22q11.2 deletion syndrome

Robin Godshalk MS MHA

Developmental Malformations

Updated 03.22.2024
Released 01.18.1999
Expires For CME 03.22.2027

22q11.2 deletion syndrome

Author: Robin Godshalk MS MHA

See Contributor Disclosures

Editor: Ganeshwaran H Mochida MD

22q11.2 deletion syndrome

In This Article

Quick Link

Introduction

Overview

DiGeorge and velocardiofacial syndrome (22q11.2 deletion syndrome) is the most common microdeletion disorder in humans and, hence, one of the most common multiple malformation syndromes, with an estimated prevalence of 1 in 2000 to 1 in 4000 (35). It is characterized by craniofacial anomalies, conotruncal heart disease, thymic aplasia and hypoplasia, hypocalcemia, and psychiatric illness. In this article, the author reviews the history, clinical features, and genetic basis of this common disorder.

Key points

	• DiGeorge and velocardiofacial syndrome (22q11.2 deletion syndrome) is the most common microdeletion disorder in humans and, hence, one of the most common multiple malformation syndromes, with an estimated prevalence of 1 in 2000 to 4000.
	• It is characterized by craniofacial anomalies, conotruncal heart disease, thymic aplasia or hypoplasia, hypocalcemia, and psychiatric illness.

Historical note and terminology

In 1968, DiGeorge described congenital absence of the thymus and parathyroid glands in four infants with recurrent infections and hypocalcemia (43). In 1979, Conley and co-workers broadened the phenotype of DiGeorge syndrome to include conotruncal (outflow tract) defects of the heart as well as characteristic facial features, including a bulbous nose, dysplastic ears, and micrognathia (33).

Strong reported a familial syndrome of the right-sided aortic arch, facial dysmorphism, and cognitive and psychiatric dysfunction in 1968 (176). Ten years later, Shprintzen and colleagues profiled a series of 12 patients with a combination of cleft palate, congenital heart disease, unique facial features (long face with malar flattening, small palpebral fissures, long nose with bulbous tip, dysplastic ears, and micrognathia), learning disabilities, and short stature and called the condition velocardiofacial syndrome (165). Conotruncal anomaly face syndrome, originally described in the Japanese literature (98), comprises clinical features of both DiGeorge syndrome and velocardiofacial syndrome.

The initial evidence for involvement of genes on chromosome 22 in the etiology of DiGeorge syndrome included a family with a chromosome 2;22 translocation. Family members with an unbalanced rearrangement that resulted in monosomy 22q11.2 had clinical features of DiGeorge syndrome (38). Subsequently, cytogenetically visible interstitial deletions of 22q11 were detected in approximately 25% of patients with DiGeorge syndrome (158). Southern blotting and DNA dosage analysis revealed microdeletions within 22q11 in DiGeorge syndrome patients (56). The finding of several patients with velocardiofacial syndrome and a deletion 22q11.2 using fluorescence in-situ hybridization suggested that DiGeorge syndrome and velocardiofacial syndrome were related disorders (159). It is evident that the overlapping features of DiGeorge syndrome and velocardiofacial syndrome presumably result from haploinsufficiency for the same genes (95).

With the advent of molecular genetics, DiGeorge syndrome, velocardiofacial syndrome, and conotruncal anomaly face syndrome were found to have a similar 22q11.2 microdeletion as the basis for their overlapping clinical features (158; 159; 24). This 22q11.2 deletion syndrome is now recognized as one of the most common multiple malformation syndromes. The acronym “CATCH22” (cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, and hypocalcemia) was conceived; however, because this term may be construed as insensitive, it is not universally accepted (212; 217). The compound term “DiGeorge and velocardiofacial syndrome” calls attention to the phenotypic spectrum using historically familiar names (106) and is especially applicable when phenotypic features manifest in the absence of the chromosomal deletion (126).

Clinical manifestations

Presentation and course

Broad inter- and intrafamilial variability exists in the clinical spectrum of DiGeorge and velocardiofacial syndrome (81). The phenotype has expanded considerably within the last several years and includes over 150 associated findings. The following are the major clinical manifestations:

Audiologic findings. Hearing impairment (conductive, sensorineural, or mixed hearing loss) is present in 40% to 60% of patients and seems to be due to cochlear damage (45; 125; 195).

Cardiovascular findings. Congenital heart disease (conotruncal defects) is present in approximately 68% of individuals to 85% of individuals with DiGeorge and velocardiofacial syndrome (221; 106). Indeed, the presence of conotruncal defects, especially coupled with psychiatric disorders, is a compelling reason to pursue cytogenetic analysis, even in adults (202). The most common anomalies include ventricular septal defect, tetralogy of Fallot, and aortic arch anomalies--for example, interrupted aortic arch and right-sided aortic arch (221; 115; 154; 143). Anomalies of the internal carotid arteries are also reported (64). Non-compaction of the left ventricular myocardium has been reported in this condition (145; 44), but the association is not understood and could be coincidental (172). Vascular anomalies may be encountered in the cervical region (eg, medial deviation of the internal carotid artery) (175).

Craniofacial findings. Microcephaly is present in approximately 40% of individuals (64), and craniosynostosis has been recognized in a small subset of patients (02). Characteristic facial features include a long face with malar flattening, short palpebral fissures, small dysplastic ears, prominent nose with broad nasal root, bulbous tip, and deficiency of the nasal alae, and micrognathia. Dental anomalies include enamel hypoplasia, hypodontia, aberrant tooth shape, and delayed tooth eruption (99). The occurrence of cleft palate ranges from 33% (115) to 98% (64). Discrepancies between reported series probably reflect ascertainment bias with higher frequencies of cleft palate in those series originating from craniofacial clinics. The majority of affected individuals, with or without overt cleft palate, typically have hypernasal speech (the result of velopharyngeal insufficiency) complicated by upper airway asymmetry, platybasia, muscle hypotonia, adenoid hypoplasia, and other neuroanatomical abnormalities (211). Velopharyngeal insufficiency may also predispose to otitis media and conductive hearing loss. Hearing loss may also be associated with malformations of the middle or inner ear, identifiable by CT or MR imaging (197). Velopharyngeal insufficiency and compromised nasal airway patency may impact olfaction as well (169). Others have also noted abnormalities in olfaction, which are not related to age or sex (129). Anterior glottic webs are found in a minority of individuals with DiGeorge and velocardiofacial syndrome (128). Speech delay, coupled with learning disability, hearing loss, and dysmorphic facies, is suggestive of the condition and indicates further workup (199).

Endocrinologic findings. Hypocalcemia is seen in 20% to 63% of patients, typically presenting between birth and 3 months of age (64; 115; 106). Approximately 10% of these infants present with hypocalcemic-related seizures (212), and Chvostek and Trousseau signs may not be present. Most patients have resolution of hypocalcemia by 1 year of age; however, recurrence of hypocalcemia in later childhood or adulthood, secondary to transient congenital hypoparathyroidism, is reported (74; 181). Hypothyroidism, autoimmune hyperthyroidism, and growth hormone deficiency may be seen in these individuals (64; 210; 161; 189). In fact, thyroid disease (hyper- or hypothyroidism) has been diagnosed in nearly 10% of patients in one study (166). Hypercalcemia in early childhood has been reported in a patient with a de novo mutation in AP2S1 (186).

Genitourinary findings. Renal anomalies are present in up to 40% of individuals and include absent, dysplastic, or multicystic kidneys, obstructive abnormalities, duplicated kidney and collecting system, and vesicoureteral reflux (42; 154; 193). Utero-vaginal aplasia (Mayer-Rokitansky-Kuster-Hauser syndrome) has been reported in a few patients (131). Cryptorchidism, hypospadias, and imperforate anus are occasionally present (64; 154; 216).

Gastrointestinal findings. Feeding difficulties are present in approximately one-third of infants, often necessitating gastrostomy tube or nasogastric tube placement (125). Esophageal abnormalities, Hirschsprung disease, and anteriorly placed anus are less common (51).

Immunologic findings. Defects in T-cell production and function (secondary to thymic aplasia or hypoplasia) are present in 25% to 75% of patients (154; 177). Infections, thus, pose a substantially increased risk over the general population and may be life-threatening. Secondary humoral deficiencies can also occur, resulting in a form of variable combined immunodeficiency (187). Some patients with severe combined immunodeficiency (SCID) are subsequently found to have 22q11 deletion syndrome (15). In addition, autoimmunity is not uncommon (61). Vitamin D supplementation may help prevent the development of autoimmune or proinflammatory disease (109). Juvenile rheumatoid arthritis-like polyarthritis is reported in individuals with DiGeorge and velocardiofacial syndrome (178). Idiopathic thrombocytopenic purpura is described in some individuals (112).

Musculoskeletal findings. Short stature is present in approximately one-third of individuals (64). Cervical spine abnormalities (eg, open or cleft vertebral arch, platybasia, fused vertebrae) are relatively common, and so precautions should be taken during medical treatments and even during the pursuit of ordinary life functions (80; 175). In one review, vertebral arch anomalies were recognized in some 60% of patients but were not associated with spinal cord encroachment or impingement (100). Other anomalies of the skeletal system include Sprengel anomaly, scoliosis, and limb abnormalities, most commonly talipes equinovarus, polydactyly, and syndactyly (154; 152). Of these, scoliosis has been observed in nearly one half of patients (82). Approximately 60% of individuals have long, slender fingers (64). Inguinal and umbilical hernias are also common.

Neurologic findings. Seizures were reported in approximately 21% of individuals in one large series (154). The majority of seizures are associated with hypocalcemia, although febrile seizures and true epilepsy must also be considered (49). In the latter instance, cognitive development, psychology, and motor impairment are recognized associations. In adult patients, the prevalence of epilepsy and acute symptomatic seizures is more likely due to exposure to antipsychotic and antidepressant medication (213). One case of both hypocalcemia-induced seizure and epilepsy associated with spina bifida has been reported (97). Hypotonia in infancy and early childhood is present in most patients, resulting in delayed motor milestones. Movement disorders may occur secondary to endocrine diseases or musculoskeletal anomalies; patients may also be susceptible to early-onset Parkinson disease (21; 136; 147). Motor signs include bradykinesia, rigidity, and rest tremors, which together are apparent in almost one-half of patients (22). These signs tend to increase with age and are likely caused by a number of factors, one of which may be calcification of the basal ganglia, itself an effect of the calcium derangements common to the syndrome (22). In one study, the mean age of onset of Parkinson disease in patients with 22q11.2 deletion syndrome was 39 to 40 years; diagnosis tended to be delayed if patients carried a previous diagnosis of psychosis, seizure disorder, or mood disorder or anxiety (20). In a study of younger patients (median age 12.7 years), dystonia occurred in isolated fashion or with upper limb involvement (36). Asymmetrical facies and facial nerve palsies are described (154). Cognitive impairment is common, with mean verbal IQ scores in the borderline range of mental deficiency in both preschool and school-aged children (65). More severe deficits are noted in receptive language than expressive language (62). Verbal IQ scores are generally higher than performance IQ scores (179), consistent with a nonverbal learning disability. A specific cognitive profile with impairments in visuospatial, arithmetical, and executive tasks is noted (222). Problems in social-emotional functioning and attention and concentration are common.

