DiGeorge Syndrome
DiGeorge syndrome is a congenital condition caused by 22q11.2 microdeletion, presenting in infancy and childhood with thymic hypoplasia (T-cell immunodeficiency), hypoparathyroidism (hypocalcemia), conotruncal cardiac defects, and characteristic facial features.
DiGeorge Syndrome (22q11.2 Deletion Syndrome)
DiGeorge Syndrome (DGS) is a primary immunodeficiency and congenital malformation syndrome caused by a heterozygous microdeletion on chromosome 22q11.2 [1][2]. It results from abnormal development of the 3rd and 4th pharyngeal pouches during embryogenesis, leading to a classical constellation of defects remembered by the mnemonic CATCH-22 [3]:
- C – Cardiac defects (conotruncal anomalies)
- A – Abnormal facies
- T – Thymic hypoplasia/aplasia → T-cell deficiency
- C – Cleft palate
- H – Hypocalcaemia (due to hypoparathyroidism)
- 22 – Chromosome 22q11.2 deletion
The syndrome is also historically known as velocardiofacial syndrome (VCFS), Shprintzen syndrome, and conotruncal anomaly face syndrome. These are now considered part of the same spectrum — the unifying term is 22q11.2 deletion syndrome [1][2].
"DiGeorge" = deletion → development of pharyngeal pouches goes wrong → thymus, parathyroids, heart outflow tract, and face all affected because they all derive from the same embryological structures.
Why One Deletion Causes So Many Problems
The 22q11.2 region contains the TBX1 gene (a T-box transcription factor) that orchestrates neural crest cell migration into pharyngeal arches 3 and 4. Neural crest cells are the "Swiss army knife" of embryology — they contribute to the cardiac outflow tract, thymus, parathyroids, craniofacial structures, and the aortic arch. A single deletion disrupts all of these simultaneously.
| Parameter | Detail |
|---|---|
| Incidence | 1 in 3,000–6,000 live births [1] |
| Sex ratio | M = F (no sex predilection) [1] |
| Inheritance | ~90–93% de novo (sporadic); ~7–10% inherited in autosomal dominant pattern [1][2] |
| Recurrence risk | If a parent carries the deletion: 50% per pregnancy; if de novo: ~1% (due to gonadal mosaicism) |
| Frequency among primary immunodeficiencies | One of the most common microdeletion syndromes and an important cause of T-cell immunodeficiency in children |
| Hong Kong context | Relatively well-recognised; newborn screening for T-cell receptor excision circles (TRECs) can detect severe cases; genetic testing via FISH or chromosomal microarray is standard in Hong Kong |
High Yield — Exam Point
DGS is the most common microdeletion syndrome in humans (1/3,000–6,000). It is also the most common syndromic cause of palatal abnormalities and a leading cause of secondary hypoparathyroidism in neonates and infants.
- Family history: An affected parent confers a 50% risk to offspring (autosomal dominant with variable expressivity)
- Advanced maternal age — weakly associated with de novo deletions
- Maternal diabetes mellitus — associated with DiGeorge-like phenotype (diabetic embryopathy can mimic DGS, though the mechanism is phenocopy rather than genetic)
- Teratogen exposure (retinoic acid, alcohol) — can produce a DGS-like phenocopy by disrupting neural crest migration
Most cases are de novo — i.e., no family history. This is critical for counselling: parents should be offered FISH/microarray testing to determine recurrence risk.
Anatomy and Function: The Pharyngeal Pouch System
Understanding DGS requires understanding pharyngeal arch embryology.
During weeks 4–7 of embryonic development, six pairs of pharyngeal (branchial) arches form. Each arch contains:
- Mesoderm (forms muscles, vessels)
- Neural crest cells (forms connective tissue, bones, outflow tract septum)
The arches are separated internally by pharyngeal pouches (endodermal evaginations) and externally by pharyngeal clefts (ectodermal invaginations).
| Pharyngeal Pouch | Derivative |
|---|---|
| 1st pouch | Middle ear cavity, Eustachian tube |
| 2nd pouch | Palatine tonsils |
| 3rd pouch | Inferior parathyroids + Thymus |
| 4th pouch | Superior parathyroids + Parafollicular C-cells of thyroid |
| 5th/6th pouch | Ultimobranchial body (C-cells) |
Key Concept — Why 3rd and 4th Pouches Matter
The 3rd pharyngeal pouch gives rise to both the thymus (T-cell maturation site) and the inferior parathyroid glands (calcium homeostasis). The 4th pharyngeal pouch gives rise to the superior parathyroid glands and contributes to the cardiac outflow tract via neural crest cell migration. A deletion affecting neural crest cell development at these sites explains the entire CATCH-22 phenotype [2][3].
Neural crest cells from the cardiac neural crest (posterior hindbrain region) migrate into pharyngeal arches 3, 4, and 6 to:
- Septate the cardiac outflow tract (truncus arteriosus → aorta + pulmonary artery)
- Induce thymus and parathyroid development in the 3rd/4th pouches
- Contribute to craniofacial mesenchyme (jaw, palate, ear)
In DGS, the TBX1 gene on 22q11.2 is haploinsufficient → neural crest cell migration and proliferation are impaired → all of these structures develop abnormally [2].
Aetiology
| Feature | Detail |
|---|---|
| Chromosomal abnormality | Hemizygous (heterozygous) microdeletion at 22q11.2 [1][2] |
| Size of deletion | Typically ~3 Mb (megabases) encompassing ~30–40 genes; smaller 1.5 Mb nested deletions also occur |
| Key gene | TBX1 — a T-box transcription factor gene; haploinsufficiency of TBX1 is considered the critical gene responsible for most of the phenotype [2] |
| Inheritance | Autosomal dominant with variable expressivity (even within the same family, severity varies enormously) [1][3] |
| De novo rate | 90–93% [1][2] |
| Detection method | FISH (Fluorescence In Situ Hybridisation) using a probe for the DiGeorge critical region (DGCR); chromosomal microarray (CMA) is now standard and more sensitive [4] |
High Yield — Exam Favourite
Standard karyotype is NORMAL in DiGeorge syndrome because the deletion is a microdeletion (too small to be seen on conventional G-banding). You need FISH or chromosomal microarray to detect it [4].
- 10p13-14 deletion (DiGeorge syndrome type 2) — rare
- TBX1 point mutations — very rare, proves TBX1 is the critical gene [2]
- CHARGE syndrome (CHD7 mutation) — can phenocopy DGS but distinguished by coloboma, choanal atresia, and genital anomalies [2]
- Maternal diabetes — diabetic embryopathy phenocopy
- Fetal alcohol syndrome — neural crest disruption phenocopy
Even though the deletion is (usually) the same ~3 Mb, patients range from near-normal to complete DiGeorge (no thymus at all). This is because:
- Modifier genes on the non-deleted chromosome 22
- Epigenetic factors
- Stochastic developmental variation in neural crest cell migration
- Size of deletion (1.5 Mb vs 3 Mb) — though correlation with phenotype is imperfect
Pathophysiology (Organ-by-Organ)
- The thymus is derived from the 3rd pharyngeal pouch endoderm, with neural crest–derived mesenchyme providing structural support
- In DGS, neural crest deficiency → thymic hypoplasia (small but present, "partial DGS" — majority) or thymic aplasia (absent, "complete DGS" — <1% of cases)
- Without a functional thymus, T-cell maturation cannot occur → ↓ naïve T-cells → T-cell lymphopenia
- Most patients have partial DiGeorge with mild-moderate T-cell deficiency → susceptibility to viral and fungal infections but often improve with age as peripheral T-cell expansion occurs
- Complete DiGeorge (absent thymus) → profound T-cell deficiency resembling SCID → life-threatening opportunistic infections; requires thymus transplantation or haematopoietic stem cell transplant (HSCT)
Why does T-cell function often improve with age in partial DGS? Because even a hypoplastic thymus can produce some naïve T-cells, and homeostatic peripheral expansion (existing T-cells proliferating in the periphery) compensates to some degree — but the T-cell receptor (TCR) repertoire remains restricted.
High Yield — Complete vs Partial DiGeorge
A common exam mistake is assuming all DGS patients have severe immunodeficiency. In reality, < 1% have complete DiGeorge (no thymus at all). Most have partial DiGeorge with mild T-cell deficiency that may even normalise by school age. However, even "mild" cases should avoid live vaccines until immune function is formally assessed [5].
- Both inferior (3rd pouch) and superior (4th pouch) parathyroid glands may be hypoplastic or absent
- → Hypoparathyroidism → ↓ PTH → ↓ calcium reabsorption in kidneys, ↓ osteoclast activity, ↓ 1,25-dihydroxyvitamin D synthesis → hypocalcaemia
- Neonatal hypocalcaemia is often the first presenting sign — may present with neonatal seizures, jitteriness, tetany, prolonged QTc
- Hypocalcaemia may be transient (resolving in weeks–months as residual parathyroid tissue hypertrophies) or permanent (requiring lifelong calcium + vitamin D supplementation)
- Can recur during physiological stress (puberty, pregnancy, surgery, intercurrent illness)
Why neonatal seizures? Low ionised calcium → neuronal membrane hyperexcitability → ↓ threshold for action potential firing → seizures, laryngospasm, carpopedal spasm.
Neural crest cells are essential for septation of the truncus arteriosus into the aorta and pulmonary artery, and for aortic arch patterning.
Common cardiac defects in DGS [2][3]:
| Defect | Notes |
|---|---|
| Tetralogy of Fallot (TOF) | Most common cardiac defect in DGS (~20%) |
| Interrupted aortic arch (IAA) type B | Between left carotid and left subclavian; very strongly associated with DGS (~50% of IAA type B have 22q11.2 deletion) |
| Truncus arteriosus (persistent) | Failure of outflow tract septation; ~35% have DGS |
| Ventricular septal defect (VSD) | Very common, can be isolated or part of complex |
| Right aortic arch | Present in 20–25% |
| Pulmonary atresia with VSD | |
| Aberrant subclavian artery |
High Yield — When to Suspect DGS in a Cardiac Patient
Any infant presenting with truncus arteriosus, interrupted aortic arch type B, TOF, or pulmonary atresia with VSD should be tested for 22q11.2 deletion. These are "conotruncal" defects — the hallmark cardiac lesions of DGS [3].
- Overt cleft palate (often posterior/submucous) or velopharyngeal insufficiency (VPI) without overt cleft
- Submucous cleft palate: may be occult — check for bifid uvula, zona pellucida, palpable notch in posterior hard palate
- VPI → hypernasal speech, nasal regurgitation of fluids, feeding difficulties in infancy
- Palatal abnormalities are extremely common (up to 70% of DGS patients)
Velocardiofacial syndrome ("velo" = palate, "cardio" = heart, "facial" = face) was the name used when palatal and speech abnormalities were the predominant presenting features.
The neural crest contributes to craniofacial mesenchyme (bones, cartilage of the face). Classic facial features in DGS include:
| Feature | Pathophysiology |
|---|---|
| Microcephaly | Reduced neural crest–derived cranial vault growth |
| Prominent but simple (overfolded) ears | Abnormal external ear cartilage (1st/2nd arch derivative) [1] |
| Bulbous nasal tip with hypoplastic nasal alae | Deficient nasal cartilage (neural crest–derived) [1] |
| Thin upper lip | [1] |
| Retrognathia (small receding chin) | Mandibular hypoplasia (1st arch) [1] |
| Short philtrum | [1] |
| Upslanting or downslanting palpebral fissures | Variable |
| Absent or small adenoids and tonsils | Lymphoid tissue hypoplasia (immune deficiency) [1] |
The facial features are often subtle — you need to look for them specifically. They become more recognisable with experience. In exams, a photograph of a child with a long face, tubular nose with bulbous tip, small mouth, and overfolded ears should trigger suspicion for 22q11.2 deletion.
- Developmental delay — usually mild [1]; speech delay is particularly common (partly due to VPI and palatal dysfunction)
- Hypotonia in infancy [1]
- Learning difficulties — average IQ ~70–75 (borderline intellectual disability); full-scale IQ range is wide
- Behavioural/psychiatric — very high rates of:
- ADHD
- Autism spectrum disorder (ASD)
- Anxiety disorders
- Schizophrenia — 20–30× increased risk compared to general population; ~25% of DGS patients develop psychotic disorders by adulthood [6]
High Yield — DGS and Schizophrenia
22q11.2 deletion confers a 20–30× increased risk of schizophrenia, making it the strongest known genetic risk factor for schizophrenia. Up to ~1% of all schizophrenia patients carry this deletion. Psychiatric follow-up should be part of the long-term management plan [6].
