22q11.2 Deletion and Duplication Syndromes

Literature and regulatory information updated: 6 October 2026.

22q11.2 deletion syndrome (DiGeorge syndrome, velocardiofacial syndrome, Shprintzen syndrome, conotruncal anomaly face syndrome) and reciprocal 22q11.2 duplication syndrome

0. Initial Reference Table

1. Introduction

22q11.2 deletion syndrome is the most common chromosomal microdeletion syndrome in humans and one of the most common genetic causes of congenital heart disease, syndromic cleft palate, primary T-cell immunodeficiency and monogenic risk of schizophrenia [1, 22]. Its history comprises several independent clinical descriptions that were treated as distinct entities for three decades because each specialty encountered a different aspect of the condition. In 1965, the paediatric endocrinologist Angelo DiGeorge, commenting on a presentation on the cellular basis of immunity, described infants with hypoparathyroidism and cellular immunodeficiency secondary to thymic hypoplasia or absence; the phenotype was soon expanded to include other defects derived from the third and fourth pharyngeal arches and facial abnormalities [3, 23]. In 1978, Robert Shprintzen and colleagues, working in a cleft palate clinic, reported children with cleft palate or velopharyngeal incompetence, heart disease, a prominent nose and learning difficulties, which they termed velocardiofacial syndrome [24]. Japanese descriptions of conotruncal anomaly face syndrome and Cayler cardiofacial syndrome (asymmetric crying facies) followed; both are now recognised as expressions of the same deletion [1].

Molecular findings unified these conditions. In 1992, Driscoll, Budarf and Emanuel demonstrated consistent deletions and microdeletions at 22q11 in patients with DiGeorge syndrome, and Scambler and colleagues showed in the same year that velocardiofacial syndrome was associated with chromosome 22 deletions encompassing the DiGeorge locus [25, 26]. The two syndromes subsequently came to be understood as different manifestations of the same genetic defect [3]. Fluorescence in situ hybridisation (FISH) with probes for the critical region, used since 1992–1993, became a classic example of molecular cytogenetic diagnosis in cardiogenetics and remains illustrated in textbooks as a rapid means of confirming a recognisable phenotype [10, 27, 28]. In 2001, three groups showed in mouse models that Tbx1 haploinsufficiency reproduces aortic arch and cardiac outflow tract defects, and in 2003 Yagi and colleagues identified TBX1 variants in patients without a deletion, establishing TBX1 as the principal contributor to the physical phenotype [29–32].

Current nomenclature reflects this history. “22q11.2 deletion syndrome” encompasses the phenotypes previously described as DGS, VCFS, CTAF, Cayler syndrome and some cases of autosomal dominant Opitz G/BBB syndrome, whose descriptions reflected ascertainment biases; GeneReviews now reserves “DiGeorge syndrome” for individuals with the clinical phenotype but no identified 22q11.2 deletion [1]. In immunology, “complete DiGeorge syndrome” (or complete DiGeorge anomaly) remains the term for the minority with congenital athymia [19].

22q11.2 duplication syndrome is the reciprocal product of the same recombination mechanism. Although deletions and duplications were expected to arise in similar proportions, very few duplications were known until 2003, when Ensenauer and colleagues at the Mayo Clinic described 13 patients with 22q11.2 microduplication identified predominantly by interphase FISH, with mild to severe phenotypes and a shared tendency towards velopharyngeal insufficiency, proposing a new syndrome [5]. Widespread use of chromosomal microarray showed that the duplication is frequent, generally inherited from a parent with a mild or normal phenotype, has incomplete penetrance and, unlike the deletion, reduces the risk of schizophrenia [3, 8, 16].

Clinical practice recommendations for the deletion were published by the International 22q11.2 Deletion Syndrome Consortium in 2011 (children) and 2015 (adults) and comprehensively revised in 2023 by the 22q11.2 Society, based on a systematic review of 2,441 publications (1992–2021) and expert consensus from 9 countries (children) and 8 countries (adults), covering 24 subspecialties; the evidence remains limited and the recommendations predominantly represent consensus statements on good practice [17, 18, 33, 34].

2. Molecular Genetics and Pathophysiology

2.1 Genomic architecture of the 22q11.2 region and rearrangement mechanism

The 22q11.2 region contains eight blocks of chromosome 22-specific low-copy repeats (LCR22), designated A to H, with high sequence homology. Misalignment of these blocks during meiosis permits non-allelic homologous recombination (NAHR), generating deletions or duplications of the flanked intervals according to the direction of the exchange [2, 3]. Because the deletions are recurrent and mediated by segmental duplications, the unique sequence removed is identical in all individuals with the same deletion type, although reported size varies with microarray design and whether adjacent segmental duplications are included [1].

Approximately 85% of patients have the LCR22A–D deletion, described on microarrays as 2.54 Mb (chr22:18,912,231–21,465,672, GRCh37/hg19; ClinGen ISCA-37446) and historically as “3 Mb”; approximately 5% have the proximal A–B deletion of 1.5 Mb, approximately 2% an A–C deletion and approximately 5% smaller B–D or C–D deletions [1]. In the ClinGen curated region list (April 2026 version), ISCA-37446 encompasses the proximal A–B, A–C and A–D deletions (chr22:18,924,718–21,111,383 in GRCh38) and has a score of 3 for both haploinsufficiency and triplosensitivity (last assessed in July 2025), whereas ISCA-37516, which GeneReviews associates with the 1.5 Mb deletion, corresponds in ClinGen to the central B–D or C–D region containing CRKL (chr22:20,731,986–21,465,672 in GRCh37); the interval should therefore be confirmed from its coordinates rather than from the identifier alone [1, 35]. Smith's textbook, drawing on a different case series, reports A–D in 85–90% and A–B in 8–10%, while the Oxford Desk Reference summarises that ~96% of patients have a defined 1.5–3 Mb deletion containing 24–30 genes; Smith's reports at least 30 genes in the critical region [2, 3]. Fewer than 1% of individuals with the phenotype have structural rearrangements involving 22q11.2, such as unbalanced translocations removing 22pter→q11, and a 20 kb deletion within the typically deleted region, disrupting UFD1L and CDC45L, was described in a patient with the classical phenotype [1].

Recent optical mapping studies in genomes from Black individuals revealed extensive variability in the copy number and orientation of LCR22 elements, with haplotypes and NAHR configurations not observed in genomes from White individuals; the authors propose that these configurations may reduce the likelihood of NAHR and contribute to the lower observed prevalence of the deletion in Black populations [36].

2.2 TBX1: the principal gene

TBX1 (22q11.21; OMIM 602054) encodes the transcription factor T-box 1, a developmental regulator that controls pharyngeal arch segmentation, cardiac outflow tract development from the second heart field, craniofacial muscle formation and, upstream, thymus and parathyroid formation from the third pharyngeal pouch [1, 32]. Evidence for its central role rests on two findings: Tbx1-null mice exhibit all malformations associated with the deletion, and isolated haploinsufficiency causes aortic arch defects [3, 29–31]; and individuals with pathogenic TBX1 variants without a deletion have features consistent with the syndrome [32]. In Yagi's series, three TBX1 variants were found in two sporadic individuals and one family among 13 patients without a deletion, whereas 96% of clinically diagnosed patients had the deletion [32]. These rare patients with a TBX1 point variant appear to have the complete pharyngeal phenotype but lack the mild learning difficulties frequently associated with the full deletion [2]. Truncating loss-of-function variants, which remove the nuclear localisation signal and transactivation domain, and gain-of-function missense variants have been described; families with truncating variants in exon 9C had craniofacial abnormalities and hypocalcaemia, with deafness in one family and no heart disease, showing that both deficient and excessive TBX1 activity are pathogenic [37–39]. In Ogata's Japanese family (variant c.1253delA, p.Y418fsX459, in the original nomenclature), three members had craniofacial abnormalities and hypocalcaemia and two had craniofacial abnormalities only; in Alghamdi's Saudi family (a father and three children; c.1158_1159delinsT, p.(Gly387Alafs*73)), there was congenital hypoparathyroidism, facial asymmetry and deafness, with normal intelligence and no heart disease; both variants were described on the isoform C transcript and their conversion to the MANE transcript is presented in 5.6 [38, 39]. A variant in the 5' untranslated region of TBX1 that doubled translation efficiency in vitro was proposed as a possible functional equivalent of gene duplication [40]. OMIM associates TBX1 with DiGeorge syndrome (188400), velocardiofacial syndrome (192430), conotruncal anomaly face syndrome (217095) and tetralogy of Fallot (187500), and Orphanet lists combined immunodeficiency due to a TBX1 variant (ORPHA:685017) only within the prevalence category below 1/1,000,000, which is not a numerical estimate [41]. Dysregulation of TBX1 dosage in animal models confirms its role in both deletion and duplication syndromes [3].

Two caveats guide laboratory interpretation. First, 22q11.2DS is a contiguous gene disorder: TBX1 predominantly explains cardiac, palatal, thymic and parathyroid defects, and proximal deletions encompassing it are associated with lower CD3 and CD4 counts, but the full phenotype — particularly neurocognitive and psychiatric features — is not a monogenic TBX1 disorder [1, 42]. Second, TBX1 variants have been found in a small proportion of nonsyndromic tetralogy of Fallot cases, and congenital athymia has been described with TBX1 haploinsufficiency [43, 44]; in the RETHYMIC® registration trial, one patient had a TBX variant [1, 19].

2.3 Other genes of interest in the region

Unmasking of autosomal recessive disorders through hemizygosity explains some phenotypic variability in a subgroup of patients: in addition to CEDNIK (SNAP29) and Bernard-Soulier (GP1BB), Kousseff syndrome (sacral myelomeningocele, tetralogy of Fallot, agenesis of the corpus callosum and microcephaly) and the autosomal recessive form of Opitz G/BBB syndrome have been described through a similar mechanism [1, 2]. The Oxford Desk Reference recommends considering this possibility whenever a child's phenotype differs from that of a parent carrying the same copy-number variant [8]. GeneReviews on TANGO2 deficiency explicitly lists episodes of paroxysmal deterioration or metabolic crises (rhabdomyolysis, hypoglycaemia, prolonged QTc, ventricular arrhythmias) in a person with a 22q11.2 deletion as suggestive of a second TANGO2 alteration on the non-deleted allele; for these patients, it recommends daily supplementation with a multivitamin containing all eight B vitamins, or a B-complex supplement, at least at the age-specific recommended daily allowance, and, during a crisis, intensive care admission for severe-appearing illness, elevated creatine kinase, hypoglycaemia or prolonged QTc, with electrocardiographic monitoring and magnesium replacement; the evidence is observational [51, 52].

2.4 Tissue and organ pathophysiology

The phenotype — cardiac outflow tract, velopharyngeal, auricular, thymic and parathyroid anomalies — results from failure of formation of third and fourth pharyngeal arch derivatives during development [2]. These structures receive contributions from all three germ layers — endoderm, mesoderm and ectoderm — and from neural crest cells derived from the closing neural tube. Pharyngeal mesoderm progenitor cells give rise to craniofacial muscles and second heart field derivatives, including the outflow tract; facial bones and the bony palate derive from the neural crest or anterior mesoderm; and the parathyroids and thymus result from interactions between pharyngeal endoderm and neural crest. Defects in parathyroid development lead to hypocalcaemia and thymic defects to immunodeficiency [10].

Immunodeficiency results from thymic hypoplasia and the consequent reduction in T-cell production; newborns with the deletion have significantly fewer thymic-lineage cells, but production improves over time, particularly during the first year of life [1]. T-cell lymphopenia predominantly affects CD8 cells, and a minority (<2%) have athymia with absent T cells [53]. Secondarily, lymphopenia is associated with increased risks of atopy and autoimmunity [1]. Dysphagia predominantly arises from dysmotility in the pharyngoesophageal region, derived from the third and fourth pharyngeal pouches, rather than solely from cardiac or palatal defects [1].

In the central nervous system, MRI shows cavum septum pellucidum and/or cavum vergae, polymicrogyria or cortical dysplasia and cerebellar hypoplasia; volumetric studies show reduced posterior brain volumes, with greater loss of occipital and left parietal white matter, and multicentre diffusion tensor imaging studies show diffuse reductions in diffusivity in major cortico-cortical connections [1]. Perisylvian polymicrogyria, in particular, should prompt consideration of a 22q11.2 deletion [54].

2.5 Genotype–phenotype correlation and penetrance

Penetrance of the A–D deletion is complete in most individuals, but variability is marked, even within the same family: a parent may have cleft palate and heart disease while the child has developmental delay with a normal heart and palate [1, 2]. A–B deletions are associated with better cognitive performance than A–D deletions, are frequently inherited and are associated with a milder phenotype; nested deletions have reduced penetrance and/or milder expression [1, 3]. CD3 and CD4 counts are significantly lower in proximal deletions encompassing TBX1 (A–B, A–C, A–D) than in nested and distal deletions (B–D, C–D, D–E, D–F) [42].

2.6 Atypical central and distal deletions

Deletions distal to the proximal A–B interval differ phenotypically from the common deletion [3, 55]. Central deletions (B–D and C–D; more than 76 published cases) are associated with growth restriction (24%), developmental delay or intellectual disability (49%), upslanting palpebral fissures, ear anomalies and heart disease (20%); they frequently present prenatally with cardiac, renal or other anomalies and fetal growth restriction, have lower rates of immunodeficiency, hypotonia and palatal anomalies, are inherited in 40% of cases and have CRKL as a candidate gene. Distal deletions are divided into three types: type 1 (C–E, D–E, D–F; more than 45 cases), predominantly de novo (62%), with a high need for obstetric surveillance because of ultrasound anomalies and fetal growth restriction, preterm delivery in more than half, heart disease in 53% (conotruncal and left-sided obstructive lesions) and involvement of MAPK1/ERK2; type 2 (E–F), rare, with only eight reports, predominantly de novo, with developmental delay in 88% and increased nuchal translucency and heart disease prenatally; and type 3 (D–H, E–H, F–H; more than 17 cases), which all encompass deletion of SMARCB1 and confer a substantial risk of malignant rhabdoid tumour, with developmental delay (35%), microcephaly (24%), heart disease (29%) and ear tags or pits; in these cases, identification at a young age is associated with a poorer prognosis regarding tumour development [3].