Ocular findings. Blood-vessel anomalies (such as tortuous retinal vessels), colobomas, posterior embryotoxon, and strabismus may be associated with DiGeorge and velocardiofacial syndrome (64; 125). Additional findings include abnormalities of the orbits, eyelids, or eyes (hooding, narrow palpebral fissures, narrow or widened interorbital space, sparse and thin eyebrows and eyelashes, blepharitis, distichiasis), posterior embryotoxon, and tortuous retinal vessels; refractive errors, iris remnants, and strabismus are recognized as well (63).

Psychiatric findings. Individuals with DiGeorge and velocardiofacial syndrome are at risk of developing a range of psychiatric illnesses, most often appearing late in adolescence or early adulthood (64; 151; 91; 83). This risk has been estimated at 25 times that of the general population (164). These conditions frequently include pronounced separation anxiety and night terrors in childhood and attention deficit hyperactivity disorder, wide mood swings, and obsessive-compulsive disorder in adolescence. Altered development of early auditory processing is a marker for the later appearance of schizophrenia (26). Preadolescent and young adolescent children studied longitudinally show slowed growth in attention regulation and subclinical symptoms of schizophrenia; lower academic achievement and neurocognition, with increased social and behavioral difficulties, are reported (83). Social cognitive training has proven effective in a small group of adolescents (162). Some suggest that the predominantly affective symptoms seen in early childhood and adolescence may evolve into schizophrenia or schizoaffective disorder in adulthood (132). The deletion carries the third highest recognized risk for schizophrenia, which may develop in 20% to 25% of patients (150; 144; 31). In addition to the presence of the deletion, a wide range of polygenic and other factors may elevate the risk of developing psychosis. These include neuropsychological deficits, symptoms of depression, premature birth, and bullying (191; 124; 148). The diagnosis of Parkinson disease may be overlooked if signs are interpreted as a side effect of antipsychotic medication (223).

Catatonia is recognized, especially in patients with psychiatric symptoms that are refractory to treatment (55; 25). Interictal schizophrenia-like psychosis has been reported in an adult who had experienced childhood-onset epilepsy (184). In addition, reports describe a spectrum of bipolar disorders, including bipolar I, bipolar II (ultracyclers), cyclothymic, and schizoaffective (manic) disorders in these individuals with onset in late childhood or early adolescence (mean age of onset is 12 years) (141). Chronic mania has been reported (149), but it is not clear if behavior remains stable during the patient’s lifetime (06). Autism spectrum disorders are present in about 18% to 50% of children with 22q11.2 deletion syndrome (204; 140). The severity of behavioral and psychiatric disorders is such that a majority of caregivers believe they are the most challenging aspect of this disorder (90).

Prognosis and complications

Prognosis in the neonatal period usually depends on the severity of the cardiac malformation, if present, and immune function. Cardiac surgery may be complicated by depressed immune status, neonatal hypocalcemia, pulmonary vascular reactivity and increased airway bleeding, and a number of structural airway anomalies, including tracheomalacia, bronchomalacia, bronchospasm, and malpositioned bronchus. Cardiac transplantation has been employed in patients with severe cardiac anomalies. In one series, median age at transplant was 5 years; median survival posttransplant was 5.4 years, with no differences observed in the incidence of rejection, infection, or survival between patients with or without the deletion (215). Malformations of the larynx may include laryngeal (glottic) web or cleft, subglottic stenosis, laryngeal paralysis, vocal nodule, and laryngomalacia (28; 111), and they may require surgery in the majority of cases (88). Not surprisingly, hospital stays in general are longer and require more resources (134). Most individuals will have some degree of developmental delay and learning disabilities (64); however, a great degree of variability exists between and within families (115; 106). Obesity with hyperphagia in a small subset of patients may have a psychiatric basis (16). Intellectual development can be moderately, severely, or profoundly affected (53). Children are challenged by cognitive, social, and emotional issues, but these can be counterbalanced by strengths such as kindness, humor, persistence, and enthusiasm; in quality-of-life testing, boys score significantly lower than girls (116). These attributes may stem from the observation that patients’ verbal skills outweigh performance IQ and visuospatial memory (59). Such deficits in spatial and temporal processing, whereby individuals cannot remember the positions of objects, are complex and influence the performance of patients’ working- or short-term memory (214; 11). Disruption in the neural circuitry critical to working memory may be suggestive of a psychotic disorder (130). Patients have difficulty focusing, planning, and executing specific acts (59). Depressive, defiant, and anxiety disorders may be predictive of later psychosis (07). Psychosis has also been correlated with progressive intellectual decline (54). Approximately 10% to 30% of individuals will develop psychiatric illness ranging from mild depression to frank psychosis (64; 151). In one study, diffusion tensor MRI identified white matter abnormalities, with apparent lower axonal integrity, in these patients (13). In another study, the technique demonstrated disruption of axonal coherence in the right inferior fronto-occipital fasciculus—a finding thought to have prognostic implications for cognition and psychosis (137).

Cognitive and behavioral issues play a very significant role in determining quality of life (118). The precise nature of the cytogenetic abnormality may also have a bearing on prognosis. One woman with apparent “genetic dosage compensation,” ie, deletion of one copy of 22q11.2 and reciprocal duplication of the other copy, was phenotypically normal (03). Early-onset Parkinson disease is an indication for genetic workup (147).

In one large study (n=434), the risk for substance abuse in later life was reduced for patients with the deletion (201). Adults are at risk for sudden death. Mechanisms are probably multiple and may include fatal arrhythmia. Again, mechanisms are unclear; in a study of five patients, for example, sympathetic activity was normal (198). Life expectancy is reduced for patients compared to unaffected family members. In a study of 309 patients, the median age at death was 46.4 years (192). The presence of congenital heart disease plays an important role in the course; the probability of surviving to age 45 is 72% for those with heart defects and 95% for those without.

Clinical vignette

A 15-year-old boy with mild mental retardation and unusual facial features began to experience behavioral changes, which were first interpreted as isolation and depression. He soon developed auditory and visual hallucinations as well as delusions. His past medical history is significant for "failure to thrive" during infancy due to difficulty breastfeeding and recurrent nasal regurgitation. Developmental milestones were delayed; he began to walk at 17 months and first spoke single words around 18 months of age. He had recurrent otitis media with persistent conductive hearing loss and had tympanostomy tubes placed at 18 months of age. An inguinal hernia was repaired at 4 years of age. A neurodevelopmental evaluation at 9 years of age noted hypernasal speech and estimated cognitive abilities in the borderline to mild range of mental deficiency.

He was hospitalized and evaluated by psychiatry and neurology services. He was noted to have unique facial features, which included a relatively long face with malar flattening, long nose with a bulbous nasal tip, short palpebral fissures, small ears with thickened helices, long slender fingers, flat affect, tremor, and a slow, awkward gait. Repeat neuropsychological testing revealed a 30-point decline in his full-scale IQ. EEG and head CT scan were normal. A fluorescence in situ hybridization test for DiGeorge and velocardiofacial syndrome showed a 22q11.2 deletion. Echocardiogram and renal ultrasound were normal. Parental fluorescence in-situ hybridization studies were normal.

Biological basis

Etiology and pathogenesis

Approximately 76% of individuals to 90% of individuals with DiGeorge and velocardiofacial syndrome have a chromosome 22q11.2 microdeletion recognizable by fluorescence in-situ hybridization (46; 115). Approximately 10% to 25% are inherited in an autosomal dominant fashion (79). The de novo occurrence of 22q deletion is observable in about 90% to 95% of affected individuals in all populations (182). Other chromosomal rearrangements, including an interstitial deletion at 10p13, are reported in individuals with the DiGeorge syndrome phenotype (37).

Cytogenetics. Approximately 76% of patients to 90% of patients with DiGeorge and velocardiofacial syndrome have a 1.5 Mb to 3 Mb microdeletion within chromosome 22q11, referred to as the "typically deleted region." The typically deleted region is subdivided into five intervals, encompassing some 50 genes (180). To date, no significant correlation exists between the size of the deletion and the severity of the phenotype (27). Furthermore, considerable variability occurs in the phenotype observed within individual families, indicating that the phenotype is not solely related to the size of the deletion (40; 115; 27). Both deletions and reciprocal duplications have been identified in patients with varying phenotypes by chromosomal microarray analysis (110). Genetic factors play a major role in the phenotypic variability of a mouse model of DiGeorge syndrome (183). Some reports have shown that the proximal or distal location of the microdeletion is related to the prevalence of associated features (34).

The following table lists some of the DiGeorge and velocardiofacial syndrome candidate genes within the typically deleted region. TBX1 is the most likely of the candidate genes and is located in the 22q11 region most often deleted (84). Mutations in TBX1 have also been identified in non-deleted patients and are thought to be causal based on functional and experimental data (173; 01). TBX is the most important gene for expression of cardiovascular phenotype. This gene regulates tissue and organ morphogenesis during embryogenesis, especially of the heart outflow tracts. It also impairs the development of neural crest-derived mesenchymal cells that surround the third pharyngeal pouch leading to thymic hypoplasia (34). Other genes remain under investigation.

