Severe Combined Immunodeficiency (SCID)
• Definition: (N Engl J Med 2000;343:1313)
• Most severe 1° immunodef, lymphopenia, no thymocytes, incompatible w/ life
• Mostly T-cell deficiency, but can also involve B cells and NK cells (combined)
• Pathophysiology: (J Allergy Clin Immunol 2009;124:1161)
• Multiple gene loci including: T-B+ SCID: IL2RG encoding γ-chains of interleukins (most common), Jak3, IL7RA, CD3, CD45;T-B– SCID: RAG1/RAG2, ADA deficiency, Omenn syndrome, Artemis deficiency
• Inheritance autosomal recessive and X-linked (for IL2RG)
• Generally small thymus, w/ poor thymocyte production (no T cells)
• Epidemiology: Affects 1 in 100,000 (Pediatrics 2010;125:e1226)
• For X-linked all are male, but overall SCID has small female predominance
• Clinical manifestations: (J Pediatr 1997;130:378)
• Infant p/w FTT, chronic diarrhea, PNA, OM, sepsis, opportunistic infxns, cutaneous Candida, thrush, recurrent RSV, frequent HSV outbreaks
• Candida albicans, PCP, varicella, measles, Paraflu3, CMV, EBV, Adeno
• Diagnostic studies: At birth, WBC <2,000/mm3, abs lymphocytes very ↓, ↓/absent T cells (<20% of total lymphocytes are T cells)
• Can have absent B cells as well and absent NK cells depending on genotype
• Absent mitogen stim response, can have delayed hypersensitivity skin testing
• Serum immunoglobulins ↓, no antibodies after vaccination
• Newborn screening (Curr Opin Allergy Clin Immunol 2010;10:521)
• Detection of T-cell receptor excision circles (TRECs) = marker of # of naïve T cells
• Low TRECs → repeat analysis of TRECs and β-actin (to ensure integrity of DNA) → TRECs still low → flow cytometry
• Management: Pediatric emergency (Eur J Pediatr 2011;170:561)
• Hematopoietic stem cell transplant (success rate ≈90% in best circumstances)
• For ADA deficiency: Enzyme replacement is an alternative tx
• New innovations: Gene Rx (for ADA and IL2RG)
• Complications: GVHD to nonirradiated blood products or to BMT w/ T cells
• Severe sepsis, severe viral infections because of immunocompromised state
Ataxia-Telangiectasia
• Definition: (Pediatr Allergy Immunol 2005;16:615)
• Progressive disorder w/ cerebellar ataxia, oculocutaneous telangiectasias and combined immunodeficiency (T and sometimes B)
• Pathophysiology
• Mutation in AT on long arm chromo 11q22–23 (encodes DNA-dependent protein kinase involved in DNA repair, cell cycle signaling and meiotic control)
• ↓ CD3 & CD4 counts, ↓ response to T- & B-cell mitogens, helper T-cell & B-cell defects
• Epidemiology: Equal male and female incidence, 1 in 40,000–100,000 births
• Autosomal recessive, so consanguinity increases risk of disease
• Clinical manifestations: (J Pediatr 2004;144:505)
• Early deterioration of gait beginning 1–4 yo with ataxia (wheelchair by 10–12 yo)
• Extrapyramidal deterioration, oculomotor apraxia, nystagmus, poor articulation
• Telangiectasias in conjunctiva and skin appear by age 3–6 yr after neurologic signs
• Concurrent sinopulmonary infections (70%) severe PNA
• Diagnostic studies
• Selective absence of IgA (50–80%), IgG and IgE generally ↓, often T-cell deficiency (60–75%), and more rarely B cells ↓ as well
• Elevated AFP, abnormal ATM kinase activity (if lab can obtain test)
• MRI w/ degeneration of granular and Purkinje cells (Neuroradiology 2003;45:315)
• Management: Prophylactic antibiotics if indicated; IVIG for hypogammaglobulinemia or specific antibody defect; supportive measures
• Complications: ↑ incidence (200×) malignancies; lymphoma, leukemia, and adeno Ca
• Extreme sensitivity to radiation
Wiskott–Aldrich
• Definition: (N Engl J Med 2006;355:1759, Curr Opin Hematol 2008;15:30)
• X-linked d/o w/ AD, thrombocytopenic purpura, dysfunction of platelets
leading to bleeding and predisposition to infection
• Pathophysiology (Curr Opin Hematol 2005;12:284)
• WASP (Wiskott–Aldrich syndrome protein) mutated (Xp11.22–11.23) >160 muts
• WASP, normally expressed in lymphocytes and megakaryocytes, controls actin assembly for microvesicles involved with tyrosine kinase and protein kinase c signaling affecting B, T, and NK cells
• T cells cannot interact w/ APC, B-cell adhesion inhibited by poor cytoskeleton reorganization and poor cell motility
• Epidemiology: X-linked recessive syndrome, generally only affects males
• Clinical manifestations: (N Engl J Med 1995;333:431)
• Bloody diarrhea, bruising, bleeding after circ, thrombocytopenia neonatally
• Frequent OM, PNA, sinusitis, and opportunistic infections; severe eczema
• Diagnostic studies: Serum IgM decreased, IgA and IgE often increased, total Ig normal
• T cells low w/ poor mitogen response, B cells can be increased
• Thrombocytopenia <50,000/μL and small volume platelets seen
• Management: (J Allergy Clin Immunol 2006;117:725, Curr Opin Hematol 2008;15:30)
• Hematopoietic stem cell transplantation (HSCT) is the mainstay of treatment (5 yr survival rate of 87% if HLA match)
• If HSCT not possible: IVIG q3–4wk, consider antibiotic prophylaxis (amoxicillin 20mg/kg qd), Splenectomy: Increased platelets but also increased risk of sepsis
• Gene Rx w/ WASP shown to be feasible & effective (N Engl J Med 2010;363:1918)
• Complications: Autoimmune disease in as high as 40% of affected pts; ITP, hemolytic anemia, vasculitis, IBD, nephritis
• Lymphoma and other malignancies (13%) (J Allergy Clin Immunol 2007;120:795)