22q11 Deletion Syndrome
|[del 22q11. Includes:
Shprintzen Syndrome, DiGeorge Syndrome (DGS), Velocardiofacial Syndrome (VCFS),
Conotruncal Anomaly Face Syndrome (CTAF), Caylor Cardiofacial Syndrome, Opitz
SummaryDisease characteristics. Individuals with 22q11 deletion syndrome (del 22q11) have a range of findings, including congenital heart disease (74% of patients), particularly conotruncal malformations (tetralogy of Fallot, interrupted aortic arch, and truncus arteriosus); palatal abnormalities (69%), particularly velopharyngeal incompetence (VPI), submucosal cleft palate, and cleft palate; characteristic facial features (present in the majority of individuals); and learning difficulties (70 - 90%). Hypocalcemia and immune deficiency are typical but less common.
Diagnosis/testing. Del 22q11 is diagnosed in individuals with a submicroscopic deletion of chromosome 22 detected by fluorescence in situ hybridization (FISH) using DNA probes from the DiGeorge chromosomal region (DGCR). Such FISH testing is widely available for the clinical and prenatal diagnosis of del 22q11. Fewer than 5% of patients with the clinical symptoms of del 22q11 have normal routine cytogenetic studies and negative FISH testing. They are presumed to have variant deletions of DGCR which may be detectable on a research basis only.
Genetic counseling. Del 22q11 is inherited as a deletion syndrome. About 94% of probands have a de novo deletion of 22q11 and 6% have inherited the 22q11 deletion from a parent. Prenatal testing is possible for fetuses determined to be at 50% risk by family history and for fetuses not known by family history to be at increased risk for del 22q11 but with findings of congenital heart disease and/or cleft palate detected by ultrasound examination.
DiagnosisThe 22q11 deletion syndrome (del 22q11) is suspected in individuals with characteristic clinical findings and confirmed in more than 95% of cases by detection of submicroscopic deletion of chromosome 22 by fluorescence in situ hybridization (FISH) using DNA probes from the DiGeorge chromosomal region (DGCR) [Driscoll, Budarf et al 1992; Wilson et al 1992; Driscoll et al 1993; Desmaze et al 1993]. Such FISH testing is widely available for the clinical and prenatal diagnosis of del 22q11 [Driscoll, Chen et al 1995].
Clinical DiagnosisThe diagnosis of del 22q11 is suspected in patients with a range of findings that may include some combination of the following: congenital heart disease (particularly conotruncal malformations), palatal abnormalities [especially velopharyngeal insufficiency (VPI)], hypocalcemia, immune deficiency, learning difficulties, and, at times, characteristic facial features. Del 22q11 is detected by FISH testing in the vast majority of cases with this combination of findings [Driscoll et al 1993].
TestingCytogenetic testing. When del 22q11 is suspected in a patient, it is recommended that routine cytogenetic analysis be performed at the time of FISH testing because a small percentage of patients with clinical findings of del 22q11 have chromosomal rearrangements involving 22q11, such as a translocation between chromosome 22 and another chromosome.
Molecular Genetic TestingThe 22q11 deletion syndrome (del 22q11) is diagnosed in individuals with a submicroscopic deletion of chromosome 22 detected by fluorescence in situ hybridization (FISH) using DNA probes from the DiGeorge chromosomal region (DGCR) [Driscoll, Budarf et al 1992; Wilson et al 1992; Driscoll et al 1993; Desmaze et al 1993]. Such FISH testing is widely available for the clinical and prenatal diagnosis of del 22q11 [Driscoll, Chen et al 1995].
A few patients with clinical symptoms of del 22q11 show normal routine cytogenetic studies and negative FISH testing when the commercially available probes are used, but have variant deletions of the DGCR detected with probes that are available on a research basis only.
Yamagishi et al  recently suggested that the gene responsible for the features of the 22q11 deletion syndrome had been determined. The gene that they implicated, UFD1L, was originally described by Pizzuti et al . This gene is one of many genes deleted in all of the individuals who test positive in the FISH testing using the commercially available probes N25 or TUPLE 1. The discovery should not alter the methodology by which testing is currently performed, as the majority of patients have the same large deletion of the DGCR.