Table 1. DiGeorge and Velocardiofacial Syndrome Candidate Genes within the Typically Deleted Region

Gene	Function	Reference
CLTD	Encodes a protein with homology to human clathrin heavy-chain	(68)
COMT	Catechol-O-methyltransferase: a CNS enzyme involved in the metabolic degradation of dopamine and norepinephrine; increased prefrontal dopamine may affect cognition and contribute to psychosis in patients.	(76; 70)
CRKL	Encodes an SH2-SH3-SH3 adaptor protein	(77)
CTP	Mitochondrial citrate transport protein	(66)
DGCR2 or LAN or IDD	Encodes a potential adhesion receptor protein	(39; 205)
DGCR6	Encodes a putative protein that has homology to the human laminin gamma-1 chain and Drosophila gonadal protein	(41)
DGCR8	Encodes a protein containing one WW motif and two DSRM motifs	(163)
DVL-22	A human homologue of the Drosophila disheveled segment-polarity gene	(146)
GNB1L	Encodes a G-protein beta-subunit-like polypeptide	(67)
GSCL	Homology to the homeodomain family of transcription factors (goosecoid-like homeobox gene)	(71)
HIRA	Human homologue of the S cerevisiae HIR1 and HIR2 transcriptional repressors (essential for hematopoiesis experimentally)	(103; 29)
PCQAP	Encodes a protein subunit of the multiprotein complex PC2	(17)
RanBP1	Binding partner of the Ras-related nuclear protein Ran/TC4	(122)
TBX1	T-box transcription factor	(87; 173)
TMVCF	Encodes a transmembrane protein	(168)
TUPLE1	A putative transcription factor	(78)
UFD1L	Encodes a protein involved in degradation of ubiquitinated proteins	(218)
ZNF74	A putative transcription factor	(12)

Central nervous system findings. The 22q11.2 region contains many genes that are critical to neuronal development and migration, so it follows that brain morphology and genetic variation at this locus are closely related (114). Neuroanatomic anomalies may be seen on CT and MRI scans in a minority of individuals with DiGeorge and velocardiofacial syndrome, and to date, they vary considerably. Findings include cerebral atrophy, hypoplasia of the cerebellar vermis, small posterior fossa, small cysts adjacent to the anterior horns, gray matter heterotopias consistent with abnormal neuronal migration, hippocampal hypoplasia, Chiari malformation, focal white matter signal hyperintensities, enlargement of the corpus callosum, and polymicrogyria (154; 05). A study of cortical architecture revealed cortical dysplasia in one affected patient; this form of arrested maturation was evident in all lobes of the cortex and probably represents the persistence of the normal radial columnar architecture of the neocortical plate in the first half of gestation (157). Quantitative volumetric neuroimaging studies show reduced tissue volumes in the nonfrontal lobar regions of the brain, consistent with the neurocognitive profile of DiGeorge and velocardiofacial syndrome (94). High-resolution imaging studies show a significant reduction in frontal deep white matter, suggesting frontostriatal dysfunction, a finding noted in individuals with schizophrenia (93). Decreased cortical gyrification in medial temporal and occipital regions is associated with increases in negative psychiatric symptomatology (127). Diffusion tensor imaging has demonstrated altered integrity of white matter in the superior and inferior longitudinal fasciculi and thalamic to frontal tracts, which may contribute to behavioral abnormalities or deficits in visual-spatial memory in patients (96; 200). It has been hypothesized that the psychiatric and cognitive deficits may be due to disordered structural and functional connectivity, as well as abnormalities in association pathways and midline structures (eg, corpus callosum, cingulate gyrus) (160). Widespread alterations in the subcortical regions of affected patients are associated with size of deletion and degree of psychosis; these changes overlap with those in patients manifesting idiopathic schizophrenia and other forms of severe psychiatric disease (30; 153).

Congenital heart disease, craniofacial malformations, endocrinopathies, and immunodeficiencies. During the fourth week of embryonic development, neural crest cells migrate into the pharyngeal arches and participate in the formation of the craniofacial region, aortic arches and conotruncus, thymus, and parathyroid glands (18). It is likely that the recognizable features in DiGeorge and velocardiofacial syndrome patients (unique facial features, congenital heart disease, thymus hypoplasia, parathyroid hypoplasia) result from either aberrant neural crest cell migration or from a disorder of cell interaction with pharyngeal pouch endoderm from which the affected structures are derived (18).

DiGeorge and velocardiofacial syndrome studies suggest a role for TBX1 in mediating epithelial-mesenchymal signaling in regions of the developing face of the mouse (224). The transcription factor encoded by TBX1 is important to cardiac development and is often deleted in patients (174). It is also required for the elongation and elevation of palatal shelves (72) and pharyngeal development (47).

Several patients have been reported with primary lymphedema, which may result from an altered influence of TBX1 on lymphangiogenesis (190).

Neurochemical or neuropsychiatric disorders. The catechol-O-methyltransferase gene is located within the region typically deleted in DiGeorge and velocardiofacial syndrome (76). The gene encodes an enzyme that inactivates catecholamines such as dopamine, norepinephrine, and epinephrine (48). Presence of catechol-O-methyltransferase (COMT) activity may serve as a functional barrier for catecholamines in the brain (89) and placenta (14). Catechol-O-methyltransferase occurs in soluble and membrane-bound forms but resides predominantly in the cytoplasm. The soluble form has high and low activity alleles. Low catechol-O-methyltransferase activity has been reported in women with primary affective disorder (32).

Individuals hemizygous for the catechol-O-methyltransferase gene (such as those with a 22q11.2 deletion) and carrying a low activity allele on their nondeleted chromosome may be predisposed to the development of psychotic features (102). This could occur either due to decreased inactivation of catecholamines in the brain, increased placental transfer of catecholamines, or both. The specific catabolic clearance of dopamine has been implicated as well (10). Approximately 23% of a randomly selected population was classified as "low" metabolizers (209); therefore, the frequency of the low activity allele in the DiGeorge and velocardiofacial syndrome population may be significant. This functional COMT polymorphism may have a gender-moderated effect on the neuroanatomic phenotype in individuals with DiGeorge and velocardiofacial syndrome (92).

Expression studies performed in mice and humans show that most 22q11.2 genes are expressed in the brain during multiple stages of development (123). Thus, the neuropsychiatric findings in individuals with DiGeorge and velocardiofacial syndrome may be the result of the deletion of multiple 22q11.2 genes. Additional experimental evidence suggests that deficits in emotional memory and in establishing proper contexts for emotions may be due to microRNA-dependent disruption of thalamic synaptic transmission to the amygdala (52).

Renal anomalies. Urologic malformations associated with 22q11.2 deletions may represent variable expression of an embryologic defect of the lower or upper ureteral bud (42). Anorectal anomalies may be related to a defect in mesenchyme cell migration, an abnormality of the cell matrix, or defect in programming (216).

Management

Initial laboratory evaluations in the neonatal period should include serum calcium measurements and absolute lymphocyte count determination. Low calcium warrants calcium supplementation. Calcium homeostasis typically normalizes with age, although recurrence of hypocalcemia in later childhood and adulthood has been reported (74; 181). Therefore, periodic serum calcium screening is recommended (185). A low absolute lymphocyte count necessitates evaluation of T-cell and B-cell subsets and immunology referral. Partial immunodeficiency is a cause of recurrent sinus and pulmonary infection in childhood (60). Infants with severe immunocompromise should not receive live vaccines (oral polio or measles, mumps, rubella vaccine) and should be re-evaluated before receiving a live vaccine during childhood. Likewise, patients need to receive irradiated blood products to avoid the serious complication of transfusion-associated graft-versus-host disease (133). Severe immune deficiency may require bone marrow transplantation (107). Transplantation of T cells or cultured thymus tissue has proven successful, eliminating the need for prophylactic antibiotics and immunoglobulin therapy (119; 126; 60). Infusion of HLA-matched sibling donor T lymphocytes has proven successful in combating severe adenovirus infection (86). Transplantation of thymic and parathyroid tissue is in the early stages of development (101).

Renal ultrasound is recommended due to the increased incidence (approximately 30%) of structural renal abnormalities in these individuals that are not readily detectable by other means (42).

An endocrine workup is indicated. Children with short stature should be evaluated for growth hormone deficiency as they may be at increased risk for pituitary abnormalities (210). Abnormal pituitary development also confers increased susceptibility to atypical neurodevelopment and psychopathology (156). Reduced growth may also result from genetic factors or cardiovascular deficiency (121). Growth tends to be restricted at all ages, and at adulthood, patient height will probably be in the low-normal range (113). In addition, hypoparathyroidism and hypocalcemia can lead to reduced mineralization of bone and can require monitoring of bone metabolism and bone mineral density (57).

Early educational intervention is suggested. Speech and language assessment may aid in diagnosing a congenital or iatrogenic (for example, paralyzed vocal cord) airway abnormality, with subsequent referral to an appropriate specialist for management (50). Cephalometry (ie, measurement of cranial base angle, nasopharyngeal depth, velum and velopharyngeal length, and other dimensions) may help assess the severity of velopharyngeal dysfunction (196). Candidates for pharyngeal flap correction of velopharyngeal insufficiency should have an MRA to identify ectopic internal carotid arteries that may pose a risk for surgery (138). In one study, pharyngoplasty proved more efficacious than palatoplasty alone, which may require additional surgery (170). Velopharyngoplasty results in normal voice resonance in about one-half of patients, although this may take up to 5 years to develop following surgery; the remainder may manifest residual hypernasality or require further surgery (171). Superiorly based pharyngeal flap surgery has led to improvement in hypernasality, audible nasal emission, and speech intelligibility in a group of 12 patients (58). Combined palatoplasty and sphincter pharyngoplasty have proven effective as well (19). Poor sleep quality may result from elevated inflammatory markers recognized in the syndrome and may contribute to gastrointestinal symptoms (eg, nausea, diarrhea, abdominal pain, constipation) and cognitive impairment (105; 220). Sleep difficulties appear to be lessened with improved bedtime routine and sleep environment, rather than medication (08). Formal neuropsychological testing is strongly recommended for all children (139).

The use of methylphenidate for ADHD in this population is routinely avoided due to concerns about psychotic exacerbation. However, an open-label study notes that methylphenidate is both a safe and effective treatment for ADHD in children with DiGeorge and velocardiofacial syndrome (69). S-adenosyl-L-:methionine (SAMe) is thought to enhance the COMT enzyme and has proven to be effective in the treatment of patients with depression with or without psychotic symptoms, though no improvement in ADHD symptoms was apparent (73).

The risk of psychiatric illness is present at birth, of course, and early diagnosis and treatment may lead to improved outcomes. Longitudinal studies have identified certain childhood predictors of adult socialization, especially child internalizing symptoms and adolescent problem behavior (206). These are conditions that warrant early intervention. Unfortunately, it is not clear that young patients with psychiatric disorders at the milder end of the spectrum (ie, nonpsychotic) receive the help they need. In one Italian study, only 27% of children and teens received psychiatric treatment (09). Genetic counselors play an integral but also challenging role in this (120) and should realize that parents use the internet for their main source of information about the syndrome (194).

Dysfunction in fast intracortical oscillatory processing, identified by EEG, may serve as a risk marker for schizophrenia in some patients (104). Treatment of the psychiatric illness of patients with DiGeorge and velocardiofacial syndrome is challenging, and patients may show varied response to neuroleptic therapy (135; 04).

Practice guidelines for managing pediatric patients were first published in 2011 (139) and for adult patients in 2015 (23). It is important to know that adults with 22q11.2 deletion syndrome require follow-up, regardless of age of diagnosis (23).

