Dermatologic Manifestations of Severe Combined Immunodeficiency 

  • Author: Henry K Wong, MD, PhD; Chief Editor: Dirk M Elston, MD   more...
 
Updated: Jul 14, 2010
 

Background

Severe combined immunodeficiency (SCID) is a syndrome first coined by John Soothill, MD, in 1975 at a World Health Organization Expert Committee on primary immunodeficiency. The immunodeficiency is severe because, if unrecognized, it often proves fatal before the patient is aged 2 years, and it is combined because there is a pronounced defect in both cell-mediated and humoral immunity. Patients with SCID have profound defects in the adaptive immune system, and both T-cell and B-cell functions are affected. Combined deficiencies account for approximately 20% of primary immunodeficiencies.

SCID can be classified into 2 groups: SCID with B cells (70% of patients with SCID) and SCID without B cells. T-cell function is affected in all forms of SCID. A T-cell abnormality can lead to defects in B-cell function because B cells require T-cell help for proper activation of the production of antibodies.

Over the past few decades, the diverse molecular genetic causes of SCID have been identified with progress from studies of the immune system.[1] A committee of experts, initially sponsored by the World Health Organization (WHO), meets every 2 years with the goal to classify the group of primary immunodeficiency diseases based on our understanding of the pathways that become defective in the immune system.[2] Eight classification groups have been determined, with SCID being one of the best studied.

Despite the heterogeneity in the pathogenesis of immune defects, common cutaneous manifestations and typical infections can provide clinical clues in diagnosing this pediatric emergency.[3] Appropriate diagnosis is essential because instituting proper treatment is life saving. With the advances in bone marrow transplantation and gene therapy, patients now have a better likelihood of developing a functional immune system in a previously lethal genetic disease. However, once an infant develops serious infections, intervention is rarely successful.

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Pathophysiology

Severe combined immunodeficiency (SCID) can be caused by a variety of distinct genetic defects that interfere with lymphocyte development and function. These defects lead to loss of function of both B and T cells. A defect that affects early lymphocyte development, such as progenitor cells, can lead to an inability to produce both B cells and T cells. Also, a defect of T cells alone can lead to combined immune defects because B cells are dependent on T-cell help for a response to antigen and immunoglobulin class-switching. Although novel causes of SCID continued to be revealed, the pathogenesis can be grouped into mechanisms that are related to lymphocyte development and function.

A defect in lymphoid stem cell development can lead to profound deficiency of both B cells and T cells, such as reticular dysgenesis.

An early block may occur within the T-cell differentiation pathway. The most common form, occurring in 40-60% of patients with SCID, is the X-linked form, SCID-X1, which arises from defects in the common g chain of interleukin receptors. This molecular defect results in absent T- and natural killer (NK)–cell maturation, although recent evidence suggests that the g chain is also involved in B-cell development.

The g chain is a member of the hematopoietic cytokine receptor family. Interleukin 2Ra (IL-2Ra) and interleukin 2Rb (IL-2Rb), in combination with the g chain, recruits interleukin 2 (IL-2), resulting in signal transduction by means of activation of its tyrosine kinase Janus kinase 3 (JAK3). Phosphorylation of signal transducers and activators of transcription 5 (STAT-5) proceeds, enabling its translocation to the nucleus for transcription of genes involved in cell division. Mutation of JAK3 results in the absence of T- and NK-cell function as in SCID-X1.

In addition, the g chain is a member of the interleukin 4 (IL-4), interleukin 7 (IL-7), interleukin 9 (IL-9), interleukin 15 (IL-15) and interleukin 21 (IL-21) receptors, which also function to increase cytokine binding affinity and signal transduction.[4, 5] In addition, defects in signaling molecules that associate with the T-cell receptor can lead to SCID; examples include mutations in the Lck and Zap70 genes. Other cytokine receptor–associated genes include JAK1 and JAK3, which, when defective, can lead to SCID.

Defects in the CD45 molecule, the common leukocyte antigen that functions as a protein phosphatase, can lead to SCID. CD45 is essential in regulating the transmission of cell surface signals in B cells and T cells.

Defects in the expression of the major histocompatibility complex (MHC) lead to bare lymphocyte syndrome, which then results in an inability of the T cells to function. Patients with this condition can have defects in the regulatory region of the MHC class II gene or a defect in a transcription regulator, CTIIA, which is responsible for controlling the expression of MHC class II genes.

