22q11.2 Deletion syndrome

What is 22q11.2 Deletion syndrome?

22q11.2 deletion syndrome, or as it is sometimes referred to, DiGeorge syndrome, is a genetic disorder. It is often referred to by several different names and presents with a wide range of symptoms that can affect almost any part of the body. The characteristics and symptoms of the syndrome vary greatly between individuals and even amongst individuals with the same family syndrome.

Syndrome Synonyms:
CATCH 22 Chromosome 22q11.2 - microdeletion Chromosome 22q11.2 Deletion Syndrome Conotruncal anomaly-facies syndrome Conotruncalanomalyfaciessyndrome DiGeorge syndrome; DGS Hypoplasia Of Thymus And Parathyroids Sedlackova syndrome Shprintzen syndrome Shprintzen Vcf Syndrome Takao syndrome Takaosyndrome Third And Fourth Pharyngeal Pouch Syndrome Velocardiofacial Syndrome

What gene changes cause 22q11.2 Deletion syndrome?

22q11.2 deletion syndrome occurs due to the deletion of DNA base pairs on chromosome 22. Known as a contiguous gene deletion syndrome, researchers are currently identifying the specific gene deletions that contribute to each of the syndrome's various symptoms.

Microdeletion inheritance occurs when there is a deletion of several genes on a chromosome. The specific chromosome on which the deletions occur will determine the syndrome they cause.

1 in every 4,000 live births in the US will present with 22q11.2 deletion syndrome, and most cases are the first in a family. In 1 in 10 cases, one parent will pass the deletion to their child.

Genes, locations, and inheritance modes
COMT, 22q11.21 - Autosomal Dominant
SEC24C, 10q22.2 - Autosomal Dominant
ARVCF, 22q11.21 - Autosomal Dominant
JMJD1C, 10q21.3 - Autosomal Dominant
DGCR6, 22q11.21 - Autosomal Dominant
FGF8, 10q24.32 - Autosomal Dominant
ESS2, 22q11.21 - Autosomal Dominant
DGCR8, 22q11.21 - Autosomal Dominant
HIRA, 22q11.21 - Autosomal Dominant
RREB1, 6p24.3 - Autosomal Dominant
CRKL, 22q11.21 - Autosomal Dominant
DGCR2, 22q11.21 - Autosomal Dominant
TBX1, 22q11.21 - Autosomal Dominant
GP1BB, 22q11.21 - Autosomal Dominant

OMIM Number - 192430 (please check the OMIM page for updated information)

What are the main symptoms of 22q11.2 Deletion syndrome?

22q11.2 deletion syndrome and DiGeorge syndrome represent a spectrum of syndromes that share congenital heart defects, immunological abnormalities, and variable facial features.

The main symptoms of 22q11.2 deletion syndrome can vary significantly between individuals. Congenital heart defects are a common feature of the syndrome. Other health conditions include cleft palate, feeding issues, gastrointestinal problems, problems with the immune system and resultant infections, low levels of calcium in the blood and related health conditions, ENT issues, and missing or damaged kidneys.

Mental health conditions associated with 22q11.2 deletion syndrome include increased risk for OCD, autism, ADD, and delays in growth, speech, and the potential for learning disabilities. Behavioral and developmental delays are common.

Possible clinical traits/features:
Underdeveloped nasal alae, Hypocalcemia, Nasal speech, Impaired T cell function, Short stature, Velopharyngeal insufficiency, Retrognathia, Open mouth, Pierre-Robin sequence, Autosomal dominant inheritance, Right aortic arch with mirror image branching, Recurrent infections, Unilateral primary pulmonary dysgenesis, Retinal vascular tortuosity, Paranoia, Microcephaly, Umbilical hernia, Ventricular septal defect, Tetralogy of Fallot, Posterior embryotoxon, Aggressive behavior, Cleft palate, Blepharophimosis, Bulbous nose, Abnormality of the endocrine system, Abnormality of the ear, Abnormality of the hand, Mood swings, Muscular hypotonia, Inguinal hernia, Intellectual disability, Specific learning disability

How does someone get tested for 22q11.2 Deletion syndrome?