References

01: Aggarwal VS, Morrow BE. Genetic modifiers of the physical malformations in velo-cardio-facial syndrome/DiGeorge syndrome. Dev Disabil Res Rev 2008;14:19-25. PMID 18636633
02: Al-Hertani W, Hastings VA, McGowan-Jordan J, Hurteau J, Graham GE. Severe craniosynostosis in an infant with deletion 22q11.2 syndrome. Am J Med Genet 2013;161A:153-7. PMID 23239640
03: Alkalay AA, Guo T, Montagna C, et al. Genetic dosage compensation in a family with velo-cardio-facial/DiGeorge/22q11.2 deletion syndrome. Am J Med Genet A 2011;155(3):548-54. PMID 21337693
04: Angelopoulos E, Theleritis C, Economou M, Georgatou K, Papageorgiou CC, Tsaltas E. Antipsychotic treatment of 22q11.2 deletion syndrome-related psychoses. Pharmacopsychiatry 2017;50(4):162-3. PMID 28511206
05: Antshel KM, Conchelos J, Lanzetta G, Fremont W, Kates WR. Behavior and corpus callosum morphology relationships in velocardiofacial syndrome (22q11.2 deletion syndrome). Psych Res 2005;138(3):235-45. PMID 15854791
06: Antshel KM, Fremont W, Kates WR. The neurocognitive phenotype in velo-cardio-facial syndrome: a developmental perspective. Dev Disabil Res Rev 2008;14:43-51. PMID 18636636
07: Antshel KM, Shprintzen R, Fremont W, Higgins AM, Faraone SV, Kates WR. Cognitive and psychiatric predictors to psychosis in velocardiofacial syndrome: a 3-year follow-up study. J Am Acad Child Adolesc Psychiatry 2010;49(4):333-44. PMID 20410726
08: Arganbright JM, Tracy M, Hughes SS, Ingram DG. Sleep patterns and problems among children with 22q11 deletion syndrome. Mol Genet Genomic Med 2020;8(6):e1153. PMID 32222065
09: Armando M, Lin A, Pontillo M, Vicari S. Prevalence and treatment of psychiatric disorders other than psychosis in children and adolescents with 22q11DS: Examining associations with social and role functioning. Psychiatry Res 2017;254:238-43. PMID 28477546
10: Armando M, Papaleo F, Vicari S. COMT implication in cognitive and psychiatric symptoms in chromosome 22q11 microdeletion syndrome: a selective review. CNS Neurol Disord Drug Targets 2012;11(3):273-81. PMID 22483289
11: Attout L, Noël MP, Rousselle L. The effect of visual arrangement on visuospatial short-term memory: Insights from children with 22q11.2 deletion syndrome. Cogn Neuropsychol 2018;35(7):352-60. PMID 29642756
12: Aubry M, Demczuk S, Desmaze C, et al. Isolation of a zinc finger gene consistently deleted in DiGeorge syndrome. Hum Mol Genet 1993;2:1583-7. PMID 8268910
13: Bakker G, Caan MW, Schluter RS, et al. Distinct white-matter aberrations in 22q11.2 deletion syndrome and patients at ultra-high risk for psychosis. Psychol Med 2016;46(11):2299-311. PMID 27193339
14: Barnea ER, Maclusky NJ, Decherney AH, Naftolin F. Catechol-O-methyltransferase activity in the human term placenta. Am J Perinatol 1988;5:121-7. PMID 3348855
15: Barry JC, Crowley TB, Jyonouchi S, et al. Identification of 22q11.2 Deletion syndrome via newborn screening for severe combined immunodeficiency. J Clin Immunol 2017;37(5):476-85. PMID 28540525
16: Bassett JK, Chandler KE, Douzgou S. Two patients with chromosome 22q11.2 deletion presenting with childhood obesity and hyperphagia. Eur J Med Genet 2016;59(8):401-3. PMID 27184501
17: Berti L, Mittler G, Przemeck GK, et al. Isolation and characterization of a novel gene from the DiGeorge chromosomal region that encodes for a mediator subunit. Genomics 2001;74:320-32. PMID 11414760
18: Bockman DE, Kirby ML. Dependence of thymus development on derivatives of the neural crest. Science 1984;223:498-500. PMID 6606851
19: Bohm LA, Miller JE, Morrell N, Sidman JD, Roby BB. Surgical outcomes for the treatment of velopharyngeal insufficiency in 22q11.2 deletion syndrome. Otolaryngol Head Neck Surg 2019;161(2):348-51. PMID 30935277
20: Boot E, Butcher NJ, Udow S, et al. Typical features of Parkinson disease and diagnostic challenges with microdeletion 22q11.2. Neurology 2018;90(23):e2059-67. PMID 29752303
21: Boot E, Butcher NJ, van Amelsvoort TA, et al. Movement disorders and other motor abnormalities in adults with 22q11.2 deletion syndrome. Am J Med Genet A 2015;167A(3):639-45. PMID 25684639
22: Boot E, Mentzel TQ, Palmer LD, et al. Age-related Parkinsonian signs in microdeletion 22q11.2. Mov Disord 2020;35(7):1239-45. PMID 32386091
23: Boot E, Óskarsdóttir S, Loo JC, et al. Updated clinical practice recommendations for managing adults with 22q11.2 deletion syndrome. Genet Med 2023;25(3):100344. PMID 36729052
24: Burn J, Takao A, Wilson D, et al. Conotruncal anomaly face syndrome is associated with a deletion within chromosome 22q11. J Med Genet 1993;30:822-4. PMID 8230157
25: Butcher NJ, Boot E, Lang AE, et al. Neuropsychiatric expression and catatonia in 22q11.2 deletion syndrome: an overview and case series. Am J Med Genet A 2018;176(10):2146-59. PMID 29777584
26: Cantonas LM, Tomescu MI, Biria M, et al. Abnormal development of early auditory processing in 22q11.2 deletion syndrome. Transl Psychiatry 2019;9(1):138. PMID 30992427
27: Carlson C, Sirotkin H, Pandita R, et al. Molecular definitions of 22q11 deletions in 151 velo-cardio-facial syndrome patients. Am J Hum Genet 1997;61:620-9. PMID 9326327
28: Carotti A, Digilio MC, Piacentini G, Saffirio C, Di Donato RM, Marino B. Cardiac defects and results of cardiac surgery in 22q11.2 deletion syndrome. Dev Disabil Res Rev 2008;14:35-42. PMID 18636635
29: Chen C, Sun MA, Warzecha C, et al. HIRA, a DiGeorge Syndrome candidate gene, confers proper chromatin accessibility on HSCs and supports all stages of hematopoiesis. Cell Rep 2020;30(7):2136-49. PMID 32075733
30: Ching CRK, Gutman BA, Sun D, et al. Mapping subcortical brain alterations in 22q11.2 deletion syndrome: Effects of deletion size and convergence with idiopathic neuropsychiatric illness. Am J Psychiatry 2020;177(7):589-600. PMID 32046535
31: Cleynen I, Engchuan W, Hestand MS, et al. Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion. Mol Psychiatry 2021;26(8):4496-510. PMID 32015465
32: Cohn CK, Dunner DL, Axelrod J. Reduced catechol-O-methyltransferase activity in red blood cells of women with primary affective disorder. Science 1970;170:1323-4. PMID 5479012
33: Conley ME, Beckwith JB, Maneer JF, Tenckhoff L. The spectrum of the DiGeorge syndrome. J Pediatr 1979;94:883-90. PMID 448529
34: Cirillo A, Lioncino M, Maratea A, et al. Clinical mManifestations of 22q 11.2 deletion syndrome. Heart Failure Clin 2022;18:155-64. PMID 34776076
35: Cortes-Martin J, Peñuela NL, Sánchez-García JC, Montiel-Troya M, Díaz-Rodríguez L, Rodríguez-Blanque R. Deletion syndrome 22q11.2: a systematic review. Children (Basel) 2022;9(8):1168. PMID 36010058
36: Cunningham AC, Fung W, Massey TH, et al. Movement disorder phenotypes in children with 22q11.2 deletion syndrome. Mov Disord 2020;35(7):1272-4. PMID 32379361
37: Dasouki M, Jurecic V, Phillips JA 3rd, Whitlock JA, Baldini A. DiGeorge anomaly and chromosome 10p deletions: one or two loci. Am J Med Genet 1997;73:72-5. PMID 9375926
38: de la Chapelle A, Herva R, Koivisto M, Aula O. A deletion in chromosome 22 can cause DiGeorge syndrome. Hum Genet 1981;57:253-6. PMID 7250965
39: Demczuk S, Aledo R, Zucman J, et al. Cloning of a balanced translocation breakpoint in the DiGeorge syndrome critical region and isolation of a novel potential adhesion receptor gene in its vicinity. Hum Mol Genet 1995a;4:551-8. PMID 7633403
40: Demczuk S, Levy A, Aubry M, et al. Excess of deletions of maternal origin in the DiGeorge/Velo-cardio-facial syndromes. A study of 22 new patients and a review of the literature. Hum Genet 1995b;96:9-13. PMID 7607662
41: Demczuk S, Thomas G, Aurias A. Isolation of a novel gene from the DiGeorge syndrome critical region with homology to Drosophila gdl and to human LAMC1 genes. Hum Mol Genet 1996;5:633-8. PMID 8733130
42: Devriendt K, Swillen A, Fryns JP, Proesmans W, Gewillig M. Renal and urological tract malformations caused by a 22q11 deletion. J Med Genet 1996;33:349-52. PMID 8730297
43: DiGeorge AM, editor. Congenital absence of the thymus and its immunologic consequences: concurrence with congenital hypothyroidism. Birth defects. Vol IV(1). White Plains, New York: March of Dimes-Birth Defects Foundation, 1968.
44: Digilio M, Bernardini L, Gagliardi M, et al. Syndromic non-compaction of the left ventricle: associated chromosomal anomalies. Clin Genet 2013;84(4):362-7. PMID 23210894
45: Digilio MC, Pacifico C, Tieri L, et al. Audiologic findings in patients with microdeletion 22q11 (DiGeorge/velocardiofacial syndrome). Br J Audiology 1999;33:329-33. PMID 10890147
46: Driscoll DA, Salvin J, Sellinger B, et al. Prevalence of 22q11 microdeletions in DiGeorge and velocardiofacial syndromes: implications for genetic counselling and prenatal diagnosis. J Med Genet 1993;30:813-7. PMID 8230155
47: Du Q, de la Morena MT, van Oers NSC. The genetics and epigenetics of 22q11.2 deletion syndrome. Front Genet 2020;10:1365. PMID 32117416
48: Dunham I, Collins J, Wadey R, Scambler P. Possible role for COMT in psychosis associated with velo-cardio-facial syndrome. Lancet 1992;340:1361-2. PMID 1360084
49: Eaton CB, Thomas RH, Hamandi K, et al. Epilepsy and seizures in young people with 22q11.2 deletion syndrome: prevalence and links with other neurodevelopmental disorders. Epilepsia 2019;60(5):818-29. PMID 30977115
50: Ebert B, Sidman J, Morrell N, Roby BB. Congenital and iatrogenic laryngeal and vocal abnormalities in patients with 22q11.2 deletion. Int J Pediatr Otorhinolaryngol 2018;109:17-20. PMID 29728175
51: Enns GM, Cox VA, Golabi M, et al. Gastrointestinal tract anomalies in velocardiofacial syndrome. Am J Med Genet 1999;84:382-3. PMID 10340658
52: Eom TY, Bayazitov IT, Anderson K, Yu J, Zakharenko SS. Schizophrenia-related microdeletion impairs emotional memory through microRNA-dependent disruption of thalamic inputs to the amygdala. Cell Rep 2017;19(8):1532-44. PMID 28538174
53: Evers LJ, De Die-Smulders CE, Smeets EE, Clerkx MG, Curfs LM. The velo-cardio-facial syndrome: the spectrum of psychiatric problems and cognitive deterioration at adult age. Genet Couns 2009;20(4):307-15. PMID 20162865
54: Evers LJ, van Amelsvoort TA, Candel MJ, Boer H, Engelen JJ, Curfs LM. Psychopathology in adults with 22q11 deletion syndrome and moderate and severe intellectual disability. J Intellect Disabil Res 2014;58(10):915-25. PMID 24528781
55: Faedda GL, Wachtel LE, Higgins AM, Shprintzen RJ. Catatonia in an adolescent with velo-cardio-facial syndrome. Am J Med Genet A 2015;167A(9):2150-3. PMID 25832449
56: Fibison WJ, Budarf M, McDermid H, Greenberg F, Emanuel BS. Molecular studies of DiGeorge syndrome. Am J Hum Genet 1990;46:888-95. PMID 2339689
57: Ficcadenti A, Zallocco F, Neri R, Giovanni L, Tirabassi G, Balercia G. Bone density assessment in a cohort of pediatric patients affected by 22q11DS. J Endocrinol Invest 2015;38(10):1093-8. PMID 25916433
