Severe Combined Immunodeficiencies - SCID

Diagnosis

Indications for Testing

• Early onset viral, fungal, or P. jirovecii infections

Laboratory Testing

• Initial testing
  • CBC – presence of lymphopenia; absolute lymphocyte count often <500 cells/µL
    • Normal lymphocyte count does not rule out SCID
  • HIV molecular PCR testing in infants ≤15 months – rule out HIV infection
  • Cell-mediated immune function (results within 24 hours) – recommended to determine necessity of immediate prophylactic treatment for children
  • T-cell and B-cell immunodeficiency profile testing
    • T-cell testing at minimum should include CD4, CD45RA, CD45RO, CD8, CD4:8 ratio, CD3, CD19, and NK cell
  • Quantitative immunoglobulins – screen for immunodeficiencies
  • Lymphocyte antigen and mitogen proliferation with cytokine response – will be abnormal
    • Test requires at least 7 days for results
• Molecular diagnosis available for prenatal testing
• Second-line testing
  • Analyte/enzyme testing – adenosine deaminase, purine nucleoside phosphorylase
  • Genetic testing – ADA, PNP, IL2RG

Clinical Background

Severe combined immunodeficiencies (SCID) are genetic disorders characterized by blocking T-lymphocyte differentiation in function and often are associated with abnormal development of other lymphocyte lineages (B cells and NK cells).

Epidemiology

• Incidence – 1/75,000-100,000
• Age – median 4-7 months
• Sex – M:F, equal, except for X-linked forms

Identified Forms of SCID

• X-linked SCID – 50-60% of SCID     
• Adenosine deaminase (ADA) deficiency – 30% of SCID
• T- and B-Cell Variants of SCID

  T- and B-Cell Variants of SCID
  Gene	T-cell	B-cell	NK-cell	Genetics*	Comment
  Impaired cytokine-mediated signalling
  IL2RG	–	+	–	XL
  JAK3	–	+	–	AR
  IL7RA	–	+	+	AR	T-cell growth IL7
  Defects in V(D)J recombination
  DCCRE1C (Artemis)	–	–	+	AR	Recombinant of T- and B-cell receptors
  RAG1	–	–	+	AR	Recombinant of T- and B-cell receptors Associated with Omenn syndrome
  RAG2	–	–	+	AR	Associated with Omenn syndrome
  PRKDC (DNA-PKcs)	–	–	+	AR	Radiosensitivity
  LIG4 (DNA ligase IV)	–	–	+	AR	Radiosensitivity, dysmorphic facies, microcephaly, psychomotor delay
  NHEJ1 (Cernunnos)	–	–	+	AR	Radiosensitivity, dysmorphic facies, microcephaly, psychomotor delay
  Impaired signalling through pre-T-cell receptors
  PTPRC (CD3Z)	–	+	+/–	AR	T-cell receptors only
  CD3D, CD3F, CD3G	–	+	+	AR	T-cell receptors only
  CK	–	+	+	AR
  ZAP70	CD4 (+) CD8 (–) Lymphocytes	+	+	AR
  Increased lymphocyte apoptosis
  ADA	–	–	–	AR	Skeletal alterations, hepatitis, neonatal sensorineural deafness
  AK2	–	+	–	AR
  NP (PNP)	–	+	–	AR	Neurological problems
  Defects in thymus embryogenesis
  Winged Helix Nude (WHN)	–	+	+	AR	Alopecia, embryonic neural tube defects
  *AR = autosomal recessive; XL = X-linked

Inheritance

• All but the X-linked forms are autosomal recessive

Pathophysiology

• Block in T-lymphocyte differentiation or growth and variable abnormal development of other lymphocyte lineages

Clinical Presentation

• Most newborns appear normal
• Early onset of severe infections (earliest are Pneumocystis jirovecii viral, also fungal, followed in many cases at 4-6 months by bacterial infection)
• Growth failure
• Persistent diarrhea
• Desquamative skin rash, elevated liver enzymes, and GI bleeding
• Occurrence of graft-versus-host disease upon exposure to maternal lymphocytes, during delivery, or by nonirradiated blood transfusion
  • Most prominent in skin and liver
  • May be associated with autoimmune thrombocytopenia or pancytopenia
  • Rejection of hematopoietic stem cell transplant from father or donors
• Omenn syndrome – atypical SCID associated with null mutations

Treatment

• Prophylaxis for P. jirovecii, fungal infections, and, in some cases, bacterial infections
• Hematopoietic stem cell transplant
• For ADA deficiency – exogenous enzyme replacement
• Gene therapy for X-linked SCID and ADA deficiency

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Adenosine Deaminase, RBC 0083001 Method: Kinetic Spectrophotometry	May be used as a marker of SCID; lack of ADA allows deoxyadenosine to accumulate and kill lymphocytes
Toll-Like Receptor Function Assay 0051589 Method: Cell Culture/Quantitative Multiplex Bead Assay
Interleukin 2 Receptor (Soluble) by MAFD 0051529 Method: Quantitative Multiplex Bead Assay	Secondary variant testing

Diagnostic Algorithm

  Immunodeficiency Evaluation for Chronic Infections in Infants and Children Testing Algorithm