Clinical DescriptionBefore the identification of the 22q11 submicroscopic deletion in 1991, 1992, and 1993 [Scambler et al 1991; Carey et al 1992; Driscoll, Budarf et al 1992; Driscoll, Spinner et al 1992; Driscoll et al 1993], patients with del 22q11 were often described as having either DiGeorge syndrome (DGS) or velocardiofacial syndrome (VCFS). DGS was originally described as a developmental field defect of the third and fourth pharyngeal pouches with a conotruncal cardiac anomaly and aplasia or hypoplasia of the thymus gland and parathyroid glands. VCFS was originally described as the combination of velopharyngeal incompetence (VPI), congenital heart disease (usually a ventricular septal defect or tetralogy of Fallot), characteristic facial features, and developmental delay or learning difficulties.
It is now recognized that the 22q11 deletion syndrome encompasses the phenotypes previously described as DGS and VCFS and that the clinical descriptions of DGS and VCFS resulted from an ascertainment bias. The majority of patients with DGS were identified in the neonatal period with a major congenital heart defect, hypocalcemia, and immunodeficiency, whereas patients with VCFS tended to be diagnosed in cleft palate or craniofacial centers when speech and learning difficulties became evident as children reached school age [Wilson et al 1993; Wulfsberg 1996; McDonald-McGinn, Zackai et al 1997; Thomas and Graham 1997]. In addition, microdeletions of chromosome 22q11 have also been detected in patients identified as having the conotruncal anomaly face syndrome (CTAF) [Matsuoka et al 1994], some cases of "Opitz" G/BBB syndrome [McDonald-McGinn et al 1995, Fryburg et al 1996, LaCassie and Arriaza 1996], and Cayler cardiofacial syndrome [Giannotti et al 1994].
Findings in 250 patients (48% male; 52% female) with del 22q11 ascertained through the Children's Hospital of Philadelphia are summarized below [McDonald-McGinn, Kirschner, Goldmuntz, Sullivan et al 1999]. The clinics from which the patients were ascertained were genetics (59%), cardiology (25%), cleft palate (10%), neurology and child development (3%), immunology and rheumatology (2%), and endocrinology (1%). Fifty-six percent of patients were five years of age or younger. Twelve percent of patients were over the age of 16 years, the majority of whom were parents of affected children. Six percent of patients were deceased, 90% of whom succumbed to complications of cardiac disease. Seventy-seven percent of the patients were Caucasian; 14% of the patients were African-American. Because African-American patients lacked many of the "typical facial characteristics" of del 22q11, they were under-represented when compared to the hospital's patient population of African-Americans, which was 42% [McDonald-McGinn et al 1996]. Six percent of cases were familial with marked inter- and intra-familial variability.
Heart. Congenital heart disease was present in 74% of patients. The primary cardiac malformations are reported in Table 2. Associated cardiac features are not included. Seventy-five percent of patients were ascertained through the mid-Atlantic region. The remainder were self-selected individuals from throughout the US, Canada, Europe, and the Middle East who sought care at our institutions.
Palate. One hundred and eighty-one patients had palatal evaluations performed by a plastic surgeon and speech pathologist using standard history, physical examination, and speech evaluation. Patients underwent videofluoroscopy and/or nasendoscopy when indicated. Velopharyngeal incompetence was not ruled out until objective evaluations by a speech pathologist and plastic surgeon were obtained and until the child was old enough to provide an adequate speech sample.
Sixty-nine percent of patients had a definitive palatal abnormality (Table 3). Of the 27% with confirmed VPI, several patients were initially diagnosed with del 22q11 because of their cardiac defect and were subsequently found to have unrecognized but clinically significant VPI [McDonald-McGinn, LaRossa et al 1997]. Only 17% of patients were determined to have no palatal involvement.
Feeding. Thirty percent of patients had a history of feeding difficulties, a component of del 22q11 that has not been previously appreciated. Seventy-five children had a history of severe dysphagia. Of these, 45% required gastrostomy tube placement and 50% required nasogastric tube feedings. Sixty percent of these patients had a cardiac defect and 24% had palatal anomalies; however, feeding difficulties were independent of other structural anomalies. Evaluation by barium swallow in 23 patients revealed a preponderance of nasopharyngeal reflux, prominence of the cricopharyngeal muscle, abnormal cricopharyngeal closure, and/or diverticulum. Thus, the underlying feeding problem in many of the patients appears to be due to dysmotility in the pharyngoesophageal area, which is derived from the third and fourth pharyngeal pouches.