58: Filip C, Matzen M, Aukner R, et al. Superiorly based pharyngeal flap for treatment of velopharyngeal insufficiency in patients with 22q11.2 deletion syndrome. J Craniofac Surg 2013;24:501-4. PMID 23524725
59: Furniss F, Biswas AB, Gumber R, Singh N. Cognitive phenotype of velocardiofacial syndrome: a review. Res Dev Disabil 2011;32(6):2206-13. PMID 21764255
60: Gennery AR. Immunological aspects of 22q11.2 deletion syndrome. Cell Mol Life Sci 2012;69(1):17-27. PMID 21984609
61: Gennery AR, Barge D, O'Sullivan JJ, Flood TJ, Abinun M, Cant AJ. Antibody deficiency and autoimmunity in 22q11.2 deletion syndrome. Arch Dis Child 2002;86(6):422-5. PMID 12023174
62: Glaser B, Mumme DL, Blasey C, et al. Language skills in children with velocardiofacial syndrome (deletion 22q11.2). J Pediatr 2002;140(6):753-8. PMID 12072882
63: Gokturk B, Topcu-Yilmaz P, Bozkurt B, et al. Ocular findings in children with 22q11.2 deletion syndrome. J Pediatr Ophthalmol Strabismus 2016;53(4):218-22. PMID 27182748
64: Goldberg R, Motzkin B, Marion R, Scambler PJ, Sphrintzen RJ. Velo-cardiofacial-syndrome. A review of 120 patients. Am J Med Genet 1993;45:313-9. PMID 8434617
65: Golding-Kushner KJ, Weller G, Sphrintzen RJ. Velo-cardio-facial syndrome: language and psychological profiles. J Craniofac Genet 1985;5:259-66. PMID 4044789
66: Goldmuntz E, Wang Z, Roe BA, Budarf ML. Cloning, genomic organization, and chromosomal localization of human citrate transport protein to the DiGeorge/velocardiofacial syndrome minimal critical region. Genomics 1996;33:271-6. PMID 8660975
67: Gong L, Liu M, Jen J, Yeh ET. GNB1L, a gene deleted in the critical region for DiGeorge syndrome on 22q11.2, encodes a G-protein beta-subunit-like polypeptide. Biochim Biophys Acta 2000;1494:185-8. PMID 11072084
68: Gong W, Emanuel BS, Collins J, et al. A transcription map of the DiGeorge and velo-cardio-facial syndrome minimal critical region on 22q11. Hum Mol Genet 1996;5:789-800. PMID 8776594
69: Gothelf D, Gruber R, Presburger G, et al. Methylphenidate treatment for attention-deficit/hyperactivity disorder in children and adolescents with velocardiofacial syndrome: an open-label study. J Clin Psychiatry 2003;64(10):1163-9. PMID 14658963
70: Gothelf D, Schaer M, Eliez S. Genes, brain development and psychiatric phenotypes in velo-cardio-facial syndrome. Dev Disabil Res Rev 2008;14:59-68. PMID 18636637
71: Gottlieb S, Emanuel BS, Driscoll DA, et al. The DiGeorge syndrome minimal critical region contains a Goosecoid-like (GSCL) homeobox gene that is expressed early in human development. Am J Hum Genet 1997;60:1194-201. PMID 9150167
72: Goudy S, Law A, Sanchez G, Baldwin HS, Brown C. Tbx1 is necessary for palatal elongation and elevation. Mech Dev 2010;127(5-6):292-300. PMID 20214979
73: Green T, Steingart L, Frisch A, Zarchi O, Weizman A, Gothelf D. The feasibility and safety of S-adenosyl-L: -methionine (SAMe) for the treatment of neuropsychiatric symptoms in 22q11.2 deletion syndrome: a double-blind placebo-controlled trial. J Neural Transm 2012;119(11):1417-23. PMID 22678699
74: Greig F, Paul E, DiMartin-Nardi J, Saenger P. Transient congenital hypoparathyroidism: resolution and recurrence in chromosome 22q11 deletion. J Pediatr 1996;128:563-7. PMID 8618195
75: Gross SJ, Ryan A, Benn P. Noninvasive prenatal testing for 22q11.2 deletion syndrome: deeper sequencing increases the positive predictive value. Am J Obstet Gynecol 2015;213(2):254-5. PMID 25986033
76: Grossman MH, Emanuel BS, Budarf ML. Chromosomal mapping of the human catechol-o-methyl-transferase gene to 22q11.1----q11.2. Genomics 1992;12(4):822-5. PMID 1572656
77: Guris DL, Fantes J, Tara D, Druker BJ, Imamoto A. Mice lacking the homologue of the human 22q11.2 gene CRKL phenocopy neurocristopathies of DiGeorge syndrome. Nat Genet 2001;27:293-8. PMID 11242111
78: Halford S, Wadey R, Roberts C, et al. Isolation of a putative transcriptional regulator from the region of 22q11 deleted in DiGeorge syndrome, Shprintzen syndrome and familial congenital heart disease. Hum Mol Genet 1993;2:2099-107. PMID 8111380
79: Hall J. CATCH 22. J Med Genet 1993;30:801-2. PMID 8230153
80: Hamidi M, Nabi S, Husein M, Mohamed ME, Tay KY, McKillop S. Cervical spine abnormalities in 22q11.2 deletion syndrome. Cleft Palate Craniofac J 2014;51(2):230-3. PMID 24003836
81: Holder SE, Winter RM, Kamath S, Scambler PJ. Velocardiofacial syndrome in a mother and daughter: variability of the clinical phenotype. J Med Genet 1993;30:825-7. PMID 8230158
82: Homans JF, Baldew VGM, Brink RC, et al. Scoliosis in association with the 22q11.2 deletion syndrome: an observational study. Arch Dis Child 2019;104(1):19-24. PMID 29627765
83: Hooper SR, Curtiss K, Schoch K, Keshavan MS, Allen A, Shashi V. A longitudinal examination of the psychoeducational, neurocognitive, and psychiatric functioning in children with 22q11.2 deletion syndrome. Res Dev Disabil 2013;34:1758-69. PMID 23506790
84: Huh SH, Ornitz DM. Beta-catenin deficiency causes DiGeorge syndrome-like phenotypes through regulation of Tbx1. Development 2010;137(7):1137-47. PMID 20215350
85: Hui L. Cell-free DNA testing for 22q11.2 deletion syndrome: appraising the viability, effectiveness and appropriateness of screening. Ultrasound Obstet Gynecol 2016;47(2):137-41. PMID 26833636
86: Ip W, Zhan H, Gilmour KC, Davies EG, Qasim W. 22q11.2 deletion syndrome with life-threatening Adenovirus infection. J Pediatr 2013;163(3):908-10. PMID 23660376
87: Jerome LA, Papaioannou VE. DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nat Genet 2001;27:286-91. PMID 11242110
88: Jones JW, Tracy M, Perryman M, Arganbright JM. Airway anomalies in patients with 22q11.2 deletion syndrome: a 5-year review. Ann Otol Rhinol Laryngol 2018;127(6):384-9. PMID 29732908
89: Kaplan GP, Hartman BK, Creveling CR. Localization of 4 catechol-O-methyltransferase in the leptomeninges, choroid plexus and ciliary epithelium: implications for the separation of central and peripheral catechols. Brain Res 1980;204:353-60. PMID 7006735
90: Karas DJ, Costain G, Chow EW, Bassett AS. Perceived burden and neuropsychiatric morbidities in adults with 22q11.2 deletion syndrome. J Intellect Disabil Res 2014;58(2):198-210. PMID 23106770
91: Karayiorgou M, Mossis MA, Morrow B, et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc Natl Acad Sci 1995;92:7612-6. PMID 7644464
92: Kates WR, Antshel KM, Abdulsabur N, et al. A ender-moderated effect of a functional COMT polymorphism on prefrontal brain morphology and function in velo-cardio-facial syndrome (22q11.2 deletion syndrome). Am J Med Genet B Neuropsychiatr Genet 2006;141(3):274-80. PMID 16511839
93: Kates WR, Burnette CP, Bessette BA, et al. Frontal and caudate alterations in velocardiofacial syndrome (deletion at chromosome 22q11.2). J Child Neurol 2004;19(5):337-42. PMID 15224707
94: Kates WR, Burnette CP, Jabs EW, et al. Regional cortical white matter reductions in velocardiofacial syndrome: a volumetric MRI analysis. Biol Psychiatry 2001;49:677-84. PMID 11313035
95: Kelly D, Goldberg R, Wilson D, et al. Confirmation that the velo-cardio-facial syndrome is associated with haplo-insufficiency of genes at chromosome 22q11. Am J Med Genet 1993;45:308-12. PMID 8434616
96: Kikinis Z, Makris N, Finn CT, et al. Genetic contributions to changes of fiber tracts of ventral visual stream in 22q11.2 deletion syndrome. Brain Imaging Behav 2013;7(3):316-25. PMID 23612843
97: Kinoshita H, Kokudo T, Ide T, et al. A patient with DiGeorge syndrome with spina bifida and sacral myelomeningocele, who developed both hypocalcemia-induced seizure and epilepsy. Seizure 2010;19(5):303-5. PMID 20430655
98: Kinouchi A, Mori K, Ando M, Takao A. Facial appearance of patients with conotruncal anomalies. Pediatr Jpn 1976;17:84.
99: Klingberg G, Oskarsdottir S, Johannesson EL, Noren JG. Oral manifestations in 22q11 deletion syndrome. Int J Paediatr Dent 2002;12(1):14-23 PMID 11853243
100: Kolman SE, Ohara SY, Bhatia A, et al. The clinical utility of flexion-extension cervical spine MRI in 22q11.2 deletion syndrome. J Pediatr Orthop 2019;39(9):e674-9. PMID 28441280
101: Kreins AY, Junghanns F, Mifsud W, et al. Correction of both immunodeficiency and hypoparathyroidism by thymus transplantation in complete DiGeorge syndrome. Am J Transplant 2020;20(5):1447-50. PMID 31663273
102: Lachman HM, Morrow B, Sphrintzen R, et al. Association of codon 108/158 catechol-O-methyltransferase gene polymorphism with the psychiatric manifestations of velo-cardio-facial syndrome. Am J Med Genet 1996;67:468-72. PMID 8886163
103: Lamour V, Lecluse Y, Desmaze C, et al. A human homolog of the S. cerevisiae HIR1 and HIR2 transcriptional repressors cloned from the DiGeorge syndrome critical region. Human Mol Genet 1995;4:791-9. PMID 7633437
104: Larsen KM, Pellegrino G, Birknow MR, et al. 22q11.2 deletion syndrome is associated with impaired auditory steady-state gamma response. Schizophr Bull 2018;44(2):388-97. PMID 28521049
105: Leader G, Murray M, O'Súilleabháin PS, et al. Relationship between parent-reported gastrointestinal symptoms, sleep problems, autism spectrum disorder symptoms, and behavior problems in children and adolescents with 22q11.2 deletion syndrome. Res Dev Disabil 2020;104:103698. PMID 32474230
106: Leana-Cox J, Pangkanon S, Eanet KR, Curtin MS, Wulfsberg EA. Familial DiGeorge/velocardiofacial syndrome with deletions of chromosome area 22q11.2: report of five families with a review of the literature. Am J Med Genet 1996;65:309-16. PMID 8923941
107: Lee KD, Okazaki T, Kato Y, Lane GJ, Yamataka A. Esophageal atresia and tracheo-esophageal fistula associated with coarcatation of the aorta, CHARGE association, and DiGeorge syndrome: a case report and literature review. Pediatr Surg Int 2008;24:1153-6. PMID 18696080
108: Lee SK, Lee EJ, Kwun KH, Kim TJ, Lee SK. Delayed diagnosis of chromosome 22q11.2 deletion syndrome due to late-onset generalized epilepsy. J Clin Neurol 2020;16(1):154-6. PMID 31942772
109: Legitimo A, Bertini V, Costagliola G, et al. Vitamin D status and the immune assessment in 22q11.2 deletion syndrome. Clin Exp Immunol 2020;200(3):272-86. PMID 32149392
110: Leite AJC, Pinto IP, Cunha DM, et al. The identification of microdeletion and reciprocal microduplication in 22q11.2 using high-resolution CMA technology. Biomed Res Int 2016;2016:7415438. PMID 27123452
111: Leopold C, De Barros A, Cellier C, Drouin-Garraud V, Dehesdin D, Marie JP. Laryngeal abnormalities are frequent in the 22q11 deletion syndrome. Int J Pediatr Otorhinolaryngol 2012;76(1):36-40. PMID 22019154
112: Levy A, Michel G, Lemerrer M, Philip N. Idiopathic thromobocytopenic purpura in two mothers of children with DiGeorge sequence: a new component manifestation of deletion 22q11. Am J Med Genet 1997;69:356-9. PMID 9098482
