ALLERGIC AND IMMUNOLOGIC CONDITIONS

DiGeorge Syndrome (22q11.2 deletion syndrome)

Classification: Congenital thymic/parathyroid developmental disorder causing variable T-cell immunodeficiency (Kishiyama et al., 2019).

Key diagnostic discriminator: Conotruncal cardiac defect plus hypocalcemia and reduced T cells should trigger evaluation for 22q11.2 deletion. Immune severity ranges from mild lymphopenia to complete thymic aplasia (Kishiyama et al., 2019).

Clinical priority: Neonatal seizure may reflect hypocalcemia. Severe infection or a very low T-cell count requires immediate immunology involvement (Kishiyama et al., 2019).

Etiology and risk factors

  • Usually caused by a chromosome 22q11.2 microdeletion that disrupts development of structures derived largely from the third and fourth pharyngeal pouches/arches (Kishiyama et al., 2019).
  • Most cases are de novo; inherited cases are autosomal dominant. Phenotype varies widely even within families (Kishiyama et al., 2019).

Pathophysiology

  • Thymic hypoplasia or aplasia impairs T-cell maturation. B-cell number is usually preserved, but impaired T-cell help can reduce specific antibody responses (Kishiyama et al., 2019).
  • Parathyroid hypoplasia reduces parathyroid hormone reserve and causes hypocalcemia. Abnormal cardiac outflow-tract development produces characteristic congenital heart disease (Kishiyama et al., 2019).

Clinical manifestations

  • Conotruncal cardiac lesions, palatal abnormalities, feeding/speech problems, characteristic facial/ear findings, developmental or psychiatric complications, and recurrent infection may occur (Kishiyama et al., 2019).
  • Hypocalcemia may present with jitteriness, tetany, prolonged QT, or seizure. Complete syndrome causes profound T-cell deficiency and opportunistic infection; partial disease may be recognized later (Kishiyama et al., 2019).

Findings that argue against or redirect

  • Normal calcium and no obvious facial pattern do not exclude 22q11.2 deletion because expression is variable (Kishiyama et al., 2019).
  • Profound combined T- and B-cell dysfunction without the developmental phenotype favors another SCID. Isolated hypocalcemia without T-cell/cardiac/palatal findings suggests other parathyroid or metabolic causes (Kishiyama et al., 2019).

Diagnostic evaluation

  • Use validated genetic testing to identify a 22q11.2 deletion. Evaluate the absolute lymphocyte count, T/B/NK subsets, immunoglobulins, calcium, parathyroid function, renal status, hearing, palate, and cardiac anatomy (Kishiyama et al., 2019).
  • Assess immune competence before live vaccines. After confirmation, offer family evaluation and genetic counseling (Kishiyama et al., 2019).

Expected diagnostic and laboratory findings

  • Definitive: pathogenic 22q11.2 deletion or related developmental-pathway abnormality (Kishiyama et al., 2019).
  • Supportive: low CD3 T cells, particularly naive T cells; low/normal B cells; variable immunoglobulin and antibody responses; hypocalcemia with inappropriately low parathyroid hormone; conotruncal cardiac lesion (Kishiyama et al., 2019).

Differential diagnosis

  • Other SCID: more global immune failure without the characteristic 22q11.2 developmental pattern (Kishiyama et al., 2019).
  • CHARGE syndrome and other thymic-development disorders: distinguish through phenotype and molecular testing (Kishiyama et al., 2019).
  • Congenital hypoparathyroidism: calcium/parathyroid abnormality without the typical immune and cardiac pattern (Kishiyama et al., 2019).
  • Isolated congenital heart disease: normal chromosome testing and immune/calcium evaluation redirect the diagnosis (Kishiyama et al., 2019).

Treatment and management

  • Treat hypocalcemia and address congenital cardiac, palatal, feeding, hearing, developmental, and psychiatric needs through coordinated specialty care (Kishiyama et al., 2019; Norris, 2020).
  • Use infection prevention and immunoglobulin replacement when antibody function warrants. Complete thymic aplasia may require thymus transplantation through a specialized center (Kishiyama et al., 2019; Norris, 2020).

Additional complications and red flags

  • Avoid automatic live-vaccine administration until immune competence has been established (Kishiyama et al., 2019).

Related YourDNP Resources

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References

Kishiyama, J. L., Chang, J. J., & Donovan, S. M. (2019). Disorders of the immune system. In G. D. Hammer & S. J. McPhee (Eds.), Pathophysiology of disease: An introduction to clinical medicine (8th ed.). McGraw-Hill Education.

Norris, T. L. (2020). Porth’s essentials of pathophysiology (5th ed.). Wolters Kluwer.