The initial testing for 22q11.2 deletion syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow. 

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing. 

Medical information on 22q11.2 Deletion syndrome

* Based on London Medical Databases (LMD)

This syndrome combines cardiac anomalies with an unusual facial appearance, cleft palate (often submucous), short stature and long, thin, hyperextensible fingers. The presentation is variable and can also include learning difficulties, feeding and swallowing issues, immune deficiency, and hypocalcemia. It is caused by deletions in 22q11.2.

Although Shprintzen has been awarded the eponym, Gorlin et al., (2001), Turnpenny et al., (2001) and Fokstuen et al., (2000) point out that Sedlackova may have reported the syndrome first. It has been suggested that all these conditions should be included under the designation CATCH 22 (Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, and Hypocalcemia resulting from 22q11 deletions) (Wilson et al., 1993), however it may be difficult to use this designation with families. Microdeletions of 22q11 have been seen in patients with DiGeorge syndrome, velo-cardio-facial (Shprintzen) syndrome, isolated conotruncal cardiac defects and truncus arteriosus-facial dysmorphism. There is considerable overlap with DiGeorge syndrome, and the majority of patients can be shown to have 22q11 deletions at the molecular level (Driscoll et al., 1992; Scambler et al., 1992; Kelly et al., 1993). Driscoll et al., (1993) showed that deletions of 22q11 are present in 76% of VCFS patients by FISH. Lindsay et al., (1995) found deletions in 81% of patients clinically diagnosed as having VCFS.

Jedele et al., (1992) reported 15 patients with a severe form of Fallot tetralogy and hypoplastic pulmonary arteries.

About 10% to 20% of cases will have a parent who also carries the deletion (Smith and Robson 1999; Swillen et al., 1998). Wilson et al., (1994) estimated the minimum prevalence of 22q11 deletions to be 1 in 4,000 births based on the fact that these deletions have been found in at least 5% of congenital heart defect patients. Du Montchel et al., (1996) found a prevalence of 1 in 10,000 in infants with a typical clinical picture. They concluded that the true prevalence accounting for milder or atypical cases is higher.

The face is characterized by a prominent nose with a squared-off nasal tip (sometimes with a dimple or groove, Kirkpatrick and Pauli 1998; Stratton and Payne 1997; Grip et al., 1997), and notched alae nasi, micrognathia, microcephaly (sometimes), and occasionally ocular abnormalities (microphthalmia, strabismus, cataracts, small optic discs and tortuous retinal vessels). Six patients reported by Binenbaum et al., (2006) had corneal clouding. Casteels and Devriendt, (2005) reported a case with unilateral Peters' anomaly. Forbes et al., (2007) review the ocular findings.

Rauch et al., (2004), suggest that in those patients with conotruncal anomalies, subclavian artery abnormalities are frequent and are the best anatomical markers for 22q11 deletions. Webber et al., (1996) showed that 22q11 deletions were present in 15-20% of cases with ventricular outflow tract defects or aortic arch abnormalities. Raymond et al., (1997) recommended carrying out FISH 22q11 analysis on all fetuses diagnosed as having conotruncal anomalies.

The cardiac anomalies can include ventriculo-septal defects, pulmonary stenosis and double outlet right ventricle. The internal carotid arteries are reported to be medially placed and tortuous (Goldberg et al., 1993).

Seaver et al., (1994) reported a group of patients with pulmonary atresia where the additional clinical features would fit into the VCF group. These children were subsequently found to have the 22q11.2 deletion characteristic of the syndrome (see below). In all cases the maternal 22 was deleted, suggesting a parent of origin effect.

Goodship et al., (1995) and Hillebrand et al., (2000) reported monozygotic twins with velo-cardio-facial/DiGeorge syndrome who were discordant for heart defects.