113: Levy-Shraga Y, Gothelf D, Goichberg Z, et al. Growth characteristics and endocrine abnormalities in 22q11.2 deletion syndrome. Am J Med Genet A 2017;173(5):1301-8. PMID 28421700
114: Lin A, Ching CRK, Vajdi A, et al. Mapping 22q11.2 gene dosage effects on brain morphometry. J Neurosci 2017;37(26):6183-99. PMID 28536274
115: Lindsay EA, Greenberg F, Shaffer LG, et al. Submicroscopic deletions at 22q11.2: variability of the clinical picture and delineation of a commonly deleted region. Am J Med Genet 1995;56:191-7. PMID 7625444
116: Looman WS, Thurmes AK, O’Conner-Von SK. Quality of life among children with velocardiofacial syndrome. Cleft Palate Craniofac J 2010;47(3):273-83. PMID 20426676
117: Madan S, Madan-Khetarpal S, Park SC, et al. Response to Drs. Stollberger and Finsterer “Noncompaction Is Already Known in DiGeorge Anomaly From 22q11.2 Deletion Syndrome.” Am J Med Genet A 2011;155:664-5.
118: Maesen A, Claes SJ, Nevrinck K. Psychiatric disorders in velo-cardio-facial syndrome. Tijdschr Psychiatr 2010;52(1):51-6. PMID 20054797
119: Markert ML, Devlin BH, McCarthy EA. Thymus transplantation. Clin Immunol 2010;135(2):236-46. PMID 20236866
120: Martin N, Mikhaelian M, Cytrynbaum C, et al. 22q11.2 deletion syndrome: attitudes towards disclosing the risk of psychiatric illness. J Genet Couns 2012;21:825-34. PMID 22833231
121: Matthiesen NB, Agergaard P, Henriksen TB, et al. Congenital heart defects and measures of fetal growth in newborns with Down syndrome or 22q11.2 deletion syndrome. J Pediatr 2016;175:116-22.e4. PMID 27245297
122: Maynard TM, Haskell GT, Bhasin N, et al. RanBP1, a velocardiofacial/DiGeorge syndrome candidate gene, is expressed at sites of mesenchymal/epithelial induction. Mech Dev 2002;111(1-2):177-80. PMID 11804793
123: Maynard TM, Haskell GT, Peters AZ, Sikich L, Lieberman JA, LaMantia AS. A comprehensive analysis of 22q11 gene expression in the developing and adult brain. Proc Natl Acad Sci 2003;100(24):14433-8. PMID 14614146
124: Mayo D, Bolden KA, Simon TJ, Niendam TA. Bullying and psychosis: the impact of chronic traumatic stress on psychosis risk in 22q11.2 deletion syndrome - a uniquely vulnerable population. J Psychiatr Res 2019;114:99-104. PMID 31054456
125: McDonald-McGinn DM, Kirschner R, Goldmuntz E, et al. The Philadelphia story: the 22q11.2 deletion: report on 250 patients. Genet Couns 1999;10:11-24. PMID 10191425
126: McDonald-McGinn DM, Sullivan KE. Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Medicine (Baltimore) 2011;90(1):1-18. PMID 21200182
127: Mihailov A, Padula MC, Scariati E, Schaer M, Schneider M, Eliez S. Morphological brain changes associated with negative symptoms in patients with 22q11.2 deletion syndrome. Schizophr Res 2017;188:52-8. PMID 28139357
128: Miyamoto RC, Cotton RT, Rope AF, et al. Association of anterior glottic webs with velocardiofacial syndrome (chromosome 22q11.2 deletion). Otolaryn Head Neck Surg 2004;130(4):415-7. PMID 15100636
129: Moberg PJ, Turetsky BI, Moberg EA, et al. Meta-analysis of olfactory dysfunction in 22q11.2 deletion syndrome. Psychiatry Res 2020;285:112783. PMID 32014626
130: Montojo CA, Ibrahim A, Karlsgodt KH, et al. Disrupted working memory circuitry and psychotic symptoms in 22q11.2 deletion syndrome. Neuroimage Clin 2014;4:392-402. PMID 24567911
131: Morcel K, Watrin T, Pasquier L, et al. Utero-vaginal aplasia (Mayer-Rokitansky-Kuster-Hauser syndrome) associated with deletions in known DiGeorge or DiGeorge-like loci. Orphanet J Rare Dis 2011;6:9. PMID 21406098
132: Murphy KC, Jones LA, Owen MJ. High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry 1999;56:940-5. PMID 10530637
133: Naqvi N, Davidson SJ, Wong D, et al. Predicting 22q11.2 deletion syndrome: A novel method using the routine full blood count. Int J Cardiol 2011;150(1):50-3. PMID 20363518
134: O’Byrne ML, Yang W, Mercer-Rosa L, et al. 22q11.2 deletion syndrome is associated with increased perioperative events and more complicated postoperative course in infants undergoing infant operative correction of truncus arteriosus communis or interrupted aortic arch. J Thorac Cardiovasc Surg 2014;148(4):1597-605. PMID 24629220
135: O’Hanlon JF, Ritchie RC, Smith EA, Patel R. Replacement of antipsychotic and antiepilaeptic medication by L-alpha-methyldopa in a woman with velocardiofacial syndrome. Int Clin Psychopharmacol 2003;18:117-9. PMID 12598825
136: Oki M, Hori S, Asayama S, Wate R, Kaneko S, Kusaka H. Early-onset Parkinson's disease associated with chromosome 22q11.2 deletion syndrome. Intern Med 2016;55(3):303-5. PMID 26831029
137: Olszewski AK, Kikinis Z, Gonzalez CS, et al. The social brain network in 22q11.2 deletion syndrome: a diffusion tensor imaging study. Behav Brain Funct 2017;13(1):4. PMID 28209179
138: Oppenheimer AG, Fulmer S, Shifteh K, et al. Cervical vascular and upper airway asymmetry in Velo-cardio-facial syndrome: correlation of nasopharyngoscopy with MRA. Int J Pediatr Otorhinolaryngol 2010;74(6):619-25. PMID 20363509
139: Oskarsdottir S, Boot E, Crowley TB, et al. Updated clinical practice recommendations for managing children with 22q11.2 deletion syndrome. Genet Med 2023;25(3):100338. PMID 36729053
140: Ousley O, Evans AN, Fernandez-Carriba S, et al. Examining the overlap between autism spectrum disorder and 22q11.2 deletion syndrome. Int J Mol Sci 2017;18(5). PMID 28524075
141: Papolos DF, Faedda GL, Veit S, et al. Bipolar spectrum disorders in patients diagnosed with velo-cardio-facial syndrome: does a hemizygous deletion of chromosome 22q11 result in bipolar affective disorder. Am J Psychiatry 1996;153:1541-7. PMID 8942449
142: Passeri E, Frigerio M, Valaperta R, Costa E, Ambrosi B, Corbetta S. Adult onset hypoparathyroidism in a patient with psychiatric illness: a 71 years delayed diagnosis of DiGeorge syndrome. J Endocrinol Invest 2010;33(11):852-3. PMID 21293174
143: Peyvandi S, Lupo PJ, Garbarini J, et al. 22q11.2 deletions in patients with conotruncal defects: data from 1,610 consecutive cases. Pediatr Cardiol 2013;34(7):1687-94. PMID 23604262
144: Philip N, Bassett A. Cognitive, behavioural and psychiatric phenotype in 22q11.2 deletion syndrome. Behav Genet 2011;41(3):403-12. PMID 21573985
145: Pignatelli RH, McMahon CJ, Dreyer WJ, et al. Clinical characterization of left ventricular noncompaction in children: a relatively common form of cardiomyopathy. Circulation 2003;108(21):2672-8. PMID 14623814
146: Pizzuti A, Novelli G, Mari A, et al. Human homologue sequences to the Drosophila disheveled segment-polarity gene are deleted in the DiGeorge syndrome. Am J Hum Genet 1996;58:722-9. PMID 8644734
147: Pollard R, Hannan M, Tanabe J, Berman BD. Early-onset Parkinson disease leading to diagnosis of 22q11.2 deletion syndrome. Parkinsonism Relat Disord 2016;25:110-1. PMID 26868161
148: Pontillo M, Menghini D, Vicari S. Neurocognitive profile and onset of psychosis symptoms in children, adolescents and young adults with 22q11 deletion syndrome: a longitudinal study. Schizophr Res 2019;208:76-81. PMID 31056275
149: Praharaj SK, Sarkar S, Sinha VK. Velocardiofacial syndrome presenting as chronic mania. Psychiatry Clin Neurosci 2010;64(6):666. PMID 21105957
150: Prasad SE, Howley S, Murphy KC. Candidate genes and the behavioral phenotype in 22q11.2 deletion syndrome. Dev Disabil Res Rev 2008;14:26-34. PMID 18636634
151: Pulver AE, Nestadt G, Goldberg R, et al. Psychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives. J Nerv Ment Dis 1994;182:476-8. PMID 8040660
152: Radio FC, Digilio MC, Capolino R, et al. Sprengel anomaly in deletion 22q11.2 (DiGeorge/Velo-Cardio-Facial) syndrome. Am J Med Genet A 2016;170(3):661-4. PMID 26686844
153: Rogdaki M, Gudbrandsen M, McCutcheon RA, et al. Magnitude and heterogeneity of brain structural abnormalities in 22q11.2 deletion syndrome: a meta-analysis. Mol Psychiatry 2020;25(8):1704-17. PMID 31925327
154: Ryan AK, Goodship JA, Wilson DI, et al. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet 1997;34:798-804. PMID 9350810
155: Sacca R, Zur KB, Crowley TB, et al. Association of airway abnormalities with 22q11.2 deletion syndrome. Int J Pediatr Otorhinolaryngol 2017;96:11-4. PMID 28390597
156: Sandini C, Chambaz M, Schneider M, et al. Pituitary dysmaturation affects psychopathology and neurodevelopment in 22q11.2 deletion syndrome. Psychoneuroendocrinology 2020;113:104540. PMID 31958652
157: Sarnat HB, Flores-Sarnat L. Radial micro-columnar cortical architecture: maturational arrest or focal cortical dysplasia. Pediatr Neurol 2013;48:259-70. PMID 23498558
158: Scambler PJ, Carey AH, Wyse RK, et al. Microdeletions within 22q11 associated with sporadic and familial DiGeorge syndrome. Genomics 1991;10:201-6. PMID 2045103
159: Scambler PJ, Kelly D, Lindsay E, et al. Velo-cardio-facial syndrome associated with chromosome 22 deletions encompassing the DiGeorge locus. Lancet 1992;339:1138-9. PMID 1349369
160: Scariati E, Padula MC, Schaer M, Eliez S. Long-range dysconnectivity in frontal and midline structures is associated to psychosis in 22q11.2 deletion syndrome. J Neural Transm (Vienna) 2016;123(8):823-39. PMID 27094177
161: Segni M, Zimmerman D. Autoimmune hyperthyroidism in two adolescents with DiGeorge/velocardiofacial syndrome (22q11 deletion). Eur J Pediatr 2002;161(4):233-4. PMID 12014397
162: Shashi V, Harrell W, Eack S, et al. Social cognitive training in adolescents with chromosome 22q11.2 deletion syndrome: feasibility and preliminary effects of the intervention. J Intellect Disabil Res 2015;59(10):902-13. PMID 25871427
163: Shiohama A, Sasaki T, Noda S, Minoshima S, Shimizu N. Molecular cloning and expression analysis of a novel gene DGCR8 in the DiGeorge syndrome chromosomal region. Biochem Biophys Res Commun 2003;304(1):184-90. PMID 12705904
164: Shprintzen RJ. Velo-cardio-facial syndrome: 30 years of study. Dev Disabil Res Rev 2008;14:3-10. PMID 18636631
165: Shprintzen RJ, Goldberg RB, Lewin ML, et al. A new syndrome involving cleft palate, cardiac anomalies, typical facies, and learning disabilities: velo-cardio-facial syndrome. Cleft Palate J 1978;5:56-62. PMID 272242
166: Shugar AL, Shapiro JM, Cytrynbaum C, Hedges S, Weksberg R, Fishman L. An increased prevalence of thyroid disease in children with 2q11.2 deletion syndrome. Am J Med Genet A 2015;167(7):1560-4. PMID 25944702
167: Simao I, Lourenço T, Lopes L, Ramos MP. First seizure as late presentation of velo-cardio-facial syndrome. J Pediatr Endocrinol Metab 2013;26:381-3. PMID 23327824
168: Sirotkin H, Morrow B, Saint-Jore B, et al. Identification, characterization, and precise mapping of a human gene encoding a novel membrane-spanning protein from the 22q11 region deleted in velo-cardio-facial syndrome. Genomics 1997;42:245-51. PMID 9192844
169: Sobin C, Kiley-Brabeck K, Dale K, et al. Olfactory disorder in children with 22q11 deletion syndrome. Pediatrics 2006;118(3):e697-703. PMID 16908619