Why schizophrenia? The 22q11.2 region contains genes involved in dopaminergic neurotransmission, synaptic plasticity, and NMDA glutamate receptor signalling — all pathways implicated in schizophrenia pathogenesis. Haploinsufficiency of these genes (e.g., COMT, PRODH, DGCR8) disrupts the neurodevelopmental trajectory.
| System | Feature | Mechanism |
|---|---|---|
| Hands | Tapered fingers [1] | Skeletal/connective tissue abnormality |
| Skeletal | Vertebral anomalies, scoliosis | Neural crest contribution to vertebral body |
| Renal | Renal anomalies (~30%) | Absent kidney, dysplastic kidney, VUR |
| GI | Feeding difficulties, dysphagia, constipation | Palatal dysfunction, pharyngeal hypotonia |
| Endocrine | Hypothyroidism, growth hormone deficiency | Variable endocrine gland dysgenesis |
| Haematological | Autoimmune cytopenias (ITP, AIHA) | Immune dysregulation from abnormal T-cell repertoire |
| Ophthalmological | Posterior embryotoxon, tortuous retinal vessels | Neural crest contribution to anterior segment |
Classification
| Type | Thymus | T-cell Function | Proportion | Clinical Severity |
|---|---|---|---|---|
| Partial DiGeorge | Hypoplastic (small but present) | Mild-moderate T-cell lymphopenia; often improves with age | ~99% | Usually mild immunodeficiency; may be clinically insignificant |
| Complete DiGeorge | Absent (aplastic) | Profound T-cell deficiency (< 50 CD3+ T-cells/μL; absent naïve T-cells) | < 1% | SCID-like phenotype; life-threatening opportunistic infections; requires thymus transplant or HSCT |
| Historical Name | Predominant Features |
|---|---|
| DiGeorge syndrome | Immunodeficiency (thymic aplasia) + hypocalcaemia + cardiac defects |
| Velocardiofacial syndrome (VCFS) | Palatal abnormalities + cardiac defects + facial dysmorphism + learning difficulties [1][2] |
| Conotruncal anomaly face syndrome | Cardiac outflow tract defects + facial features |
| Cayler cardiofacial syndrome | Asymmetric crying facies + cardiac defects |
| 22q11.2 deletion syndrome | Umbrella term now preferred as all represent the same genetic entity |
Clinical Features
| Symptom | Pathophysiological Basis |
|---|---|
| Neonatal seizures / jitteriness | Hypocalcaemia due to hypoparathyroidism → neuronal hyperexcitability |
| Poor feeding / nasal regurgitation of milk | Cleft palate (often submucous) and velopharyngeal insufficiency → failure to create adequate intraoral suction + nasal reflux |
| Cyanosis in neonatal period | Cyanotic congenital heart disease (e.g., TOF, truncus arteriosus) → right-to-left shunting |
| Breathlessness / poor feeding / failure to thrive (cardiac) | Heart failure from acyanotic lesions (large VSD, IAA type B) or cyanotic lesions |
| Recurrent infections — especially viral (respiratory viruses, herpes, candida) | T-cell immunodeficiency → impaired cell-mediated immunity; may also have humoral deficiency (T-cell help required for B-cell class switching) |
| Chronic diarrhoea | Immune dysregulation, GI dysmotility, and/or secondary infections |
| Delayed speech / hypernasal speech | Velopharyngeal insufficiency (VPI) + developmental delay + possible hearing loss |
| Global developmental delay | Neurodevelopmental effect of 22q11.2 deletion (TBX1 and other genes) |
| Behavioural difficulties (inattention, social withdrawal, repetitive behaviours) | ADHD, ASD — related to neurodevelopmental genes within the deleted region |
| Failure to thrive | Multifactorial: feeding difficulties (palate), cardiac disease, immunodeficiency, recurrent infections |
Key history points to elicit [5]:
- Growth and developmental history — weight and height curves over time; failure-to-thrive, especially with chronic diarrhoea or severe disease
- Development — especially in ataxia-telangiectasia and DiGeorge syndrome
- Immunisation history — up-to-date on vaccines? Infection by live attenuated vaccines, e.g., BCG?
High Yield — GC Lecture Slide Point
From GC 144 lecture: When taking a history in a child with recurrent infections, always ask about growth and developmental milestones (failure to thrive, developmental delay — "especially in ataxia-telangiectasia and DiGeorge syndrome") and immunisation history (including adverse reactions to live vaccines such as BCG) [5].
B. Signs (What You Find on Examination)
| Sign | Description | Basis |
|---|---|---|
| Microcephaly | Small head circumference | Reduced neural crest cranial vault |
| Prominent but simple (overfolded) ears | Low-set, posteriorly rotated | Abnormal 1st/2nd arch development [1] |
| Bulbous nasal tip + hypoplastic nasal alae | "Tubular" nose | Deficient nasal cartilage [1] |
| Thin upper lip | [1] | |
| Retrognathia / micrognathia | Small, recessed chin | Mandibular hypoplasia [1] |
| Short philtrum | Short distance from nose to upper lip | [1] |
| Cleft palate | Often posterior or submucous — may be occult | 3rd/4th arch palatal fusion failure [1] |
| Bifid uvula | Marker of submucous cleft | |
| Absent or small tonsils and adenoids | Lymphoid tissue hypoplasia [1] | |
| Hypernasal speech (in older child) | "Nasal" quality to speech | VPI |
| Sign | Associated Defect |
|---|---|
| Cyanosis (central, not correcting with O₂) | TOF, truncus arteriosus, PA + VSD |
| Systolic murmur | VSD (pansystolic at LLSB), TOF (crescendo-decrescendo at LUSB) |
| Continuous murmur | PDA, aortopulmonary collaterals |
| Signs of heart failure (tachypnoea, hepatomegaly, poor feeding, failure to thrive) | Large VSD, IAA, truncus arteriosus |
| Absent femoral pulses | Interrupted aortic arch (blood supply to lower body via PDA) |
| Single loud S2 | Truncus arteriosus (single semilunar valve) |
| Sign | Basis |
|---|---|
| Absent thymic shadow on CXR | Thymic hypoplasia/aplasia |
| Chronic/recurrent oral thrush (candidiasis) | T-cell deficiency → impaired mucocutaneous immunity |
| Chronic skin infections, viral warts, molluscum | T-cell deficiency |
| Lymphopenia on CBC | Reduced T-cell numbers |
| Opportunistic infections (PJP, CMV, etc.) — in complete DGS | Profound T-cell deficiency |
| Sign | Basis |
|---|---|
| Chvostek sign (facial muscle twitch on tapping facial nerve) | Hypocalcaemia → neuromuscular irritability |
| Trousseau sign (carpopedal spasm with BP cuff inflation) | Hypocalcaemia |
| Prolonged QTc on ECG | Hypocalcaemia → delayed ventricular repolarisation |
| Stridor / laryngospasm | Severe hypocalcaemia → laryngeal muscle spasm |
| Sign | Basis |
|---|---|
| Hypotonia | Central hypotonia — neurodevelopmental [1] |
| Tapered fingers | Skeletal anomaly [1] |
| Developmental delay (gross motor, fine motor, speech) | Neurodevelopmental — mild ID typical [1] |
Paediatric Normal Values — Calcium
- Neonatal total calcium: 2.0–2.7 mmol/L (lower than older children)
- Ionised calcium: 1.1–1.4 mmol/L
- Neonatal hypocalcaemia: total Ca < 2.0 mmol/L (term) or < 1.75 mmol/L (preterm); ionised Ca < 1.0 mmol/L
- In DGS, hypocalcaemia is typically late-onset neonatal hypocalcaemia (after 72 hours of life) — distinguishing it from early neonatal hypocalcaemia (within 72 hours, usually due to prematurity, IUGR, or maternal diabetes)
| Age | Common Presenting Feature |
|---|---|
| Neonate | Hypocalcaemic seizures, cardiac murmur/cyanosis, absent thymic shadow on CXR, feeding difficulties |
| Infant | Recurrent infections, failure to thrive, cardiac surgery complications (delayed healing, infections), feeding difficulties |
| Toddler/Preschool | Speech delay (hypernasal speech), developmental delay, recurrent infections |
| School-age | Learning difficulties, behavioural problems (ADHD), autoimmune cytopenias |
| Adolescent/Adult | Psychiatric manifestations (anxiety, psychosis/schizophrenia), autoimmune disease, delayed recognition of mild phenotype |
- Newborn screening: Hong Kong introduced expanded newborn screening including TREC-based screening which can identify infants with severe T-cell lymphopenia (including complete DGS). However, partial DGS may not be detected by TREC screening if T-cell numbers are only mildly reduced.
- Genetic testing: FISH and chromosomal microarray are readily available at Queen Mary Hospital Genetics Laboratory and other public hospital genetics services.
- Cardiac surgery: Performed at centres with paediatric cardiac surgery expertise (e.g., QMH, PWH). DGS patients undergoing cardiac surgery have increased risks related to hypocalcaemia (cardiopulmonary bypass worsens ionised calcium levels) and immunodeficiency (irradiated/CMV-negative blood products needed).
- Live vaccine caution: In Hong Kong's childhood immunisation schedule, BCG is given at birth. If DGS is suspected antenatally or at birth (e.g., prenatal diagnosis of conotruncal cardiac defect), BCG should be withheld until T-cell function is confirmed adequate [5].
High Yield Summary
- Definition: DiGeorge Syndrome = 22q11.2 microdeletion → abnormal 3rd/4th pharyngeal pouch development → CATCH-22 (Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcaemia, chromosome 22)
- Genetics: ~90–93% de novo; autosomal dominant; key gene = TBX1; detected by FISH or chromosomal microarray (NOT standard karyotype)
- Epidemiology: 1/3,000–6,000; most common microdeletion syndrome; M=F
- Pathophysiology: Neural crest cell migration failure → thymus (T-cell deficiency), parathyroids (hypocalcaemia), cardiac outflow (conotruncal defects), face (dysmorphism), palate (cleft/VPI)
- Cardiac: TOF, interrupted aortic arch type B, truncus arteriosus, VSD — any infant with these should be tested for 22q11.2 deletion
- Immune: Most have partial DGS (mild T-cell deficiency); < 1% have complete DGS (SCID-like); avoid live vaccines until T-cell function confirmed
- Hypocalcaemia: From hypoparathyroidism; may present as neonatal seizures; can be transient or permanent
- Neurodevelopmental: Mild ID typical; speech delay; 20–30× increased risk of schizophrenia
- Facial features: Bulbous nasal tip, overfolded ears, thin upper lip, retrognathia, short philtrum
- Variable expressivity: Same deletion → spectrum from near-normal to complete DGS
Active Recall - DiGeorge Syndrome (Definition, Epidemiology, Aetiology, Pathophysiology, Clinical Features)
[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (p515 — DiGeorge syndrome section) [2] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p875 — DGS Etiology, Pathophysiology, Differential Diagnosis) [3] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p581–583 — CATCH-22 mnemonic, cardiac associations) [4] Lecture slides: GC 238. Rare Disease Genetic Testing for Precision Medicine.pdf; GC 151. The malformed child hereditary syndromes and anomalies.pdf [5] Lecture slides: GC 144. A child with recurrent infections Primary immunodeficiencies.pdf (p15 — growth/developmental history, immunisation history, DiGeorge) [6] Senior notes: Ryan Ho Psychiatry.pdf (p134 — 22q11.2 deletion and 20–30× increased risk of schizophrenia) [7] Senior notes: Ryan Ho Fundamentals.pdf (p392 — lymphopenia causes including DiGeorge) [8] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p638 — T-cell defect, DiGeorge classical triad, features suggestive of PID) [9] Lecture slides: GC 096. Why do I always get sick.pdf; Jerry's immunodeficiencies.pdf
Differential Diagnosis of DiGeorge Syndrome
When you encounter a child with features suggestive of DiGeorge Syndrome — e.g., a neonate with hypocalcaemic seizures, a conotruncal cardiac defect, absent thymic shadow, cleft palate, or dysmorphic facies — you must think systematically about what else could produce this constellation. The differential diagnosis is best organised by the presenting feature that first raises suspicion, because DGS is rarely diagnosed "as a whole" at first glance. Instead, one feature leads to investigation, and the other features then confirm or refute DGS.
DGS has five cardinal domains (CATCH-22). Each domain has its own differential:
When a child presents with a conotruncal cardiac defect (TOF, interrupted aortic arch, truncus arteriosus, pulmonary atresia + VSD), the following syndromes must be considered alongside DGS [1][10]:
| Syndrome | Genetic Basis | Cardiac Defects | Distinguishing Features from DGS |
|---|---|---|---|
| DiGeorge syndrome (22q11.2 deletion) | 22q11.2 microdeletion | Conotruncal: TOF, IAA type B, truncus arteriosus, VSD [1][10] | CATCH-22 features; absent thymus; hypocalcaemia |
| Down syndrome (Trisomy 21) | Trisomy 21 | AVSD (most characteristic), VSD, ASD, PDA, TOF [1][10] | Upslanting palpebral fissures, flat nasal bridge, protruding tongue, brachycephaly, single palmar crease, hypotonia — very different facial gestalt from DGS |
| Turner syndrome (45,X) | 45,X or mosaic | Left-sided lesions: coarctation of aorta, bicuspid aortic valve, HLHS [1][10] | Female only; short stature, webbed neck, wide-spaced nipples, cubitus valgus — and left-sided rather than conotruncal defects |
| Williams syndrome (7q11.23 deletion) | 7q11.23 microdeletion (elastin gene) | Supravalvular aortic stenosis, peripheral pulmonary artery stenosis [1][10] | Elfin facies (full cheeks, long philtrum, prominent lips, wide mouth), hypercalcaemia (opposite of DGS!), intellectual disability with overly friendly personality, stellate iris |
| Noonan syndrome | RAS-MAPK pathway genes (PTPN11 most common) | Right-sided lesions: pulmonary valve stenosis (dysplastic valve), ASD, HCM [1][10] | Turner-like but affects both sexes; ptosis, downslanting palpebral fissures, hypertelorism, cryptorchidism in males, short stature — right-sided rather than conotruncal |
| CHARGE syndrome | CHD7 mutation (AD) | TOF, atrioventricular canal, aortic arch anomalies [2] | Distinguished by Coloboma, choanal Atresia, genital anomalies — features NOT seen in DGS; overlaps with DGS for cardiac, cleft palate, ear anomalies [2] |
| Alagille syndrome | JAG1 mutation (AD) | Peripheral pulmonary artery stenosis, TOF | Intrahepatic bile duct paucity → cholestatic jaundice; butterfly vertebrae; posterior embryotoxon; characteristic triangular facies |
High Yield — Syndrome-Cardiac Defect Associations for Exams
Know these classic pairings [1][10]:
- Down → AVSD
- Turner → Coarctation of aorta, bicuspid aortic valve (left-sided)
- Williams → Supravalvular AS (+ hypercalcaemia — the opposite calcium abnormality to DGS)
- Noonan → Pulmonary stenosis (dysplastic valve), HCM (right-sided)
- DiGeorge → Conotruncal: TOF, interrupted aortic arch type B, truncus arteriosus [1][10]
- CHARGE → TOF, AVSD (overlap with DGS, but choanal atresia + coloboma distinguish it)
Why Williams has hypercalcaemia while DiGeorge has hypocalcaemia: Williams syndrome involves deletion of the elastin gene on 7q11.23, which also affects calcium metabolism through mechanisms not fully understood (possibly increased vitamin D sensitivity or abnormal calcitonin response). DGS causes hypocalcaemia because of parathyroid hypoplasia → ↓ PTH. These are mechanistically unrelated — the calcium abnormality points you toward the right syndrome.