2.7 Molecular basis of 22q11.2 duplication

Reciprocal duplications of all microdeletion intervals (A–H) have been described in a combined total of more than 200 patients [3]. The typical duplication spans the A–D interval: in the series of 216 patients from the Children's Hospital of Philadelphia, 54.6% of mapped duplications lay between LCR22A and LCR22D [6]. In the original series, duplications ranged from 3–4 Mb to 6 Mb, with crossover points in the LCRs, and analysis of 15 microsatellite markers confirmed three alleles at at least one locus [5]. The penetrance table by Rosenfeld and colleagues, reproduced in the Oxford Desk Reference, places the 22q11.21 duplication (TBX1; chr22:17.2–19.9 Mb, hg18) among neurodevelopmental susceptibility loci: a frequency of 136/48,637 (0.28%) in postnatal microarray cases versus 12/22,246 (0.05%) in controls (p ≪ 0.0001), de novo occurrence in 12/47 (25.5%) of tested cases and an estimated penetrance of 21.9% (95% CI 14.7–31.8) [8, 56]. TBX1 dosage is implicated in structural phenotypes [3], and in fetuses, duplications encompassing LCR22C–D (and CRKL) appear to cause more cardiac and renal malformations, whereas cleft lip and palate have been observed with duplications encompassing A–B or the SPECC1L gene [7].

3. Clinical Spectrum and Manifestations by System

3.1 22q11.2 deletion syndrome — overview

The phenotype of 22q11.2 deletion is multisystemic and highly variable, even within families; more than 180 features have been associated with the deletion, and none is obligatory [1, 57]. Published frequencies vary according to the source of ascertainment — cardiology, cleft palate, immunology or psychiatry clinics — the age at assessment and how actively each finding is sought. The following table therefore presents ranges from the main series rather than a single estimate [1].

3.2 Heart and great vessels

Congenital heart disease is the most frequently recognised manifestation and the leading cause of mortality, accounting for approximately 87% of all deaths in children with the deletion [1]. In a review of 1,421 records from the 22q and You Center (Philadelphia), 64% had heart disease, predominantly conotruncal outflow tract defects, and ventricular septal defect was the most frequent echocardiographic finding [1, 60]. The distribution in that series is shown in the table.

Source: Campbell et al. 2018, reproduced in GeneReviews [1].

Other series report higher frequencies owing to differences in ascertainment: Smith reports heart disease in 85%, with VSD in 62%, right-sided aortic arch in 52%, tetralogy of Fallot in 21%, aberrant left subclavian artery, truncus arteriosus and type B interrupted aortic arch; the Oxford Desk Reference reports significant heart disease in 50–85% and tetralogy of Fallot in almost 20%, with VSD and interrupted aortic arch being the next most frequent defects [2, 3]. A broad additional spectrum has been described: atrial septal defect, truncus, right-sided aorta, pulmonary stenosis, aortic valve anomalies, aberrant subclavian arteries, vascular ring, anomalous carotid origin, transposition of the great arteries and tricuspid atresia; anomalies of the internal carotid arteries and other major cervical arteries are frequent, and approximately 5% of infants with congenital heart disease have the deletion, depending on the study [2]. The deletion is the principal syndromic cause of interrupted aortic arch and truncus arteriosus, and a significant proportion of children with tetralogy of Fallot have the deletion [61]. A subgroup has aortic root dilatation, whose natural history is unknown, and adults die prematurely, with sudden death and heart failure being the most frequent causes, even in individuals without congenital heart disease [1].

The French PNDS attributes more than 90% of all deaths associated with the deletion to heart disease (GeneReviews reports ~87% in children) and reproduces an older GeneReviews distribution, with heart disease in 76% of patients: tetralogy of Fallot 20%, VSD 14%, type B interrupted aortic arch 13%, truncus arteriosus 6%, vascular arch anomalies 5.5%, VSD with ASD 4%, isolated ASD 3.5% and other 10%; the fall to approximately 40% for conotruncal heart disease in more recent series reflects the age of the studies and recruitment from cardiology clinics [1, 13]. When not detected prenatally, the heart disease usually becomes apparent in the maternity unit through a murmur, tachypnoea or absent femoral pulses; tetralogy of Fallot and pulmonary atresia progress to cyanosis, interrupted aortic arch and coarctation to cardiovascular collapse, and VSD, ASD and anomalous vascular arches may present later with feeding or respiratory difficulties, including stridor and dysphagia when the vascular ring compresses the trachea and oesophagus [13]. In France, surgical management of complex heart disease is covered by the specific PNDS for tetralogy of Fallot/pulmonary atresia with ventricular septal defect/absent pulmonary valve, for truncus arteriosus and for simple transposition of the great arteries [13].

3.3 Palate, airway, ear and communication

In the review of 1,048 patients by Jackson and colleagues, 67% had a palatal anomaly; velopharyngeal incompetence (VPI) was the most common and may be structural (short palate), functional (hypotonia of the velopharyngeal muscles) or both [1].

Source: Jackson et al. 2019, reproduced in GeneReviews [1].

Other series report cleft palate in 9–11%, submucous cleft in 5%, cleft lip and palate in 2% and velopharyngeal insufficiency in 32–67% [2, 3, 10]. The French PNDS describes palatal anomalies in 40–100% depending on the team and the examining specialist, with cleft palate in 9%, bifid uvula in 5%, submucous cleft in 16–38%, cleft lip and palate in 2% and isolated functional velopharyngeal incompetence in 27%; across all children, velopharyngeal insufficiency reaches approximately 70% [13]. Children diagnosed following identification of heart disease frequently prove to have previously unrecognised, clinically significant VPI [1]. Speech is almost always hypernasal, with hypotonia of the pharyngeal muscles; small or absent adenoids exacerbate VPI, and VPI surgery improves intelligibility but may increase the risk of obstructive sleep apnoea [3]. Internal carotid artery anomalies (enlargement, medial displacement, tortuosity; 25%) may be diagnosed by visualising pulsations in the posterior pharyngeal wall on fibre-optic nasopharyngoscopy or by magnetic resonance imaging, with implications for pharyngeal surgery [3].

Laryngotracheoesophageal anomalies include vascular ring, laryngeal web, laryngotracheomalacia, subglottic stenosis and, rarely, laryngeal atresia and laryngeal cleft; any of these may cause stridor [1, 3]. Chronic otitis media with effusion occurs in 75%, and sensorineural hearing loss, usually unilateral and mild to moderate, in up to 15% [2]. According to the PNDS, hearing loss is conductive in 45% (with minor aplasias of the ossicular chain, in addition to otitis media with effusion) and sensorineural in 15%; the prevalence of hearing impairment has been estimated at 60% in a paediatric population and remains at 40% in adults; between 12 months and 6 years, otitis media with effusion causes conductive hearing loss greater than 30 dB in one-third of cases, sufficient to compromise language, and tends to settle after 6 years [13]. Language delay averages approximately two years, affects both receptive and expressive language and tends to diminish between 3 and 5 years [13]. More than 90% have communication difficulties of multifactorial origin (hypernasality, mild cognitive and language delay); early speech milestones are delayed by several months, and phrase speech may be delayed until 3 years, with rapid language development between 3 and 4 years [2]. Smith reports first words at 19 months and phrases at 34.5 months, and GeneReviews describes many children as non-verbal at 2–3 years [1, 3].

3.4 Immune system, autoimmunity and haematology

The defect in cellular immunity varies. In earlier studies, 67% had reduced T-cell production and 19% impaired T-cell function; in the series of 1,421 patients, 50% had abnormal T-cell populations [1]. Most recover normal or near-normal T-cell counts and function by 2 years, although preliminary data suggest a further decline in adolescence; only approximately 1% have a major immune abnormality, and many have recurrent minor infections during the first 2 years that subsequently resolve [2]. Complete athymia, with absent T cells and an indication for thymus implantation, occurs in approximately 1% (<2% in other estimates) [3, 53]. Humoral immune abnormalities occur in 17%, and IgA deficiency in 13%, particularly in patients with autoimmunity; hypogammaglobulinaemia in the first year generally resolves, and hypergammaglobulinaemia may develop after 5 years; some patients have functional antibody defects, particularly a poor response to pneumococcal polysaccharide vaccine [1]. Older children and adults continue to have infections — recurrent sinusitis or otitis in 25–33% and recurrent lower respiratory tract infections in 4–7% — to which palatal dysfunction, gastro-oesophageal reflux, aspiration and malnutrition contribute; nevertheless, few school-age children require active management of immunodeficiency [1]. The PNDS cites a study of immune function in 60 children, with abnormalities in 77%: defective T-lymphocyte production in 67%, impaired T-cell function in 19%, humoral deficiency in 23% and IgA deficiency in 13%; the deficiency is generally minor, manifests as frequent common viral infections (particularly ear, nose and throat infections) and corrects with age, whereas the severe form (≤ 1%), with a T-cell deficiency predominantly affecting CD8+ cells and sometimes T-cell alymphocytosis, is a diagnostic and therapeutic emergency to be directed to a paediatric immunodeficiency centre [13].

Atopy (77%) and autoimmunity are frequent [3]; the PNDS estimates autoimmune diseases at approximately 10%, with immune thrombocytopenic purpura in 3% and hypothyroidism in 6%, and includes constitutional thrombocytopenia among the haematological abnormalities [13]. Juvenile idiopathic arthritis is approximately 20 times more frequent than in the general population, begins between 17 months and 5 years, and is generally polyarticular and difficult to control; immune thrombocytopenic purpura is approximately 200 times more frequent [1]. Other associated autoimmune diseases include Graves' disease, hypothyroidism/Hashimoto's thyroiditis, vitiligo, autoimmune haemolytic anaemia, autoimmune neutropenia, aplastic anaemia, type 1 diabetes and coeliac disease [1–3]. Mild thrombocytopenia is common: even when immune thrombocytopenic purpura is excluded, the mean platelet count is ~70% of that in the control population, and large platelets with impaired function (including Bernard–Soulier syndrome due to unmasking of GP1BB) warrant assessment before surgery [1, 2].

3.5 Endocrine system and growth

Hypoparathyroidism with hypocalcaemia occurs in 17–60% and is typically most severe in the neonatal period, when it may cause seizures that cease with calcium supplementation [1, 2]. Calcium homeostasis often normalises with age, but hypocalcaemia recurs during physiological stress — illness, surgery, puberty and pregnancy — and latent or late-onset hypocalcaemia has been reported [1, 3]. Beyond the neonatal period, Taylor and Greenhalgh found hypocalcaemia in ~30% and ~42% of children, respectively [2]. In an adult study, 80% had experienced hypocalcaemia at some point, with hypoparathyroidism, hypothyroidism and hypomagnesaemia contributing [1, 58]. The initial presentation may occur in adulthood, as a tonic–clonic seizure due to severe hypocalcaemia with basal ganglia calcification [57].

Thyroid dysfunction is frequent and often appears after 10 years of age; hypothyroidism is the most common form and hyperthyroidism is generally autoimmune, and thyroid development depends in part on TBX1 [13]. In a series of 169 patients attending a multidisciplinary clinic, 1.8% had hyperthyroidism and 7.7% hypothyroidism, and 42% of subclinical or prodromal forms progressed to overt disease [2]. Growth impairment is common: 83% have height or weight below the 50th percentile and 36% below the 3rd percentile [2]. Among 95 children aged 1–15 years, 41% were below the 5th percentile for height; four were far below it, all with low IGF-1 and IGFBP-3, three with growth hormone deficiency and a small pituitary gland, and two responded to growth hormone [1]. Most adults have normal stature, and obesity affects up to 35% of adults; syndrome-specific growth charts are available [1]. The PNDS describes short stature of around −2 standard deviations in most children, constitutional and only rarely associated with growth hormone deficiency, and appends the CHOP-GOSH charts (Children's Hospital of Philadelphia and Great Ormond Street Hospital) for white children, with 9th, 25th, 50th, 75th and 91st percentiles for weight, height, body mass index and head circumference, based on the WHO references up to 5 years and on the CDC (weight, height, BMI) or UK (head circumference) references from 5 to 20 years; it recommends using general population charts in parallel, because only these identify children below the population standard who may benefit from growth hormone [13]. Hypoparathyroidism may become apparent postoperatively, particularly after cardiac surgery, which warrants calcium monitoring during these procedures [13].

3.6 Digestive system and feeding

Approximately 36% of children have significant feeding difficulties, often severe dysphagia requiring nasogastric tube feeding or gastrostomy, even without heart disease or palatal anomalies; assessment reveals nasopharyngeal reflux, a prominent cricopharyngeal muscle, abnormal cricopharyngeal closure or a diverticulum [1]. Smith reports feeding problems in 68% (poor sucking, nasopharyngeal reflux, gastro-oesophageal reflux in 10% and dysphagia with aspiration risk), and aspiration should be considered as a cause of respiratory compromise, recurrent pneumonia or bronchial hyperreactivity [1, 3]. Constipation is chronic in most patients [1]. Structural anomalies have been described: imperforate or anteriorly placed anus, intestinal malrotation and non-rotation, congenital diaphragmatic hernia (1%), oesophageal atresia with tracheoesophageal fistula, jejunal atresia, Hirschsprung's disease, accessory spleens, and umbilical and inguinal hernias [1, 3, 10]. Lower limb pain of unexplained cause is common in childhood [2]. The PNDS attributes the feeding difficulties to a mixed origin (gastro-oesophageal reflux, incoordination and hypotonia of the laryngopharyngeal muscles), describes constipation as usually functional and only rarely secondary to Hirschsprung's disease or to stenosis or anomalous placement of the anus, and notes that, with age, satiety disturbances with excess weight may appear [13]. Respiratory problems result mainly from aspiration due to impaired swallowing and reflux, sometimes from laryngomalacia or from bronchomalacia due to compression by an anomalous vascular arch, and sleep apnoea is associated with pharyngeal or digestive abnormalities and, sometimes, with anxiety [13].