Abnormal purine metabolism may be involved. Adenosine deaminase (ADA) deficiency accounts for 20% of all SCID cases. The enzyme deficiency results in the accumulation of intermediates, such as adenosine diphosphate, guanosine triphosphate, and deoxyadenosine triphosphate (dATP), which results in lymphocyte toxicity, particularly with immature thymic lymphocytes. Purine nucleoside phosphorylase (PNP) deficiency is mechanistically similar to ADA deficiency in that the accumulation of deoxyguanosine triphosphate (dGTP) exerts a lymphotoxic effect. In both conditions, T-cell function is most severely affected.

Abnormal recombination of genes may occur. Both B-cell maturation and T-cell maturation involve a process of recombination in which various combinations of variable, diversity, and joining (VDJ) genes are assembled to create unique and specific antigen receptors. Two recombination activating genes, recombinase activating gene 1 (RAG1) and recombinase activating gene 2 (RAG2), which mediate initial DNA double-strand breaking at specific sequences, enable subsequent joining of the various gene segments. Both RAG1 and RAG2 mutations result in a T-B-NK+ SCID phenotype and Omenn syndrome, in which residual VDJ recombination activity occurs.

The gene DNA-PK is a DNA-dependent serine-threonine protein kinase that is required for correct recombination. Mutations in this gene are autosomal recessive and can also lead to combined deficiency. DNA from the cells of these patients is associated with an increased radiosensitivity.

The ARTEMIS gene, located on chromosome 10, encodes a product that plays a role in VDJ recombination and is associated with SCID that develops from an early block in B- and T-cell development.

Reticular dysgenesis is a rare form of SCID that arises from the lack of appropriate stem cell development. Patients with this disease have agranulocytosis in addition to a lack of both B cells and T cells in the adaptive immune system.

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Epidemiology

Frequency

United States

To the author's knowledge, no population surveys have been performed. However, interest has been garnered in implementing screening to identify affected newborns.[6]

International

The frequency is estimated to be 1 case in 50,000-500,000 births.

Mortality/Morbidity

Diagnosis must be made before severe life-threatening infections occur so that the immunity can be restored with enzyme replacement or bone marrow transplantation. Otherwise, the mortality rate is close to 100%.

Sex

Overall, the male-to-female ratio is 3:1 because some forms of SCID are X-linked, whereas other forms of SCID are autosomal recessive.

Age

The mean patient age at diagnosis is 6.5 months.

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Contributor Information and Disclosures
Author

Henry K Wong, MD, PhD  Associate Professor of Dermatology, Ohio State University College of Medicine

Henry K Wong, MD, PhD is a member of the following medical societies: American Academy of Dermatology, American Association of Immunologists, International Society for Cutaneous Lymphomas, and Society for Investigative Dermatology

Disclosure: Amgen Consulting fee Speaking and teaching; Centocor Honoraria Speaking and teaching; Celgene Grant/research funds None; Abbott Labs Grant/research funds Independent contractor

Specialty Editor Board

James Fulton Jr, MD, PhD  Center for Cosmetic Dermatology; Consultant, Vivant Pharmaceuticals, LLC

James Fulton Jr, MD, PhD is a member of the following medical societies: American Academy of Cosmetic Surgery, American Academy of Dermatology, American Society for Laser Medicine and Surgery, Dermatology Foundation, International Society of Cosmetic and Laser Surgeons, and Skin Cancer Foundation

Disclosure: Vivant Pharmaceuticals Grant/research funds Consulting

David F Butler, MD  Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Jeffrey P Callen, MD  Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine

Jeffrey P Callen, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and American College of Rheumatology

Disclosure: Amgen Honoraria Consulting; Abbott Honoraria Consulting; Electrical Optical Sciences Consulting fee Consulting; Celgene Honoraria Safety Monitoring Committee; GSK - Glaxo Smith Kline Consulting fee Consulting; TenXBioPharma Consulting fee Safety Monitoring Committee

Catherine M Quirk, MD  Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania

Catherine M Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD  Director, Ackerman Academy of Dermatopathology, New York

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

References
  1. Notarangelo LD. Primary immunodeficiencies. J Allergy Clin Immunol. Feb 2010;125(2 Suppl 2):S182-94. [Medline].