When a neonate presents with hypocalcaemic seizures or jitteriness, the differential includes DGS but also many non-syndromic causes [3]:
| Cause | Timing | Mechanism | How to Distinguish from DGS |
|---|---|---|---|
| DiGeorge syndrome | Late neonatal (> 72h) | Hypoparathyroidism → ↓PTH → ↓Ca | Dysmorphic features, cardiac defect, absent thymic shadow, low PTH, confirm with FISH/microarray |
| Prematurity / low birth weight | Early (< 72h) | Immature PTH response + ↓ calcium stores + ↑ calcitonin | No dysmorphism; resolves quickly with supplementation |
| Infant of diabetic mother (IDM) | Early (< 72h) | Maternal hyperglycaemia → fetal hyperinsulinism → functional hypoparathyroidism + ↑ calcitonin | LGA infant; maternal history of diabetes; also hypoglycaemia, polycythaemia |
| Maternal hyperparathyroidism | Early–late | Chronic fetal hypercalcaemia suppresses fetal parathyroids → rebound hypocalcaemia after birth | Maternal history; PTH low initially, recovers over days–weeks |
| Hypomagnesaemia | Any | Mg is required for PTH secretion and action; ↓Mg → functional hypoparathyroidism | Check Mg; Ca unresponsive to calcium supplementation alone until Mg corrected |
| Pseudohypoparathyroidism | Childhood (not neonatal) | PTH resistance (Gsα mutation) → high PTH but low Ca | Albright hereditary osteodystrophy features (short 4th/5th metacarpals, round face, obesity); PTH is HIGH (vs. LOW in DGS) |
| Isolated congenital hypoparathyroidism | Neonatal–infancy | Various gene mutations (GCM2, PTH, CASR gain-of-function) | No other CATCH-22 features; no cardiac defect or thymic abnormality; isolated low PTH + low Ca |
| Vitamin D deficiency | Infancy–toddler | ↓ 25-OH vitamin D → ↓ 1,25-(OH)₂D → ↓ Ca absorption | Usually presents later (not neonatal); rickets features; 25-OH vitamin D low; PTH appropriately HIGH |
Key distinguishing test in neonatal hypocalcaemia: Serum PTH level. In DGS, PTH is low or undetectable (hypoparathyroidism). In vitamin D deficiency or pseudohypoparathyroidism, PTH is high (secondary hyperparathyroidism or PTH resistance, respectively). This single test narrows the differential enormously.
When a child presents with T-cell lymphopenia, absent thymic shadow on CXR, or recurrent opportunistic infections, consider [8][9]:
| Condition | Mechanism | How to Distinguish from DGS |
|---|---|---|
| DiGeorge syndrome (partial or complete) | Thymic hypo/aplasia from 3rd pouch maldevelopment → ↓ T-cell maturation [8] | CATCH-22 features; 22q11.2 deletion on FISH/microarray |
| Severe combined immunodeficiency (SCID) | Multiple genetic causes (IL2RG [X-linked], ADA, RAG1/2, JAK3, etc.) → absent/dysfunctional T ± B ± NK cells [9] | Low TREC on newborn screening; absent naive T-cells; NO cardiac or facial features of DGS; absent thymus on CXR is also seen; lymphopenia < 2500/μL in infants [8] |
| CHARGE syndrome | CHD7 → thymic hypoplasia (variable) | Coloboma, choanal atresia, genital anomalies distinguish from DGS; no 22q11.2 deletion [2] |
| FOXN1 deficiency (Nude/SCID phenotype) | Thymic epithelial development failure (FOXN1 mutation) | Alopecia universalis, nail dystrophy — very rare; AR inheritance |
| Ataxia-telangiectasia | ATM gene → defective DNA repair → progressive T-cell deficiency + ↑cancer risk | Cerebellar ataxia, oculocutaneous telangiectasias, elevated AFP; developmental delay more progressive; onset at age 1–2y [8] |
| Wiskott-Aldrich syndrome | WAS gene (X-linked) → cytoskeletal defect in haematopoietic cells | Triad: eczema + microthrombocytopenia + immunodeficiency; X-linked (males); bloody diarrhoea from thrombocytopenia [8][9] |
| Complete DiGeorge vs SCID — these can be clinically almost indistinguishable | Complete DGS will have CATCH-22 features + 22q11.2 deletion; SCID will NOT have cardiac/facial/calcium abnormalities |
High Yield — GC Lecture Point
From GC 144: When evaluating a child with recurrent infections and suspected primary immunodeficiency, development is especially important in ataxia-telangiectasia and DiGeorge syndrome [5]. Also ask about immunisation history — infection by live attenuated vaccines, e.g., BCG (disseminated BCG is a red flag for T-cell deficiency including complete DGS and SCID) [5].
Why absent thymic shadow on CXR is NOT specific for DGS: The thymus is a stress-sensitive organ — it involutes rapidly during illness, surgery, steroid use, or malnutrition. An absent thymic shadow in a sick neonate may be physiological stress involution. However, in an otherwise well neonate with no recent stress, an absent thymic shadow is more concerning and should prompt investigation. In SCID, the thymus is also absent/hypoplastic — so you cannot distinguish DGS from SCID on CXR alone. You need the clinical phenotype + genetic testing.
| Condition | Key Features | How to Distinguish from DGS |
|---|---|---|
| Isolated cleft palate | No other syndromic features | No cardiac defects, no thymic abnormality, no hypocalcaemia; family history may be positive |
| Pierre Robin sequence | Micrognathia → glossoptosis → airway obstruction + U-shaped cleft palate | Can occur in isolation or as part of a syndrome (including DGS); if associated features present → pursue genetic testing |
| Stickler syndrome | COL2A1/COL11A1 mutation → Pierre Robin sequence + myopia + sensorineural hearing loss + joint hypermobility | Eye findings (myopia, retinal detachment) and marfanoid habitus distinguish from DGS |
| Treacher Collins syndrome | TCOF1 mutation → mandibulofacial dysostosis → downslanting palpebral fissures, malar/mandibular hypoplasia, ear anomalies | Severe ear malformations + conductive hearing loss; NO thymic or cardiac conotruncal defects |
| Van der Woude syndrome | IRF6 mutation → cleft lip/palate + lip pits | Lower lip pits are pathognomonic; no cardiac/immune features |
| CHARGE syndrome | CHD7 mutation | Coloboma + choanal atresia distinguish from DGS [2] |
| Condition | Genetic Basis | Facial Features | How to Distinguish from DGS |
|---|---|---|---|
| DiGeorge | 22q11.2 del | Long face, bulbous nose, overfolded ears, thin upper lip, retrognathia [1] | CATCH-22 features |
| Cri du Chat | 5p microdeletion [1] | Round face, hypertelorism, downslanting palpebral fissures, micrognathia | High-pitched cat-like cry in infancy (pathognomonic); moderate-severe ID (more severe than DGS); cardiac: most common PDA (not conotruncal) [1] |
| Smith-Magenis syndrome | 17p11.2 deletion | Broad face, brachycephaly, tented upper lip | Self-injurious behaviour (self-hugging, onychotillomania); sleep disturbance (inverted circadian melatonin) |
| Kabuki syndrome | KMT2D or KDM6A | Long palpebral fissures, arched eyebrows with lateral notching, depressed nasal tip | Fingertip pads; congenital heart defects but different facial gestalt |
| Cornelia de Lange syndrome | NIPBL, SMC1A, etc. | Synophrys, long philtrum, thin upper lip, micrognathia | Upper limb reduction defects; severe growth restriction; hirsutism |
| Fetal alcohol spectrum disorder | Teratogenic (alcohol) | Smooth philtrum, thin upper lip, short palpebral fissures | Maternal alcohol history; NO genetic deletion; phenocopy of some DGS features |
Exam Trap — Phenocopies
Diabetic embryopathy and fetal alcohol syndrome can produce a DGS-like phenotype (conotruncal cardiac defects, facial dysmorphism) without a 22q11.2 deletion. Always confirm with genetic testing (FISH or chromosomal microarray) before labelling a child as DGS. A negative 22q11.2 FISH does not exclude a DGS phenocopy — it means you need to consider other diagnoses [2][4].
CHARGE syndrome deserves special mention because it is the single most important differential diagnosis of DiGeorge syndrome. They share multiple overlapping features [2]:
| Feature | DGS (22q11.2 deletion) | CHARGE (CHD7 mutation) |
|---|---|---|
| Cardiac defect | Yes (conotruncal) | Yes (similar spectrum + AVSD) |
| Cleft palate | Yes | Yes |
| Hearing loss | Occasionally | Yes — very common |
| Thymic hypoplasia | Yes | Variable (milder) |
| Coloboma | No | Yes — hallmark |
| Choanal atresia | No | Yes — hallmark |
| Genital anomalies | Rarely | Yes (cryptorchidism, micropenis) |
| Renal anomalies | ~30% | Common |
| Ear anomalies | Overfolded ears | Small, cup-shaped, short-incus |
| Growth/development | Mild ID | Variable; can be severe |
| Genetic test | FISH/CMA: 22q11.2 deletion | CHD7 sequencing |
How to remember: CHARGE has Coloboma + Choanal atresia + Genital anomalies — three features that are NOT part of DiGeorge. If you see any of these, think CHARGE over DGS [2].
Interrupted aortic arch (IAA) type B is so strongly associated with 22q11.2 deletion that it warrants its own mention [1]:
- ~50% of all IAA type B cases have 22q11.2 deletion [3]
- Absence of thymus on CXR in a neonate with IAA type B is highly suggestive → "Should prompt further blood investigations → CBC (lymphopenia), CaPO4 (hypocalcaemia), lymphocyte function, chromosomal study for 22q11.2 deletion" [3]
- IAA type B presents as duct-dependent systemic circulation → collapse when PDA closes in the first 2 weeks of life → absent femoral pulses, differential cyanosis, shock
- Type A (distal to left subclavian artery) is more common overall but less strongly associated with DGS
- Type B (between left carotid and left subclavian artery) — think DiGeorge [1][3]
High Yield — IAA Type B + Absent Thymus = Test for 22q11.2
Any neonate with interrupted aortic arch type B should be tested for 22q11.2 deletion. If the CXR also shows an absent thymic shadow, this is essentially diagnostic until proven otherwise. Simultaneously check serum calcium, PTH, CBC with differential (lymphocyte count), and T-cell subsets [3].
| Feature | DiGeorge | SCID | CHARGE | Williams | Down | Noonan |
|---|---|---|---|---|---|---|
| Cardiac type | Conotruncal | None | Conotruncal/AVSD | Supravalvular AS | AVSD | PS, HCM |
| Calcium | ↓ (hypoCa) | Normal | Normal | ↑ (hyperCa) | Normal | Normal |
| Thymus | Hypo/aplastic | Absent | Variable | Normal | Normal | Normal |
| T-cells | ↓ | ↓↓↓ | ± ↓ | Normal | Normal | Normal |
| Coloboma | No | No | Yes | No | No | No |
| Choanal atresia | No | No | Yes | No | No | No |
| 22q11.2 deletion | Yes | No | No | No | No | No |
Active Recall - DiGeorge Syndrome Differential Diagnosis
References
[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (p184–185, p212, p411, p515) [2] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p874–875 — DGS overview, CHARGE as differential) [3] Senior notes: Adrian Lui Pediatrics Notes.pdf (p212 — interrupted aortic arch type B and DiGeorge) [4] Lecture slides: GC 238. Rare Disease Genetic Testing for Precision Medicine.pdf; GC 151. The malformed child hereditary syndromes and anomalies.pdf [5] Lecture slides: GC 144. A child with recurrent infections Primary immunodeficiencies.pdf (p15 — growth/developmental history, immunisation history, DiGeorge) [8] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p638 — T-cell defect, DiGeorge classical triad, features of PID) [9] Senior notes: Jerry's immunodeficiencies.pdf (p1–2 — SCID, WAS, Hyper-IgE, CGD) [10] Senior notes: Ryan Ho Cardiology.pdf (p185 — syndrome-cardiac defect associations table)
Diagnostic Criteria, Algorithm, and Investigations for DiGeorge Syndrome
Unlike many conditions, DiGeorge Syndrome does not have a single universally agreed set of formal diagnostic criteria (like the Jones criteria for rheumatic fever or the ESID criteria for CVID [11]). Instead, diagnosis rests on the combination of:
- A compatible clinical phenotype (one or more CATCH-22 features)
- Confirmation of the 22q11.2 deletion by genetic testing
In practice, the diagnosis is established when:
A patient has clinical features consistent with CATCH-22 AND a confirmed hemizygous microdeletion at 22q11.2 by FISH or chromosomal microarray (CMA).
However, there are important nuances:
- ~5–10% of patients with a DGS phenotype do NOT have the 22q11.2 deletion — these may have TBX1 point mutations, 10p deletions, CHD7 mutations (CHARGE), or phenocopies (diabetic embryopathy, fetal alcohol) [2]
- Variable expressivity means some patients have only 1–2 features (e.g., isolated cardiac defect + mild facial features), while others have the full CATCH-22
- A negative FISH does not exclude a DGS-like syndrome — it excludes the 22q11.2 deletion specifically. If clinical suspicion is high, proceed to CMA (which also detects smaller/atypical deletions) and then CHD7 sequencing or broader genetic panels [4]
High Yield — There Is No Formal 'Diagnostic Criteria Checklist'
For exam purposes, the diagnosis of DiGeorge syndrome = compatible clinical phenotype + 22q11.2 deletion confirmed by FISH or chromosomal microarray. You do NOT need a minimum number of CATCH-22 features — even a single feature in the right clinical context warrants genetic testing.
The diagnostic pathway depends on which feature prompts suspicion. Here is the comprehensive approach:
Why test parents? Because ~7–10% of cases are inherited (autosomal dominant). If a parent carries the deletion, the recurrence risk is 50% per future pregnancy. If de novo, recurrence risk is very low (~1%, accounting for gonadal mosaicism). This changes reproductive counselling dramatically.