3.7 Neurodevelopment, cognition and neurology

Motor milestones are delayed (walking at a mean age of 16 months according to Smith and 18 months according to GeneReviews), with hypotonia and axial instability [1, 3]. In a large international cohort, mean full-scale, verbal and performance intelligence quotients (IQs) were 75, 75 and 73 (standard deviation 14) [3]. Among 55 young children assessed using the Bayley scales, mental development was average in 22%, mildly delayed in 20% and significantly delayed in 58%; among 24 preschool children, full-scale IQ was 78 ± 12; and among 80 school-age children, mean IQ was 76.8 ± 13.0, with 39% in the average range, 31% in the low-average range and 31% in the borderline range [1]. The Oxford Desk Reference summarises the distribution as normal development in one-third, mild learning difficulties in one-third and moderate learning difficulties in one-third; severe intellectual disability is rare [2]. The PNDS reports IQ above 71 in 55%, mild intellectual disability (IQ 55–69) in approximately one-third and moderate to severe disability in fewer than 10%, with most in the borderline range (IQ 70–84); most children progress in mainstream education, at a slower pace or with adaptations, and others require smaller, more structured settings [13].

The neuropsychological profile is atypical: in 66% of school-age children, verbal IQ exceeds performance IQ, a pattern consistent with non-verbal learning disorder, which is rare in the general population. Relative strengths include verbal rote learning, reading decoding and spelling, whereas deficits affect non-verbal processing, visuospatial skills, complex verbal memory, attention, working memory and mathematics; full-scale IQ alone therefore does not reflect abilities, and verbal and performance IQs should be considered separately [1]. Attention disorders affect approximately 50% of school-age children, often persist into adolescence and adulthood and, in most cases, are not accompanied by hyperactivity; the PNDS summarises as strengths auditory and verbal rote memory, reading decoding and comprehension of simple, concrete instructions, and as weaknesses executive functions (planning, reasoning, flexibility, regulation of action), working and visuospatial memory, reading comprehension, mathematical logic and abstraction, with deficits in number comparison and problem solving that persist into adulthood, as well as deficits in face and emotion recognition [13]. Socialisation skills may exceed intellectual abilities, and personality tends towards perseverative behaviour and concrete thinking [3]. A subgroup shows cognitive decline over time, particularly in verbal IQ, preceding psychosis (see 3.8) [3, 62].

Epilepsy occurs in 11% and febrile seizures in 24%; approximately 15% have unprovoked seizures, and the deletion lowers the seizure threshold in adults without epilepsy [1, 3, 63]. Microcephaly is reported in 24–50% [1, 3]. Early-onset Parkinson's disease has a prevalence of 5.9%, and other movement disorders have been described [1, 3]. Sleep disorders affect 60% [3]. Structural brain anomalies include cerebral atrophy, cerebellar hypoplasia, cyst and cavum of the septum pellucidum, white matter abnormalities, hydrocephalus, corpus callosum hypoplasia, polymicrogyria, periventricular nodular heterotopia and ventriculomegaly [3]. The common deletion confers a risk of myelomeningocele 12 to 23 times that in the general population, a risk partly attenuated by folate supplementation [45].

3.8 Psychiatric disorders and schizophrenia

Behavioural, psychological and psychiatric problems affect ~93% of patients, who frequently have difficulty establishing and maintaining friendships [2]. Neuropsychiatric phenotypes are age-dependent: attention-deficit/hyperactivity disorder (ADHD, 32%) and autism spectrum disorder (ASD, 21%) at younger ages; anxiety (35%) at all ages; mood disorders (depression) over time; and schizophrenia spectrum disorders in 24% of young adults and 41% of individuals older than 25 years, according to the cohort of the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome [3, 64]. GeneReviews estimates that 60% of adults have a psychiatric disorder and that schizophrenia occurs in ~25%, a figure also reported in the Brazilian handbook; temperament may range from disinhibition and impulsivity to shyness and withdrawal [1, 10]. Earlier estimates, reproduced in the Oxford Desk Reference, reported psychiatric disorders (including bipolar disorder and schizophrenia) in up to 18% of adults and at least one psychotic episode in 6.5% [2].

The 22q11.2 deletion is the known genetic risk factor with the largest individual effect on schizophrenia, although it accounts for fewer than 2% of schizophrenia cases in the general population [2, 22]. Psychosis associated with the deletion is clinically similar to idiopathic schizophrenia, and cognitive decline precedes its onset: among 411 patients assessed longitudinally, 13.4% developed a psychotic disorder; these patients had lower baseline IQ (65.5 vs. 74.0) and more pronounced decline, particularly in verbal IQ, distinguishable from 11 years of age; downward deviation from the mean cognitive trajectory was associated with an increased risk of psychosis (odds ratio 2.49; 95% CI 1.24–5.00) [62]. This finding supports serial cognitive assessment as a tool for psychiatric surveillance. The French PNDS, based on series predating 2015, gives wider ranges: anxiety disorders in 40–76% in childhood and adolescence, mood disorders in 9–35% of adults, ADHD in 40% of children and 16% of adults (versus 4% in the general population), oppositional defiant disorder in 9–43%, ASD between 0% and 80% depending on the assessment method (overall risk estimated at 14–50%, higher when there are difficulties with social relationships and emotion recognition) and schizophrenia in 10% of adolescents aged 13–17 years, 25% of those aged 18–25 years and 23–43% of adults, with a mean age at onset of psychotic disorders of 17.7 years [13]. It identifies prior cognitive decline, stress and anxiety disorders as risk factors for psychosis, and associates social cognition deficits with social anxiety and later psychosis; when ASD is suspected, it recommends assessment at a Centre Ressource Autisme with ADOS and ADI-R [13].

3.9 Musculoskeletal system

In a systematic review, 90.5–100% of individuals undergoing occipitocervical imaging (10 studies, 408 individuals) had at least one anomaly: flattening of the skull base, a dysmorphic atlas or open atlas arch, and a dysmorphic odontoid process; increased segmental mobility on flexion–extension radiographs was reported in 56% [1]. Scoliosis prevalence ranges from 0.6–60% depending on the study; Smith reports 50%, with 5–6% requiring surgery [1, 3]. Other abnormalities include rib anomalies (2–19%; 13 pairs of ribs), butterfly vertebrae and other vertebral anomalies (1.1–11%), clubfoot (1.1–13.3%), patellar dislocation (10–20%), preaxial and postaxial polydactyly, syndactyly, camptodactyly, shoulder deformities and overlapping toes; slender, hyperextensible hands and fingers occur in 63% [1, 3, 10]. Craniosynostosis occurs in ~1% [2, 13]. The PNDS distinguishes early scoliosis, associated with vertebral malformations (17%), from late idiopathic scoliosis, with peak incidence in adolescence, and places the acquisition of walking at around 16 months [13].

3.10 Kidneys, genitourinary tract and other systems

Renal anomalies were identified in 16% (unilateral hydronephrosis, renal agenesis, multicystic dysplastic kidney), with isolated upper urinary tract dilatation in most (63%); boys more frequently had genitourinary anomalies (8% vs. 0.5%), with cryptorchidism and hypospadias in 4% each [1]. Wu and colleagues found undescended testes in 6% and hypospadias in 8% of male patients, and the Oxford Desk Reference reports structural urinary tract anomalies in 36%, including vesicoureteral reflux [2]. Horseshoe kidney, duplicated collecting system, posterior urethral valves, ureterocele, megalourethra, uterus didelphys, vaginal agenesis and absent uterus have been described [1, 3]. The PNDS reports renal anomalies in approximately 35% (agenesis, hypoplasia or dysplasia in 17%, obstructive uropathy in 10% and vesicorenal reflux in 4%) and, in boys, hypospadias in 8% and cryptorchidism in 5% [13]. In a microarray study of 522 children with renal agenesis, hypoplasia or dysplasia, the most frequent imbalances involved the HNF1B and DiGeorge/velocardiofacial loci [59].

Ocular findings in a prospective series of 90 patients included posterior embryotoxon (49%), retinal vessel tortuosity (34%), hooded eyelids (20%), strabismus (18%), ptosis (4%), amblyopia (4%) and distichiasis (2%); cataracts, colobomas, sclerocornea, microphthalmia and anophthalmia are rare [1, 10]. Enamel hypoplasia and dental caries are frequent [1]. The PNDS distinguishes enamel hypoplasias (localised quantitative defects of morphology) from hypomineralisations (altered colour and loss of translucency), which affect both the primary and permanent dentitions, and highlights, on the ocular side, refractive errors, strabismus, amblyopia and conjunctivitis, malformations being rare (posterior embryotoxon, coloboma, ptosis) [13]. Neoplasms have an overall prevalence of ~6% and include hepatoblastoma, renal cell carcinoma, thyroid carcinoma, melanoma, leukaemia, Wilms tumour and neuroblastoma; abnormal pulmonary lobulation has also been described [1].

3.11 Facial features

Facial features are subtle and variable: narrow or short palpebral fissures with telecanthus, hooded eyelids, ptosis, a broad and prominent nasal root and bridge (a “tubular nose” with a square root and narrow alar base), a bulbous or bifid nasal tip and nasal dimple, malar hypoplasia, vertical maxillary excess with an elongated face, retrognathia with a small chin, a small mouth and rounded external ears with a deficient or overfolded superior helix, sometimes with preauricular pits or tags [1–3, 65]. Hair may be abundant [3]. Asymmetric crying facies occurs in 8–14% and corresponds to the former Cayler cardiofacial syndrome [1]. Photographs of children aged 8 months to 3 years and of a 12-year-old boy reproduced in Smith's handbook (Figures 1 and 2, pp. 390–391) illustrate the narrow nose with a square root, narrow nasal alae, short palpebral fissures and smooth philtrum [3]. The facial features may be absent, particularly in people of African ancestry [1, 66].

3.12 22q11.2 duplication syndrome

The duplication phenotype is highly variable and generally milder than that of the deletion, ranging from normal cognition to learning difficulties or intellectual disability, and the subtle dysmorphic features do not form a recognisable pattern [3, 67]. Manifestations shared with the deletion occur much less frequently: heart disease in ~25% (mainly outflow tract anomalies, but also hypoplastic left heart and atrial septal defect), urogenital anomalies and velopharyngeal insufficiency with or without cleft palate; occasionally, Robin sequence, glaucoma and oesophageal atresia [3]. In the prospective series by Wenger and colleagues (37 patients with duplication), 38% of children aged 2–18 years had a community diagnosis of ASD, but only 14–25% met criteria based on ADI-R and ADOS; testing for duplications was prompted mainly by developmental delay, and application of the deletion screening protocol identified previously undetected, clinically relevant medical problems [15]. Duplications confer a risk of ASD, speech and language delays, and behavioural abnormalities, including hyperactivity and aggression; among reports of psychiatric symptoms in duplications of the B–D region, 19% included aggression [3, 68].

A retrospective review from a US centre suggests that the incidence of congenital anomalies is higher than previously described, with increased risks of gastrointestinal complications, endocrine dysfunction, ophthalmological abnormalities, palatal anomalies, heart disease, and musculoskeletal and neurological abnormalities [14]. In the immunological series of 216 patients, T-cell subsets were relatively preserved, but class-switched memory B cells, immunoglobulins and specific antibodies were reduced in a subgroup: 21.5% had at least two low immunoglobulin measurements, 11.7% had panhypogammaglobulinaemia and four children were receiving immunoglobulin replacement; asthma and eczema were the predominant atopic manifestations [6]. In contrast to the deletion, 22q11.2 duplication is less frequent in people with schizophrenia than in the general population (0.014% vs. 0.085%; odds ratio 0.17), and was the first putative protective variant described for this disease, a finding replicated in independent samples [16].

The prenatal phenotype described in a systematic review including 12 new cases mainly comprises increased nuchal translucency and heart disease, with mild renal and skeletal anomalies; almost 60% of duplications were inherited from an apparently healthy parent, and 8% of cases had another copy number variant [7].

4. Clinical Recognition and Warning Signs

The diagnosis should be considered in any child with congenital heart disease, cleft palate or palatal insufficiency [2]. The most useful warning signs are grouped by age and clinical setting.

Several findings have particular diagnostic relevance. In the genetic evaluation of congenital heart disease, hypernasal speech and submucous cleft palate should be assessed, and urgent 22q11 FISH or microarray testing may be necessary in a critically ill newborn for prognostic and surgical reasons; an isolated VSD in a child without other findings has a very low diagnostic yield, so testing is not usually indicated in these circumstances [61]. In Robin sequence, the 22q11 deletion accounted for 11% of syndromic cases in one series and, together with Stickler syndrome, is one of the most common causes in the complex group [69]. In the cleft palate clinic, hypernasal speech requires careful examination for a submucous cleft and exclusion of the deletion, while a history of learning delay, hypocalcaemia, immunodeficiency or heart disease points towards it [70]. Polymicrogyria and renal agenesis or multicystic dysplasia associated with heart disease are also indications for testing the region [54, 59]. Newborn screening for severe combined immunodeficiency by quantification of TRECs (T-cell receptor excision circles), which was not designed for this condition, has enabled early identification of the ~1% with severe immunodeficiency and many who will prove immunocompetent; testing for the deletion is recommended in infants with a positive screen who do not have SCID [3]. In population screening in Ontario, samples with the deletion had a median TREC value of 108.9 versus 602.5 copies/3 µL in samples without the deletion [11].

The history should cover neonatal problems (nasal regurgitation, seizures), heart disease and previous surgery, developmental and speech progression, infection history, and family history of heart disease, cleft palate and psychosis; examination should include growth parameters (weight, height, head circumference), facial features, cardiac examination and assessment of the palate — does the child speak clearly or have a nasal voice? Is there a bifid uvula or submucous cleft? [2].

