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Digeorge SyndromeEdit

DiGeorge syndrome, also called 22q11.2 deletion syndrome and historically referred to by several other names such as velocardiofacial syndrome, is a chromosomal microdeletion disorder that affects multiple organ systems. The condition arises from a missing segment on chromosome 22q11.2, typically about 1.5 to 3 million base pairs in length, and leads to a wide range of clinical features. The phenotype is highly variable, with some individuals experiencing major congenital anomalies and others presenting primarily developmental or psychiatric concerns as they age. The deletion is usually de novo (appearing for the first time in a family), but in a minority of cases it is inherited from a parent who carries the deletion.

DiGeorge syndrome presents a spectrum of manifestations across three broad domains: congenital heart disease, immune system differences, and endocrine or developmental concerns, often with overlapping features that complicate diagnosis. The syndrome’s breadth has led to it being viewed not as a single disease but as a family of related presentations tied to the same genetic deletion. The core driver appears to involve the TBX1 gene and neighboring genes, which together influence the development of the heart, thymus, parathyroid glands, palate, and brain. The condition is connected to a number of alternative clinical labels and historical descriptions, reflecting evolving understanding of its genetic basis and clinical variability. For an overview of the genetic basis and nomenclature, see 22q11.2 deletion syndrome and velocardiofacial syndrome.

Signs and symptoms

  • Heart defects: Conotruncal heart defects are the most common serious early manifestations. These include tetralogy of Fallot, interrupted aortic arch, and other abnormal connections that may require surgical repair in infancy or early childhood. See tetralogy of Fallot and interrupted aortic arch.
  • Palatal and feeding issues: Palatal abnormalities such as velopharyngeal insufficiency or submucous cleft palate can cause feeding and speech difficulties. See velopharyngoplasty and palatal anomaly.
  • immune system involvement: Thymic hypoplasia or aplasia can lead to varying degrees of T-cell deficiency, with infection risk that is highest in infancy but can improve over time in many individuals. See thymus and primary immunodeficiency.
  • endocrine problems: Hypoparathyroidism can cause hypocalcemia, presenting with jitteriness, seizures, or prolonged QT intervals if not treated. See hypoparathyroidism.
  • Neurodevelopment and psychiatric risk: Intellectual disability or learning differences are common, along with attention problems and social communication challenges. In adolescence and adulthood, there is an elevated risk of anxiety disorders, mood disorders, and schizophrenia-spectrum conditions relative to the general population. See schizophrenia and developmental disability.
  • Facial and growth features: Some individuals exhibit distinct facial features, growth differences, and minor skeletal anomalies, though these are not universal and vary by person. See craniofacial anomalies.

Genetics and pathophysiology

  • Genetic basis: The syndrome results from a deletion at chromosome 22q11.2. The deleted region typically spans about 1.5–3 Mb and encompasses many genes, with TBX1 being a major contributor to the heart, thymus, and craniofacial features. See TBX1 and chromosomal deletion.
  • Inheritance and variability: Most cases arise de novo, but a minority are inherited from a parent who carries the same deletion. Even within a family, the clinical presentation can vary widely from almost no recognizable features to severe multi-organ involvement. See genetic anticipation and variable expressivity.
  • Pathophysiology: The loss of function for TBX1 and neighboring genes disrupts development of the pharyngeal arches, which are critical in forming the great arteries, thymus, and parathyroid glands, as well as palate and brain structures. This explains the clustering of congenital heart disease, immune deficiency, hypocalcemia, and palate and neurodevelopmental issues observed in many patients. See pharyngeal arches and embryology.

