Inheritance Pattern of Infant with Thrush, Recurrent Infections, and Absent Thymic Shadow
The inheritance pattern depends on the specific diagnosis: 22q11.2 deletion syndrome (DiGeorge syndrome) is typically sporadic (90-95% de novo) with autosomal dominant transmission in familial cases, while SCID demonstrates variable inheritance including X-linked recessive (most common), autosomal recessive, or sporadic patterns depending on the genetic defect. 1, 2
Distinguishing Between DiGeorge Syndrome and SCID
The clinical presentation of thrush, recurrent infections, and absent thymic shadow requires differentiation between complete DiGeorge anomaly and SCID, as these conditions have distinct inheritance patterns and management implications. 1, 3
DiGeorge Syndrome (22q11.2 Deletion)
Inheritance characteristics:
- 90-95% of cases are de novo (sporadic) with no family history 2, 4
- 5-10% are inherited in an autosomal dominant pattern 2
- Affected individuals have a 50% recurrence risk for their offspring 2
- Most commonly caused by 22q11.2 deletion, though TBX1 deficiency, TBX2 deficiency, and FOXI3 haploinsufficiency can also cause autosomal dominant DiGeorge features 1
Key diagnostic features beyond immune deficiency:
- Congenital cardiac defects (particularly conotruncal malformations) present in most cases 1, 4
- Hypoparathyroidism with hypocalcemia 1, 2
- Facial dysmorphism 1, 4
- Palatal abnormalities 1
SCID Inheritance Patterns
The inheritance pattern in SCID varies by genetic defect: 5, 6
X-linked recessive (most common, ~45% of cases):
- X-linked SCID due to IL2RG (gamma chain) deficiency 5
- Affects males; females are carriers 1
- Family history may reveal affected maternal male relatives (cousins, uncles, nephews) 1
- T-B+NK- phenotype is characteristic 5
Autosomal recessive patterns:
- JAK3 deficiency (T-B+NK- phenotype) 5
- ADA deficiency (T-B-NK- phenotype with most profound lymphopenia) 5
- RAG1/2 deficiencies (T-B-NK+ phenotype) 5
- IL-7 receptor deficiency (T-B+NK+ phenotype) 5
- Artemis deficiency (T-B-NK+ phenotype) 7
- 25% recurrence risk for subsequent pregnancies 6
Sporadic cases:
Critical Diagnostic Distinction
This distinction is urgent because treatment differs fundamentally: 3, 7
- SCID requires hematopoietic stem cell transplantation (HSCT) as definitive treatment 3
- Complete DiGeorge anomaly requires thymus transplantation, as HSCT alone is ineffective without a thymus to educate donor T cells 1, 7
- Two reported cases initially diagnosed as complete DiGeorge anomaly were later found to have both 22q11.2 deletion AND Artemis deficiency (SCID), illustrating the complexity and importance of genetic testing 7
Diagnostic Workup to Determine Inheritance Pattern
Immediate laboratory evaluation: 1, 5
- CD3+ T-cell count: <50 cells/μL suggests complete athymia; <300 cells/μL defines SCID 1
- T, B, and NK cell enumeration by flow cytometry to determine phenotype (T-B+NK-, T-B-NK+, etc.) 5
- TREC levels (very low or absent in both conditions) 5
- Lymphocyte proliferation to mitogens 1, 5
Genetic testing to establish inheritance pattern: 1, 2
- 22q11.2 deletion testing (FISH or microarray) for DiGeorge syndrome 1, 4
- Targeted gene sequencing or whole-exome sequencing for SCID genes 1, 8
- Molecular diagnosis permits accurate genetic counseling and identifies specific inheritance pattern 8
Common Pitfalls
Do not assume DiGeorge syndrome based solely on absent thymic shadow - complete DiGeorge can present without the classic triad of hypocalcemia, cardiac defects, or facial dysmorphism 9
Do not delay genetic testing - the phenotypic overlap between complete DiGeorge anomaly and SCID (particularly T-B-NK+ SCID) requires molecular diagnosis, as both can present identically but require different treatments 7
Consider maternal engraftment - this can confuse laboratory findings and delay diagnosis in both conditions 6