There is no specific set of clinical warning signs for the duplication: most cases are identified by microarray performed for developmental delay, ASD or congenital anomalies, or through cascade family testing after identification in a proband [3, 15].

The French PNDS adds the following circumstances that should prompt testing: in the newborn, laryngeal malformation (web or cleft), early immune deficiency with T-cell predominance (particularly CD8+), a renal anomaly associated with another suggestive sign and the combination of sucking difficulty with recurrent nasal regurgitation; in early childhood, psychomotor delay with suggestive somatic signs or dysmorphism, recurrent upper or lower respiratory tract infections with suggestive morphology and velar insufficiency with delayed language or learning; later, school or social integration difficulties with a hypernasal voice, psychiatric disorders with suggestive morphology and, in adults, early-onset Parkinson's disease; and, at any age, hypoparathyroidism or autoimmune disease with suggestive morphology or development [13]. It further recommends that any malformation at birth be investigated by chromosomal analysis, preferably by microarray, which reveals the deletion even when the clinical picture is atypical, and that the parents of every affected child be tested for the deletion [13].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Diagnostic criteria

There are no formal clinical criteria: diagnosis is established in a proband by identifying a heterozygous deletion at 22q11.2 using chromosomal microarray or another genomic analysis [1]. The recurrent deletion cannot be identified by G-banded karyotyping, although it was first demonstrated by conventional cytogenetics in rare cases with larger deletions [1, 10].

5.2 Laboratory methods

Targeted analysis (FISH, qPCR, MLPA) is not appropriate in an individual whose microarray designed to cover the region was normal [1]. Mosaicism below approximately 20% is not detected by microarray and may require FISH in several tissues [28]. According to the summary in the French PNDS, testing for the microdeletion confirms the diagnosis in more than 95% of patients in whom it is clinically suspected; the FISH probe used by most laboratories targets TBX1 and detects the deletion in more than 90% of patients with a suggestive phenotype; MLPA and PCR, used alone, do not usually define the size of the deletion, whereas GeneReviews accepts sizing by LCR with MLPA kits carrying probes distributed across the region, a difference that depends on kit design; the typical deletion contains approximately 60 genes, and the PNDS recognises no clear phenotypic differences between large and small deletions [1, 13].

5.3 Additional investigations after diagnosis

The initial assessment recommended by GeneReviews and the 2023 recommendations includes cardiac assessment with chest radiography, electrocardiography and echocardiography (thoracic magnetic resonance imaging if a vascular ring is suspected); clinical assessment of the palate and feeding; full blood count with differential, and, if the absolute lymphocyte count is reduced, T- and B-cell subsets and referral to immunology, with flow cytometry, immunoglobulins and T-cell function; haematological assessment if bleeding occurs, including platelet volume and function studies before surgery; ionised calcium and intact parathyroid hormone (PTH); TSH and free T4; growth assessment (referral to endocrinology if height < 2nd percentile); ophthalmological and audiological assessment; neurological assessment if seizures are suspected; speech and language assessment by 1 year of age with referral for early intervention; psychological or psychiatric assessment for anxiety, mood disorder, behavioural changes or psychosis (including risk behaviours in adolescents and adults); chest radiography for thoracic vertebral anomalies and cervical spine radiographs in 6 views (flexion, extension, anteroposterior, lateral, open mouth and skull base) in everyone older than 4 years — the age of ossification — and before cervical hyperextension during surgery or sport; renal ultrasonography; and a genetics clinic referral [1, 17]. The Oxford Desk Reference additionally recommends serum immunoglobulins and antibody titres against tetanus, diphtheria and Haemophilus influenzae type b in children older than 4 months, and testing of both parents by FISH, qPCR or microarray [2]. Expert opinion is divided on routine cervical radiography, but symptoms of spinal cord compression require urgent neurological referral [2]. The French PNDS organises the assessment by age. In the infant: complete cardiovascular examination with blood pressure, electrocardiography and Doppler echocardiography; abdominal, renal and transfontanellar ultrasonography and ophthalmological examination; serum calcium, ionised calcium, serum phosphate, serum protein, 25-hydroxyvitamin D and PTH; velopalatal assessment; investigation of reflux and airway compression; lymphocyte phenotyping and immunoglobulin measurement; and hearing screening by otoacoustic emissions and/or auditory evoked potentials. In childhood: growth and nutrition, feeding and bowel transit, endocrine and autoimmunity assessment (clinical and, if necessary, autoantibodies), ear, nose and throat assessment and hearing, ophthalmology, dental status, neurodevelopmental assessment (psychomotor or neuropsychological, speech and language therapy, ADHD screening, behaviour, social skills and autonomy, school integration), full blood count and calcium–phosphate and immune studies. In adolescence: puberty, spinal alignment (clinical examination and, if necessary, radiography or computed tomography), schooling and vocational guidance, and mental state. In adults: cardiology consultation with electrocardiography, calcium–phosphate studies with bone densitometry for osteoporosis, neurological examination focused on Parkinson's disease, neuropsychological and psychiatric assessment, and social and occupational integration [13].

5.4 Prenatal diagnosis

Diagnosis may be made prenatally during investigation of a pregnancy with cardiac or structural renal anomalies, or when microarray is used to investigate other anomalies; if fetal ultrasound or echocardiography shows tetralogy of Fallot, interrupted aortic arch or VSD, microarray or FISH for 22q11.2 should be requested [2, 10]. Diagnosis by targeted FISH, MLPA or microarray on chorionic villi or amniotic fluid is possible, and screening using circulating cell-free fetal DNA (cfDNA) is technically feasible [2]. In the largest prospective multicentre study (21 centres, 6 countries; 18,289 pregnancies with a genetic result), SNP-based cfDNA screening detected 9 of 12 cases (sensitivity 75.0%; 95% CI 42.8–94.5), with specificity of 99.84%, positive predictive value of 23.7% and negative predictive value of 99.98%; an updated algorithm detected 10 of 12 (83.3%), with a positive predictive value of 52.6%; the observed prevalence was 1:1,524, with 5 of the 12 cases representing nested deletions [12]. A positive cfDNA result requires confirmation by invasive diagnostic testing. The French PNDS acknowledges that there is no consensus on the ultrasound findings that justify targeted testing, but recommends it in the presence of conotruncal heart disease (approximately 40% of people with the deletion have conotruncal heart disease and 13–18% of fetuses or patients with conotruncal heart disease have the deletion; some authors extend the indication to septal defects) and in the presence of cleft palate or cleft lip and palate, sometimes with polyhydramnios, the risk being exceptional in isolated cleft lip; non-visualisation of the thymus is a strong argument in these settings, and unilateral renal agenesis, renal hypoplasia and hydronephrosis should also raise suspicion of the deletion [13]. The detection rate from fetal malformations is low, because malformations detectable on ultrasound are present only in a minority and atypical phenotypes do not prompt targeted FISH or MLPA; systematic microarray for any fetal malformation circumvents this limitation, although in 2015 it was not yet reimbursed in France [13]. At the time of the PNDS, screening by fetal DNA in maternal blood was neither validated nor reimbursed; subsequent evidence (the prospective Dar study and the 2023 ACMG conditional recommendation) supersedes that position, while maintaining the requirement for invasive confirmation [12, 13, 71]. Establishing the diagnosis even late in pregnancy is useful for perinatal management [1]. The 2023 evidence-based guideline of the American College of Medical Genetics and Genomics (ACMG) gives a conditional recommendation for 22q11.2 deletion (weaker than the strong recommendation for trisomies 21, 18 and 13) that cfDNA screening be offered to all pregnant women, owing to the smaller number of available studies; this is a US position, and the observed positive predictive value (23.7–52.6% in the Dar study) shows that a positive screening result alone is not diagnostic [12, 71]. Some positive results reflect maternal rather than fetal deletions: in a routine screening programme involving 38,495 pregnancies in Shenzhen (China), 8 of 17 positive results investigated by amniocentesis were confirmed in the fetus, and in 3 of the 9 unconfirmed cases the pregnant woman had the deletion, requiring maternal testing to be offered [72].

5.5 Diagnostic algorithm

1. Clinical suspicion (conotruncal heart disease, cleft/VPI, hypocalcaemia, T-cell lymphopenia/low TREC, psychiatric phenotype with dysmorphic features or learning difficulties, suggestive prenatal anomaly) → chromosomal microarray [1]. The 2023 paediatric recommendations indicate MLPA or microarray in the proband, with FISH only when it is the sole method available, and regard microarray as the test providing the most clinical information for diagnosis and counselling, because it defines the size of the deletion and detects other relevant CNVs; FISH and MLPA require a prior index of suspicion [17, 18].
2. If microarray shows an A–D, A–B, A–C or nested deletion → diagnosis of 22q11.2DS; multisystem assessment (5.3) and targeted parental testing [1, 2].
3. If microarray shows a central or distal deletion → specific counselling (type 3 distal deletions: rhabdoid tumour surveillance) [3].
4. If microarray is normal and the phenotype is typical → TBX1 sequencing; consider differential diagnoses (CHD7, JAG1, del10p13-p14, embryopathies) and exome sequencing [1, 10].
5. If the phenotype differs from that of the carrier parent or is atypical (ichthyosis, keratoderma, neuropathy, macrothrombocytopenia, metabolic crises, 2-hydroxyglutaric aciduria) → investigate a variant in the remaining allele [1, 8].
6. If microarray shows 22q11.2 duplication → parental testing, application of the deletion screening protocol and counselling about incomplete penetrance; consider a second genetic event when the phenotype is severe [7, 8, 15].

5.6 Limitations of genetic tests and report content

Each method has its own coverage. Chromosomal microarray detects recurrent and atypical deletions and duplications in the region, but does not identify balanced rearrangements (for example, a balanced parental translocation involving 22q11.2), does not detect low-level mosaicism (below approximately 20%) and localises breakpoints only to the LCR22 repeats, whose segmental duplications are not precisely interrogated by probes [1, 28]. FISH with N25, TUPLE (HIRA) or TBX1 probes detects only deletions encompassing the LCR22A–B interval, and MLPA depends on the probes included in the commercial kit; neither method detects sequence variants [1, 10]. TBX1 sequencing does not detect the deletion and should therefore be requested only after normal copy number analysis [10, 32]; microarray reveals CNVs, whereas exome or genome sequencing serves to identify other types of variants, including those on the remaining allele [18]. A negative test does not exclude the condition in the presence of a convincing phenotype if the method did not cover the affected interval or type of alteration [1].

A copy number variant report should provide ISCN nomenclature with the reference genome version (GeneReviews coordinates use GRCh37 and ClinGen coordinates also use GRCh38), the LCR22 interval involved, the included dosage-sensitive genes (TBX1, CRKL, SMARCB1), zygosity (heterozygous for the deletion or duplication) and classification according to the 2020 ACMG/ClinGen technical standards for copy number variants [35, 73]. In ClinGen, the proximal region (ISCA-37446) has sufficient evidence for haploinsufficiency and triplosensitivity (scores 3 and 3), the type I distal region (D–E or D–F; ISCA-37397) and the type III region containing SMARCB1 (ISCA-46294) have sufficient evidence for haploinsufficiency (3), the central B–D or C–D region (ISCA-37516) has some evidence (2), and the type II distal region (E–F; ISCA-37488) has little evidence (1); evidence for triplosensitivity is limited (1) or absent (0) outside the proximal region [35]. Proximal duplication can therefore be classified as pathogenic while having a penetrance of approximately 22%; the report should explicitly state this incomplete penetrance, particularly prenatally [8, 56].

Sequence variants should be described using HGVS nomenclature on the versioned MANE Select transcript. For TBX1, MANE Select (GRCh38, version 1.5) is NM_001379200.1 (transcript variant D, encoding a 504-amino-acid protein), whereas much of the literature and some databases use NM_080647.1 (variant C, 495 amino acids); the two coding sequences differ at the start, and positions downstream of the divergence increase by 27 nucleotides and 9 codons in the MANE transcript [74, 75]. Thus, the variant in the Alghamdi family, NM_080647.1:c.1158_1159delinsT p.(Gly387Alafs*73), corresponds to NM_001379200.1:c.1185_1186delinsT p.(Gly396Alafs*73), and the variant in the Ogata family, published as c.1253delA (p.Y418fsX459), corresponds to NM_080647.1:c.1253del p.(Tyr418Phefs*42) and NM_001379200.1:c.1280del p.(Tyr427Phefs*42); both correspondences were confirmed by genomic mapping in GRCh38 (NC_000022.11:g.19766537_19766538delinsT and NC_000022.11:g.19766632del, respectively) [38, 39, 75, 76]. The MANE Select transcripts of genes whose remaining allele may be investigated in an atypical phenotype are SNAP29 NM_004782.4, GP1BB NM_000407.5, TANGO2 NM_152906.7, SLC25A1 NM_005984.5, PRODH NM_016335.6, CRKL NM_005207.4, COMT NM_000754.4 and SMARCB1 NM_003073.5 [74]. In these cases, the variant in the non-deleted allele is hemizygous rather than homozygous, and the report should state this, because interpretation depends on demonstrating that it is in trans with the deletion (through parental testing) [1, 48]. Two examples are CEDNIK syndrome (cerebral dysgenesis, neuropathy, ichthyosis and palmoplantar keratoderma), caused by a 22q11.2 deletion on one allele and a loss-of-function variant in SNAP29 on the other, to be considered when the child's phenotype is discordant with that of the carrier parent [8], and hyperprolinaemia type I, an autosomal recessive deficiency of proline dehydrogenase (PRODH, located in the deleted region), diagnosed by plasma amino acids (proline usually below 2,000 µM; normal 100–450 µM) and confirmed by molecular testing, because the enzyme is not expressed in leucocytes or fibroblasts; heterozygotes may have mild hyperprolinaemia, and the prognosis is generally excellent, with no indication for dietary treatment, although in some individuals it may contribute to the risk of schizophrenia or of cognitive and behavioural abnormalities [77].

