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

Editor: Ganeshwaran H Mochida MD

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

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22q11.2 deletion syndrome

Differential Diagnosis

autosomal dominant Opitz GBBB syndrome
CHARGE association
Kabuki syndrome

Also Relevant

Cavum septi pellucidi and cavum vergae
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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

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Also in This Category

Walker-Warburg syndrome

Porencephaly

Cavum septi pellucidi and cavum Vergae

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Reducing body myopathy

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

Walker-Warburg syndrome

Porencephaly

Cavum septi pellucidi and cavum Vergae

Aicardi-Goutieres syndrome

Oral-facial-digital syndromes

Rett syndrome

Myelomeningocele

Reducing body myopathy

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