Worthington et al., (1998) studied 90 children with conotruncal malformations and found 22q11 deletions in 15 (17%). All the children with the deletions were said to have dysmorphic facies. Johnson et al., (1997) also found a high incidence among cases with tetralogy of Fallot/pulmonary atresia, as well as interrupted aortic arch anomalies and truncus arteriosus.

Fokstuen et al., (1998) found no 22q11 deletions in 59 cases of non-syndromic congenital heart defect. They provide a good review of the studies up to that point.

Lu et al., (1999) studied 18 patients with pulmonary atresia and found six (33%) had a 22q11 microdeletion. Of 66 patients with pulmonary stenosis, eight (12%) had a deletion. Seven percent of parents were found to have a deletion.

McElhinney et al., (2001) found cardiac malformations in 11 out of 29 patients diagnosed after the age of six months. These included three with vascular rings, three with a right aortic arch with mirror-image branching of the brachiocephalic arteries, one with a patent ductus arteriosus and four with an aberrant right subclavian artery.

Voigt et al., (2002) studied 100 patients with isolated and syndromic conotruncal heart defects and found 22q11 deletions in two cases. No cases with 10p13-14 deletions were detected.

McElhinney et al., (2003) studied 125 cases with a VSD. A 22q11 deletion was detected in 12 (10%) of the 125 patients. Anatomic features that were significantly associated with a chromosome 22q11 deletion included abnormal aortic arch sidedness, an abnormal aortic arch branching pattern, a cervical aortic arch, and discontinuous pulmonary arteries. There was no correlation between the type of VSD and chromosome 22q11 deletion. Of 20 patients with an abnormal aortic arch and/or discontinuous pulmonary arteries, 45% had a chromosome 22q11 deletion, compared with only 3% of those with a left aortic arch, normal aortic arch branching pattern, and continuous branch pulmonary arteries.

Cunningham et al., (2003), Conway et al., (2002), and Fitoz et al., (2001) reported cases with unilateral pulmonary agenesis. Tanaka et al., (2001) reported a case with a dissecting pulmonary arterial aneurysm presenting at 10 days of age, having been born at 34 weeks. Marino et al., (1997) reported two cases with tricuspid atresia associated with 22q11 deletion. Marble et al., (1998) reported a case with transposition of the great arteries.

Cleft lip and palate can occasionally be a feature (Schulze et al., 2001). In these cases, there may be significant hypertelorism. Ruiter et al., (2003) found one 22q11 FISH deletion out of 45 patients with isolated cleft palate and from the literature estimated the prevalence of deletions in this group to be 1%. Van den Elzen et al., (2001) found that 8% and Holder-Espinasse et al., (2001) found that 3% of cases of a series of Pierre-Robin syndrome had 22q11 deletions. Mingarelli et al., (1996) found no cases with a 22q11 deletion by FISH in 38 cases with isolated cleft palate.

Intellectual disability, defined as an IQ below 70, is present in less than 50% of cases and is usually mild (Swillen et al., 1997). Gerdes et al., (1999) studied 40 preschool children and found language and speech delays, not explained by palatal or cardiac defects with therapeutic intervention. The average IQ was about 80. Waite et al., (2002) studied 211 children with developmental delay and found no individuals with 22q11 deletions.

Scherer et al., (1999) reported specific speech and language development deficits in young children. Swillen et al., (2002) studied 31 children with a control group of children with speech-language impairment and found that the del 22q11 children had a greater tendency to withdraw from others, but were less aggressive. Glaser et al., (2002) studied 27 children with the condition and found that there were more severe deficits in receptive than expressive language abilities. In addition, children had significantly higher receptive language abilities if the deletion was of paternal origin.

Middle and inner ear abnormalities were commented on by Devriendt et al., (2004).

Shprintzen et al., (1992) reported that over 10% of their original cases had developed personality disturbance in adolescence or later evidence of chronic schizophrenia with paranoid delusions. Chow et al., (1994) gave detailed case reports of two patients with psychotic disorders. Three further patients were reported by McCandless et al., (1998).

Further adult cases with schizophrenia and 22q11 deletions were reported by Basset et al., (1998) and in a further study, Bassett et al., (2005) reported on 78 adults. Twenty-two percent had developed schizophrenia. A slightly larger number had cardiac problems.