A variant of uncertain significance in TBX1 or a gene on the remaining allele does not become pathogenic on the basis of treatment response, resemblance to the deletion phenotype or segregation in a small number of affected relatives; segregation analysis should be described as an investigation, with reclassification when evidence satisfying ACMG/AMP criteria becomes available [73]. The 2023 recommendations advise against disregarding clinical findings atypical for the deletion and, in their presence, recommend considering targeted, exome or genome sequencing to look for single-nucleotide variants or small CNVs on the intact allele; they also recommend always testing the parents, even when both have a negative history, because they may have a mild phenotype and somatic and germline mosaicism occurs [17].

6. Differential Diagnosis

All manifestations of the deletion can occur individually in healthy people; the following conditions may produce a similar phenotype [1].

The PNDS adds practical discriminating features: in CHARGE syndrome, facial asymmetry results from facial nerve palsy rather than hypoplasia of the depressor anguli oris muscle, and semicircular canal agenesis, olfactory bulb agenesis and asymmetric auricular dysplasia point to the diagnosis; in Alagille syndrome, peripheral pulmonary stenoses, cholestasis due to bile duct paucity and posterior embryotoxon distinguish it, and the cause is a heterozygous JAG1 variant or a 20p12 deletion including JAG1; in a suggestive patient without a 22q11.2 deletion, microarray immediately detects other microdeletions with an overlapping phenotype, such as 15q24 [13].

In immunology, congenital athymia (complete DiGeorge syndrome) should be distinguished from severe combined immunodeficiency, FOXN1 deficiency and forms associated with CHARGE or del10p13; in the RETHYMIC® trial, 38% of patients with athymia had 22q11.2 deletion and 24% had CHARGE syndrome [19, 53].

For duplication, the differential diagnosis encompasses any non-specific developmental delay or ASD, and the critical issue is interpretation: because the duplication is frequently inherited from a healthy parent and has a penetrance of ~22%, its presence in a patient with a severe phenotype does not exclude another cause, and some laboratories do not report it prenatally because of prognostic uncertainty [7, 8].

7. Treatments and Risk Management Strategies

7.1 General principles

There is no therapy targeting either the deletion or duplication; management is multidisciplinary, anticipatory and age-specific, and is based on the 22q11.2 Society's 2023 recommendations for children and adults, which updated the 2011 and 2015 guidelines [17, 18, 33, 34]. The British organisation Max Appeal coordinated a consensus document whose table of age-specific assessments, reproduced in the Oxford Desk Reference, serves as a checklist [2]. The main interventions by system are summarised in the table.

7.2 Hypocalcaemia and hypoparathyroidism

In acute symptomatic neonatal hypocalcaemia (seizures, tetany), correction is achieved with slow intravenous 10% calcium gluconate under electrocardiographic monitoring, followed by oral supplementation; in chronic hypoparathyroidism, conventional first-line therapy is oral calcium with active vitamin D (calcitriol — Rocaltrol® — or, in Europe, alfacalcidol — for example, One-Alpha®/Etalpha®), with correction of native vitamin D insufficiency and hypomagnesaemia, titrated to maintain calcium at the lower limit of normal while avoiding hyperphosphataemia, hypercalciuria and declining renal function [1, 78]. Reference doses: in newborns (≤ 1 month) with symptomatic hypocalcaemia, the US label for injectable calcium gluconate (100 mg/mL, containing 9.3 mg elemental calcium/mL) specifies a bolus of 100–200 mg/kg calcium gluconate (1–2 mL/kg of the 10% solution), diluted to 10–50 mg/mL and administered at no more than 100 mg/min, repeatable every 6 hours if necessary, or continuous infusion starting at 17–33 mg/kg/hour; serum calcium is measured every 4–6 hours with intermittent boluses and every 1–4 hours during infusion, with electrocardiographic monitoring and secure intravenous access (risk of calcinosis cutis and necrosis following extravasation), and concomitant intravenous ceftriaxone is contraindicated in newborns aged 28 days or younger [79]. For paediatric chronic hypoparathyroidism, a recent review proposes 25–50 mg/kg/day elemental calcium (citrate, carbonate or gluconate) in 3–4 divided doses, to a maximum of 1,000–2,000 mg/day, and calcitriol starting at 0.04–0.08 µg/kg/day in infants or 0.25 µg/day in children, with increases of 0.25 µg every 2–4 weeks, to maintenance doses of 0.25–0.75 µg/day (1–5 years) or 0.5–2 µg/day (older than 5 years) [80]. The calcitriol label (for comparison) specifies the same initial morning dose of 0.25 µg/day, increases at 2–4-week intervals, 0.5–2 µg/day in most adults and children aged 6 years or older and 0.25–0.75 µg/day at 1–5 years, with no maximum dose defined in the label, with serum calcium at least twice weekly during titration and periodic calcium, phosphorus and 24-hour urinary calcium; it differs in having no dosing for hypoparathyroidism below 1 year of age, so the weight-based infant dose falls outside the labelled conditions [81]. The UK SmPC for alfacalcidol (One-Alpha®), also for comparison, includes weight-based initial doses for all indications: 0.05–0.1 µg/kg/day in newborns and preterm infants, 0.05 µg/kg/day below 20 kg and 1 µg/day in adults and children above 20 kg, with increases of 0.25–0.5 µg, weekly plasma calcium at the start, response in most adults at 1–3 µg/day and usual maintenance of 0.25–1 µg/day; the SmPC defines no maximum dose, but refers to 3–5 µg for more rapid correction of severe hypocalcaemia in hypoparathyroidism (with calcium supplements) and up to 2 µg/kg/day in severe cases of neonatal hypocalcaemia [82]. In adults, calcitriol is typically used at 0.5–2.0 µg/day (half-life 4–6 hours, in one or two doses) and alfacalcidol at 1.0–4.0 µg/day, the upper limit of which exceeds the 1–3 µg/day at which most adults respond according to the One-Alpha® SmPC [82]; elemental calcium, as carbonate (40% elemental calcium) or citrate (21%; absorption independent of gastric acid, preferable with proton pump inhibitors or achlorhydria), should be divided into doses no greater than 500–600 mg; European guidelines regard requirements exceeding 2.5 g/day calcium, 1.5 µg/day calcitriol or 3.0 µg/day alfacalcidol as a criterion for considering PTH therapy [83]. These doses are for reference only and are individualised according to serum and urinary calcium; the main adverse effects of conventional therapy are hypercalciuria, nephrocalcinosis, renal stones and episodes of hypercalcaemia, which is why GeneReviews recommends nephrology referral for prolonged supplementation [1, 78]. Carbonated drinks and alcohol may exacerbate hypocalcaemia [1]. Since hypocalcaemia recurs under physiological stress, calcium should be checked before and after surgery, during hospital admissions and regularly in pregnancy, and many centres check it whenever blood is drawn for another reason [1, 2].

Palopegteriparatide (Yorvipath®), a sustained-release PTH(1-34) prodrug, was authorised by the European Commission on 17 November 2023 (orphan medicinal product; adults with chronic hypoparathyroidism) and by the FDA on 9 August 2024 (adults with hypoparathyroidism; not studied in acute postsurgical hypoparathyroidism) [20, 84, 85]. Both labels specify a starting dose of 18 µg subcutaneously once daily, with 3 µg adjustments guided by serum calcium, but their limits differ: the US label sets a maximum dose of 30 µg once daily, always as a single injection (two injections increase the risk of unintended calcium variations), and the titration regimen was evaluated only in adults who had previously achieved albumin-corrected calcium ≥ 7.8 mg/dL with conventional therapy; the European Summary of Product Characteristics (SmPC) permits 6 to 60 µg/day, allows two consecutive injections at different sites for some doses, permits increases only at intervals of at least 7 days and reductions at intervals of at least 3 days, and requires normal 25-hydroxyvitamin D and stable serum calcium within or slightly below the normal range (1.95–2.64 mmol/L; 7.8–10.6 mg/dL) in the two weeks before initiation [84, 85]. Adverse effects occurring in ≥ 5% include injection-site reactions, vasodilatory symptoms, headache, diarrhoea, back pain, hypercalcaemia and oropharyngeal pain, and warnings address severe hypercalcaemia and hypocalcaemia, potential osteosarcoma risk, orthostatic hypotension and digoxin toxicity; the August 2026 revision of the US label added a warning about hypersensitivity reactions [78, 85]. Neither label establishes safety and efficacy below 18 years, making use in children and adolescents off-label; an open-label, single-arm phase 3 trial in adolescents aged 12–17 years (NCT07706764; 12 planned participants; composite endpoint at week 26) began recruitment in April 2026 [84–86]. Recombinant PTH(1-84) (Natpar®), authorised in the European Union in 2017 as adjunctive therapy for adults inadequately controlled with conventional therapy, is listed as withdrawn in the EMA medicines data file and is therefore no longer a European alternative [20]. Eneboparatide, a PTH receptor agonist, is undergoing a placebo-controlled phase 3 trial in adults (CALYPSO, NCT05778071; primary completion in November 2024), with no results posted in the registry at the time of this review [87]. The 2025 international recommendations position it as an option when conventional therapy is inadequate or poorly tolerated [78]. We identified no published data specifically addressing its use in patients with 22q11.2 deletion; the indication is adult chronic hypoparathyroidism regardless of cause. The differential diagnosis of genetic hypoparathyroidism includes the monogenic and syndromic causes of parathyroid hormone deficiency — isolated forms due to GCM2 and PTH, autosomal dominant hypocalcaemia due to gain of function of CASR and GNA11, GATA3, AIRE, FAM111A, TBCE and mitochondrial forms —, and its management encompasses the biochemical targets and urinary calcium limits during conventional therapy, the criteria for moving to parathyroid hormone replacement and the long-term renal and neurological surveillance plan, within which the parathyroid component of the 22q11.2 deletion is placed.

7.3 Immunity, vaccination and transfusions

Live vaccines should not be administered to infants with lymphocyte abnormalities; immune status should be reassessed before any live vaccine, and antibodies should be measured at 9–12 months to assess seroconversion [1]. The Oxford Desk Reference pragmatically recommends withholding live vaccines (oral polio, BCG) until immune function has been assessed; offering MMR (measles, mumps, rubella) at 18 months to children with at least 75% of the normal T-cell count and normal responses to tetanus and Hib vaccines; applying the same criterion to varicella vaccine; using inactivated polio vaccine; and administering BCG only after a risk assessment demonstrates that benefit outweighs risk [2]. In a retrospective study, varicella and MMR vaccines caused mild adverse effects at frequencies similar to those in the general population in patients without severe immunocompromise (9% for varicella; 23% for MMR, with fever, rash and constitutional symptoms), whereas 63% of children unvaccinated against varicella contracted the disease [88]. Transfusion products should be irradiated and CMV-negative in children younger than 6 months or with T-cell lymphopenia (for example, CD4 < 500/µL), and GeneReviews recommends irradiated products until immune normalisation is confirmed [1, 2]. The 2023 paediatric recommendations include, at diagnosis and at reassessments throughout childhood and adolescence, T-cell phenotyping (CD3, CD4 and CD8 counts, with CD4/CD45RA cells) and B-cell phenotyping (CD19 and class-switched memory B cells, CD19 or CD20+, CD27+IgM−), measurement of IgG, IgA, IgM and IgE not before 6 months of age, and vaccine responses with antibodies against tetanus, diphtheria and pneumococcus [17]. They recommend checking immune status before live vaccines, not administering them when T cells are very low (CD4 < 400 or naïve CD4 < 100 cells/mm³), completing the remaining scheduled vaccines with confirmation of immunity by antibody measurement, and not transfusing non-irradiated products to infants with severe T-cell lymphopenia [17]. In adults, immunological assessment is reserved for recurrent infections (dependent on IgG, IgA or IgM) or opportunistic infections (dependent on T cells) and for severe atopy; a minority require immunoglobulin replacement, and all benefit from the usual vaccines, including against COVID-19 and influenza, although the response may be reduced [18].

7.4 Congenital athymia (complete DiGeorge syndrome): thymic tissue implantation

Approximately 1% of patients have congenital athymia; without treatment, this condition is fatal in childhood — in a natural history population of 49 patients (1991–2017) receiving supportive care alone, survival at 2 years was 6%, and all died by 3 years, mainly from infection [3, 19]. Processed, thymocyte-depleted allogeneic thymic tissue (RETHYMIC®; Sumitomo Pharma America) was approved by the FDA in October 2021 for immune reconstitution in paediatric patients with congenital athymia; it is not indicated for severe combined immunodeficiency [19, 89]. It is administered in a single surgical procedure by implantation of tissue slices into the quadriceps muscle, at a dose of 5,000–22,000 mm² of RETHYMIC surface area per m² of recipient body surface area; patients with maternal engraftment or a high response to phytohaemagglutinin receive immunosuppression (rabbit antithymocyte globulin, methylprednisolone, ciclosporin, sometimes basiliximab or mycophenolate) [19]. Efficacy is based on 10 prospective, open-label, single-centre studies involving 105 patients (95 in the efficacy analysis; median age 9 months; 38% with 22q11.2 deletion): estimated survival was 77% at 1 year and 76% at 2 years, and 94% of those alive at 1 year were alive at a median follow-up of 10.7 years [19]. The most frequent adverse reactions were hypertension (19%), cytokine release syndrome (18%, all associated with antithymocyte globulin), hypomagnesaemia (16%), rash (15%), renal failure (12%), thrombocytopenia (12%) and graft-versus-host disease (10%); protective immune reconstitution develops only 6–12 months after implantation, requiring infection control measures and immunoglobulin replacement until immune criteria are met, and warnings address autoimmune disease, lymphoproliferative disease, infection transmission, pre-existing cytomegalovirus infection and pre-existing renal impairment as risk factors for death [19]. The regulatory approval identified is in the United States; the product is not listed in the European Medicines Agency medicines data file consulted on 6 October 2026 [20]. Haematopoietic cell transplantation from a matched sibling donor was a life-saving alternative in a patient with TBX1-related athymia and severe adenoviraemia [44].