Immune function. Nineteen infants had T-cell studies at birth and again at one year of age. Compared to control patients without the deletion, newborns with del 22q11 had significantly fewer cells of thymic lineage; however, improvement in T-cell production did occur. Patients with the most significant deficiencies in T-cell production improved most in the first year of life [Sullivan et al 1999]. Sixty patients over the age of six months had immunological evaluations. In all patients, T-cell production and gross T-cell function were evaluated. In those over one year of age, immunoglobulin production and function, as well as more sensitive studies of T-cell function, were evaluated. Of the 60 patients, 77% were considered to be immunodeficient regardless of their clinical presentation. Sixty-seven percent had impaired T-cell production, 19% had impaired T-cell function, 23% had humoral defects, and 13% had IgA deficiency [Sullivan et al 1998, Smith et al 1998].
Parathyroid function. Forty-nine percent of 158 patients had confirmed hypocalcemia. Calcium homeostasis typically normalizes with age, although recurrence of hypocalcemia in later childhood has been reported. Two patients (ages eight and twelve years) who were receiving ongoing follow-up by an endocrinologist for their hypocalcemia, which had presented in infancy, were not diagnosed with the 22q11 deletion until school age.
Craniofacial. Craniofacial findings included auricular abnormalities, hypoplastic alae nasae leading to the appearance of a bulbous nasal tip, prominent nasal root [Gripp et al 1997], and "hooded eyelids". However, the presence of these features as well as other facial findings such as a long face and malar flatness, were quite variable. In fact, some patients offered no clues to their underlying diagnosis based on their facial features, especially African-American patients [McDonald-McGinn et al 1996].
Eyes. A prospective evaluation for ocular abnormalities in 33 patients revealed hooding of the upper lid (41%), ptosis (9%), hooding of the lower lid (6%), epicanthal folds (3%), and distichiasis (3%). Other findings included posterior embryotoxon (69%), isolated corneal nerves (3%), sclerocornea (3%), deep iris crypts (10%), tortuous retinal vessels (58%), small optic nerves (7%), and tilted discs (3%). Strabismus was observed in 13% and amblyopia in 6%.
Although posterior embryotoxon was observed in 12 to 32% of controls, the incidence in this group of patients with del 22q11 was almost as high as that seen in Alagille syndrome (89%) [Krantz et al 1997]. The incidence of astigmatism, myopia, and hyperopia were comparable to the incidence in the general population. No patient had cataracts or colobomas.
Ear, nose, and throat. Ear abnormalities included overfolded or squared off helices; cupped, microtic, and protuberant ears; preauricular pits or tags, and narrow external auditory meati. A prominent nasal root, bulbous nasal tip, hypoplastic alae nasae, and a nasal dimple/bifid nasal tip were common [Gripp et al 1997]. Stridor due to vascular ring, laryngomalacia, and laryngeal webs were observed. Chronic otitis media and chronic sinusitis were common.
Central nervous system. Although the majority of patients had a history of hypotonia in infancy and learning disabilities [Moss et al 1995], specific neurologic manifestations were rare. Seizures were seen in some patients and were most often associated with hypocalcemia. Several patients had asymmetric crying facies [Cayler 1969, Giannotti et al 1994, Levin et al 1982, Sanklecha et al 1992, Silengo et al 1986]. Three patients were ataxic, one of whom had atrophy of the cerebellum [Lynch et al 1995]. Additional CNS abnormalities included multicystic white matter lesions of unknown significance and perisylvian dysplasia [Bingham et al 1997]. Overall, the pattern of CNS abnormalities was diffuse and overlapped with that seen in some cases of Opitz G/BBB syndrome [Guion-Almeida and Richieri-Costa 1992, MacDonald et al 1993, Neri et al 1987].
Psychosocial development and IQ. Patients can be divided into three categories based on age: toddler, preschooler, and school-aged.
In a series of 28 toddlers assessed using the Bayley Scale of Infant Development, the mean Mental Developmental Index was 70±15. The mean Psychomotor Developmental Index was 60±12. In mental development 21% were average, 32% were mildly delayed, and 46% were significantly delayed; in motor development 8% were average, 13% were mildly delayed, and 79% were significantly delayed. Language assessment using the Preschool Language Scale-Revised revealed total language 73±14, expressive language 71±16, and receptive language 78±12.