Investigation Modalities — Systematic Approach
The investigations for DiGeorge syndrome serve two purposes:
- Confirm the diagnosis (genetic testing)
- Define the extent of multisystem involvement (phenotypic workup)
| Test | What It Detects | Sensitivity | When to Use | Key Findings |
|---|---|---|---|---|
| FISH for 22q11.2 | Specific microdeletion at DiGeorge critical region | ~95% for typical 3 Mb deletion | First-line if classic DGS suspected | Absent signal from one chromosome 22 at the DGCR probe locus = hemizygous deletion confirmed |
| Chromosomal microarray (CMA / aCGH) | All copy number variants genome-wide, including atypical/smaller 22q11.2 deletions | > 95%; detects atypical deletions missed by FISH | Now preferred first-line over FISH in many centres (including HK) [2][4] | Deletion at 22q11.2 region; also detects other CNVs (e.g., 10p13) |
| Standard karyotype (G-banding) | Large chromosomal abnormalities (> 5–10 Mb) | Cannot detect microdeletions | NOT sufficient to rule out DGS | Will be NORMAL in DGS — the deletion is too small (~3 Mb) |
| MLPA (Multiplex Ligation-dependent Probe Amplification) | Targeted copy number at specific loci | High for targeted region | Alternative to FISH; can be batched | Reduced copy number at 22q11.2 probes |
| Whole exome/genome sequencing | Point mutations (e.g., TBX1, CHD7) | Variable | When deletion-negative but phenotype strongly suggestive | TBX1 pathogenic variant; or CHD7 variant (→ CHARGE) |
Why FISH? Fluorescence In Situ Hybridisation uses a fluorescently-labelled DNA probe complementary to the DiGeorge critical region on 22q11.2. In a normal individual, the probe binds to both copies of chromosome 22 → two fluorescent signals. In DGS, one copy is deleted → only one fluorescent signal → confirms hemizygous deletion.
Why CMA is now preferred: CMA (comparative genomic hybridisation array) detects ALL copy number variants across the genome in a single test, including atypical/nested deletions at 22q11.2 that standard FISH probes might miss. It also detects other chromosomal abnormalities that could be causing the phenotype. Most international and Hong Kong guidelines now recommend CMA as the first-tier genetic test for congenital anomalies and syndromic presentations [4].
This is critical because DGS is classified as a primary immunodeficiency (inborn error of immunity, IEI) under IUIS Category 2: "CID with associated or syndromic features" [9].
From GC 144 lecture — approach to immunological workup [5]:
| Investigation | What to Look For | Interpretation in DGS |
|---|---|---|
| Complete blood count (CBC) | Absolute lymphocyte count (ALC) | ALC low: < 3000/μL (age < 1y) or < 1000/μL (age > 1y) → suggests combined immunodeficiency [5]. In partial DGS, may be mildly low or normal. In complete DGS, profoundly low. |
| Lymphocyte subsets (flow cytometry) | T-cells (CD3+), CD4+, CD8+, B-cells (CD19/20+), NK cells (CD16/56+) | Low T-cells (with or without low B and/or NK) → combined immunodeficiencies [5]. DGS typically shows ↓ CD3+ T-cells (especially CD4+), with normal or ↑ B-cells and NK cells (T⁻B⁺NK⁺ pattern in partial DGS) |
| Naïve vs memory T-cell subsets | CD4+CD45RA+ (naïve) vs CD4+CD45RO+ (memory) | ↓ Naïve T-cells (because thymus is not producing new T-cells); memory T-cells may be relatively preserved from peripheral expansion |
| IgG, IgA, IgM levels (IgGAME) | Immunoglobulin quantitation | Variable in DGS — may be normal, low, or have ↓ IgA or ↓ IgM. Humoral immunity depends on T-cell help for class switching. In complete DGS, IgG may be low. |
| Vaccine responses (functional antibody production) | Anti-tetanus, anti-pneumococcal, anti-Hib antibodies post-vaccination | Poor vaccine responses suggest impaired T-cell–dependent B-cell function. Important for deciding on live vaccine eligibility and need for immunoglobulin replacement [11] |
| T-cell proliferation assay (mitogen stimulation) | Response to PHA, ConA, anti-CD3 | Assesses T-cell function (not just numbers). In partial DGS, may be normal or mildly reduced. In complete DGS, absent/severely reduced. |
| TREC (T-cell receptor excision circles) | Marker of recent thymic emigrants | Low/absent TRECs — reflects inadequate thymic output. This is how newborn screening programs detect severe T-cell lymphopenia (including complete DGS and SCID) [9] |
High Yield — GC 144 Lecture Slide: CBC and Lymphocyte Subsets in IEI
From the GC 144 lecture [5]:
- ALC low < 3000 (age < 1y) or < 1000 (age > 1y) → severe combined immunodeficiencies
- Low T-cells (with or without low B and/or NK) → combined immunodeficiencies
- In some forms of CID, T-cell count may be normal but function is impaired, or they may be maternally grafted memory T-cells (Omenn syndrome, a form of SCID)
- IgGAME levels: check for panhypoglobulinaemia or selective deficiency
- Many IEIs require tailored investigations, and cannot be picked up by initial screening tests. Always consult immunology when clinically suspicious.
Why are B-cells and NK cells usually normal in DGS? Because B-cells develop in the bone marrow (not the thymus), and NK cells mature in the bone marrow and peripheral tissues. The thymus is specifically required for T-cell maturation. So a thymic defect predominantly affects T-cells. However, T-cell help is needed for B-cells to undergo class switching (IgM → IgG/IgA) and affinity maturation, so humoral immunity may be secondarily impaired even though B-cell numbers are normal.
| Investigation | Findings in DGS | Interpretation |
|---|---|---|
| Serum total calcium | Low (< 2.0 mmol/L in term neonates; age-specific thresholds apply) | Reflects hypoparathyroidism from 3rd/4th pouch maldevelopment |
| Ionised calcium | Low (< 1.0 mmol/L) — more reliable than total Ca, especially if albumin is abnormal | Direct measure of biologically active calcium fraction |
| Serum phosphate | High (hyperphosphataemia) | PTH normally promotes renal phosphate excretion; ↓ PTH → phosphate retention |
| Serum magnesium | Check to exclude hypomagnesaemia as confounder | Low Mg → functional hypoparathyroidism (Mg required for PTH secretion and action). Must correct Mg before Ca will respond to treatment |
| Intact PTH level | Low or inappropriately normal (should be elevated in response to hypocalcaemia) | KEY distinguishing test: Low PTH + low Ca = primary hypoparathyroidism (DGS). High PTH + low Ca = vitamin D deficiency or pseudohypoparathyroidism |
| 25-OH Vitamin D | Usually normal (unless coexistent deficiency) | Helps exclude nutritional rickets as the cause of hypocalcaemia |
| 1,25-(OH)₂ Vitamin D | Low (PTH stimulates 1-alpha hydroxylase in the kidney; ↓ PTH → ↓ active vitamin D synthesis) | Explains why calcium absorption from the gut is impaired in DGS |
| ECG | Prolonged QTc interval | Hypocalcaemia delays ventricular repolarisation → ↑ risk of torsades de pointes. Must monitor during correction |
| Urine calcium:creatinine ratio | Usually low (↓ filtered calcium load because serum Ca is low) | Helps in monitoring supplementation — avoid overtreatment causing hypercalciuria and nephrocalcinosis |
Why does DGS cause late-onset neonatal hypocalcaemia? The parathyroid glands are non-functional or hypoplastic from birth. However, in the first 48–72 hours, calcium is maintained by transplacental calcium transfer stores. After this runs out, the neonate depends on their own PTH → but PTH is absent/low → calcium drops. This is why DGS hypocalcaemia typically presents after 72 hours (late-onset), unlike early neonatal hypocalcaemia from prematurity or maternal diabetes.
~75–80% of patients with 22q11.2 deletion have a cardiac abnormality [2][10]. The cardiac workup is critical:
| Investigation | Purpose | Key Findings in DGS |
|---|---|---|
| Echocardiography (transthoracic) | First-line cardiac imaging; defines anatomy | Conotruncal defects: TOF (VSD + overriding aorta + RVOT obstruction + RVH), interrupted aortic arch type B, truncus arteriosus, isolated VSD; also right aortic arch (20–25%) [2] |
| CXR | Cardiac size, pulmonary vascularity, thymic shadow | Absent thymic shadow (highly suggestive in a neonate); boot-shaped heart in TOF; cardiomegaly in IAA/truncus with heart failure; absence of thymus in a neonate with IAA type B should prompt further blood investigations → CBC (lymphopenia), CaPO4 (hypocalcaemia), lymphocyte function, chromosomal study for 22q11.2 deletion [3] |
| ECG | Conduction, hypertrophy, QTc | RAD + RVH in TOF; prolonged QTc from hypocalcaemia |
| Cardiac catheterisation | Haemodynamic assessment; coronary anatomy pre-surgery | Assess RV outflow obstruction, branch PA anatomy, aortopulmonary collaterals, coronary artery course (critical before TOF repair — aberrant LAD from RCA may cross RVOT) [2] |
| CT angiography / cardiac MRI | Aortic arch anatomy, vascular rings, collaterals | Defines IAA type, vascular ring anatomy, aberrant subclavian artery |
High Yield — Absent Thymic Shadow + IAA Type B
From Adrian Lui notes [3]: "Absence of thymus on CXR: characteristic of DiGeorge syndrome → suggestive of type B interruption. Should prompt further blood Ix → CBC (lymphopenia), CaPO4 (hypoCa), lymphocyte function, chromosomal study for 22q11.2 deletion."
| Investigation | Purpose | Key Findings |
|---|---|---|
| Clinical palatal examination | Detect overt or submucous cleft palate | Posterior cleft palate, bifid uvula, zona pellucida (thin translucent midline of soft palate), palpable posterior hard palate notch |
| Nasopharyngoscopy | Assess velopharyngeal function | Velopharyngeal insufficiency (VPI) — incomplete palatal closure during speech/swallowing → hypernasal speech, nasal regurgitation |
| Speech and language assessment | Formal evaluation of speech and resonance | Hypernasal resonance; compensatory misarticulations; expressive > receptive language delay |
| Audiology (OAE, ABR, pure tone audiometry) | Screen for hearing loss | Conductive (recurrent otitis media, middle ear effusion) or sensorineural hearing loss. Hearing aids if needed |
| Investigation | Purpose | Key Findings |
|---|---|---|
| Renal ultrasound | Screen for structural renal anomalies (~30%) | Absent kidney, dysplastic kidney, vesicoureteric reflux (VUR), duplex collecting system |
| MCUG (micturating cystourethrogram) | If VUR suspected | Reflux grading |
| Renal function tests | Baseline | Usually normal unless significant structural anomaly |
| Investigation | Purpose | Age Group |
|---|---|---|
| Developmental assessment (Griffiths/Bayley) | Formal quantification of developmental milestones | Infants and toddlers |
| Cognitive/IQ testing (WISC-V) | Assess intellectual functioning; average IQ in DGS ~70–75 | School-age |
| Speech-language pathology assessment | Formal speech and language evaluation | Preschool onwards |
| Behavioural screening (Conners, ADOS-2) | Screen for ADHD and ASD | School-age |
| Psychiatric assessment | Screen for anxiety, psychosis, schizophrenia | Adolescents and adults — 22q11.2 deletion confers 20–30× increased risk of schizophrenia [6] |
| Investigation | Purpose |
|---|---|
| Thyroid function tests (TSH, fT4) | Hypothyroidism occurs in ~20% (thyroid also 4th pouch–related + autoimmune thyroiditis from immune dysregulation) |
| Growth hormone assessment | If growth failure disproportionate to cardiac/nutritional factors |
| Skeletal survey | If skeletal anomalies suspected (vertebral anomalies, scoliosis) |
| Ophthalmological exam | Posterior embryotoxon, tortuous retinal vessels |
| Parental genetic testing | FISH/CMA on both parents → determine if inherited (50% recurrence risk) or de novo (~1% recurrence risk from gonadal mosaicism) |
From the Investigations of Imm Disorders 2025 lecture [11]:
Approach to diagnosis of PID:
- Clinical history
- Physical examination
- Phenotypic investigations:
- IgG, IgA, IgM levels
- Vaccine responses
- T, B, NK cell enumerations
- Lymphocyte subsets: e.g., CD4⁻CD8⁻TCRαβ⁺ cells for autoimmune lymphoproliferative syndrome
- Cell function: e.g., expression of CD40-ligand on activated T-cells for hyper-IgM syndrome
- Genetic testing has an important role in:
- Diagnosis (all cases)
- Family studies
- Prognostication
- Prenatal diagnosis
- Defining new diseases
This framework applies to DiGeorge syndrome: clinical assessment (CATCH-22 features) → phenotypic immunological workup (lymphocyte subsets, Ig levels) → genetic confirmation (22q11.2 FISH/CMA).