Diagnosis

  • Clinical suspicion: The combination of congenital heart defects, palatal anomalies, immune deficiency, and/or hypocalcemia in a newborn or infant prompts genetic testing for 22q11.2 deletions.
  • Genetic testing: The preferred method is a chromosomal microarray (array comparative genomic hybridization, or array CGH), which detects most 22q11.2 deletions. Fluorescence in situ hybridization (FISH) and other targeted tests are older methods and may miss atypical or smaller deletions; newer two-dimensional and sequencing approaches provide broader detection. See array CGH and FISH.
  • Prenatal testing: If there is a known familial deletion or a high-risk pregnancy, prenatal testing via amniocentesis with microarray can identify the deletion before birth. See prenatal testing.
  • Differential diagnosis: Other disorders with overlapping features (certain syndromic congenital heart defects, immune deficiencies, or craniofacial anomalies) may be considered, and a comprehensive evaluation is often necessary. See conotruncal abnormality.

Management and treatment

  • Multidisciplinary care: Optimal management typically involves a team approach, including pediatric cardiology, immunology, endocrinology, genetics, speech and feeding therapists, audiology, and developmental pediatrics. See pediatric cardiology, immunology, and speech therapy.
  • Cardiac interventions: Surgical repair or interventions for CHD may be required in infancy or early childhood, with ongoing cardiology follow-up. See cardiac surgery.
  • Immunology and infection risk: Immune workups guide vaccination plans and infection prevention. Live vaccines may be avoided or delayed in those with significant T-cell deficiency, while in others, standard vaccination schedules can proceed with medical guidance. See vaccination and immunodeficiency.
  • Endocrine management: Calcium supplementation and monitoring are important for those with hypoparathyroidism, and long-term endocrine follow-up is common. See calcium and parathyroid gland.
  • Palatal and speech therapies: Early speech therapy and, when needed, surgical repair or augmentation for palatal function can improve feeding, swallowing, and speech outcomes. See speech-language pathology.
  • Developmental and educational support: Individualized education plans and early intervention services support cognitive and social development. See educational psychology.
  • Genetic counseling: Families receive information about recurrence risks, which are low for de novo cases but higher if a parent carries the deletion; testing of family members can be discussed. See genetic counseling.

Controversies and policy considerations

  • Screening and diagnosis: A central policy question concerns the scope of genetic screening. Advocates for targeted screening emphasize catching major health issues early to reduce long-term costs and improve outcomes, while critics worry that broad genetic screening could lead to anxiety, misinterpretation, or unwanted information without clear benefit. Proponents argue that early knowledge enables better planning for surgical, immunologic, and developmental needs; opponents caution against overmedicalization and potential discrimination.
  • Newborn screening versus family-centered testing: Some observers favor offering genetic testing in the context of newborn screening when there are clear clinical cues (such as CHD with additional features) to avoid unnecessary genetic labeling in otherwise asymptomatic infants. Others support more expansive testing to identify milder or atypical presentations earlier, arguing that knowledge empowers families and clinicians to tailor care.
  • Prenatal options and ethics: Preimplantation genetic testing and prenatal diagnosis raise questions about reproductive choices and the balance between identifying a deletion and respecting parental autonomy. Supporters say such options enable informed decision-making, while critics worry about eugenic implications or pressure on families to avoid disability. In practice, many families prioritize preparation for medical care and educational needs rather than evading a diagnosis entirely.
  • Healthcare costs and care coordination: 22q11.2 deletion syndrome often requires specialized, lifelong care across multiple specialties. A fiscally conservative perspective emphasizes streamlining care pathways, reducing bureaucratic overhead, and investing in centers that coordinate multidisciplinary services to maximize outcomes while containing expenses. Critics of this view may push for broader government programs or public funding to ensure access regardless of family means.
  • Disability advocacy and cultural dialogue: Debates around disability identity and medical labeling surface in discussions about 22q11.2 deletion syndrome. While some disability advocates emphasize social inclusion and accommodations, others argue for focusing on medical interventions that improve function and independence. From a pragmatic vantage point, meaningful progress tends to come from high-quality medical care, evidence-based therapies, and family-centered support that respect individual outcomes without reducing a person to a label.

See also