In a series of 12 preschoolers assessed using the WPPSI-R, the Full Scale IQ was 78±11, the mean Performance IQ was 78±14, and the mean Verbal IQ was 82±15. For the 12 preschoolers, 33% were average, 33% were mildly delayed, and 33% were significantly delayed. The mean language scores for the 12 preschool-age patients were: total language 73±18, expressive language 76±16, and receptive language 77±16. In total language, 16% were average, 44% were mildly delayed, and 40% were significantly delayed; in expressive language, 9% were average, 38% were mildly delayed, and 53% were significantly delayed; and in receptive language, 26% were average, 48% were mildly delayed, and 26% were significantly delayed [Solot et al 1998].
In a series of 55 school-age patients with del 22q11 assessed with the age-appropriate Weschler IQ battery, 13% attained full scale IQ scores in the average range, 26% in the low average range, 35% in the borderline range, and 27% in the retarded range. However, detailed analysis of the battery became important. As an example, one patient had a verbal IQ of 111, which is above the average range, but a performance IQ of 65, which falls in the retarded range, bringing his full scale IQ down to 87, which is in the low average range. This split between verbal and performance IQ was consistent with a nonverbal learning disability. This nonverbal learning disability was seen in 66% of patients with a mean split between verbal comprehension and perceptual organization of 11 points [Moss et al 1995]. Therefore, the full scale IQ scores alone did not accurately represent the abilities of many of these patients; for each patient verbal and performance IQ scores should be considered separately.
On memory testing, verbal learning was superior to visual memory (p=.01) and was even superior to VIQ (p=.001). On scholastic testing, all individual reading skills were significantly stronger than all individual math skills. Overall reading was therefore much stronger than overall math (p<.0001), perhaps reflecting the strong rote verbal memory skills. The evidence of stronger verbal than visual memory skills and stronger reading than math skills also supports the presence of a nonverbal learning disorder. These findings are of particular importance because the cognitive remediation, behavior management, and parental counseling are specific to this type of non-verbal learning disability, which is rare in the general population [Wang et al 1998].
Psychiatric illness. Psychiatric illness has been implicated in some individuals and has included schizophrenia, rapid cycling bipolar disorder, and depression. The prevalence and exact nature of these findings are still being investigated [Yan et al 1998, Bassett et al 1998, Shprintzen et al 1992, Chow et al 1994]
Growth. In a series of 95 patients between the ages of one and 15 years, 41% were below the 5th percentile in height, four of whom were significantly below the 5th percentile. Evaluation revealed low levels of growth factors IGF1 and IGFBP3 in all four patients. Three had evidence of growth hormone deficiency, three had a small pituitary gland on MRI, and two responded to growth hormone therapy [Weinzimer et al 1998].
Musculoskeletal system. Polyarticular juvenile rheumatoid arthritis (JRA) occurs in children with del 22q11 at a frequency 150 times that of the general population rate. The age of onset of JRA has ranged from 17 months to five years. HLA types that are permissive for the development of JRA are observed [Sullivan et al 1997, Keenan et al 1997].
Of 108 patients evaluated for skeletal abnormalities, 6% had upper extremity anomalies, including pre- and post-axial polydactyly, and 15% had lower extremity anomalies including post-axial polydactyly, club foot, overfolded toes, and 2,3 syndactyly [Ming et al 1997].
Of 63 patients on whom chest films were examined, 19% had vertebral anomalies including butterfly vertebrae, hemivertebrae, and coronal clefts. Rib anomalies, most commonly supernumerary or absent ribs, occurred in 19%. Other anomalies, such as hypoplastic scapula, were seen in 1.5% of patients [Ming et al 1997].
Kidneys. A prospective evaluation using renal ultrasonography in 67 patients with del 22q11 who had no prior history of uropathy revealed renal or GU abnormalities in 37%. These included single kidney, echogenic kidney, multicystic dysplastic kidney, small kidneys, calculi, bladder wall thickening, horseshoe kidney, duplicated collecting system, and renal tubular acidosis. This high incidence of renal abnormalities is similar to that reported by Devriendt et al .
Other. Other findings included: abnormal lung lobation; imperforate anus; hypospadias and undescended testes; hematologic abnormalities including idiopathic thrombocytopenia and, in one patient, Bernard-Soulier syndrome [Budarf et al 1995]; umbilical and inguinal hernia; significant constipation; bed wetting; leg pain; and craniosynostosis [McDonald-McGinn et al 1995, McDonald-McGinn et al 1999].