| Domain | Key Tests | Critical Finding |
|---|---|---|
| Genetic | FISH or CMA for 22q11.2 | Hemizygous deletion |
| Immune | CBC (ALC), T/B/NK subsets, naïve T-cells, TRECs, IgGAM, vaccine responses | ↓ T-cells (esp. naïve CD4+); normal B/NK; variable Ig |
| Calcium | Ca, PO4, Mg, PTH, 25-OH Vit D | ↓ Ca, ↑ PO4, ↓ PTH |
| Cardiac | Echo, CXR, ECG ± cardiac cath/CT | Conotruncal defects; absent thymic shadow; prolonged QTc |
| Palate/ENT | Clinical exam, nasopharyngoscopy, audiology | Posterior/submucous cleft; VPI; hearing loss |
| Renal | Renal US | Structural anomalies in ~30% |
| Neurodevelopment | Formal developmental/cognitive assessment | Mild ID; speech delay; ADHD/ASD |
| Parental | FISH/CMA on parents | Inherited (50% risk) vs de novo (1% risk) |
High Yield Summary — Diagnosis of DiGeorge Syndrome
- No formal diagnostic criteria checklist — diagnosis = compatible phenotype + confirmed 22q11.2 deletion
- Standard karyotype is NORMAL — must use FISH or chromosomal microarray
- CMA is now the preferred first-tier test — detects atypical deletions + other CNVs simultaneously
- Immunological workup: ALC, T/B/NK subsets, naïve T-cells, TRECs, IgGAM, vaccine responses
- Calcium: Low Ca + high PO4 + low PTH = hypoparathyroidism (vs. pseudohypoparathyroidism where PTH is HIGH)
- CXR: Absent thymic shadow in neonate with conotruncal defect → test for 22q11.2 deletion
- Always test parents to determine recurrence risk
- Always consult immunology when clinically suspicious [5]
Active Recall - DiGeorge Syndrome Diagnostic Criteria, Algorithm, and Investigations
References
[2] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p271, p874–875 — genetic testing, FISH/aCGH, CATCH-22, cardiac features) [3] Senior notes: Adrian Lui Pediatrics Notes.pdf (p212 — IAA type B, absent thymus on CXR, prompt for further investigations) [4] Lecture slides: GC 238. Rare Disease Genetic Testing for Precision Medicine.pdf; GC 151. The malformed child hereditary syndromes and anomalies.pdf [5] Lecture slides: GC 144. A child with recurrent infections Primary immunodeficiencies.pdf (p50 — CBC, ALC thresholds, lymphocyte subsets, IgGAME, consult immunology) [6] Senior notes: Ryan Ho Psychiatry.pdf (p134 — 22q11.2 deletion and schizophrenia risk) [9] Senior notes: Jerry's immunodeficiencies.pdf (p2–3 — SCID, TREC, CID with syndromic features, immunological tests) [10] Senior notes: Ryan Ho Cardiology.pdf (p185 — syndrome-cardiac defect associations) [11] Lecture slides: Investigations of Imm Disorders 2025.pdf (p10, p16 — approach to PID diagnosis, phenotypic investigations, genetic testing role, ESID criteria for CVID)
Management of DiGeorge Syndrome
DiGeorge syndrome is a multisystem disorder — there is no single treatment. Management requires a coordinated, multidisciplinary approach addressing each affected organ system simultaneously. Think of it like managing five diseases at once in one patient:
- Cardiac — the most acute and life-threatening component in the neonatal period
- Immunological — determines infection risk, vaccine safety, and long-term immune surveillance
- Metabolic (calcium) — can cause seizures and arrhythmias acutely; may need lifelong supplementation
- Palatal/ENT — affects feeding, speech, hearing
- Neurodevelopmental/Psychiatric — lifelong follow-up for learning, behaviour, and psychosis risk
Additionally: 6. Genetic counselling — for the family 7. Transition care — paediatric to adult services
Core Concept — DGS Management is Lifelong and Multidisciplinary
There is no cure for DiGeorge syndrome. Management is supportive, preventive, and system-specific. The goals are: (1) treat life-threatening complications early (cardiac surgery, hypocalcaemia correction), (2) protect the immunodeficient child from infection, (3) optimise development and quality of life, and (4) provide anticipatory care and surveillance for complications that emerge over time (autoimmunity, psychiatric illness).
1. Acute Neonatal Management
~75–80% of DGS patients have a cardiac abnormality [10]. Cardiac lesions are the leading cause of morbidity and mortality in the neonatal period.
| Clinical Scenario | Immediate Management | Definitive Management |
|---|---|---|
| Duct-dependent systemic circulation (IAA type B, critical coarctation) | Prostaglandin E1 (PGE1) infusion — keeps PDA open → maintains systemic perfusion | Surgical repair (aortic arch reconstruction + VSD closure) |
| Duct-dependent pulmonary circulation (severe TOF, PA + VSD) | PGE1 infusion → maintains pulmonary blood flow via PDA | Staged repair or primary repair (Blalock-Taussig shunt → later complete repair; or primary repair if anatomy favourable) |
| Truncus arteriosus | Medical stabilisation → manage heart failure (diuretics, fluid restriction) | Rastelli operation (close VSD + conduit from RV to PA) — typically within first weeks of life |
| Isolated VSD with heart failure | Anti-failure therapy: furosemide, captopril, nutritional optimisation | Surgical closure if large/symptomatic |
Why PGE1? In utero, the ductus arteriosus is kept open by circulating prostaglandins (from the placenta and the ductus wall). After birth, rising oxygen tension and falling prostaglandin levels trigger duct closure. In duct-dependent lesions, closure is fatal — so exogenous PGE1 maintains ductal patency. Side effects of PGE1: apnoea (requires monitoring ± intubation readiness), hypotension, fever, flushing. Dose: 5–10 ng/kg/min IV initially, titrate down to lowest effective dose (often 1–5 ng/kg/min).
Special considerations for cardiac surgery in DGS patients:
- Use irradiated, CMV-negative, leukocyte-depleted blood products — to prevent transfusion-associated graft-versus-host disease (TA-GvHD) in T-cell–deficient patients, and CMV transmission [8][9]
- Monitor ionised calcium closely during cardiopulmonary bypass — haemodilution and citrated blood products worsen hypocalcaemia
- Assess thymic tissue intra-operatively — the surgeon may encounter absent/ectopic thymus
- Infection prophylaxis peri-operatively — these patients are immunocompromised
High Yield — Irradiated Blood Products
Any DGS patient requiring blood transfusion must receive irradiated, CMV-negative blood products. Why? Irradiation kills donor T-lymphocytes, preventing TA-GvHD — a condition where donor T-cells attack the immunodeficient host's tissues. This is uniformly fatal if it occurs. The same principle applies to SCID patients [9].
| Phase | Treatment | Details |
|---|---|---|
| Acute symptomatic (seizures, tetany, prolonged QTc) | IV calcium gluconate 10% | 0.5–1 mL/kg (= 0.11–0.22 mmol/kg of elemental Ca) slow IV over 5–10 minutes with continuous cardiac monitoring. NEVER give rapid bolus — risk of bradycardia/arrest. Avoid extravasation — causes severe tissue necrosis. |
| Acute stabilisation | IV calcium gluconate infusion | Continuous infusion: 2–4 mL/kg/day of 10% calcium gluconate, titrate to maintain ionised Ca > 1.0 mmol/L |
| Chronic maintenance | Oral calcium supplements + active vitamin D | Calcium carbonate or calcium citrate: 50–100 mg/kg/day of elemental Ca in divided doses. Calcitriol (1,25-dihydroxyvitamin D): 0.25–0.5 mcg/day (neonates) or 0.25–1 mcg/day (older children). Why calcitriol and not plain vitamin D? Because PTH is needed to activate 25-OH-D to 1,25-(OH)₂D via renal 1-alpha-hydroxylase — without PTH (hypoparathyroidism), the kidney cannot produce the active form, so you must give the already-active form. |
| Monitoring | Serum Ca, PO4, Mg, urine Ca:Cr | Aim total Ca 2.0–2.2 mmol/L (lower end of normal — avoid hypercalcaemia and nephrocalcinosis). Monitor urine Ca:Cr to avoid hypercalciuria (target < 0.6 mmol/mmol in infants, < 0.4 in children). |
Why check magnesium? Hypomagnesaemia causes functional hypoparathyroidism (Mg is required for PTH secretion and for PTH to act on its receptor). If Mg is low, Ca correction will fail until Mg is replenished. Always check Mg in any hypocalcaemic patient.
Hypoparathyroidism in DGS may be:
- Transient (~50–60%): resolves within weeks–months as residual parathyroid tissue hypertrophies. Can taper and stop supplements.
- Permanent (~40–50%): requires lifelong oral calcium + calcitriol
- Latent → recurrent: Some patients are normocalcaemic at baseline but develop hypocalcaemia during physiological stress (illness, surgery, puberty, pregnancy). These patients need monitoring even if supplements are stopped.
2. Immunological Management
This is where DGS management diverges from other syndromic conditions. The approach depends on whether the patient has partial or complete DiGeorge [8][9].
| Aspect | Management | Rationale |
|---|---|---|
| Initial assessment | T-cell subsets (CD3, CD4, CD8, naïve CD4+CD45RA+), B and NK cells, IgGAM, vaccine responses, T-cell proliferation to PHA [5][11] | Quantify the degree of T-cell deficiency; many partial DGS patients have only mildly low T-cells |
| Serial monitoring | Annual T-cell subsets and Ig levels until stable (usually by school age) | T-cell numbers often improve with age due to peripheral homeostatic expansion |
| Live vaccine assessment | Live vaccines (MMR, VZV, rotavirus, BCG, OPV) are withheld until T-cell function confirmed adequate [5] | Live attenuated organisms can cause disseminated disease in T-cell–deficient patients. Criteria for live vaccine eligibility vary by centre but generally require: CD4 > 500/μL, CD8 > 200/μL, normal mitogen proliferation response |
| Inactivated vaccines | Give all inactivated vaccines on schedule (DTaP-IPV-Hib, PCV13, HBV, HPV, influenza inactivated) | These cannot replicate and are safe regardless of immune status; however, immune response may be suboptimal — check post-vaccination titres |
| Antibiotic prophylaxis | Generally not required for partial DGS unless recurrent infections or severe T-cell deficiency | Unlike SCID, most partial DGS patients handle routine infections reasonably well |
| IVIG replacement | Only if significant humoral deficiency (low IgG with poor vaccine responses despite adequate T-cells) | Some DGS patients develop humoral deficiency even with adequate T-cells due to B-cell intrinsic defects or impaired T-B cooperation |
| Infection surveillance | Low threshold for investigation and treatment of infections | Even mild T-cell deficiency increases susceptibility to viral infections (herpes, respiratory viruses) |
High Yield — Live Vaccine Caution in DGS
From GC 144 lecture [5]: "Infection by live attenuated vaccines, e.g., BCG" is an important history point. BCG is given at birth in Hong Kong — if DGS is suspected antenatally or at birth (e.g., prenatal diagnosis of conotruncal cardiac defect), BCG should be withheld until immune assessment is complete. If BCG has already been given and the patient is later diagnosed with complete DGS, monitor closely for BCG-itis or disseminated BCG disease.
This is a paediatric emergency — essentially managed like SCID [9].
| Aspect | Management | Rationale |
|---|---|---|
| Diagnosis | Absent naïve T-cells (< 50 CD3+ T-cells/μL with < 5% naïve), absent/severely impaired PHA proliferation | Confirms absent thymic function |
| Isolation | Protective isolation — strict infection control; avoid exposure to sick contacts | Profound T-cell deficiency → opportunistic infections rapidly fatal |
| Infection prophylaxis | TMP-SMX (PJP prophylaxis) + fluconazole/itraconazole (antifungal) + consider aciclovir (anti-herpes) | These are the same prophylactic agents used in SCID patients |
| IVIG replacement | Regular IVIG (0.4–0.6 g/kg every 3–4 weeks) | Functional antibody production is absent without T-cell help |
| Blood products | Irradiated, CMV-negative, leukocyte-depleted [9] | Prevent TA-GvHD and CMV transmission |
| No live vaccines | Absolutely contraindicated | Will cause disseminated disease (e.g., vaccine-strain measles, BCG-osis) |
| Definitive treatment | Thymus transplantation (preferred for complete DGS) or HSCT | See below |
Thymus Transplantation
- Preferred definitive treatment for complete DiGeorge syndrome specifically
- Involves transplanting cultured postnatal thymus tissue (from infants undergoing cardiac surgery who donate thymic tissue that would otherwise be discarded)
- The transplanted thymus tissue creates a microenvironment in which the recipient's haematopoietic progenitors can undergo T-cell maturation
- Results: ~70% of transplanted patients develop functional T-cells within 6–12 months, with sustained immune reconstitution
- Key advantage over HSCT: Thymus transplant provides the missing organ (thymus), allowing the patient's own precursors to mature — producing a diverse, self-tolerant T-cell repertoire. HSCT provides mature donor T-cells but does NOT address the lack of thymic education, so there is higher risk of autoimmunity and restricted TCR repertoire
Why not just do HSCT for all complete DGS? HSCT works well for SCID (where the bone marrow defect prevents T-cell precursor production). In complete DGS, the bone marrow is normal — the problem is the absent thymus. Transplanting donor stem cells into a host without a thymus results in donor T-cells that cannot be properly educated → higher risk of GvHD and autoimmunity. Thymus transplant is therefore pathophysiologically more logical for complete DGS. However, HSCT remains an option where thymus transplant is unavailable (it is only offered at a very small number of centres worldwide).
