absence of myeloperoxidase enzyme in phagocytes → preserved respiratory burst (since NADPH oxidase intact) but inability to form hypochlorous acid (HClO)
  • Etiology: autosomal recessive mutation in the MPO gene
  • Clinical features
  • Diagnosis
    • Positive nitroblue tetrazolium test (intact NADPH oxidase)
    • Absent myeloperoxidase on staining
    • Mutations in MPO gene on sequencing
  • Treatment: no specific treatment or prophylaxis is indicated. Treating fungal infections with minimal therapy is advised.

Severe congenital neutropenia


Congenital complement deficiencies

Complement deficiencies are rare (≤ 2%) deficiencies of complement components or inhibitors.

C1-esterase inhibitor deficiency (hereditary angioedema)

Terminal complement deficiency (C5–C9 deficiency)

C3 deficiency

  • Definition: deficiency of the complement factor C3 and its cleaved fragments (e.g., C3b)
  • Etiology: primary or secondary due to impairment in the regulatory proteins factor I or factor H
  • Pathophysiology: decreased levels of the opsonin C3b → impaired opsonization of pathogens by the innate immune system and reduced clearance of C3b-bound immune complexes
  • Clinical features


  • 1. Yel L . Selective IgA deficiency. J Clin Immunol. 2010; 30(1): pp. 1–16. doi: 10.1007/s10875-009-9357-x.
  • 2. Fernandez J . Selective IgA Deficiency. http://www.msdmanuals.com/professional/immunology-allergic-disorders/immunodeficiency-disorders/selective-iga-deficiency. Updated August 1, 2016. Accessed May 15, 2017.
  • 3. Azizi G, Ziaee V, Tavakol M, et al. Approach to the management of autoimmunity in primary immunodeficiency. Scand J Immunol. 2017; 85(1): pp. 13–29. doi: 10.1111/sji.12506.
  • 4. Coombs C, Kirk AS. Oski's Pediatric Certification and Recertification Board Review. Lippincott Williams & Wilkins; 2011.
  • 5. Taneja A, Chhabra A. Bruton Agammaglobulinemia. url: https://www.ncbi.nlm.nih.gov/pubmed/28846295 Accessed January 29, 2018.
  • 6. Cunningham-Rundles C. The many faces of common variable immunodeficiency. Hematology Am Soc Hematol Educ Program. 2012; 2012: pp. 301–305. url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066657/.
  • 7. Sneller MC. New insights into common variable immunodeficiency. Ann Intern Med. 1993; 118(9): p. 720. doi: 10.7326/0003-4819-118-9-199305010-00011.
  • 8. Kasper DL, Fauci AS, Hauser SL, Longo DL, Lameson JL, Loscalzo J. Harrison's Principles of Internal Medicine. New York, NY: McGraw-Hill Education; 2015.
  • 9. Caragol I, Casanova JL. Inherited disorders of the Interleukin-12/ Interferon-gamma axis: Mendelian predisposition to mycobacterial disease in man. Inmunología. 2003; 22(3): pp. 263–276. url: http://www.inmunologia.org/Upload/Articles/6/0/601.pdf.
  • 10. Palamaro L, Giardino G, Santamaria F et al . Interleukin 12 receptor deficiency in a child with recurrent bronchopneumonia and very high IgE levels. Ital J Pediatr. 2012; 38(46). doi: 10.1186/1824-7288-38-46.
  • 11. Prando C, Samarina A, Bustamante J et al. . Inherited IL-12p40 deficiency. Medicine (Baltimore). 2013; 92(2): pp. 109–122. doi: 10.1097/MD.0b013e31828a01f9.
  • 12. Edgar JDM. Immunology. Elsevier Health Sciences; 2006.
  • 13. Fomin AB, Pastorino AC, Kim CA, Pereira C, Carneiro-Sampaio M, Abe-Jacob CM. DiGeorge Syndrome: a not so rare disease. Clinics. 2010; 65(9): pp. 865–869. doi: 10.1590/s1807-59322010000900009.
  • 14. Khan K, Wozniak SE, Giannone AL, Abdulmassih ME. A boy with relentless pruritus: Job’s Syndrome. Am J Case Rep. 2016; 17: pp. 104–110. doi: 10.12659/ajcr.896798.
  • 15. Murphy KM. Janeway's Immunobiology. New York, NY: Garland Science; 2011.
  • 16. Estupiñan BA. Chronic Mucocutaneous Candidiasis. In: Elston DM. Chronic Mucocutaneous Candidiasis. New York, NY: WebMD. https://emedicine.medscape.com/article/1091928. Updated April 17, 2017. Accessed May 14, 2018.
  • 17. Le T, Bhushan V, Chen V, King M. First Aid for the USMLE Step 2 CK. McGraw-Hill Education; 2015.
  • 18. Le T, Bhushan V. First Aid for the USMLE Step 1 2015. McGraw-Hill Education; 2014.
  • 19. Johnson J, Filipovich AH, Zhang K. X-Linked Hyper IgM Syndrome. url: https://www.ncbi.nlm.nih.gov/books/NBK1402/ Accessed January 30, 2018.
  • 20. Puck JM, Stiehm ER, TePas E. UpToDate - Severe Combined Immunodeficiency (SCID): An Overview. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/severe-combined-immunodeficiency-scid-an-overview. Last updated April 18, 2018. Accessed July 19, 2018.
  • 21. Mayo Clinic Staff. Dihydrorhodamine (DHR) Flow Cytometric Phorbol Myristate Acetate (PMA) Test, Blood. https://www.mayomedicallaboratories.com/test-catalog/Overview/62765. Updated January 1, 2018. Accessed July 19, 2018.
  • 22. Oliveira JB, Fleisher TA. Laboratory evaluation of primary immunodeficiencies. J Allergy Clin Immunol. 2009; 125(2): pp. 297–305. doi: 10.1016/j.jaci.2009.08.043.
  • 23. Ram S, Lewis LA, Rice PA. Infections of people with complement deficiencies and patients who have undergone splenectomy. Clin Microbiol Rev. 2010; 23(4): pp. 740–780. doi: 10.1128/cmr.00048-09.
  • 24. Le T, Bhushan V,‎ Sochat M, Chavda Y, Zureick A. First Aid for the USMLE Step 1 2018. New York, NY: McGraw-Hill Medical; 2017.
  • 25. S. Reis E, Falcao DA, Isaac L. Clinical aspects and molecular basis of primary deficiencies of complement component C3 and its regulatory proteins factor I and factor H. Scand J Immunol. 2006; 63(3): pp. 155–168. doi: 10.1111/j.1365-3083.2006.01729.x.
last updated 04/15/2019
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