Cohen et al., (1999) reviewed the clinical features in an adult population. Thirty six percent of cases had psychiatric problems as compared to 18% reported in the European study (Ryan et al., 1997). Arinami et al., (2001) studied 300 patients with schizophrenia and found a 22q11 deletion in only one.

Carlson et al., (1997) studied 26 patients. Four out of six children under 10 years of age were diagnosed with attention-deficit disorder, and four of the six patients over 20 years of age had psychotic symptoms. Nineteen patients out of twenty over 11 years of age were affected with bipolar spectrum disorders. More details are given by Papolos et al., (1996). Gothelf et al., (1997) studied schizophrenic patients with features of VCFS and found 22q11 deletions in three out of 15.

Patients with thrombocytopenia showed an increased risk of developing schizophrenia. Kato et al., (2003) studied patients with thrombocytopenia and 22q11 deletions. They had a larger mean platelet volume, lower agglutination to ristocetin, and lower protein level of glycoprotein Ib-beta than control patients.

Salvesen-Sykes et al., (1997) reported three cases where hypocalcemia became apparent in early adolescence. Hypocalcemia may be present in 10-30% of cases after the neonatal period (Taylor et al., 2003). Brauner et al., (2003) studied 39 cases and found that parathyroid function was abnormal in 27 (69%). This was not diagnosed in the majority.

Jawad et al., (2001) review the immunological abnormalities in these conditions, which consist of diminished T-cell counts. Rasmussen et al., (1996) reported two cases with juvenile rheumatoid arthritis. Further cases with this association have also been reported (Verloes et al., 1998; Keenan et al., 1997; Sullivan et al., 1997). The clinical features can be very variable (Britt Ravnan et al., 1996).

Eicher et al., (2000) discuss the association of early dysphagia in these children and suggest that dysmotility is a cause. Zori et al., (1998) found 22q11 deletions in six out of 16 patients with velopharyngeal insufficiency of unknown cause. Versteegh et al., (2000) reported a case with Duane syndrome - there was a laryngeal web (see below).

Fokstuen et al., (1997) reported three cases with the 22q11 deletion who had a type III laryngeal atresia (Glottic web). Marble et al., (1998) reported a mother and son with similar features. Stoler et al., (1998) reported two children with anterior laryngeal webs. McElhinney et al., (2002) found a chromosomal abnormality in seven of 12 patients with a laryngeal web, including a 22q11 deletion in six and trisomy 21 in one.

A number of tooth anomalies have been reported, including abnormalities of enamel, tooth shape, numbers of teeth and dental eruption (Heliovaara et al., 2011, Klingberg et al., 2002). Oberoi and Vargervik (2005) reported three affected sibs, one of whom had a single central, mandibular incisor and another with a single central maxillary incisor.

Coppola et al., (2001) reported two cases with idiopathic partial seizures in the absence of hypocalcemia. Roubertie et al., (2001) reported a case with atypical absence epilepsy. In the cohort of patients studied by Kao et al., (2004), 7% had an unprovoked seizure. Baralle et al., (2002) reported a mother and child with a myoclonic movement disorder.

Kawame et al., (2001) reported four patients who present with hyperthyroidism between the ages of 27 months and 16 years.

Occasional cases have had craniosynostosis (Yamamoto et al., 2006; De Silva et al., 1995). The case reported by lida et al., (1995) may be an example, but FISH studies were not carried out - see also the comments by Dean et al., (1998). Derbent et al., (2003) reported a case with features of hemifacial microsomia, and craniosynostosis was found by Karteszi et al., (2004), to be the presenting feature. Nickel et al., (1994) reported two cases associated with meningomyeloceles, however, Nickel and Magenis (1996) found that 22q11 deletions were infrequent in a general population of patients with neural tube defects.