Partial vs Complete DGS — Management Summary
| Feature | Partial DGS | Complete DGS |
|---|---|---|
| T-cell deficiency | Mild–moderate; often improves | Profound; SCID-like |
| Live vaccines | Withhold until immune assessment confirms eligibility | Absolutely contraindicated |
| Prophylaxis | Usually not required | TMP-SMX + antifungal + IVIG |
| Blood products | Irradiated, CMV-negative if transfused | Always irradiated, CMV-negative |
| Definitive therapy | Not usually needed | Thymus transplant (preferred) or HSCT |
| Prognosis | Generally good immune prognosis | Poor without definitive therapy |
| Problem | Management | Timing |
|---|---|---|
| Overt cleft palate | Surgical repair (palatoplasty) — typically at age 9–12 months | Standard cleft palate repair timing; coordinate with cardiac surgery schedule |
| Submucous cleft palate | Observation → repair if VPI causes significant speech/feeding problems | Some do not require surgery |
| Velopharyngeal insufficiency (VPI) | Speech therapy first-line; if persistent, pharyngeal flap surgery or sphincter pharyngoplasty | Caution: Pharyngeal flap surgery is contraindicated if adenoids are absent/small (as in DGS) — risk of severe obstructive sleep apnoea. DGS patients have small/absent adenoids, so this must be carefully considered. |
| Feeding difficulties (infancy) | Specialised feeding assessment; modified nipples/bottles; NG tube if required; consider posterior pharyngeal flap vs. speech bulb prosthesis | Early dietitian and SLT involvement |
| Hearing loss | Audiology screening → hearing aids if needed; grommets for recurrent otitis media with effusion | Annual audiology until school age |
| Recurrent otitis media | Low threshold for ENT referral; grommets if recurrent/persistent OME | DGS patients are prone due to eustachian tube dysfunction + immunodeficiency |
Why are adenoids absent in DGS? Adenoids are lymphoid tissue in the nasopharynx. In DGS, lymphoid tissue is hypoplastic due to the T-cell deficiency (T-cells are needed for lymphoid follicle formation). This has important surgical implications — pharyngeal flap surgery relies on a posterior pharyngeal wall with bulk to create a seal, but without adenoidal tissue, the procedure is less effective and riskier.
| Domain | Management | Details |
|---|---|---|
| Early intervention | Referral to child development centre; physiotherapy for hypotonia; occupational therapy | Begin as soon as diagnosis is made — do not wait for "obvious delay" |
| Speech and language therapy | Critical and often the most prominent area of delay; address VPI + expressive language delay | Ongoing through preschool and primary school years |
| Educational support | Formal cognitive assessment (school age); individualised education plan; special educational needs (SEN) support in mainstream or special school | Average IQ ~70–75; significant proportion need SEN support |
| Behavioural management | Screening for ADHD (Conners questionnaire) and ASD (ADOS-2, ADI-R); appropriate pharmacotherapy (methylphenidate for ADHD) and behavioural intervention | High prevalence in DGS |
| Psychiatric surveillance | Screen for anxiety disorders (from school age); screen for psychotic symptoms (from adolescence) | 22q11.2 deletion confers 20–30× increased risk of schizophrenia [6]; early intervention for psychosis improves outcomes |
| Psychiatric treatment | Standard pharmacotherapy for psychosis (atypical antipsychotics), anxiety (SSRIs), ADHD (stimulants) | No DGS-specific modifications; use standard paediatric/adolescent psychiatric protocols |
High Yield — Psychiatric Surveillance
~25% of DGS patients develop a psychotic disorder by adulthood [6]. This means every patient with confirmed 22q11.2 deletion should have regular psychiatric assessment from adolescence onwards. Prodromal symptoms (social withdrawal, declining school performance, perceptual disturbances) should prompt urgent psychiatric referral.
| Condition | Monitoring | Treatment if Needed |
|---|---|---|
| Hypocalcaemia / hypoparathyroidism | Serum Ca, PO4, Mg, PTH — every 3–6 months in first 2 years; annually thereafter; more frequently during illness/stress/puberty | Oral calcium + calcitriol (see section above). Titrate to maintain low-normal Ca, avoid hypercalciuria |
| Hypothyroidism (~20%) | TSH and fT4 annually | Levothyroxine if confirmed hypothyroid |
| Growth failure | Height, weight, head circumference on growth charts at every visit | Assess for growth hormone deficiency if growth velocity persistently poor despite nutritional optimisation and cardiac repair |
| Obesity | Monitor BMI | Common in older children/adolescents with DGS; dietary counselling |
- Renal ultrasound at diagnosis — ~30% have structural renal anomalies (absent kidney, dysplasia, VUR)
- If VUR detected → voiding cystourethrogram (MCUG), antibiotic prophylaxis per local protocol, urology follow-up
- Monitor renal function annually if structural anomaly present
| Aspect | Details |
|---|---|
| Parental testing | Both parents should undergo FISH/CMA for 22q11.2 — if one parent carries the deletion, recurrence risk is 50% per pregnancy |
| De novo | If neither parent carries it, recurrence risk is ~1% (gonadal mosaicism) |
| Prenatal diagnosis | Available via chorionic villus sampling (CVS) at 11–13 weeks or amniocentesis at 15–18 weeks; FISH/CMA on fetal cells |
| Preimplantation genetic testing (PGT) | Available for families with known 22q11.2 deletion — embryos can be screened during IVF |
| Family-centred care | Explain the lifelong nature of the condition; connect family with support groups (e.g., 22q Foundation); address parental guilt (especially for de novo cases — parents did nothing wrong) |
| Reproductive counselling for the patient | DGS patients who reach adulthood have a 50% chance of passing the deletion to their own children |
Communication with families: Use plain language. Explain that DGS is a genetic condition, not caused by anything the parents did. Emphasise the spectrum — many children do very well, especially with early intervention. Acknowledge the burden of coordinating multiple specialists.
DGS is increasingly recognised as a lifelong condition requiring adult follow-up for:
- Ongoing endocrine monitoring (calcium, thyroid)
- Psychiatric surveillance (schizophrenia risk peaks in early adulthood)
- Immune monitoring (some patients develop progressive antibody deficiency in adulthood)
- Reproductive counselling
- Cardiac follow-up (residual lesions, reintervention)
Structured transition programs (paediatric → adult medicine, immunology, psychiatry, endocrinology) should begin at age 14–16.
| Medication | Indication | Paediatric Dose | Key Considerations |
|---|---|---|---|
| Prostaglandin E1 (Alprostadil) | Duct-dependent cardiac lesion | 5–10 ng/kg/min IV, titrate to lowest effective dose | Monitor for apnoea; may need intubation |
| IV Calcium gluconate 10% | Acute symptomatic hypocalcaemia | 0.5–1 mL/kg slow IV over 5–10 min | Cardiac monitoring; avoid extravasation (tissue necrosis); never rapid bolus |
| Oral calcium carbonate | Chronic hypoparathyroidism | 50–100 mg/kg/day elemental Ca in divided doses | Monitor urine Ca:Cr to avoid nephrocalcinosis |
| Calcitriol | Chronic hypoparathyroidism | 0.25–0.5 mcg/day (neonates); 0.25–1 mcg/day (children) | Active vitamin D — bypasses the need for PTH-dependent renal activation |
| TMP-SMX (Septrin) | PJP prophylaxis in complete DGS | 150 mg/m²/day TMP component, 3× per week | Also covers some bacterial infections |
| IVIG | Antibody deficiency | 0.4–0.6 g/kg every 3–4 weeks | Trough IgG target > 5 g/L; pre-medicate with paracetamol + antihistamine for first doses |
| Levothyroxine | Hypothyroidism | 5–10 mcg/kg/day (neonates); adjust per TSH | Standard thyroid replacement |
| Methylphenidate | ADHD | Start 5 mg once daily, titrate | Standard stimulant for ADHD; monitor appetite, growth |
| Item | Contraindication/Caution | Reason |
|---|---|---|
| Live vaccines (BCG, MMR, VZV, rotavirus, OPV, LAIV) | Contraindicated until T-cell function confirmed adequate [5] | Risk of disseminated vaccine-strain infection in T-cell–deficient patients |
| Non-irradiated blood products | Contraindicated | Risk of TA-GvHD (donor T-cells attack immunodeficient host) [9] |
| Pharyngeal flap surgery | Use with extreme caution | DGS patients have absent/small adenoids → risk of obstructive sleep apnoea; alternative VPI procedures preferred |
| General anaesthesia | Caution — check calcium pre-operatively | Hypocalcaemia → prolonged QTc → risk of intra-operative arrhythmia |
| Calcium chloride IV | Avoid in peripheral IV (caustic) | Use calcium gluconate peripherally; calcium chloride only via central line |
High Yield Summary — Management of DiGeorge Syndrome
- Acute neonatal priorities: (a) PGE1 for duct-dependent cardiac lesions, (b) IV calcium gluconate for symptomatic hypocalcaemia, (c) withhold live vaccines (including BCG), (d) irradiated CMV-negative blood products
- Partial DGS (~99%): Monitor T-cells annually; most improve; assess live vaccine eligibility (CD4 > 500, normal PHA); inactivated vaccines on schedule; IVIG only if humoral deficiency
- Complete DGS (< 1%): Manage like SCID — isolation, TMP-SMX + antifungal + IVIG; definitive therapy = thymus transplant (preferred) or HSCT
- Calcium: Calcitriol (not plain vitamin D) because PTH is needed to activate 25-OH-D → 1,25-(OH)₂D; monitor urine Ca:Cr to avoid nephrocalcinosis
- Palate: Palatoplasty at 9–12 months; speech therapy; caution with pharyngeal flap surgery (absent adenoids)
- Development: Early intervention, speech therapy, educational support; formal cognitive assessment at school age
- Psychiatry: Screen for psychosis from adolescence — 20–30× increased schizophrenia risk
- Genetic counselling: Test parents; 50% recurrence if inherited; prenatal diagnosis available
- Lifelong follow-up: Calcium, thyroid, immune, psychiatric, cardiac surveillance into adulthood
Active Recall - DiGeorge Syndrome Management
References
[5] Lecture slides: GC 144. A child with recurrent infections Primary immunodeficiencies.pdf (p15, p50 — live vaccine caution, BCG, immune assessment approach) [6] Senior notes: Ryan Ho Psychiatry.pdf (p134 — 22q11.2 deletion and 20–30× increased risk of schizophrenia) [8] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p638 — T-cell defect, classical triad, features of PID) [9] Senior notes: Jerry's immunodeficiencies.pdf (p2–3 — CID with syndromic features, SCID management, HSCT, irradiated blood products) [10] Senior notes: Ryan Ho Cardiology.pdf (p185 — syndrome-cardiac defect associations, DiGeorge 80% cardiac) [11] Lecture slides: Investigations of Imm Disorders 2025.pdf (p10 — approach to PID diagnosis, phenotypic investigations, genetic testing)
Complications of DiGeorge Syndrome
Complications in DiGeorge syndrome span virtually every organ system and emerge at different ages across the lifespan. The key to understanding them is recognising that each complication traces back to one of the core pathophysiological defects: abnormal neural crest migration (cardiac, craniofacial), thymic hypoplasia (immune), parathyroid hypoplasia (calcium), and haploinsufficiency of neurodevelopmental genes (brain). Many complications are chronic and cumulative — the disease does not "stop" after neonatal repair.
~75–80% of DGS patients have congenital heart disease [10]. Cardiac complications are the leading cause of mortality in the first year of life.
| Complication | Mechanism | Clinical Significance |
|---|---|---|
| Heart failure (neonatal) | Large left-to-right shunts (VSD, truncus arteriosus) → pulmonary overcirculation → volume overload; or duct-dependent lesions (IAA type B) → systemic hypoperfusion on duct closure | Presents with tachypnoea, poor feeding, hepatomegaly, failure to thrive in the first weeks of life |
| Cardiovascular collapse / shock | Duct-dependent systemic circulation (IAA type B) → PDA closes → catastrophic loss of lower body perfusion | Presents day 2–14 with pallor, absent femoral pulses, metabolic acidosis, oliguria — a surgical emergency |
| Eisenmenger syndrome | Uncorrected large L→R shunt → progressive pulmonary vascular remodelling → irreversible pulmonary hypertension → shunt reversal (R→L) → cyanosis | Now rare with early surgical repair, but historically a devastating long-term complication of unrepaired VSD/truncus |
| Post-operative complications | Impaired wound healing (immunodeficiency), infections (T-cell deficiency), persistent hypocalcaemia (worsened by CPB), chylothorax (thoracic duct injury during arch surgery) | DGS patients have higher perioperative morbidity than non-DGS children with the same cardiac lesion — multifactorial: immunodeficiency, hypocalcaemia, feeding difficulties |
| Residual/recurrent lesions | Re-stenosis of conduit (after Rastelli for truncus), RVOT re-obstruction after TOF repair, aortic regurgitation | Require lifelong cardiac follow-up; conduit revisions every 5–10 years in growing children |
| Arrhythmias | Post-surgical scarring + prolonged QTc from hypocalcaemia → substrate for ventricular arrhythmias | Monitor ECG; correct calcium; avoid QTc-prolonging drugs |
Why do DGS patients have higher surgical morbidity? It is the combination of immunodeficiency (poor infection clearance, impaired wound healing), hypocalcaemia (worsened by cardiopulmonary bypass which uses citrated blood → chelates calcium), and feeding difficulties (palatal dysfunction → poor nutritional status) that creates a "triple hit" not seen in non-syndromic cardiac patients.
2. Immunological Complications
| Type | Pathogens | Mechanism |
|---|---|---|
| Recurrent respiratory infections | Respiratory viruses (RSV, influenza, parainfluenza), Haemophilus, Streptococcus pneumoniae | Mild T-cell deficiency + impaired T-cell–dependent antibody responses + palatal dysfunction (aspiration) + eustachian tube dysfunction |
| Chronic/recurrent otitis media | S. pneumoniae, H. influenzae, Moraxella | Eustachian tube dysfunction (craniofacial abnormality) + immunodeficiency → recurrent middle ear infections → conductive hearing loss |
| Opportunistic infections (complete DGS only) | PJP (Pneumocystis jirovecii), CMV, disseminated VZV, chronic mucocutaneous candidiasis, disseminated BCG | Profound T-cell deficiency → cannot mount cell-mediated immune responses against intracellular pathogens |
| Disseminated vaccine-strain infection | BCG-osis, vaccine-strain measles, vaccine-strain VZV [5] | Administration of live vaccines to a T-cell–deficient patient → uncontrolled replication of attenuated organism → disseminated disease, potentially fatal |
| Bronchiectasis | Chronic/recurrent lower respiratory tract infections → airway destruction → permanent dilation | Long-term consequence of inadequately treated recurrent pneumonia in immunodeficient patients |
High Yield — BCG Dissemination
From GC 144 [5]: "Infection by live attenuated vaccines, e.g., BCG" is a key complication of T-cell immunodeficiency. In Hong Kong, BCG is given at birth — before DGS may be diagnosed. If a patient with complete DGS receives BCG, they may develop BCG-itis (local disease at injection site with regional lymphadenopathy) or disseminated BCG disease (multi-organ involvement — lung, liver, bone, CNS). This is a medical emergency requiring anti-mycobacterial therapy. This is why prenatal suspicion of DGS (e.g., conotruncal cardiac defect on fetal echo) should prompt withholding BCG at birth.
