Overview
Definition:
22q11.2 deletion syndrome is a microdeletion syndrome caused by a deletion on the long arm of chromosome 22 (22q11.2)
It is characterized by a wide spectrum of clinical manifestations affecting multiple organ systems, including cardiac, immune, endocrine, craniofacial, and neurological development
The syndrome is inherited in an autosomal dominant manner, although most cases arise de novo
It is one of the most common chromosomal abnormalities in humans.
Epidemiology:
The prevalence is estimated to be between 1 in 2,000 to 1 in 4,000 live births
It is the second most common chromosomal syndrome after Down syndrome
There is no significant predilection for sex or ethnicity
The diagnosis can be missed or delayed due to the variable expressivity of the phenotype.
Clinical Significance:
Understanding 22q11.2 deletion syndrome is crucial for pediatricians and residents preparing for DNB and NEET SS examinations due to its high prevalence and significant morbidity
The complex interplay of immunodeficiency, hypocalcemia, and cardiac anomalies necessitates early diagnosis and multidisciplinary management to improve patient outcomes and prevent life-threatening complications
Recognizing the diverse presentations is key to accurate diagnosis and appropriate referral.
Clinical Presentation
Symptoms:
Cardiac defects (conotruncal anomalies like tetralogy of Fallot, truncus arteriosus, interrupted aortic arch)
Recurrent infections due to T-cell deficiencies (thymic hypoplasia/aplasia)
Hypocalcemia due to parathyroid hypoplasia/aplasia, leading to seizures, tetany, or tremors
Craniofacial abnormalities (e.g., micrognathia, small ears, wide nasal bridge, palatal abnormalities like cleft palate or submucous cleft)
Developmental delay, learning disabilities, and behavioral issues (e.g., ADHD, autism spectrum disorder)
Psychiatric disorders in adolescence and adulthood (e.g., schizophrenia, bipolar disorder)
Gastrointestinal problems (e.g., feeding difficulties, reflux)
Renal anomalies
Characteristic facies (long face, prominent nose, small mouth, hooded eyelids).
Signs:
Pallor or cyanosis if significant cardiac defect
Poor weight gain and failure to thrive
Lymphadenopathy may be absent due to immune deficiency
Tetany or carpopedal spasm on Chvostek or Trousseau sign provocation
Characteristic facial features as described above
Absence of palpable thymic tissue
Abnormalities of the palate
Findings suggestive of opportunistic infections.
Diagnostic Criteria:
While there are no universally applied formal diagnostic criteria for 22q11.2 deletion syndrome, a diagnosis is strongly suspected in individuals with characteristic features, particularly a combination of cardiac defects, immune deficiency, and hypocalcemia
Definitive diagnosis is made through genetic testing, typically fluorescence in situ hybridization (FISH) or chromosomal microarray analysis (CMA), which can detect the specific deletion at the 22q11.2 locus.
Diagnostic Approach
History Taking:
Detailed family history for similar features or unexplained infant deaths
History of recurrent infections in infancy and childhood, including type and frequency
History of neonatal hypocalcemic seizures or tetany
Presence of congenital heart defects or murmurs
Feeding difficulties or failure to thrive
Developmental milestones and learning difficulties
History of cleft palate or velopharyngeal insufficiency
Psychiatric history in family members.
Physical Examination:
Thorough cardiac auscultation for murmurs
Evaluation for characteristic facial dysmorphia
Examination of the palate for clefts or submucous clefts
Assessment of thymic "waving" or palpable thymic tissue in infants
Neurological examination to assess for signs of hypocalcemia or developmental delay
Assessment of skin for any opportunistic infections.
Investigations:
Genetic testing: FISH for 22q11.2 deletion or CMA is the gold standard
Complete blood count (CBC) with differential to assess lymphocyte subsets (T, B, NK cells)
Serum calcium, phosphorus, and parathyroid hormone (PTH) levels to assess for hypocalcemia
Echocardiogram to evaluate for congenital heart disease
Renal ultrasound to assess for renal anomalies
Skeletal survey for vertebral anomalies
Electroencephalogram (EEG) if seizures are present
Immunological workup including T-cell proliferation assays if immunodeficiency is suspected
Chest X-ray may show small or absent thymus.
