What is the appropriate work‑up and management for a child with an absent thymus discovered on imaging or presenting with severe T‑cell immunodeficiency?

Absent Thymus: Work-up and Management

An absent thymus on imaging in an infant is a medical emergency requiring immediate comprehensive immunologic evaluation for severe combined immunodeficiency (SCID) or other life-threatening T-cell deficiencies, with urgent referral to a tertiary immunology center for consideration of hematopoietic stem cell transplantation or thymus transplantation. 1

Immediate Diagnostic Work-up

Critical Laboratory Tests

• Complete blood count with differential to assess for lymphopenia (88% of SCID patients have absolute lymphocyte count <3000/mm³) 2
• Flow cytometry for lymphocyte subsets including CD3+ T cells, CD4+ T cells, CD8+ T cells, CD19+ B cells, and NK cells to determine the specific immunophenotype (T-B+NK-, T-B-NK+, T-B-NK-, or T-B+NK+) 3
• Quantification of naive T cells (CD45RA+ CCR7-) which are typically very low or absent in SCID 1
• T-cell receptor excision circles (TRECs) which will be very low or absent in complete athymia 4, 3
• Serum immunoglobulin levels (IgG, IgA, IgM) noting that IgG may be falsely normal due to maternal transfer 1, 3
• T-cell proliferation assays to mitogens (PHA, ConA) and antigens, which show profoundly reduced responses in SCID 1, 3

Genetic and Syndromic Evaluation

• Chromosomal microarray or karyotype to evaluate for 22q11.2 deletion (DiGeorge syndrome) 1, 5
• Targeted genetic testing for FOXN1 (Nude SCID), PAX1 (Otofaciocervical syndrome type 2), CHD7 (CHARGE syndrome), FOXI3 (2p11.2 microdeletion), and TBX1 mutations 1, 5
• Physical examination specifically looking for cardiac anomalies, ear abnormalities, choanal atresia, growth restriction, genital abnormalities, and coloboma (features of CHARGE syndrome) 1

Differential Diagnosis Based on Thymic Absence

Complete Athymia (Actionable - Requires Urgent Intervention)

• SCID variants with absent thymic tissue showing <5% naive T cells and insignificant TRECs 4
• Complete 22q11.2 deletion syndrome (DiGeorge syndrome) eligible for thymus transplantation 1
• CHARGE syndrome with athymia requiring thymus transplantation 1
• FOXN1 deficiency (Nude SCID) requiring thymus transplantation 1, 5
• PAX1 deficiency requiring thymus transplantation 1, 5

Thymic Hypoplasia (May Be Actionable)

• Partial DiGeorge syndrome with reduced but present thymic function showing reduced TRECs and naive T cells at all ages 4
• Stress-induced thymic involution in critically ill infants without primary immunodeficiency (thymus can shrink dramatically during metabolic stress) 1

Important Caveat

Some forms of SCID (CD3δ deficiency, coronin 1A deficiency) may have a normal-appearing thymus on imaging despite severe T-cell immunodeficiency, so normal thymic shadow does not exclude SCID 1

Immediate Management Priorities

Infection Prevention and Control

• Strict protective isolation to prevent exposure to pathogens 1
• Avoid all live-attenuated vaccines (rotavirus, MMR, varicella, BCG) as vaccine-strain organisms cause serious infections in T-cell deficient patients 1
• Prophylactic antimicrobials: trimethoprim-sulfamethoxazole for Pneumocystis jiroveci pneumonia prevention 2
• Antifungal prophylaxis (fluconazole) given high risk of oral candidiasis (43% of SCID patients) 2
• Antiviral prophylaxis (acyclovir) given high risk of viral infections (35.5% of SCID patients) 2
• Use only CMV-negative, irradiated blood products if transfusion needed 1

Immunoglobulin Replacement

• Initiate intravenous immunoglobulin (IVIG) replacement immediately if hypogammaglobulinemia is present 1

Urgent Referral

• Immediate referral to tertiary immunology center with experience in SCID management and transplantation 1
• Multidisciplinary team coordination including immunology, infectious disease, genetics, and transplant services 1

Definitive Treatment Options

Hematopoietic Stem Cell Transplantation (HSCT)

• HSCT is the definitive treatment for SCID and profound T-cell lymphopenia not meeting all SCID criteria but eligible for transplantation 1, 3
• Timing is critical: outcomes are significantly better when HSCT is performed before 3.5 months of age 3
• T-cell depleted HLA-haploidentical or HLA-identical transplants are standard approaches 2

Thymus Transplantation

• Thymus transplantation is indicated for complete 22q11.2 deletion syndrome, CHARGE syndrome, athymic FOXN1 deficiency, and PAX1 deficiency 1
• These conditions represent actionable findings where urgent intervention results in demonstrated improvement in outcome 1

Clinical Presentation Patterns to Recognize

Classic SCID Presentation

• Recurrent, persistent, or severe infections with bacterial, viral, or fungal pathogens starting in early infancy 1
• Failure to thrive (50% have weight <5th percentile) 2
• Oral candidiasis (43% of cases) 2
• Pneumocystis jiroveci pneumonia (26% of cases) 2
• Chronic diarrhea and malabsorption 3
• Absence of palpable lymphoid tissue (lymph nodes, tonsils) 1

Key Historical Features

• Positive family history of early infant death or known SCID (37% of cases) leads to earlier diagnosis (mean 2.0 months vs 6.6 months without family history) 2
• Maternal male relatives (cousins, uncles, nephews) dying of similar disease suggests X-linked inheritance 6

Common Pitfalls to Avoid

• Do not assume normal thymus excludes SCID: CD3δ and coronin 1A deficiencies can have normal-appearing thymus 1
• Do not delay evaluation in stressed/ill infants: while stress can cause thymic involution, this must be distinguished from true athymia through immunologic testing 1
• Do not confuse with agammaglobulinemia: absent thymus with T-cell deficiency is distinct from X-linked agammaglobulinemia (which has normal T cells, absent B cells, and normal thymus) 6
• Do not wait for genetic confirmation to initiate treatment: begin protective measures and IVIG immediately based on clinical and immunologic findings 1, 6
• Recognize that thymic dysplasia shows lack of Hassall's corpuscles and absent corticomedullary architecture on pathology, distinguishing it from secondary thymic atrophy 1, 7