This is a critically important and often under-appreciated aspect of DGS.
| Autoimmune Condition | Prevalence in DGS | Mechanism |
|---|---|---|
| Autoimmune cytopenias (ITP, AIHA, Evans syndrome) | ~10–15% | Impaired thymic selection → escape of autoreactive T-cells → break in self-tolerance → T-cell–mediated autoimmunity and autoantibody production |
| Autoimmune thyroiditis (Hashimoto) | ~5–20% | Same mechanism; additionally, thyroid is a 4th pouch derivative and may be structurally abnormal |
| Juvenile idiopathic arthritis (JIA)–like arthritis | ~5% | Immune dysregulation → inflammatory joint disease |
| Autoimmune haemolytic anaemia | Part of the cytopenia spectrum | Autoreactive B-cells producing anti-RBC antibodies, with inadequate T-regulatory cell suppression |
| Vitiligo, alopecia areata | Uncommon but recognised | Organ-specific autoimmunity |
| Coeliac disease | Increased prevalence | Unclear mechanism; possibly related to aberrant mucosal immunity |
Why does an immunodeficiency cause autoimmunity? This seems paradoxical. The thymus is responsible not only for positive selection (allowing T-cells that recognise MHC to survive) but also for negative selection (eliminating T-cells that react strongly to self-antigens). When the thymus is hypoplastic, negative selection is impaired → autoreactive T-cells escape into the periphery → autoimmune disease. Additionally, the T-cell repertoire is oligoclonal (restricted diversity from peripheral expansion) → these oligoclonal T-cells are more prone to cross-reactivity with self-antigens. Finally, T-regulatory cells (Tregs, CD4+CD25+FoxP3+), which normally suppress autoreactive lymphocytes, are produced in the thymus — reduced thymic output → fewer Tregs → less suppression of autoimmunity.
Key Concept — Immunodeficiency ≠ Only Infection
A fundamental teaching point: Primary immunodeficiency presents with three categories of complications [5][9]:
- Recurrent/severe infections — the "obvious" manifestation
- Autoimmunity — paradoxical but very common in DGS
- Malignancy — due to impaired immune surveillance
Students often forget categories 2 and 3. In DGS, autoimmunity is more common than malignancy.
| Complication | Mechanism |
|---|---|
| Lymphoma | Impaired T-cell immune surveillance → failure to eliminate EBV-transformed B-cells → increased risk of B-cell lymphoma |
| Hepatocellular carcinoma | Theoretically from impaired viral clearance (HBV/HCV) → chronic infection → malignant transformation; rare in DGS |
| Overall malignancy risk | Modestly increased but not as dramatically as in SCID or ataxia-telangiectasia; risk concentrated in lymphoid malignancies |
| Complication | Mechanism | Clinical Features |
|---|---|---|
| Neonatal seizures | Hypocalcaemia → ↓ threshold for neuronal depolarisation → seizures | Often the first presenting feature of DGS; may occur before cardiac lesion is detected |
| Tetany / carpopedal spasm | Neuromuscular hyperexcitability from low ionised Ca | Trousseau sign, Chvostek sign |
| Laryngospasm | Severe hypocalcaemia → laryngeal muscle spasm → stridor, airway obstruction | Emergency — can be fatal if unrecognised |
| Prolonged QTc / cardiac arrhythmias | Hypocalcaemia delays phase 2 (plateau) of the cardiac action potential → prolonged QTc → risk of torsades de pointes | Must check ECG; avoid QTc-prolonging drugs (macrolides, domperidone, ondansetron) |
| Recurrent hypocalcaemia during stress | Latent hypoparathyroidism unmasked by physiological stress: intercurrent illness, surgery (especially cardiac), puberty, pregnancy | Patients "outgrow" neonatal hypocalcaemia but relapse during stress — requires lifelong vigilance |
| Nephrocalcinosis / renal calculi | Over-treatment with calcium ± calcitriol → hypercalciuria → calcium deposition in renal parenchyma or stone formation | Iatrogenic complication — monitor urine Ca:Cr ratio regularly |
| Enamel hypoplasia | Chronic hypocalcaemia during tooth development | Dental abnormalities requiring paediatric dental follow-up |
| Basal ganglia calcification | Chronic hypocalcaemia/hyperphosphataemia → calcium-phosphate product deposition in basal ganglia | Usually incidental on CT; may contribute to movement disorders in severe cases |
Why does hypocalcaemia recur during puberty? During puberty, rapid skeletal growth increases calcium demand enormously. If the parathyroid glands cannot upregulate PTH output (because they are hypoplastic), the increased calcium demand outstrips supply → hypocalcaemia recurs. Female DGS patients are also at risk during pregnancy for the same reason.
| Complication | Mechanism | Consequence |
|---|---|---|
| Feeding difficulties (infancy) | Cleft palate or submucous cleft → inability to create adequate intraoral suction + nasopharyngeal reflux | Failure to thrive; need for specialised feeding techniques or NG/gastrostomy |
| Aspiration pneumonia | VPI + pharyngeal incoordination → aspiration of feeds into lower airways | Recurrent pneumonia; may be misattributed solely to immunodeficiency |
| Hypernasal speech | VPI → air escapes through the nose during speech | Significant impact on communication, social interaction, self-esteem |
| Compensatory misarticulations | Child learns abnormal articulatory patterns to compensate for VPI | Require intensive speech therapy; harder to correct if not addressed early |
| Chronic serous otitis media → conductive hearing loss | Eustachian tube dysfunction from palatal abnormality + immunodeficiency → persistent middle ear effusion | Hearing loss → further speech/language delay; grommets may be needed |
| Complication | Prevalence | Mechanism | Age of Onset |
|---|---|---|---|
| Intellectual disability (usually mild, IQ ~70–75) | >90% have some learning difficulty | Haploinsufficiency of neurodevelopmental genes within 22q11.2 region | Apparent from infancy–toddler age |
| Speech and language delay | ~75% | Multifactorial: VPI, hearing loss, neurodevelopmental | Toddler–preschool |
| ADHD | ~30–40% | Neurodevelopmental genes (COMT on 22q11.2 regulates prefrontal dopamine) | School age |
| Autism spectrum disorder | ~15–25% | Neurodevelopmental — shared genetic pathways | Early childhood |
| Anxiety disorders | ~30–50% | Likely related to amygdala/prefrontal circuit dysfunction | School age–adolescence |
| Schizophrenia / psychotic disorders | ~25% by adulthood | 22q11.2 deletion confers 20–30× increased risk [6]; COMT, PRODH, DGCR8 haploinsufficiency → dopaminergic/glutamatergic dysfunction | Late adolescence–early adulthood |
| Social cognitive deficits | Very common | Difficulty reading social cues, facial expressions, understanding intentions | Childhood onwards |
High Yield — Psychiatric Complications Are the Major Long-Term Morbidity
Cardiac defects can be surgically repaired. Hypocalcaemia can be supplemented. But the psychiatric burden of 22q11.2 deletion is the leading cause of disability in adulthood. ~25% develop frank psychosis [6], and many more have anxiety, ADHD, or social cognitive deficits that impair educational attainment, employment, and independent living. This is why psychiatric surveillance from adolescence is mandatory.
Why COMT matters: The COMT (catechol-O-methyltransferase) gene is located within the 22q11.2 deleted region. COMT metabolises dopamine in the prefrontal cortex. Haploinsufficiency → altered dopamine turnover → impaired prefrontal function (working memory, executive function, attention). The COMT Val158Met polymorphism on the remaining allele further modifies risk — the Met allele (low COMT activity) is associated with better prefrontal cognition but potentially higher psychosis risk. This gene-environment interaction is an active area of research.
| Complication | Prevalence | Mechanism |
|---|---|---|
| Short stature | ~35–40% | Multifactorial: cardiac disease → chronic hypoxia and heart failure → poor nutrition; feeding difficulties; growth hormone deficiency (rare); chronic illness effect |
| Growth hormone deficiency | ~5% | Possible hypothalamic-pituitary axis involvement (22q11.2 genes may affect hypothalamic development) |
| Hypothyroidism | ~20% | Autoimmune thyroiditis (Hashimoto) from immune dysregulation; additionally, thyroid C-cells derive from 4th pouch (may be structurally abnormal) |
| Obesity | Increasingly recognised in adolescence/adulthood | Reduced physical activity, developmental limitations, psychiatric medications (antipsychotics → metabolic syndrome) |
| Complication | Mechanism |
|---|---|
| Scoliosis | Vertebral body anomalies (neural crest contribution); also muscular hypotonia |
| Vertebral anomalies (butterfly vertebrae, hemivertebrae) | Neural crest maldevelopment affecting vertebral body formation |
| Osteoporosis | Chronic hypocalcaemia + hypoparathyroidism → impaired bone mineralisation; compounded by reduced physical activity |
| Craniosynostosis (rare) | Possible neural crest contribution to cranial suture development |
| Complication | Prevalence | Mechanism |
|---|---|---|
| Structural renal anomalies (absent kidney, renal dysplasia, duplex system) | ~30% | Neural crest cells contribute to renal development; also UB/WD interaction may be disrupted |
| Vesicoureteric reflux (VUR) | Part of structural anomaly spectrum | Abnormal ureteric budding → incompetent vesicoureteric junction |
| Recurrent UTIs | Consequence of VUR + immunodeficiency | Reflux + poor immune clearance → ascending infection |
| Nephrocalcinosis | Iatrogenic — from calcium/calcitriol over-replacement | Must monitor urine Ca:Cr ratio |
| Age Group | Key Complications to Anticipate |
|---|---|
| Neonate (0–28 days) | Cardiac failure/collapse (duct closure), hypocalcaemic seizures, feeding difficulties, disseminated BCG (if vaccinated) |
| Infant (1–12 months) | Failure to thrive, recurrent infections, cardiac surgery complications, aspiration pneumonia |
| Toddler/Preschool (1–5 years) | Speech/language delay, recurrent otitis media, autoimmune cytopenias, developmental delay becoming apparent |
| School age (5–12 years) | Learning difficulties, ADHD/ASD diagnosis, anxiety, autoimmune thyroiditis, bronchiectasis |
| Adolescence (12–18 years) | Recurrent hypocalcaemia (puberty growth spurt), psychotic prodrome, anxiety/depression, obesity, scoliosis progression |
| Adulthood (> 18 years) | Schizophrenia onset, progressive antibody deficiency, autoimmune disease, cardiac reintervention, reproductive counselling |
| System | Acute Complications | Chronic Complications |
|---|---|---|
| Cardiac | Heart failure, cardiovascular collapse, post-operative infections | Residual lesions, conduit failure, arrhythmias, Eisenmenger (if uncorrected) |
| Immune | Disseminated BCG/vaccine-strain infection, opportunistic infections | Bronchiectasis, autoimmune cytopenias, lymphoma |
| Calcium | Neonatal seizures, tetany, laryngospasm, prolonged QTc | Nephrocalcinosis (iatrogenic), enamel hypoplasia, basal ganglia calcification |
| Palate/ENT | Feeding difficulty, aspiration pneumonia | Hypernasal speech, conductive hearing loss |
| Neurodevelopment | — | Intellectual disability, speech delay, ADHD, ASD |
| Psychiatric | — | Schizophrenia (~25%), anxiety (~40%), depression |
| Endocrine | — | Hypothyroidism, short stature, GH deficiency, obesity |
| Renal | — | Structural anomalies, VUR, recurrent UTIs, nephrocalcinosis |
| Skeletal | — | Scoliosis, vertebral anomalies, osteoporosis |
High Yield Summary — Complications of DiGeorge Syndrome
- Cardiac — leading cause of neonatal mortality; post-surgical morbidity is higher than in non-syndromic CHD due to immunodeficiency + hypocalcaemia + feeding difficulties
- Infections — spectrum from recurrent URTIs (partial DGS) to opportunistic/disseminated infections (complete DGS); BCG dissemination if vaccinated before immune assessment [5]
- Autoimmunity — paradoxical but common (~15%); impaired thymic negative selection + oligoclonal T-cells + reduced Tregs → ITP, AIHA, thyroiditis, coeliac disease
- Hypocalcaemia — can cause neonatal seizures, laryngospasm, prolonged QTc; may be transient or permanent; recurs during stress/puberty/pregnancy
- Speech/feeding — VPI, aspiration, hypernasal speech, conductive hearing loss from recurrent OME
- Psychiatric — the major long-term morbidity; 25% develop psychosis by adulthood [6]; ADHD and anxiety also very common
- Malignancy — modestly increased risk (mainly lymphoma); due to impaired immune surveillance
- Iatrogenic — nephrocalcinosis from calcium/calcitriol over-supplementation; obstructive sleep apnoea from pharyngeal flap surgery in patients with absent adenoids
Active Recall - Complications of DiGeorge Syndrome
References
[5] Lecture slides: GC 144. A child with recurrent infections Primary immunodeficiencies.pdf (p15, p50 — live vaccine complications, BCG dissemination, immunodeficiency manifestations) [6] Senior notes: Ryan Ho Psychiatry.pdf (p134 — 22q11.2 deletion and 20–30× increased risk of schizophrenia, ~25% develop psychotic disorders) [9] Senior notes: Jerry's immunodeficiencies.pdf (p2–3 — CID with syndromic features, infection susceptibility, autoimmunity and malignancy as consequences of immunodeficiency) [10] Senior notes: Ryan Ho Cardiology.pdf (p185 — DiGeorge syndrome 80% cardiac abnormalities, conotruncal defects)
High Yield Summary
- Definition: DiGeorge Syndrome = 22q11.2 microdeletion → abnormal 3rd/4th pharyngeal pouch development → CATCH-22 (Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcaemia, chromosome 22)
- Genetics: ~90–93% de novo; autosomal dominant; key gene = TBX1; detected by FISH or chromosomal microarray (NOT standard karyotype)
- Epidemiology: 1/3,000–6,000; most common microdeletion syndrome; M=F
- Pathophysiology: Neural crest cell migration failure → thymus (T-cell deficiency), parathyroids (hypocalcaemia), cardiac outflow (conotruncal defects), face (dysmorphism), palate (cleft/VPI)
- Cardiac: TOF, interrupted aortic arch type B, truncus arteriosus, VSD — any infant with these should be tested for 22q11.2 deletion
- Immune: Most have partial DGS (mild T-cell deficiency); < 1% have complete DGS (SCID-like); avoid live vaccines until T-cell function confirmed
- Hypocalcaemia: From hypoparathyroidism; may present as neonatal seizures; can be transient or permanent
- Neurodevelopmental: Mild ID typical; speech delay; 20–30× increased risk of schizophrenia
- Facial features: Bulbous nasal tip, overfolded ears, thin upper lip, retrognathia, short philtrum
- Variable expressivity: Same deletion → spectrum from near-normal to complete DGS
High Yield Summary — Diagnosis of DiGeorge Syndrome
- No formal diagnostic criteria checklist — diagnosis = compatible phenotype + confirmed 22q11.2 deletion
- Standard karyotype is NORMAL — must use FISH or chromosomal microarray
- CMA is now the preferred first-tier test — detects atypical deletions + other CNVs simultaneously
- Immunological workup: ALC, T/B/NK subsets, naïve T-cells, TRECs, IgGAM, vaccine responses
- Calcium: Low Ca + high PO4 + low PTH = hypoparathyroidism (vs. pseudohypoparathyroidism where PTH is HIGH)
- CXR: Absent thymic shadow in neonate with conotruncal defect → test for 22q11.2 deletion
- Always test parents to determine recurrence risk
- Always consult immunology when clinically suspicious [5]
High Yield Summary — Management of DiGeorge Syndrome
- Acute neonatal priorities: (a) PGE1 for duct-dependent cardiac lesions, (b) IV calcium gluconate for symptomatic hypocalcaemia, (c) withhold live vaccines (including BCG), (d) irradiated CMV-negative blood products
- Partial DGS (~99%): Monitor T-cells annually; most improve; assess live vaccine eligibility (CD4 > 500, normal PHA); inactivated vaccines on schedule; IVIG only if humoral deficiency
- Complete DGS (< 1%): Manage like SCID — isolation, TMP-SMX + antifungal + IVIG; definitive therapy = thymus transplant (preferred) or HSCT
- Calcium: Calcitriol (not plain vitamin D) because PTH is needed to activate 25-OH-D → 1,25-(OH)₂D; monitor urine Ca:Cr to avoid nephrocalcinosis
- Palate: Palatoplasty at 9–12 months; speech therapy; caution with pharyngeal flap surgery (absent adenoids)
- Development: Early intervention, speech therapy, educational support; formal cognitive assessment at school age
- Psychiatry: Screen for psychosis from adolescence — 20–30× increased schizophrenia risk
- Genetic counselling: Test parents; 50% recurrence if inherited; prenatal diagnosis available
- Lifelong follow-up: Calcium, thyroid, immune, psychiatric, cardiac surveillance into adulthood
High Yield Summary — Complications of DiGeorge Syndrome
- Cardiac — leading cause of neonatal mortality; post-surgical morbidity is higher than in non-syndromic CHD due to immunodeficiency + hypocalcaemia + feeding difficulties
- Infections — spectrum from recurrent URTIs (partial DGS) to opportunistic/disseminated infections (complete DGS); BCG dissemination if vaccinated before immune assessment [5]
- Autoimmunity — paradoxical but common (~15%); impaired thymic negative selection + oligoclonal T-cells + reduced Tregs → ITP, AIHA, thyroiditis, coeliac disease
- Hypocalcaemia — can cause neonatal seizures, laryngospasm, prolonged QTc; may be transient or permanent; recurs during stress/puberty/pregnancy
- Speech/feeding — VPI, aspiration, hypernasal speech, conductive hearing loss from recurrent OME
- Psychiatric — the major long-term morbidity; 25% develop psychosis by adulthood [6]; ADHD and anxiety also very common
- Malignancy — modestly increased risk (mainly lymphoma); due to impaired immune surveillance
- Iatrogenic — nephrocalcinosis from calcium/calcitriol over-supplementation; obstructive sleep apnoea from pharyngeal flap surgery in patients with absent adenoids
Memory palace hooks for DiGeorge Syndrome
How to Use This Memory Palace
Each numbered symbol is a recall hook mapped back to this page's own notes. The Note concept column is the source of truth; the symbol logic explains why the visual cue should trigger that concept.