Differential Diagnosis:
Other syndromes with similar features: CHARGE syndrome, Down syndrome, Smith-Lemli-Opitz syndrome, Kabuki syndrome
Isolated cardiac defects
Isolated immunodeficiencies (e.g., SCID)
Isolated hypocalcemia (e.g., due to Albright hereditary osteodystrophy)
Developmental delay of other etiologies.
Management
Initial Management:
Stabilization of any acute issues like severe hypocalcemia or cardiac decompensation
Prompt treatment of infections
Nutritional support for feeding difficulties.
Medical Management:
Calcium and Vitamin D supplementation for hypocalcemia, titrated to maintain normal serum calcium levels
Management of recurrent infections with prophylactic antibiotics, intravenous immunoglobulin (IVIG) in severe cases, and prompt treatment of acute infections
Management of cardiac defects with appropriate medical therapy or referral for surgical correction
Antiepileptic drugs for seizure management
Speech therapy for velopharyngeal insufficiency
Behavioral therapies and educational support for developmental and learning disabilities.
Surgical Management:
Surgical correction of congenital heart defects is a critical component of management, often requiring complex procedures
Surgical repair of cleft palate
Potential need for tracheostomy in cases of severe airway compromise.
Supportive Care:
Multidisciplinary team approach is essential, including geneticists, cardiologists, immunologists, endocrinologists, neurologists, developmental pediatricians, speech therapists, and educational specialists
Long-term follow-up for cardiac, immune, endocrine, developmental, and psychiatric issues
Parental education and genetic counseling are vital.
Complications
Early Complications:
Severe hypocalcemic seizures and tetany
Life-threatening congenital heart defects leading to heart failure
Severe recurrent infections, including opportunistic infections and sepsis
Airway anomalies causing respiratory distress
Feeding difficulties and aspiration
Neonatal mortality due to severe cardiac or immune issues.
Late Complications:
Chronic immune deficiency with recurrent infections
Long-term cardiac sequelae and potential for pulmonary hypertension
Developmental delay, learning disabilities, and behavioral problems
Psychiatric disorders in adolescence and adulthood
Chronic kidney disease
Dental abnormalities
Hearing loss.
Prevention Strategies:
Early and accurate diagnosis is key
Prophylactic measures for hypocalcemia with consistent supplementation
Prophylactic antibiotics and prompt treatment of infections in immunocompromised individuals
Regular cardiac surveillance and timely surgical intervention
Early intervention programs for developmental delays and behavioral issues
Genetic counseling for affected families.
Prognosis
Factors Affecting Prognosis:
The severity of cardiac defects
The degree of T-cell deficiency
The presence and severity of other organ system involvement
Timeliness and appropriateness of medical and surgical interventions
Cognitive and behavioral outcomes can vary widely
Early diagnosis and comprehensive management significantly improve outcomes.
Outcomes:
With advances in cardiac surgery, immunology, and supportive care, the prognosis has significantly improved
Many individuals with milder forms can lead relatively normal lives
However, those with severe cardiac or immune involvement may have significant long-term challenges
Psychiatric manifestations are common in adulthood
Life expectancy is variable but has increased considerably.
Follow Up:
Lifelong multidisciplinary follow-up is essential
Regular monitoring of cardiac function, immune status, calcium levels, growth and development, and mental health
Educational and behavioral support throughout childhood and adolescence
Genetic counseling for reproductive planning.
Key Points
Exam Focus:
CATCH-22 mnemonic (Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia, Chromosome 22 deletion)
High yield for DNB/NEET SS
Recognize the triad of cardiac defects, immune deficiency, and hypocalcemia
Understand the genetic basis and diagnostic modalities (FISH, CMA)
Multidisciplinary management is crucial
Know the common cardiac anomalies (TOF, Truncus, IAA)
Recognize the spectrum of immune dysfunction.
Clinical Pearls:
Always suspect 22q11.2 DS in an infant with conotruncal heart defects and/or neonatal hypocalcemia
Palpating for thymic "wave" in newborns can be a subtle clue
Serum calcium and T-cell counts are essential initial investigations
Early referral to specialists is paramount
Be aware of the increased risk of psychiatric illness in adulthood.
Common Mistakes:
Missing the diagnosis due to variable presentation
Underestimating the severity of immune deficiency
Inadequate management of hypocalcemia, leading to seizures
Delay in cardiac intervention
Not considering psychiatric comorbidities in older children and adults.