7.5 Mental health, neurology and cognition

Screening for psychiatric abnormalities should begin before 10 years, with surveillance for changes in behaviour, emotional state and thinking, including hallucinations and delusions; in adolescents and adults, it should include risk behaviours (sexual activity, alcohol and drug use) [1, 2]. Psychiatric disorders respond to standard treatments. Clozapine (Leponex®/Clozaril®) is effective in treatment-resistant schizophrenia associated with the deletion: in a systematic review of 26 articles involving 57 patients, mean or median doses were relatively low and approximately 65.5% had a good response; seizures were the most frequent serious adverse effect, but most patients could continue or restart the drug with dose reduction and/or addition of an antiseizure medication, particularly valproate; consideration of seizure prophylaxis, screening for and correction of hypoparathyroidism/hypocalcaemia before initiation, and serum level monitoring are recommended [90]. The usual requirements for clozapine haematological monitoring (risk of neutropenia/agranulocytosis) and surveillance for myocarditis, constipation and metabolic effects remain applicable [90]. The current US clozapine label (Clozaril®, June 2025) no longer refers to a REMS distribution programme, but retains baseline and serial absolute neutrophil counts, with specific thresholds for benign ethnic neutropenia associated with the Duffy-null phenotype, and a boxed warning for severe neutropenia, orthostatic hypotension, seizures and myocarditis; approved indications are treatment-resistant schizophrenia and reduction of the risk of suicidal behaviour, with safety and efficacy not established in paediatric patients, while national SmPCs apply in Europe [91]. Drugs that lower the seizure threshold should be used cautiously because the deletion lowers the threshold even in adults without epilepsy [63]. Caffeine may contribute to or exacerbate anxiety [1]. The 2023 adult recommendations advise treating psychiatric disorders according to general clinical guidelines, with drugs of proven efficacy (antipsychotics, anxiolytics and antidepressants), monitoring and proactively managing the adverse effects expected from the comorbidities of the deletion, and accept a “start low, go slow” titration, exemplified by clozapine, in which the low seizure threshold is managed with this strategy and with consideration of a prophylactic antiseizure medication; the fear and stigma associated with psychiatric treatments should not prevent recommended treatment [18]. In children, the 2023 recommendations indicate the usual treatment of ADHD, ASD, anxiety and psychotic disorders, assessment of psychopathology in the context of the linguistic, cognitive and physical profile (including thyroid dysfunction and hypocalcaemia), and stress reduction with avoidance of alcohol and drugs, particularly early and chronic cannabis use [17].

7.6 Risk management and surveillance strategies

The table combines GeneReviews surveillance with the age-specific assessment checklist in the British consensus document reproduced in the Oxford Desk Reference [1, 2].

In adults, the 2023 recommendations guide recognition, assessment, surveillance and management of emerging and chronic multisystem morbidities, as well as genetic counselling and psychosocial issues in a growing adult population [18]; the 2015 guidelines already addressed neuropsychiatric, endocrine, cardiovascular, reproductive and psychosocial aspects [34]. Conditions requiring surveillance in adults include hypothyroidism, obesity, seizures, early-onset Parkinson's disease, hearing loss and dental caries [1]. Early detection of cognitive decline is a marker of psychosis risk [62]. The 2023 paediatric recommendations include measurement of PTH, calcium, magnesium, creatinine, TSH and free T4 at diagnosis and annually or every two years, measurement of calcium parameters (total or ionised calcium, PTH, magnesium and 25-hydroxyvitamin D) at least once a year and during stress, informing parents about hypocalcaemia symptoms, maintaining calcium at the lower limit of normal to reduce hypercalciuria and nephrolithiasis and, with prolonged calcium or calcitriol, annual urinary calcium and renal ultrasonography at intervals of a few years; TSH and free T4 are monitored every 1–2 years, whereas GeneReviews and the British consensus indicate annual monitoring [1, 2, 17]. In adults, regular measurement of calcium, PTH, magnesium, TSH and creatinine is recommended, with targeted calcium monitoring in the perioperative and perinatal periods, in pregnancy and in acute illness, daily vitamin D supplementation in all adults and annual assessment of thyroid function [18]. On the musculoskeletal side, the paediatric recommendations propose scoliosis screening with a scoliometer and radiography when clinically indicated (some centres do so from 6 years of age, with radiography every 2 years until skeletal maturity) and a single cervical spine radiograph at around 4 years, with atlanto-dental measurements in flexion and extension, particularly before VPI surgery [17]. They also recommend long-term cardiological follow-up of all patients with heart disease, with transition to adult congenital heart disease cardiology, periodic surveillance for arrhythmias and aortic root dilatation even in the absence of heart disease, and staged preparation for transition, with referral of all patients for follow-up in adulthood [17]; in the adult recommendations, transition is planned from puberty onwards and is organised by the paediatric team [18]. For surgery, the recommendations describe increased perioperative risk in conotruncal defects (for example, longer mechanical ventilation and hospital stay), recommend perioperative monitoring of calcium and full blood count, and advise against adenoidectomy without consulting the cleft palate team, because of the risk of causing or worsening hypernasality [17].

7.7 Management of 22q11.2 duplication

There are no dedicated international consensus recommendations. Wenger and Bartik recommend applying the deletion medical screening protocol to all patients, including those diagnosed solely because of developmental delay or ASD: cardiac, palatal, renal, endocrine, ophthalmological, hearing and developmental assessment, with care coordinated by a multidisciplinary team [14, 15]. Given the frequency of humoral immune abnormalities in a series of 216 patients, it is reasonable to include immunoglobulins and vaccine responses in patients with recurrent infections [6]. Neurodevelopmental assessment (ASD, language, behaviour) is the intervention with the greatest impact [3, 15]. The 2023 international recommendations of the 22q11.2 Society apply only to the deletion [17, 18].

7.8 Investigational therapies

GeneReviews identifies no specific clinical trials and refers readers to ClinicalTrials.gov and the EU Clinical Trials Register [1]. Research directions include population newborn screening for the deletion, whose feasibility has been demonstrated using qPCR on dried blood spots and whose rationale is early action on treatable features [11], and prevention of neural tube defects through folate supplementation, suggested by the effect of maternal folate deficiency on penetrance in Crkl-haploinsufficient mice [45]. At the time of this review, no pharmacological therapies targeting the syndrome's cognitive deficits or psychosis risk are approved. Registered neuropsychiatric drug trials in deletion have been small and mostly inconclusive or discontinued. In a placebo-controlled crossover trial of riluzole (a glutamate–GABA modulator; 32 participants with psychotic and/or cognitive symptoms, 8 weeks of placebo followed by 8 weeks of riluzole 100 mg/day in a fixed sequence), there was no significant effect on PANSS total or subscale scores, or on accuracy or reaction time in the computerised neurocognitive battery compared with placebo; improvements in executive function, social cognition and non-verbal reasoning were only relative to baseline [92]. NB-001, a non-stimulant modulator of metabotropic glutamate receptors, was tested in a randomised crossover trial with 6 weeks per period in 37 children and adolescents aged 6–17 years (NCT05290493); the primary endpoint was safety, and global improvement (CGI-I) did not differ significantly from placebo (least-squares mean 3.34 vs. 3.69; p = 0.067), according to results posted in the registry, with no peer-reviewed publication identified [93]. In the open-label phase 2 INSPIRE trial, transdermal cannabidiol (ZYN002) in 20 participants aged 4–17 years was associated after 14 weeks with a 40.6% reduction in the PARS-R anxiety scale and a 36.3% reduction in the ABC-C irritability subscale, with 17 participants completing the first period; the absence of a control group precludes attributing the effect to the drug, and the trial registry lists 12 participants with any treatment-emergent adverse event and 3 with a serious adverse event, figures described differently in the article (mild events in 35%) [94]. A metyrosine trial in velocardiofacial syndrome psychosis (NCT01127503) was terminated with 2 participants because of recruitment and design difficulties, and a risperidone trial addressing cognition (NCT04639960) was terminated with 16 participants because of recruitment and funding [95, 96]. A randomised trial of sertraline versus placebo for anxiety in children and adolescents with neurodevelopmental disorders, including deletion, is ongoing (NCT06081348; 130 planned participants; endpoint: parent-report SCARED at 16 weeks) [97].

7.9 Pivotal trials and limitations of interpretation

These data do not permit ranking of interventions or direct extrapolation to 22q11.2 deletion. RETHYMIC® was evaluated without a randomised control group, against a historical cohort, in a population in which only 38% had the deletion; PaTHway included adults with chronic hypoparathyroidism of various causes, not specifically associated with deletion, and its composite endpoint measures independence from conventional therapy rather than reductions in seizures, nephrocalcinosis or mortality; the eGFR gain at 2 years comes from a post hoc analysis of the open-label extension. Neuropsychiatric trials are small, short, sometimes uncontrolled and have primary safety endpoints; improvement relative to baseline in an open-label trial or a phase without a concurrent comparison does not establish efficacy, and terminated or negative trials (riluzole, NB-001, metyrosine, risperidone) form part of the evidence. Response percentages in the clozapine systematic review come from case reports and series, rather than trials [90].

7.10 Evidence hierarchy, regulatory status and off-label use

The evidence presented here distinguishes peer-reviewed publications (trials, cohorts and guidelines), trial registry results without publication, sponsor press releases and regulatory decisions. A positive opinion from the Committee for Medicinal Products for Human Use (CHMP) is not an authorisation, and European Commission or FDA authorisation does not guarantee marketing, reimbursement or access in each country; no specific decisions concerning the medicines in the table were identified for Portugal (INFARMED) or Brazil (ANVISA/CONITEC) in the consulted sources.

Off-label use is defined by each jurisdiction's label, age and approved indication, rather than evidence quality. Palopegteriparatide in an adolescent girl with 22q11.2DS and hypoparathyroidism is off-label in the US and EU, even though the pathophysiology is shared with adults; a dose of 60 µg/day is within the European SmPC but exceeds the US label maximum. Clozapine in an adolescent girl with treatment-resistant schizophrenia is off-label for paediatric use under the US label, even when efficacy in deletion is extrapolated from adult series. Pregnancy in a woman with deletion and hypoparathyroidism treated with palopegteriparatide is a setting for which the sponsor maintains a prospective pregnancy registry, indicating that safety data remain limited [100]. Extrapolating evidence from hypoparathyroidism of other causes, or idiopathic schizophrenia, to deletion is a reasonable clinical inference in the absence of specific studies, but should be presented as such.

7.11 French protocol (HAS PNDS): therapeutic measures and divergences from the other guidelines

The French PNDS (French National Diagnosis and Care Protocol), drafted by the Montpellier reference centre for developmental anomalies with the federation of developmental anomaly centres (FéCLAD), CEREDIH immunologists, the MAFACE facial malformation centre and the Génération 22 association, follows the 2012 HAS method and describes the reference care pathway in France; it predates the 2023 recommendations and, on several points, is more restrictive or recommends less frequent surveillance [13, 17, 18].

Heart disease and endocarditis prevention. Cardiac surgery, whether palliative or corrective, is performed in centres specialising in congenital heart disease, with postoperative follow-up often extending into adulthood; the attending physician or paediatrician is responsible for endocarditis prevention [13]. The PNDS considers prevention indicated in all patients with heart disease, but refers to the 2011 Afssaps recommendations, which no longer indicate antibiotic prophylaxis for dental care in moderate-risk heart disease and leave inclusion of immunocompromised patients in the risk category to the joint judgement of the dentist and physicians [13]. The 2023 European Society of Cardiology guideline is the current reference: general measures (twice-daily toothbrushing, professional dental review at least every six months in high-risk patients and annually in others, skin hygiene, discouraging piercings and tattoos) apply to everyone, but antibiotic prophylaxis is reserved for high-risk patients — previous endocarditis, surgical or transcatheter prosthetic valves and valve repair material, unrepaired cyanotic congenital heart disease, congenital heart disease repaired with prosthetic material for 6 months after the procedure or lifelong if a residual shunt or valvular regurgitation persists, and ventricular assist devices — undergoing at-risk dental procedures (extractions, oral surgery, gingival or periapical manipulation, including scaling and endodontic treatment) [101]. The regimen is a single dose 30–60 minutes before the procedure: amoxicillin 2 g orally in adults and 50 mg/kg orally in children (maximum 2 g), or ampicillin at the same dose intramuscularly or intravenously, or cefazolin or ceftriaxone 1 g intramuscularly or intravenously (children 50 mg/kg, maximum 1 g); in penicillin allergy, cefalexin 2 g orally (children 50 mg/kg, maximum 2 g) or cefazolin or ceftriaxone at the same doses, cephalosporins being avoided after anaphylaxis, angioedema or urticaria with penicillin or ampicillin, or azithromycin or clarithromycin 500 mg (children 15 mg/kg, maximum 500 mg); clindamycin is no longer recommended because of the risk of Clostridioides difficile infection [101]. Many patients with the deletion operated on for truncus arteriosus or pulmonary atresia have conduits or prosthetic valves and therefore belong to the high-risk group [13, 101].

Otorhinolaryngology, palate and language. Otitis media with effusion is sought at every visit and treated to prevent hearing loss; recurrent otitis that does not resolve warrants tympanostomy tubes, and swimming pools are permitted with earplugs [13]. Recurrent rhinosinusitis is treated in early childhood with nasal irrigation one to several times a day [13]. In cleft lip and palate, the usual schedule in France is veloplasty at around 6 months, combined with cheilorhinoplasty when there is a cleft lip, with closure of the bony cleft between 12 and 18 months; surgery for velopharyngeal insufficiency (velopharyngoplasty, usually pharyngoplasty) is decided on the basis of anatomy, nasal regurgitation and progress in speech and language therapy, which always precedes and prepares for it [13]. Otological interventions include tympanostomy tubes, sometimes tympanoplasty, conventional hearing aids and, more rarely, non-conventional ones [13]. Speech and language therapy starts early: in the newborn with impaired swallowing (orofacial praxis, sucking and swallowing) and, for language, before 1 year with parental guidance, from 6 months; it works with the otorhinolaryngology, plastic surgery and maxillofacial teams [13].