Genotype-Phenotype CorrelationsThe majority of patients have the same large deletion of the DGCR; the size of the deletion remains unchanged with parent to child transmission. The great inter- and intrafamilial clinical variability makes genotype-phenotype correlations difficult [Driscoll, Randall et al 1995].
PrevalenceEstimates of prevalence vary from one in 4000 [Wilson et al 1994] to one in 6395 [Devriendt et al 1998]. Given the variable expression of del 22q11, the incidence is probably much higher than previously estimated.
Differential DiagnosisIt is appropriate to evaluate patients with a combination of the characteristic abnormalities or with single abnormalities such as conotruncal cardiac anomalies (interrupted aortic arch, truncus arteriosus, tetralogy of Fallot), VPI, unexplained hypocalcemia, or a non-verbal learning disability for 22q11 deletion.
In screening 251 patients based solely on their cardiac lesions, del 22q11 was found in 50% of patients with an interrupted aortic arch type B, 34.5% of patients with truncus arteriosus, 33% of patients with a conoventricular septal defect, and 16% of patients with tetralogy of Fallot [Goldmuntz et al 1993]. The frequency of del 22q11 did not vary with the presence of pulmonary atresia as compared to pulmonary stenosis with tetralogy of Fallot. There may be an increased frequency of del 22q11 in patients with tetralogy of Fallot and absent pulmonary valve syndrome [Johnson et al 1995]. This latter study supports evaluating patients with these specific cardiac anomalies in order to provide appropriate recurrence risk counseling and clinical management for these patients and their families.
It is important to note that the 22q11 deletion should now be included in the differential diagnosis of many disorders, such as Smith-Lemli-Opitz syndrome (when polydactyly and cleft palate are present) and Alagille syndrome (when butterfly vertebrae, congenital heart disease, and posterior embryotoxon are present), VATER, and oculo-auriculo vertebral syndrome (Goldehar). Furthermore, it should be noted that routine cytogenetic studies should be performed on all individuals suspected of having del 22q11 because they may have a chromosome abnormality involving some other chromosomal region.
ManagementDepending on the age and presenting problems of the child, a multidisciplinary evaluation involving healthcare providers from the following specialties is often necessary: genetics, plastic surgery, speech pathology, otolaryngology, audiology, dentistry, cardiology, immunology, child development, child psychology, neurology, and general pediatrics. Some patients also require evaluation by healthcare providers specializing in feeding, endocrinology, rheumatology, gastroenterology, neurosurgery, general surgery, orthopedics, urology, hematology, psychiatry, and ophthalmology.
Genetic CounselingGenetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. T
Mode of InheritanceThe 22q11 deletion is inherited as a deletion syndrome.
Risk to Family MembersParents of a proband. About 94% of probands have a de novo deletion of 22q11 and 6% have inherited the 22q11 deletion from a parent; thus, both parents of an individual with del 22q11 should have FISH testing.
Offspring of a proband. Offspring of individuals with the 22q11 deletion have a 50% chance of inheriting the 22q11 deletion.
Sibs of a proband. If the parents of an individual with del 22q11 have normal FISH studies, the recurrence risk is quite small, assuming a very low, and as yet undefined, risk of germline mosaicism.
Prenatal TestingHigh-risk pregnancies. Prenatal testing using FISH analysis is possible for fetuses at 50% risk. Chromosome preparations obtained from fetal cells obtained by amniocentesis at 14-16 weeks gestation or CVS at 9-11 weeks gestation can be analyzed using FISH in the same manner described in Molecular Genetic Testing. In addition, high-risk fetuses may be evaluated between 18 and 22 weeks gestation by high-resolution ultrasound examination for palatal anomalies and by echocardiography for cardiac anomalies.
Low-risk pregnancies. In some fetuses not known by family history to be at increased risk for del 22q11, findings of congenital heart disease and/or cleft palate detected by routine ultrasound examination may suggest the diagnosis in particular in those patients with conotruncal cardiac anomalies such as interrupted aortic arch, truncus arteriosus, tetralogy of Fallot, and ventricular septal defect. Chromosome preparations obtained from fetal cells can be analyzed using FISH. Establishing the diagnosis of the 22q11 deletion even late in gestation can be useful for perinatal management.
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Articles on 22q11 Deletion Syndrome