Mitnick et al., (1994) and Altman et al., (1995) discussed brain abnormalities in cases with this condition. These included a small cerebellar vermis, cysts adjacent to the frontal horns, a small posterior fossa, and focal signal hyperintensities in the white matter on MRI scanning. Devriendt et al., (1996) reported a case with cerebellar hypoplasia. Lynch et al., (1995) reported an adult case with cerebellar atrophy.

Robin et al., (2006) concluded that perisylvian polymicrogyria (especially unilateral lesions) were a common occurrence in 22q11.2 deletion cases. Worthington et al., (2000) reported a familial case with the condition who had polymicrogyria. They discuss other reports (see also Ghariani et al., 2002). Ehara et al., (2003) report a case with pachygyria and polymicrogyria. Koolen et al., (2004) noted pachygyria in their case.

Squires et al., (1998) reported a case with features of CHARGE association and a Dandy-Walker malformation. Bird and Scambler (2000) reported two cases with a 22q11 deletion associated with cortical dysgenesis. Bird (2001) briefly reported two further cases.

Devriendt et al., (1996) noted a possible increased incidence of urological abnormalities. Devriendt et al., (1997) reported a female case with absent kidneys and uterus who had inherited a 22q11 deletion from her classically affected father. Czarnecki et al., (1998) reported a mother and child with cystic dysplastic kidneys.

Cheroki et al., (2006) reported a patient with Mayer-Rokitansky syndrome. Primary amenorrhea and an absent uterus (also unilateral renal agenesis) were features in two patients reported by Sundaram et al., (2007), and Uliana et al., (2008), comment on the overlap with MURCS.

Worthington et al., (1997) reported three cases with anal anomalies (anal stenosis in one case, a covered anus with a perineal fistula in a second and anal stenosis in a third). Kerstjens-Frederiske et al., (1999) reported a boy with a 22q11 deletion with features of velo-cardio-facial syndrome, but also with Hirschsprung disease and paroxysmal hypoventilation. Digilio et al., (1999) studied 15 patients with esophageal atresia and found one with a 22q11 deletion. This case also had tetralogy of Fallot and anal atresia.

Basset et al., (2016) described two unrelated patients with chromosome 22q11.2 deletion presenting with childhood obesity and hyperphagia. Additional clinical features included developmental delay, aggressive behaviour and recurrent chest infections.

Ryan et al., (1997) and McDonald-McGinn et al., (1997) provide good reviews of the range of clinical features in individuals with 22q11 deletions. Scambler (2000) and Swillen et al., (2000) provide good reviews of the clinical and molecular features of the condition.

Edelmann et al., (1999) provided evidence that low-copy repeats might be responsible for the common 3-Mb deletion of 22q11. Baumer et al., (1998) and Edelmann et al., (1999) presented data suggesting that unequal crossing over was responsible for many deletions. Carlson et al., (1997) provide data on the extent of deletions in 151 cases.

Hatchwell et al., (1998) reported two sibs with 22q11 deletions where they showed convincing evidence that the mother was mosaic for this deletion.

Ten familial cases were reported by Adeyinka et al., (2004), and in seven families the deletion was smaller than the usual 3Mb. A similarly increased rate of smaller deletions in familial patients was reported from Spain (Fernandez et al., 2005). Two families with multiple affected members had cardiac features in fewer than 50% (Shooner et al., 2005), but all were dysmorphic.

Some patients overlapping with DiGeorge syndrome might have a deletion of 10p13 (Lipson et al., 1996). Pierpont et al., (1996) showed that cases with the so-called conotruncal face syndrome have similar deletions.

Jaeken et al., (1996) reported a case with a 22q11 deletion who was shown to be heterozygous for heparin cofactor I deficiency and for hyperprolinemia type I (proline oxidase deficiency). The authors suggested a contiguous gene syndrome.

Garcia-Minaur et al., (2002) reported a child with features of the condition and his asymptomatic father, who was found to be negative for a FISH test with commercial probes. An atypical distal deletion in the 22q11.2 region was demonstrated.

Unolt et. al., (2018) described lymphedema and lymphatic anomalies in four patients with 22q11.2 microdeletion syndrome.

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