  2. Geha RS, Notarangelo LD, Casanova JL, et al. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. J Allergy Clin Immunol. Oct 2007;120(4):776-94. [Medline].

  3. Rosen FS. Severe combined immunodeficiency: a pediatric emergency. J Pediatr. Mar 1997;130(3):345-6. [Medline].

  4. Kovanen PE, Leonard WJ. Cytokines and immunodeficiency diseases: critical roles of the gamma(c)-dependent cytokines interleukins 2, 4, 7, 9, 15, and 21, and their signaling pathways. Immunol Rev. Dec 2004;202:67-83. [Medline].

  5. Roifman CM, Zhang J, Chitayat D, Sharfe N. A partial deficiency of interleukin-7R alpha is sufficient to abrogate T-cell development and cause severe combined immunodeficiency. Blood. Oct 15 2000;96(8):2803-7. [Medline].

  6. Puck JM,. Population-based newborn screening for severe combined immunodeficiency: steps toward implementation. J Allergy Clin Immunol. Oct 2007;120(4):760-8. [Medline].

  7. Baker MW, Grossman WJ, Laessig RH, et al. Development of a routine newborn screening protocol for severe combined immunodeficiency. J Allergy Clin Immunol. Sep 2009;124(3):522-7. [Medline].

  8. Grunebaum E, Mazzolari E, Porta F, et al. Bone marrow transplantation for severe combined immune deficiency. JAMA. Feb 1 2006;295(5):508-18. [Medline].

  9. Tsuji Y, Imai K, Kajiwara M, et al. Hematopoietic stem cell transplantation for 30 patients with primary immunodeficiency diseases: 20 years experience of a single team. Bone Marrow Transplant. Mar 2006;37(5):469-77. [Medline].

  10. Railey MD, Lokhnygina Y, Buckley RH. Long-term clinical outcome of patients with severe combined immunodeficiency who received related donor bone marrow transplants without pretransplant chemotherapy or post-transplant GVHD prophylaxis. J Pediatr. Dec 2009;155(6):834-840.e1. [Medline].

  11. Ariga T. Gene therapy for primary immunodeficiency diseases: recent progress and misgivings. Curr Pharm Des. 2006;12(5):549-56. [Medline].

  12. Fischer A, Hacein-Bey S, Le Deist F, de Saint Basile G, Cavazzana-Calvo M. Gene therapy for human severe combined immunodeficiencies. Immunity. Jul 2001;15(1):1-4. [Medline].

  13. Qasim W, Gaspar HB, Thrasher AJ. Progress and prospects: gene therapy for inherited immunodeficiencies. Gene Ther. Nov 2009;16(11):1285-91. [Medline].

  14. Friedrich W, Hönig M, Müller SM. Long-term follow-up in patients with severe combined immunodeficiency treated by bone marrow transplantation. Immunol Res. 2007;38(1-3):165-73. [Medline].

  15. Bonilla FA, Geha RS. 2. Update on primary immunodeficiency diseases. J Allergy Clin Immunol. Feb 2006;117(2 Suppl Mini-Primer):S435-41. [Medline].

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Table. Common Causes of SCID, Cellular Defects, and Inheritance Pattern
Genetic DiseaseT-Cell DefectB-Cell DefectNK-Cell DefectInheritance Pattern
Reticular dysgenesisYesYesYesAutosomal recessive
ADA deficiencyYesYesYesAutosomal recessive
RAG1 and RAG2 deficiencyYesYesNoAutosomal recessive
T-cell receptor and B-cell receptor recombination gene deficiencyYesYesNoAutosomal recessive
Common g chain deficiencyYesNoYesX-linked
JAK3 deficiencyYesNoNoAutosomal recessive
IL-7Ra deficiencyYesNoNoAutosomal recessive
Omenn syndromeYesNoNoAutosomal recessive
ZAP-70 kinaseCD4+ presentNoNoAutosomal recessive
CD4+ lymphopeniaCD8+



present



NoNoAutosomal recessive
MHC II deficiencyCD8+



present



NoNoAutosomal recessive
p56lck deficiencyCD8+



present



NoNoAutosomal recessive
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