This first pass maps the supplied DiGeorge labels 1-27 plus the Williams syndrome comparison labels that are already covered in this page's DDx tab. Supplied Williams-only labels 29, 31-34, 37-38, 41-42, 46-51, and 53-54 should be added only if the DiGeorge page is expanded to cover those details.
| No. | Symbol | Source tab | Note concept | Etymology / symbol logic |
|---|---|---|---|---|
| 1 | "22q11.2" beside George Washington | Summary / Etiology | DiGeorge syndrome is 22q11.2 deletion syndrome, also known as velocardiofacial syndrome, with cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, and hypocalcaemia. | George cues DiGeorge; the 22q11.2 label anchors the chromosomal deletion behind CATCH-22. |
| 2 | T3A/TE4 pouches | Etiology | The syndrome results from abnormal development of the 3rd and 4th pharyngeal pouches. | The pouch labels make the embryology visible: 3rd pouch for thymus/inferior parathyroids and 4th pouch for superior parathyroids. |
| 3 | Deleted letter "g" | Etiology | The genetic lesion is a heterozygous microdeletion at 22q11.2 involving TBX1, a key gene for heart, palate, thymus, and craniofacial development. | A missing letter cues "deletion"; the "g" keeps it tied to DiGeorge. |
| No. | Symbol | Source tab | Note concept | Etymology / symbol logic |
|---|---|---|---|---|
| 4 | Pregnant figure with ultrasound bullhorn | Dx / Mx | A conotruncal cardiac defect can raise suspicion for 22q11.2 deletion, including antenatally or at birth. | The ultrasound cue makes the cardiac finding an early trigger for testing and vaccine caution. |
| 5 | "Colonel's trunk" | Etiology / Dx | Conotruncal cardiac defects include tetralogy of Fallot, truncus arteriosus, interrupted aortic arch type B, VSD, and related outflow tract lesions. | "Colonel's trunk" sounds like conotruncal/truncus, pointing to cardiac outflow tract maldevelopment. |
| 6 | Dysmorphic mask | Etiology / Dx | Craniofacial dysmorphism is part of CATCH-22 and reflects abnormal neural crest contribution to the face. | The mask cues an abnormal facial gestalt rather than one isolated sign. |
| 7 | Blue heart coat | Etiology / Dx | Cyanotic congenital heart disease may present with cyanosis in the neonatal period. | Blue clothing over the heart cues cyanosis from right-to-left shunting lesions. |
| 8 | Falling milk bottles with shaky lines | Etiology / Dx | Hypocalcaemia from hypoparathyroidism may present with neonatal seizures, jitteriness, tetany, prolonged QTc, or laryngospasm. | Milk cues calcium; falling and shaking cue symptomatic low calcium. |
| 9 | Pulse-ox lighthouse | Dx | Cardiac signs include cyanosis from TOF, truncus arteriosus, or pulmonary atresia with VSD. | The lighthouse/pulse-ox cue highlights low oxygen saturation from cyanotic heart disease. |
| 10 | Mask with distinctive nose, eyes, ears, cheeks, and chin | Etiology / Dx | Classic facial features include bulbous nasal tip, overfolded ears, thin upper lip, retrognathia or micrognathia, and short philtrum. | The detailed mask turns the dysmorphic face into a checklist. |
| 11 | Cleft hat | Etiology / Dx | Palatal abnormalities include overt or submucous cleft palate and bifid uvula. | A split hat cues a cleft palate; the small split detail cues bifid uvula. |
| No. | Symbol | Source tab | Note concept | Etymology / symbol logic |
|---|---|---|---|---|
| 12 | Tea array | Dx / Summary | Diagnosis is confirmed by FISH or chromosomal microarray; standard karyotype is usually normal. | "Tea array" cues microarray, the preferred first-tier genetic test. |
| 13 | Fallen milk bottles | Etiology / Dx | DiGeorge syndrome causes hypocalcaemia due to parathyroid hypoplasia. | Milk stands for calcium; fallen bottles cue low calcium. |
| 14 | Fallen "PthD" | Etiology / Dx | Hypoparathyroidism gives low or inappropriately normal PTH with low calcium and high phosphate. | The fallen PTH label cues the endocrine mechanism, not just the calcium result. |
| 15 | 22q11.2 deletion syndrome DDx sign | DDx | Differential diagnoses include other syndromic causes of cardiac defects, hypocalcaemia, T-cell deficiency, cleft palate, and dysmorphic facies, especially CHARGE syndrome and Williams syndrome. | The DDx sign reminds you to sort by the presenting CATCH-22 domain. |
| 16 | "Team George" | Mx | Care is lifelong and multidisciplinary, involving cardiac, immune, calcium, palatal/ENT, neurodevelopmental, psychiatric, endocrine, renal, and genetic counselling follow-up. | A team around George cues that no single specialty manages the whole syndrome. |
| 17 | Ultrasound bullhorn, "Colonel's trunk," and heart lock | Dx / Mx | Echocardiography is first-line to define conotruncal anatomy and guide cardiac management. | The ultrasound cue scans the conotruncal heart lesion. |
| 18 | Anomalous kidney pulleys | Dx / Mx | Renal ultrasound screens for structural renal anomalies such as absent kidney, dysplastic kidney, VUR, or duplex collecting system. | Pulled or misshapen kidneys cue the renal anomaly screen. |
| 19 | Ripped "T" | Dx | CBC with differential and lymphocyte subsets look for lymphopenia, especially low T-cells and low naive T-cells. | The torn T cues T-cell lymphopenia from thymic hypoplasia. |
| 20 | Skid mark | Etiology / Mx | Complete DiGeorge syndrome is SCID-like, with profound T-cell deficiency requiring SCID-style protection and definitive immune therapy. | "Skid" sounds like SCID, marking the severe complete-DGS end of the spectrum. |
| 21 | Skull and crossbones, thyme overboard, and sail | Dx | CXR may show an absent thymic shadow in a neonate, especially with conotruncal disease. | Thyme overboard cues absent thymus; the missing sail recalls loss of the normal thymic shadow. |
| 22 | "No live preservers" | Mx / Complications | Live vaccines should be withheld until T-cell function is confirmed adequate; complete DGS makes live vaccines contraindicated. | "No live" on life preservers cues avoiding live attenuated vaccines. |
| No. | Symbol | Source tab | Note concept | Etymology / symbol logic |
|---|---|---|---|---|
| 23 | Soft palate and uvula coat | Etiology / Dx / Mx | Every patient needs palatal/ENT assessment for cleft palate and velopharyngeal insufficiency. | The soft palate and uvula cue the "velo" part of velocardiofacial syndrome. |
| 24 | Floating foodstuffs | Etiology / Mx / Complications | Feeding difficulties are common from cleft palate, VPI, pharyngeal hypotonia, and cardiac or immune disease. | Food that cannot stay down cues poor suction, nasal regurgitation, aspiration, and failure to thrive. |
| 25 | "Expect Delays" sign | Etiology / Dx / Mx | Developmental delay is common and should prompt formal developmental assessment and early intervention. | The delay sign cues both the clinical feature and the need to assess milestones. |
| 26 | "Learn Sailing" sign | Etiology / Mx / Complications | Learning difficulties, ADHD, ASD, and speech/language delay are common neurodevelopmental problems. | "Learn" cues school-age cognitive and behavioural follow-up. |
| 27 | Psychotic painter | Etiology / Mx / Complications | 22q11.2 deletion confers a 20-30 times increased schizophrenia risk, so psychiatric surveillance from adolescence is needed. | The painter's psychiatric cue marks psychosis risk as a major long-term morbidity. |
| No. | Symbol | Source tab | Note concept | Etymology / symbol logic |
|---|---|---|---|---|
| 28 | Governor Williams with "7q11.23" | DDx | Williams syndrome is caused by 7q11.23 microdeletion involving the elastin gene. | Governor Williams cues Williams; 7q11.23 separates it from DiGeorge's 22q11.2. |
| 30 | Vomiting figure with raised milk bottle | DDx | Williams syndrome is associated with hypercalcaemia, the opposite calcium abnormality from DiGeorge syndrome. | The raised milk bottle cues high calcium rather than the fallen low-calcium bottles in DGS. |
| 35 | Tray of cocktails | DDx | Williams syndrome has an overly friendly "cocktail party" personality. | Cocktails cue the social, friendly personality clue. |
| 36 | Elf mask | DDx | Williams syndrome has characteristic elfin facies. | The elf mask directly cues the classic facial gestalt. |
| 39 | Elf mask with wide mouth | DDx | Williams syndrome facial clues include prominent lips and a wide mouth. | The wide mouth on the elf mask cues this DDx feature. |
| 40 | Starry glasses | DDx | Williams syndrome can have stellate iris. | Stars on the glasses cue the star-like iris pattern. |
| 43 | Tray of milks | DDx | Hypercalcaemia helps distinguish Williams syndrome from DiGeorge syndrome's hypocalcaemia. | A tray full of milk cues excess calcium. |
| 44 | Williams syndrome DDx sign | DDx | Williams, Down, Noonan, CHARGE, Turner, and other syndromes sit in the congenital-heart-disease and dysmorphic-facies differential. | The DDx sign marks Williams as a comparison syndrome, not the target diagnosis. |
| 45 | Ultrasound megaphone and heart boat whistle | DDx | Williams syndrome is classically associated with supravalvular aortic stenosis. | The ultrasound/heart cue keeps the comparison in the cardiac-defect framework. |
| 52 | "Expect Delays" buoy | DDx | Williams syndrome may include intellectual disability, which overlaps with the developmental-delay domain in DiGeorge syndrome. | The delay buoy marks shared neurodevelopmental involvement while the syndrome label keeps the DDx separate. |
Williams Syndrome
Williams syndrome is a rare genetic neurodevelopmental disorder caused by a microdeletion on chromosome 7q11.23, presenting in infancy and childhood with supravalvular aortic stenosis, distinctive elfin facies, intellectual disability, hypercalcemia, and a characteristically overly friendly personality.
Inborn Error of Metabolism
Inborn errors of metabolism are a diverse group of inherited genetic disorders, typically presenting in the neonatal or early infantile period, in which a deficiency or dysfunction of a specific enzyme or transporter disrupts normal biochemical pathways, leading to accumulation of toxic substrates or deficiency of essential products.