Adenoidectomy and tonsillectomy. The PNDS considers them contraindicated a priori, because they worsen phonation and language rehabilitation, and reserves the decision to a specialised paediatric otorhinolaryngology team after multidisciplinary consultation within the reference or competence centres [13]; the 2023 paediatric recommendations express the same concern in less absolute terms, advising against adenoidectomy without consulting the cleft palate team [17].

Hypocalcaemia. The PNDS indicates calcium supplementation with alfacalcidol (1-alpha-hydroxycolecalciferol) and close calcium–phosphate monitoring, with a serum calcium target at the lower limit of normal (approximately 2.00 mmol/L) and dose adjustment according to urinary calcium, which should remain below 0.1 mmol/kg/day (approximately 4 mg/kg/day), to prevent lithiasis and nephrocalcinosis; in hypocalcaemic seizures, intravenous calcium is given with great caution, and prescription and follow-up are the responsibility of endocrinology [13]. The PNDS does not specify doses; the reference doses and the comparison with the labels are given in 7.2 [80–82]. Recombinant PTH was then a future prospect; the current regulatory status of palopegteriparatide is described in 7.2 [13, 84, 85].

Immunity and vaccination. The decision tree appended to the PNDS (CEREDIH data, adapted from C. Picard) starts from a full blood count and T-cell phenotyping (CD3, CD4, CD8): without T lymphocytes, the patient is transferred to a paediatric immunology unit, with an indication for haematopoietic stem cell or thymus transplantation; with normal T lymphocytes, investigations end; with reduced T lymphocytes, naïve and memory T-cell populations and T-cell proliferation are studied. If these are reduced, a paediatric immunology opinion is sought, antibiotic prophylaxis is instituted and live vaccines (BCG and MMR) are contraindicated; in both cases (reduced or normal naïve cells), reassessment takes place at 1 year of age (phenotyping, T-cell proliferation, immunoglobulin measurement and post-vaccination serology), with investigations stopping if the reassessment is normal and a new immunology opinion if it is abnormal [13]. Live attenuated vaccines may be given with CD4 above 400/µL; they are contraindicated in severe deficiency and before 1 year if immune testing has not been performed, and the others follow the usual schedule; in the appended schedule, inactivated vaccines (diphtheria, tetanus, poliomyelitis, pertussis, Haemophilus influenzae b, pneumococcus, meningococcus C, papillomavirus and hepatitis B) are recommended in all cases, whereas MMR and BCG are decided at 12 months according to immune tests and after specialist advice, never at birth in the case of BCG [13]. This schedule is the French 2015 schedule and has been superseded: since 1 January 2025, the tetravalent vaccine against meningococci A, C, W and Y (at 6 and 12 months) replaces the meningococcus C vaccine, and the meningococcus B vaccine (at 3, 5 and 12 months) has become mandatory, both inactivated and without a specific immune restriction [102]. The rotavirus vaccine, recommended again in France since 2022 for all infants (two doses at 2 and 3 months with the monovalent vaccine, three at 2, 3 and 4 months with the pentavalent vaccine), is a live attenuated oral vaccine given before the 12-month immune reassessment planned by the PNDS [103]; the SmPC contraindicates it in severe combined immunodeficiency, so in a child with the deletion the decision rests on T-cell phenotyping obtained before the first dose [104]. Antibiotic prophylaxis is reserved for recurrent infections, particularly respiratory, with significant immune deficiency; intravenous immunoglobulin is exceptional and prescribed by a reference or competence centre, and thymus transplantation is performed in a specialised centre [13].

Endocrinology and common paediatric problems. Hypothyroidism is treated with levothyroxine and hyperthyroidism with antithyroid drugs; growth hormone is reserved for proven deficiency, and short stature without deficiency is assessed by paediatric endocrinology [13]. For gastro-oesophageal reflux, the PNDS escalates through lifestyle and dietary measures, anti-regurgitation milk and thickeners, H2 antagonists and proton pump inhibitors, nasogastric tube feeding and, in severe reflux with tracheobronchial aspiration, Nissen fundoplication; constipation is treated first with dietary measures, after excluding hypothyroidism and Hirschsprung's disease [13]. Dental care includes hygiene, oral or topical fluoride and orthodontics, with paediatric dental follow-up from eruption of the primary teeth if enamel dysplasia is present; refractive errors and strabismus are corrected with glasses and orthoptics, and deformities and scoliosis with physiotherapy, orthoses or surgery [13].

ADHD. The PNDS indicates treatment when there is an impact on school or social life, first with psychological, educational, social and family measures and support from a school assistant, and only then with methylphenidate (Ritaline®, Ritaline LP®, Concerta LP®, Quasym LP® in France) from 6 years of age, with an initial dose of 0.3 mg/kg, initial prescription and annual renewal by hospital specialists in neurology, psychiatry or paediatrics, and a mandatory cardiology opinion before any prescription [13]. By comparison, the Portuguese SmPC for immediate-release methylphenidate (Rubifen®) starts with 5 mg once or twice daily, with weekly increments of 5 to 10 mg up to a maximum of 60 mg/day, should not be used below 6 years and requires baseline cardiovascular assessment (blood pressure, heart rate, history) and monitoring of growth and of psychiatric and cardiovascular status [105]. The weight-based initial dose of the PNDS corresponds, in a 20 kg child, to 6 mg/day, within the initial range of the SmPC; the cardiology opinion, which the SmPC reserves for abnormalities on baseline assessment, is justified in the deletion by the frequency of congenital heart disease [13, 105].

Sleep. The PNDS proposes low-dose immediate-release melatonin (starting at 1 mg, increasing to 2–3 mg in steps) 30 minutes before bedtime, with a possible second dose if the child has not fallen asleep by midnight or wakes repeatedly, and mentions the 2 mg prolonged-release formulation (Circadin®), limited by cost and lack of reimbursement; it also treats sleep apnoea [13]. By comparison, the paediatric prolonged-release melatonin authorised in the European Union (Slenyto®, 1 mg and 5 mg tablets) is indicated for insomnia from 2 to 18 years with ASD and/or neurogenetic disorders with abnormal daytime melatonin secretion or nocturnal awakenings, and from 6 to 17 years with ADHD, when sleep hygiene measures are insufficient; it is taken once daily, 0.5–1 hour before bedtime, with or after food. In ASD and neurogenetic disorders, it starts at 2 mg, rises to 5 mg if the response is inadequate and has a maximum of 10 mg; in ADHD, it starts at 1–2 mg, is adjusted up to 5 mg and, if clinically necessary, up to 10 mg, with discontinuation attempts at least annually; in both, the effect is assessed after approximately 3 months and the patient is reassessed at least every six months [106]. The 2 mg prolonged-release formulation (Circadin®) is the adult formulation [13]. In the deletion, paediatric use falls within these indications when ASD, ADHD or nocturnal awakenings with insufficient sleep hygiene coexist; the second night-time dose proposed by the PNDS does not appear in the SmPC, which provides for a single daily dose [13, 106].

Behaviour, psychiatry and neurology. Psychotropic drugs are combined with a global approach and decided through multidisciplinary consultation [13]. For behavioural disorders, the PNDS cites risperidone (Risperdal®) above 5 years of age, with the French indication at the time for aggression towards others, self-injury, major impulsivity and severe stereotypies in autistic syndromes: below 50 kg, 0.25 mg once daily, with increases of 0.25 mg no more often than every other day, usual optimal dose of 0.5 mg/day (0.25–0.75 mg/day), and most frequent adverse effects of parkinsonism, weight gain, sedation, headache and insomnia [13]. The harmonised European SmPC for Risperdal® (Article 30 referral procedure, also applicable to the Portuguese product) retains these doses below 50 kg and adds, from 50 kg, initiation at 0.5 mg/day, increases of 0.5 mg no more often than every other day and usual optimal dose of 1 mg/day (0.5–1.5 mg/day), but frames the paediatric indication as short-term symptomatic treatment (up to 6 weeks) of persistent aggression in conduct disorder, from 5 to 18 years, with below-average intellectual functioning, as part of a psychosocial and educational programme and prescribed by a specialist in child and adolescent neurology or psychiatry or by a physician familiar with conduct disorder [107]. Psychotic disorders are treated by child and adult psychiatrists according to the standards for schizophrenia, with early screening and information for the family and patient about the increased risk of psychosis with alcohol, cannabis and other drugs; Parkinson's disease in adults is treated according to the usual standards [13].

Rehabilitation, education and family. Physiotherapy begins as soon as hypotonia is noted, often in the first year, and accelerates acquisition of motor milestones; psychomotor therapy improves gross and fine motor skills and body schema; occupational therapy is offered by early intervention services (CAMSP, early medico-social action centres) or by special education and home care services (SESSAD) [13]. Cognitive remediation uses the patient's strengths to work around difficulties and requires prior neuropsychological assessment; it also includes special education programmes, use of touch tablets, behavioural and group therapies, psychological support for the patient, parents and siblings, and regular coordination between the school, the teams and the family [13]. Therapeutic education begins when the diagnosis is disclosed, is addressed to the parents and to the adult patient, explains the medical and genetic consequences for each family member and relies on a “pivot” team that ensures continuity throughout life; contact with patient associations should be offered systematically [13].

8. Reproductive Options and Family Counselling

8.1 22q11.2 deletion

22q11.2DS is a contiguous gene deletion syndrome with autosomal dominant transmission [1]. The A–D deletion is de novo in more than 90% and inherited from a heterozygous parent in approximately 10%; other sources report 85% de novo and 15% inherited, usually from the mother, who may be undiagnosed [1–3, 10]. Nested deletions (for example, LCR22B–D) are inherited from an affected parent in ~60%, and central deletions in 40% [1, 3]. Because of variable expression, both parents should be tested using a method capable of identifying the proband's deletion; an apparently negative family history cannot be confirmed without this testing [1, 3].

If the parent is the first carrier, they may have somatic mosaicism and a mild or minimal phenotype; asymptomatic adults with mosaicism have been identified [1]. The 2023 recommendations indicate always testing the parents, to determine whether the deletion is de novo or inherited and to identify the rare parent with somatic mosaicism, and offering genetic counselling throughout life and not only at diagnosis; the parents of a child with a de novo deletion have a recurrence risk slightly above that of the general population, because of germline mosaicism, and reproductive counselling includes prenatal screening and diagnosis and preimplantation genetic testing after in vitro fertilisation [17]. The ideal time to determine risk and discuss prenatal and preimplantation testing is before pregnancy, and genetic counselling should be offered to affected or at-risk young adults, including discussion of reproductive options [1]. In Ontario population screening, samples with the deletion were associated with younger maternal age (median 25.5 vs. 32.0 years), reflecting the contribution of carrier parents with preserved fertility [11].

The French PNDS considers a genetics clinic consultation indispensable and recommends always offering parental testing, preferably before a further pregnancy, with written consent as for any genetic test; if the pregnant woman already has an affected child, referral to genetics is urgent [13]. Parental testing goes beyond counselling: a late diagnosis in a parent allows surveillance for late complications (autoimmune diseases, hypocalcaemia, thyroid dysfunction) and occult complications (renal failure due to hypoplasia) to be instituted [13]. When neither parent is a carrier, the recurrence risk of approximately 1% (germline mosaicism) justifies offering, if the couple wishes, prenatal diagnosis by chorionic villus sampling or amniocentesis, discussed at the preconception consultation; a carrier parent has a 50% risk in each pregnancy, there is no tool to predict severity and no correlation of severity between affected relatives, and the couple (or the carrier adult planning to have children) chooses between accepting the risk without prenatal diagnosis, ultrasound surveillance targeted at severe malformations, invasive prenatal diagnosis or preimplantation genetic testing [13]. In France, prenatal diagnosis and requests for termination of pregnancy for medical reasons are assessed by the multidisciplinary prenatal diagnosis centres (CPDPN), which, according to the PNDS, accept most parental requests in this situation [13].

Reproductive options include prenatal diagnosis by FISH, MLPA or microarray on chorionic villi or amniotic fluid, preimplantation genetic testing and, for those who prefer it as an alternative or complement to an invasive procedure, detailed fetal echocardiography (approximately 75% of fetuses with the deletion will have heart disease, some of which is detectable) [1, 2]. In at-risk pregnancies, high-resolution ultrasonography and echocardiography at 18–22 weeks assess the palate and other anomalies [1].

Pregnancy in a woman with the deletion requires medical monitoring of pre-existing conditions (heart disease, scoliosis, reactive airway disease), calcium, thyroid function and platelets, and immediate mental health assessment for any change in mental state or behaviour [1]. A high-risk fetus should undergo level II ultrasonography with fetal echocardiography to assess heart disease, airway, palate, swallowing and gastrointestinal anomalies (which may cause polyhydramnios), renal anomalies, clubfoot, craniosynostosis and hernias; if diagnosed prenatally, neonatal echocardiography, calcium measurement on the first day of life, feeding and palate assessment and, in collaboration with immunology, co-trimoxazole prophylaxis until immune function is known should be planned [1, 2].

Support groups include the International 22q11.2 Foundation (22q.org), Max Appeal (United Kingdom), 22Crew, Chromosome 22 Central and the European Society for Immunodeficiencies (ESID) registry [1, 2]. In Europe, 22q11 Europe brings together 14 national patient organisations [108]. The relevant European Reference Networks are ERN ITHACA (rare malformation syndromes and intellectual disability), ERN RITA (immunodeficiencies and athymia), ERN CRANIO (clefts and craniofacial anomalies), ERN GUARD-Heart (rare and complex cardiac diseases) and Endo-ERN (hypoparathyroidism) [21]. The 22q11.2 Society is the international scientific society that published the 2023 recommendations [17, 18].