170: Spruijt NE, Reijmanhinze J, Hens G, Vander Poorten V, Mink van der Molen AB. In search of the optimal surgical treatment for velopharyngeal dysfunction in 22q11.2 deletion syndrome: a systematic review. PLoS One 2012a;7(3):e34332. PMID 22470558
171: Spruijt NE, Widdershoven JC, Breugem C, et al. Velopharyngeal dysfunction and 22q11.2 deletion syndrome: A longitudinal study of functional outcome and preoperative prognostic factors. Cleft Palate Craniofac J 2012b;49(4):447-55. PMID 21740170
172: Stollberger C, Finsterer J. Noncompaction is already known in DiGeorge anomaly from 22q11.2 deletion. Am J Med Genet A 2011;155(3):662-3. PMID 21337687
173: Stoller JZ, Epstein JA. Identification of a novel nuclear localization signal in Tbx1 that is deleted in DiGeorge syndrome patients harboring the 1223delC mutation. Hum Mol Genet 2005;14(7):885-92. PMID 15703190
174: Stoller JZ, Huang L, Tan CC, et al. Ash2l interacts with Tbx1 and is required during early embryogenesis. Exp Biol Med (Maywood) 2010;235(5):569-76. PMID 20463296
175: Stransky C, Basta M, McDonald-McGinn DM, et al. Perioperative risk factors in patients with 22q11.2 deletion syndrome requiring surgery for velopharyngeal dysfunction. Cleft Palate Craniofac J 2015;52(2):183-91. PMID 24805875
176: Strong WB. Familial syndrome of right-sided aortic arch, mental deficiency, and facial dysmorphism. J Pediatr 1968;73:882-8. PMID 5696314
177: Sullivan KE, Jawad AF, Randall P, et al. Lack of correlation between impaired T cell production, immunodeficiency, and other phenotypic features in chromosome 22q11.2 deletion syndromes (DiGeorge syndrome/velocardiofacial syndrome). Clin Immunol Immunopathol 1998;86:141-6. PMID 9473376
178: Sullivan KE, McDonald-McGinn DM, Driscoll DA, et al. Juvenile rheumatoid arthritis-like polyarthritis in chromosome 22q11.2 deletion syndrome (DiGeorge anomalad/velocardiofacial syndrome/conotruncal anomaly face syndrome). Arthritis Rheum 1997;40:430-6. PMID 9082929
179: Swillen A, Devriendt K, Legius E, et al. Intelligence and psychosocial adjustment in velocardiofacial syndrome: a study of 37 children and adolescents with VCFS. J Med Genet 1997;34:453-8. PMID 9192263
180: Swillen A, McDonald-McGinn D. Developmental trajectories in 22q11.2 deletion. Am J Med Genet C Semin Med Genet 2015;169(2):172-81. PMID 25989227
181: Sykes KS, Bachrach LK, Siegel-Bartelt J. Velocardiofacial syndrome presenting as hypocalcemia in early adolescence. Arch Pediatr Med 1997;151:745-7. PMID 9232055
182: Szczawinska-Poplonyk A, Schwartzmann E, Chmara Z, et al. Chromosome 22q11.2 deletion syndrome: a comprehensive review of molecular genetics in the context of multidisciplinary clinical approach. Int J Mol Sci 2023;24(9):8317. PMID 37176024
183: Taddei I, Morishima M, Huynh T, Lindsay EA. Genetic factors are major determinants of phenotypic variability in a mouse model of DiGeorge/del22q11 syndromes. Proc Natl Acad Sci 2001;98(20):11428-31. PMID 11562466
184: Tastuzawa Y, Sekikawa K, Suda T, et al. An interictal schizophrenia-like psychosis in an adult patient with 22q11.2 deletion syndrome. Epilepsy Behav Case Rep 2015;3:36-8. PMID 25870791
185: Taylor SC, Morris G, Wilson D, Davies SJ, Gregory JW. Hypoparathyroidism and 22q11 deletion syndrome. Arch Dis Child 2003;88(6):520-2. PMID 12765920
186: Tenhola S, Hendy GN, Valta H, et al. Cinacalcet treatment in an adolescent with concurrent 22q11.2 deletion syndrome and Familial Hypocalciuric Hypercalcemia Type 3 caused by AP2S1 mutation. J Clin Endocrinol Metab 2015;100(7):2515-8. PMID 25993639
187: Thomas J, Graham J. Chromosome 22q11 deletion syndrome: an update and review for the primary pediatrician. Clin Pediatr 1997;36:253-66. PMID 9152551
188: Tsai PL, Lian LM, Chen WH. Hypocalcemic seizure mistaken for idiopathic epilepsy in two cases of DiGeorge syndrome (chromosome 22q11 deletion syndrome). Acta Neurol Taiwan 2009;18(4):272-5. PMID 20329596
189: Ueda Y, Uraki S, Inaba H, et al. Graves' disease in pediatric and elderly patients with 22q11.2 deletion syndrome. Intern Med 2017;56(10):1169-73. PMID 28502931
190: Unolt M, Barry J, Digilio MC, et al. Primary lymphedema and other lymphatic anomalies are associated with 22q11.2 deletion syndrome. Eur J Med Genet 2018;61(7):411-5. PMID 29447908
191: Van L, Boot E, Bassett AS. Update on the 22q11.2 deletion syndrome and its relevance to schizophrenia. Curr Opin Psychiatry 2017;30(3):191-6. PMID 28230630
192: Van L, Heung T, Graffi J, et al. All-cause mortality and survival in adults with 22q11.2 deletion syndrome. Genet Med 2019;21(10):2328-35. PMID 30948858
193: Van Batavia JP, Crowley TB, Burrows E, et al. Anomalies of the genitourinary tract in children with 22q11.2 deletion syndrome. Am J Med Genet A 2019;179(3):381-5. PMID 30582277
194: van den Bree MB, Miller G, Mansell E, Thapar A, Flinter F, Owen MJ. The internet is parents’ main source of information about psychiatric manifestations of 22q11.2 deletion syndrome (22q11.2DS). Eur J Med Genet 2013;56(8):439-41. PMID 23707654
195: Van Eynde C, Swillen A, Lambeens E, et al. Prevalence and nature of hearing loss in 22q11.2 deletion syndrome. J Speech Lang Hear Res 2016;59(3):583-9. PMID 27249537
196: Veerapandiyan A, Blalock D, Ghosh S, Ip E, Barnes C, Shashi V. The role of cephalometry in assessing velopharyngeal dysfunction in velocardiofacial syndrome. Laryngoscope 2011;121(4):732-7. PMID 21305558
197: Verheij E, Elden L, Crowley TB, et al. Anatomic malformations of the middle and inner ear in 22q11.2 deletion syndrome: case series and literature review. AJNR Am J Neuroradiol 2018;39(5):928-34. PMID 29545254
198: Verschure DO, Boot E, van Amelsvoort TA, et al. Cardiac sympathetic activity in 22q11.2 deletion syndrome. Int J Cardiol 2016;212:346-51. PMID 27057952
199: Vieira TP, Monteiro FP, Sgardioli IC, et al. Clinical features in patients with 22q11.2 deletion syndrome ascertained by palatal abnormalities. Cleft Palate Craniofac J 2015;52(4):411-6. PMID 24805874
200: Villalon-Reina J, Jahanshad N, Beaton E, Toga AW, Thompson PM, Simon TJ. White matter microstructural abnormalities in girls with chromosome 22q11.2 deletion syndrome, Fragile X or Turner syndrome as evidenced by diffusion tensor imaging. Neuroimage 2013;81:441-54. PMID 23602925
201: Vingerhoets C, van Oudenaren MJF, Bloemen OJN, et al. Low prevalence of substance use in people with 22q11.2 deletion syndrome. Br J Psychiatry 2019:1-7. PMID 30604657
202: Vogels A, Schevenels S, Cayenberghs R, et al. Presenting symptoms in adults with the 22q11 deletion syndrome. Eur J Med Genet 2014;57(4):157-62. PMID 24576609
203: Vora NL, O’Brien BM. Noninvasive prenatal testing for microdeletion syndromes and expanded trisomies: proceed with caution. Obstet Gynecol 2014;123(5):1097-9. PMID 24785862
204: Vorstman JA, Morcus ME, Duijff SN, et al. The 22q11.2 deletion in children: high rate of autistic disorders and early onset of psychotic symptoms. J Am Acad Child Adolesc Psychiatry 2006;45(9):1104-13. PMID 16926618
205: Wadey R, Daw S, Taylor C, et al. Isolation of a gene encoding an integral membrane protein from the vicinity of a balanced translocation breakpoint associated with DiGeorge syndrome. Hum Mol Genet 1995;4:1027-33. PMID 7655455
206: Wagner KE, Kates WR, Fremont W, Antshel KM. Childhood predictors of young adult social functioning in 22q11.2 deletion syndrome. J Autism Dev Disord 2017;47(8):2480-501. PMID 28527096
207: Walkowiak D, Domaradzki J. Parental experiences and needs of caring for a child with 22q11.2 deletion syndrome. Orphanet J Rare Dis 2023;18(1):379. PMID 38049864
208: Wapner RJ, Babiarz JE, Levy B, et al. Expanding the scope of noninvasive prenatal testing: detection of fetal microdeletion syndromes. Am J Obstet Gynecol 2015;212(3):332.e1-9. PMID 25479548
209: Weinshilboum RM, Raymond FA. Inheritance of low erythrocyte catechol-O-methyltransferase activity in man. Am J Med Genet 1977;29:125-35. PMID 848488
210: Weinzimer SA, McDonald-McGinn DM, Driscoll DA, et al. Growth hormone deficiency in patients with a 22q11.2 deletion: expanding the phenotype. Pediatrics 1998;101:929-32. PMID 9565428
211: Widdershoven JC, Beemer FA, Kon M, Dejonckere PH, Mink van der Molen AB. Possible mechanisms and gene involvement in speech problems in the 22q11.2 deletion syndrome. J Plast Reconstr Aesthet Surg 2008;61:1016-23. PMID 18554997
212: Wilson DI, Burn J, Scambler P, Goodship J. DiGeorge syndrome: part of CATCH22. J Med Genet 1993;30:852-6. PMID 8230162
213: Wither RG, Borlot F, MacDonald A, et al. 22q11.2 deletion syndrome lowers seizure threshold in adult patients without epilepsy. Epilepsia 2017;58(6):1095-101. PMID 28448680
214: Wong LM, Riggins T, Harvey D, Cabaral M, Simon TJ. Children with chromosome 22q11.2 deletion syndrome exhibit impaired spatial working memory. Am J Intellect Dev Disabil 2014;119(2):115-32. PMID 24679349
215: Woolman P, Bearl DW, Soslow JH, et al. Characteristics and outcomes of heart transplantation in DiGeorge Syndrome. Pediatr Cardiol 2019;40(4):768-75. PMID 30729260
216: Worthington S, Cooley A, Fagan K, Dai K, Lipson AH. Anal anomalies: an uncommon feature of velocardiofacial (Shprintzen) syndrome. J Med Genet 1997;34:79-82. PMID 9032655
217: Wulfsberg EA, Leana-Cox J, Neri G. What's in a name. Chromosome 22q abnormalities and the DiGeorge, velocardiofacial, and conotruncal anomaly face syndromes. Am J Med Genet 1996;65:317-9. PMID 8923942
218: Yamagishi H, Garg V, Matsuoka R, Thomas T, Srivastava D. A molecular pathway revealing a genetic basis for human cardiac and craniofacial defects. Science 1999;283:1158-61. PMID 10024240
219: Yang HC, Lin SH, Wu YY, Sung CC. Hypoparathyroidism concomitant with macrothrombocytopenia in an elderly woman with 22q11.2 deletion syndrome. Platelets 2018;29(7):733-6. PMID 29851532
220: Yirmiya ET, Mekori-Domachevsky E, Weinberger R, Taler M, Carmel M, Gothelf D. Exploring the potential association among sleep disturbances, cognitive impairments, and immune activation in 22q11.2 deletion syndrome. Am J Med Genet A 2020;182(3):461-468. PMID 31837200
221: Young D, Shprintzen RJ, Goldberg RB. Cardiac malformations in the velocardiofacial syndrome. Am J Cardiol 1980;46:643-8. PMID 7416023
222: Zinkstok J, van Amelsvoort T. Neuropsychological profile and neuroimaging in patients with 22q11.2 deletion syndrome: a review. Child Neuropsych 2005;11(1):21-37. PMID 15823981
223: Zinkstok JR, Velders F, Rieken R, et al. Psychosis and movement disorders in an adolescent with 22q11.2 deletion syndrome. Tijdschr Psychiatr 2020;62(3):229-33. PMID 32207133
224: Zoupa M, Seppala M, Mitsiadis T, Cobourne MT. Tbx1 is expressed in multiple sites of epithelial-mesenchymal interaction during early development of the facial complex. Int J Dev Biol 2006;50(5):504-10. PMID 16586352

