A 2.5-month-old-baby boy presented to his pediatrician because of a 10-day history of diarrhea, which began soon after his first series of immunizations, which included the oral rotavirus vaccine. He was born via uncomplicated vaginal delivery and his birth weight and height were at the 55 percent percentile. There were no known ill contacts. His weight and height, which had been 15 percent at two months, was now lower and he had a fever to 101F. Thrush was noted on his tongue and throat, and he was noted to have a diffuse scaling rash on the face and hands (Figures 219-1 and 219-2). A CBC with differential showed an absolute lymphocyte count of 1,200 cells/microliter. A chest x-ray was performed which showed diffuse infiltrates and the absence of a thymic shadow. He was referred to an immunologist for immediate evaluation and treatment. T and B cell subsets were obtained, which revealed that 90 percent of his lymphocytes are B cells and that he had very low numbers of T of maternal origin and NK cells. He was treated with intravenous immune globulin (IVIG), placed on trimethoprim-sulfamethoxazole for Pneumocystis jirovecii prophylaxis and referred to a specialized immunology center for a bone marrow transplant. His bone marrow transplantation was successful.
FIGURE 219-2
Exfoliative dermatitis on the palms of the same infant as in Figure 219-1. (Used with permission from Tim Niehues, MD and Gregor Dückers, MD. Reprinted from Clinical Immunology, 2010, p. 187, with permission from Elsevier.)
Combined immunodeficiency syndromes arise from genetic defects leading to T lymphocyte dysfunction. Because B cells require T cells to produce antibodies, these patients are susceptible to opportunistic infections as well as skin and sinopulmonary infections due to bacterial, viral and fungal organisms. Immune dysregulation can lead to autoimmune disease and auto-inflammation in some syndromes. A diagnosis of a Severe Combined Immunodeficiency (SCID) is fatal before the age of 2 years if untreated and is a medical emergency. Some well-defined primary immunodeficiencies including Wiskott-Aldrich Syndrome, Hyper IgE syndrome, and Ataxia Telangiectasia may present in older patients.
SCID is very rare with an incidence reported at 1.8/100,000 live births per year.1
Newborn screening with T cell receptor excision circles (Trec) has found a rate of 1.64/100,000 tests in Wisconsin. Trec screening does miss some atypical forms of SCID.2
The etiologies of these defects are variable including genetic inheritance and spontaneous mutation.
Modes of inheritance (Table 219-1).
Spontaneous mutations—All forms of congenital immune deficiency can occur as a spontaneous mutation.
The rate of all combined immunodeficiencies is likely an underestimate due to children who die at an early age before a diagnosis can be made.
| Disease | Gene Defects | Mode of Inheritance-Gene | Infections |
| Severe Combined Immunodeficiency (SCID) | |||
| T-B+NK- | Common gamma chain (Most common: 45 to 50% of cases) Janus Kinase 3 | XL-IL2RG AR-JAK3 | Mucocutaneous candidiasis, Pneumocystis, Chronic diarrhea, Severe Viral infections including from attenuated vaccines |
| T-B+NK+ | Il-7 Receptor Alpha Chain CD3 components | AR-IL-7RA AR-CD3 Delta, Epsilon, Zeta | |
| T-B-NK+ | Recombinase activating genes 1/2 | AR-RAG1/RAG2 | |
| Artemis | AR-DCLER1C | ||
| DNA Ligase IV | AR-LIG4 | ||
| T-B-NK- | Adenosine Deaminase | AR-ADA | |
| Reticular Dysgenesis | AR-AK2 | ||
| ZAP70 Deficiency | Zeta Chain Associated Protein Kinase 70kd | AR-ZAP70 | Similar to SCID |
| T+B+NK+: CD8 Lymphopenia, CD4 Dysfunction | Defective T-cell receptor–associated tyrosine kinase | AR-P56lck | |
| Complete DiGeorge Syndrome | 22q11 deletion | AD. Spontaneous- 22q11 | Similar to SCID |
| Nijmegen Breakage Syndrome | DNA Repair Mechanisms | AR-NBN | Viral URI, UTI, Gastrointestinal infections. |
| DNA Ligase IV Deficiency | DNA Repair Mechanisms | AR-LIG | Variable severity- some similar to SCID, others less severe. |
| Hyper IgE Syndrome (HIES) | Signal transducer and Activator of Transcription- 3 | AD-STAT3 | Cold Abscesses, Staphylococcus aureus– Impetigo and lung abscesses, Aspergillus Pseudomonas, Pneumocystis, Mucocutaneous Candidiasis (Figure 219-3), Sinopulmonary- Haemophilus Streptococcus pneumoniae |
| Dedicator of Cytokinesis- No skeletal anomalies | AR-DOCK8 | Severe viral skin infections- (Figures 219-4 and 219-5) molluscum, warts. Bacterial and fungal infections. Do not form abscesses or pneumatoceles | |
| Tyrosine Kinase 2 | AR-TYK2 | Nontuberculous Mycobacteria Infections | |
| Hyper IgM Syndromes | CD40 Ligand, and CD40 | XL-CD40L, AR-CD40 | Combined immune deficiency: Sinopulmonary infections (encapsulated bacteria), Pneumocystis, Cryptosporidium, Histoplasma |
| AID- B cell class switching gene Uracil DNA Glycosylase | AR-AID AR-UNG | Humoral Immune deficiency: sinopulmonary infections, no opportunistic infections | |
| Ataxia Telangiectasia | Ataxia Telangiectasia Mutated | AR-ATM | Sinopulmonary infections, rare opportunistic infections or infections outside of the respiratory tract. |
| Chronic Mucocutaneous Candidiasis | Autoimmune Regular Gene STAT1 Rare- Lyp, Dectin-1, TLR3 | AR-AIRE AD-STAT1 AR | Invasive candidal infections in mucosal surfaces, skin, and nails. |
| Wiskott-Aldrich Syndrome | Wiskott-Aldrich Syndrome Protein | XL- WAS AD=Autosomal Dominant, AR=Autosomal Recessive XL=X-Linked | S pneumoniae Neisseria meningitidis, H influenzae, Pneumocystis, Molluscum, Varicella, Fungal rare |
FIGURE 219-4
Disseminated molluscum viral infection and granulomas on upper eyelids bilaterally (A) and on close up view (B) in a young boy with AR-Hyper IgE syndrome. (Used with permission from Tim Niehues, MD and Gregor Dückers, MD. Photo B is reprinted from Journal of Allergy and Clinical Immunology, 2009, p. 1296, with permission from Elsevier.)
FIGURE 219-5
Severe viral infection of the eyelids in a patient with AR-Hyper IgE syndrome. (Used with permission from Tim Niehues, MD and Gregor Dückers, MD.)
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