In France, the PNDS organises care around the FéCLAD reference and competence centres for developmental anomalies and malformation syndromes (eight regional reference centres — Île-de-France, South-West, North, West, South-PACA, South-Languedoc-Roussillon, East and Centre-East — and competence centres in Toulon, Toulouse, Le Mans, Rouen, the Antilles and Réunion), integrated into the AnDDI-Rares health network, with support from the DéfiScience reference centres for intellectual disability, the CEREDIH reference centre for hereditary immunodeficiencies for immune deficiency, the MAFACE facial malformation centre and the Centres Ressource Autisme [13]. Coordination is the responsibility of a physician at the reference or competence centre, working with the paediatrician or family doctor, whose role in adults is to ensure follow-up, refer to the centre when necessary, ensure that surveillance follows the PNDS and monitor complications with the reference teams; the multidisciplinary team changes with age, from the CPDPN in the fetal period to psychiatry, rheumatology, neurology and internal medicine in adults [13]. The French-speaking patient associations listed are Génération 22 (France), Valentin APAC (carriers of chromosomal anomalies, France), Connect22 (Switzerland) and Relais 22 (Belgium) [13].

8.2 22q11.2 duplication

Approximately 70% of duplications are inherited, typically from an unaffected parent or one with minimal abnormalities; testing the proband's relatives is recommended [3, 67]. A carrier has a transmission risk of ~50% in each pregnancy, and recurrence risk when neither parent is a carrier is very low (~1%, due to mosaicism) [8]. Counselling is complicated by incomplete penetrance (~21.9%) and variable expressivity; there is no consensus on cascade or prenatal testing, and some laboratories do not report variants with substantially incomplete penetrance prenatally because outcomes are uncertain and they are unlikely to explain ultrasound anomalies [8, 56]. When parent and child have discordant phenotypes, a second genetic event or epigenetic or environmental variation should be considered [7, 8].

9. Special Considerations: Population Diversity and Epidemiology

9.1 Prevalence

The figure of 37.9/100,000 cited in the French PNDS differs from the current Orphanet entry (9.6/100,000, based on EUROCAT), because the latter counts only cases diagnosed in congenital anomaly registries; the PNDS range of 1:2,000–1:4,000 approaches the estimates from genetic screening [9, 11, 13]. The difference between classical estimates and universal genetic screening estimates shows that the deletion is underdiagnosed, particularly in people with mild phenotypes and in non-White populations [3, 11]. The deletion is a recurrent de novo rearrangement mediated by NAHR, so there is no founder effect.

9.2 Phenotypic diversity and diagnosis in non-European populations

In a study of 106 individuals from 11 countries, grouped by African, Asian and Latin American ancestry, phenotype varied between groups; only congenital heart disease and learning difficulties occurred in more than 50%; proportions differed significantly between populations for almost all categories except learning difficulties and ear anomalies, and, after exclusion of the African group, six additional features became independent of ethnicity [66]. Facial analysis technology, comparing 156 patients with 156 matched controls, achieved sensitivity and specificity above 96% in all populations [66]. The characteristic facial features may be absent in people of African ancestry, contributing to underdiagnosis, and LCR22 structures differ between the genomes of Black and White individuals, potentially affecting the NAHR rate [1, 36]. In Brazil, Brazil's Craniofacial Project, a collaborative network established in 2003, has conducted multicentre studies of orofacial clefts and 22q11.2 deletion and has maintained a national craniofacial anomalies database since 2006 [112]. In the US, prevalence is higher in Hispanic populations (1:3,800) [109].

9.3 Data gaps

In the consulted sources, we identified no population prevalence estimates for deletion based on universal screening in Latin America, Africa, Asia or the Middle East; this does not establish that none exist. African data are limited to congenital heart disease series (Cameroon) and multinational clinical cohorts, and Latin American data to clinical cohorts and the Brazilian handbook [10, 66, 110]. Syndrome-specific growth charts were developed in White children [1]. For duplication, birth prevalence estimates are unavailable for any region: Orphanet records only the series of 216 patients and classifies prevalence as unknown [4]. There are no data on phenotypic diversity of duplication by ancestry.

9.4 Special populations

22q11.2 deletion accounts for approximately 5% of infants with congenital heart disease (a higher proportion in interrupted aortic arch, truncus and tetralogy of Fallot), 11% of syndromic Robin sequence, a proportion of renal agenesis/dysplasia cases and fewer than 2% of schizophrenia cases, and is one of the recurrent CNVs in ASD cohorts [2, 59, 69, 113]. In myelomeningocele cohorts, the deletion was found in 6 of 715 trios [45]. Adults constitute a growing population with chronic morbidities and distinct genetic counselling and psychosocial support needs [18, 114].

10. Illustrative Clinical Case

10.1 Teaching case: prenatal diagnosis and neonatal management

Case constructed for teaching purposes from the cited recommendations; it does not represent a real patient. A 24-year-old woman in her first pregnancy undergoes an anomaly scan at 21 weeks, showing tetralogy of Fallot with a right-sided aortic arch. Fetal echocardiography confirms the finding, and amniocentesis with chromosomal microarray identifies a heterozygous 2.54 Mb deletion at 22q11.21 (LCR22A–D) [1, 2]. Targeted parental MLPA testing is normal, so a de novo deletion is presumed, with a recurrence risk of approximately 1% due to germline mosaicism [2, 3]. Delivery is planned at a centre with paediatric cardiology, and a neonatal plan is established: echocardiography, ionised calcium on the first day, feeding and palate assessment including examination for submucous cleft, flow cytometry with lymphocyte subsets, and co-trimoxazole prophylaxis pending immunological assessment, in collaboration with immunology [1, 2].

On the third day of life, the newborn has tremors and low ionised calcium with inappropriately normal PTH; this is corrected with intravenous calcium gluconate, followed by maintenance oral calcium and calcitriol [1, 78]. Flow cytometry shows moderate T-cell lymphopenia with naïve T cells present, excluding athymia; blood products for cardiac surgery are irradiated and CMV-negative [2]. Surgical correction is uneventful, with perioperative calcium monitoring. Sucking is poor and nasal regurgitation occurs; swallowing assessment shows pharyngoesophageal dysmotility, treated by modifying feeding technique and acid suppression [1]. At 12 months, the T-cell count is recovering, responses to inactivated vaccines are normal, and MMR and varicella vaccines are administered at 18 months [2, 88]. Follow-up includes speech and language therapy from the first year, palate assessment after language emerges, audiology, ophthalmology at 1–3 years, annual TSH and full blood count, cervical radiography after 4 years, and serial psychiatric and cognitive assessments from school age to identify anxiety, ADHD and cognitive decline early [1, 2, 62].

10.2 Published case report: adult presentation with a hypocalcaemic seizure

Tonelli and colleagues described a 40-year-old man with no relevant medical history, admitted following his first generalised tonic–clonic seizure, without a personal history of hypocalcaemia or seizures [57]. Examination showed short stature, hypertelorism, a prominent forehead and a nasal voice. Total calcium was 5.2 mg/dL and ionised calcium 0.69 mmol/L, with intact PTH <2.5 pg/mL (normal 14–72) and urinary calcium of 88 mg/24 h; the electrocardiogram showed a prolonged corrected QT interval, and brain computed tomography showed basal ganglia calcification, with normal echocardiography, abdominal ultrasonography and electroencephalography. Subtle physical abnormalities accompanying “idiopathic” hypoparathyroidism prompted FISH, which demonstrated 22q11.2 microdeletion. The patient responded to calcium citrate and calcitriol [57]. The open-access article (PMC2222674) includes two figures: Figure 1 shows brain computed tomography sections with basal ganglia and periventricular calcifications (https://pmc.ncbi.nlm.nih.gov/articles/PMC2222674/figure/F1/), and Figure 2 shows FISH with the TUPLE 1 (HIRA) probe, in which absence of the orange signal on one homologue indicates the deletion, with the ARSA probe as a control (https://pmc.ncbi.nlm.nih.gov/articles/PMC2222674/figure/F2/) [57]. The described treatment is that of the report and does not replace dose individualisation according to serum and urinary calcium. The case illustrates three points: hypocalcaemic seizures may be the first manifestation in adults; hypoparathyroidism without an apparent cause in an adult warrants 22q11.2 testing; and a nasal voice is a sign that persists throughout life [1, 57, 58].

10.3 Published case report: 22q11.2 duplication

Vyas, Constantino and Baldridge described a 13-year-old boy adopted early in life, with mild developmental delay and severe, chronic antisocial behaviour beginning in early childhood, with callous–unemotional traits, carrying a 737 kb microduplication in the LCR22B–D interval [68]. The authors reviewed the literature and found that, among reports of psychiatric symptoms in duplications of this region, 19% included aggression, but none had previously described callous–unemotional traits. The case demonstrates the difficulty of attributing causality to a duplication with incomplete penetrance, particularly when family history is unknown because of adoption and parental testing is not possible [8, 68].

11. Prognosis and Long-Term Follow-Up

Prognosis depends mainly on the severity of heart disease and, in survivors, the neuropsychiatric burden [3, 10]. Reported overall mortality is approximately 4%, mainly due to heart disease, with a mean age at death of 5 months; in Ryan's European series, 8% died, most within the first 6 months and all but one from severe heart disease [2, 3]. Heart disease accounts for ~87% of deaths in children [1].

In a prospective case–control study of 309 adults and 1,014 unaffected parents and siblings, deletion (hazard ratio 8.86; 95% CI 2.87–27.37) and major congenital heart disease (hazard ratio 5.03; 95% CI 2.27–11.17), but neither intellectual disability nor psychotic illness, were independent predictors of mortality; there were 31 deaths, at a median age of 46.4 years (18.1–68.6), and the probability of survival to 45 years was ~72% with major heart disease and 95% without it [114]. Smith reports survival at 40 and 50 years of 82% and 63% with major heart disease, versus 98% and 85% without heart disease, and that 23% outlive both parents [3]. Sudden death and heart failure are the most frequent causes of death in adults, even without congenital heart disease [1].

Immunity improves in most patients by 2 years; in athymia, survival after thymus implantation is 76% at 2 years and 94% in the long term among those surviving the first year [2, 19]. Hypocalcaemia tends to normalise but recurs under physiological stress and affects 80% of adults at some point [1, 58]. Cognitively, there is a mild mean decline in IQ with age, more pronounced in those developing psychosis, and schizophrenia emerges mainly in late adolescence and early adulthood, in ~25% [1, 3, 62]. Early-onset Parkinson's disease (5.9%) and obesity (up to 35%) contribute to adult morbidity [1]. Follow-up should be lifelong, continuing in adulthood according to the 2023 adult recommendations [18].

The French PNDS sets out an age-based follow-up schedule, more detailed than that of the other guidelines in the first 5 years and less frequent for laboratory surveillance at school age and in adulthood; it acknowledges that there is no single international consensus, particularly regarding biological surveillance, and leaves the decision on investigations to the reference centre physician [13]. The paediatric or family doctor visit is at least every six months until 3 years and then annual, more frequent if complications occur, and accompanies the compulsory child health examinations in France (nine in the first year) [13]. The table combines the PNDS schedule with the intervals of the 2023 recommendations, GeneReviews and the British consensus (see also 7.6 and the table of divergences in 7.11).

In duplication, prognosis is generally more favourable and depends on the congenital anomalies present, ASD and learning difficulties; there are no studies of mortality or adult outcomes, constituting a data gap [3, 15].

12. Summary and Final Considerations

22q11.2 deletion syndrome results from non-allelic homologous recombination between LCR22 repeats, most frequently between A and D, and unifies DiGeorge, velocardiofacial, conotruncal anomaly face and Cayler syndromes, and part of autosomal dominant Opitz G/BBB syndrome, under a single aetiology [1, 3]. With a birth prevalence of approximately 1:2,000 when measured by universal genetic screening, it is the most frequent microdeletion and an underdiagnosed condition, particularly in people of African ancestry and those with a mild phenotype [11, 66].

TBX1 haploinsufficiency explains most malformations derived from the pharyngeal arches — conotruncal heart disease, palatal anomalies, thymic and parathyroid hypoplasia — whereas the neuropsychiatric phenotype depends on the combined loss of several genes and modifiers; hemizygosity may also unmask recessive diseases such as CEDNIK, Bernard–Soulier syndrome, TANGO2 deficiency or D,L-2-hydroxyglutaric aciduria [1, 32, 48]. Chromosomal microarray is the first-line test; FISH misses deletions that do not encompass LCR22A–B [1].

Management is multidisciplinary and lifelong: cardiac and palatal surgery, calcium control during all periods of physiological stress, immunological assessment before live vaccines and irradiated blood products, thymic tissue implantation (RETHYMIC®) for athymia, early developmental intervention, and psychiatric and cognitive surveillance, because cognitive decline precedes psychosis and schizophrenia affects approximately one-quarter of adults [17–19, 62]. The French PNDS adds an age-based follow-up schedule and the organisation of care in developmental anomaly centres, but predates the 2023 recommendations and diverges from them in thyroid and immune surveillance, in the criteria for live vaccines, in the more absolute contraindication of adenoidectomy and in prenatal cfDNA screening [13, 17]. Transmission risk is 50% for the offspring of any carrier, and parental testing is essential because of intrafamilial variability [1]. Recent developments include the ACMG conditional recommendation to offer prenatal cfDNA screening for the deletion, differences between the US and European palopegteriparatide labels, with an adolescent trial initiated in 2026, and small neuropsychiatric trials without demonstrated efficacy against placebo [71, 84, 85, 92].

22q11.2 duplication syndrome is the reciprocal rearrangement, frequently inherited from a minimally affected or unaffected parent, with penetrance of ~22%, increased ASD risk, a milder but clinically relevant medical phenotype — including heart disease and humoral immune abnormalities — and a protective effect against schizophrenia; application of the deletion screening protocol is recommended [6, 8, 15, 16].

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