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Robin Godshalk MS MHA

Dr. Godshalk of Fragile X Center at Atlantic Health System in Morristown, New Jersey has no relevant financial relationships to disclose.
See Profile

Editor

Ganeshwaran H Mochida MD

Dr. Mochida of Boston Children's Hospital and Harvard Medical School has no relevant financial relationships to disclose.
See Profile

Former Authors

Mary Beth Dinulos MD
William D Graf MD
Joseph R Siebert PhD

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male=female
Heredity: heredity typical

heredity may be a factor

autosomal dominant
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-11: CATCH 22 phenotype: LD44.N0
OMIM: Velocardiofacial syndrome: #192430

DiGeorge syndrome: #188400

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

22q11.2 deletion syndrome

Differential Diagnosis

autosomal dominant Opitz GBBB syndrome
CHARGE association
Kabuki syndrome

Also Relevant

Cavum septi pellucidi and cavum vergae
Developmental language disorder
Intravenous immune globulin
Microcephaly
Myopathies associated with parathyroid disorders
- Polymicrogyria

22q11.2 deletion syndrome

22q11.2 deletion syndrome

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Table 1. DiGeorge and Velocardiofacial Syndrome Candidate Genes within the Typically Deleted Region

Epidemiology

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Special considerations

Pregnancy

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Cerebro-oculo-facio-skeletal syndrome

Malformations of the brain

Von Hippel-Lindau disease

Vein of Galen malformations

Mobius syndrome

Epileptic lesions due to malformation of cortical development

Agenesis of the corpus callosum

Epidermal nevus syndromes: neurologic phenotypes

22q11.2 deletion syndrome

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Table 1. DiGeorge and Velocardiofacial Syndrome Candidate Genes within the Typically Deleted Region

Epidemiology

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Special considerations

Pregnancy

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Cerebro-oculo-facio-skeletal syndrome

Malformations of the brain

Von Hippel-Lindau disease

Vein of Galen malformations

Mobius syndrome

Epileptic lesions due to malformation of cortical development

Agenesis of the corpus callosum

Epidermal nevus syndromes: neurologic phenotypes

This is an article preview.
Start a Free Account
to access the full version.