Chromosomal Deletion 22q11.2: An Important Genetic Syndrome with Psychiatric Manifestations

The deletion of chromosome 22q11 is associated with a high frequency of behavioral disorder with attention deficit disorder, oppositional defiant disorder, separation anxiety disorder, generalized anxiety disorder and depression during childhood, and psychosis (bipolar disorder and schizophrenia) during adolescence and young adulthood.

The link between the 22q11 deletion and schizophrenia is supported by recent studies showing that the rate of 22q11 deletion in adults with schizophrenia (~2 percent) is higher than it is in the general population (~1/2,000Æ1/4,000). This rate may be even higher (~6 percent) in subjects with childhood-onset schizophrenia. It also has been demonstrated that the rate of schizophrenia in the population with a 22q11 deletion is greatly increased (~25 percent) over the rate of schizophrenia in the general population (~1 percent).

The 22q11 deletion generates various phenotypes, which initially were regarded as distinct syndromes.

1. DiGeorge syndrome (DGS) was described in 1968 by immunologists. These patients demonstrated thymic and parathyroid hypoplasia with right-sided cardiac malformations.
2. A speech and language pathologist and a genetic counselor seeing patients at a craniofacial center described the velocardiofacial syndrome (VCFS) in 1978. These patients had cardiac malformations, dysmorphic facies, and learning disabilities (difficulties with expressive language, problem solving, time-budgeting, attention, and memory). Psychiatric spectrum disturbances were present in 30 percent.
3. The Takao syndrome, or conotruncal anomaly face syndrome (CTAF), was described in the late 1970s by cardiologists as a clinical condition associating cardiac abnormalities and dysmorphic facies. During the early 1990s, 22q11.2 deletion was identified as the common molecular etiology for these syndromes. It is now recognized that the 22q11deletion syndrome encompasses the phenotypes previously described as DGS and VCFS, and that the somewhat varied clinical descriptions of DGS and VCFS resulted from clinical variation and ascertainment bias.

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Features of the 22q11 Deletion Syndrome

Descriptive studies of large samples of children with a 22q11 deletion have shown the following pattern of associated symptoms:

1. Subtly dysmorphic facial features (~100 percent), commonly including long face with malar hypoplasia, retrognathia, prominent nose with squared nasal root, small ears, short and/or narrow palpebral fissures, and small, open mouth;
2. Learning difficulties (~100 percent);
3. Cardiac anomalies (~74 percent), including cardiac malformations of conotruncal types;
4. Oral abnormalities (~49 percent), including cleft palate (~69 percent), and velopharyngeal (soft palatal) hypotonia (~20 percent), which often causes speech difficulties, specifically hypernasal speech, and articulation problems;
5. Other structural defects, including renal anomalies (~35 percent), umbilical hernia (~5 percent), inguinal hernia (~25 percent), and scoliosis (~15 percent);
6. Immunologic deficiency (~10 percent), resulting in a history of recurrent infections and illnesses (e.g.. chronic bronchial and ear infections) due to absent or small thymus;
7. Endocrinologic features of hypocalcemia (~15 percent), hypoparathyroidism, hypo- or hyperthyroidism.

Few thorough studies have been conducted on large groups of adults identified as having a 22q11 deletion. Studies to date report many of the same facial features found in children, however, these features can vary in expression with age. Adults identified with a 22q11 deletion tended to report a history of learning and speech difficulties (including speech delay, hypernasal speech, and articulation problems). Some studies reported a lower incidence of congenital heart defects in adults with the deletion syndrome (~30 percent), suggesting an ascertainment bias in childhood studies toward children with more severe phenotypic expression of the syndrome.

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Raising the Index of Suspicion for a 22q11 Deletion

When providing genetic counseling for individuals with psychiatric illness, it is important to elicit any history of the possible manifestations of the 22q11 deletion syndrome.. Since the majority of 22q11 deletions occur de novo, those families reporting only one individual with a psychiatric illness raise the highest index of suspicion for the deletion syndrome.

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How to Proceed If You Suspect Chromosome 22q11 Deletion in a Proband

If the proband in a family seeking genetic counseling for a psychiatric history has learning difficulties and any of the features listed above, testing for a submicroscopic deletion of chromosome 22 by fluorescence-in situ-hybridization (FISH) using DNA probes from the 22q11.2 region is indicated. The 22q11 deletion is confirmed in more than 95 percent of cases with a clinical diagnosis of the syndrome.

The majority of patients have the same large deletion; the size of the deletion remains unchanged with parent to child transmission. Of those with a detectable 22q11 deletion, about 94 percent have a de novo deletion of 22q11 and 6 percent have inherited the 22q11 deletion from a parent; thus, both parents of an individual with the deletion should have FISH testing. The great inter- and intrafamilial clinical variability makes genotype-phenotype correlations impossible.

The 22q11 region was mapped and sequenced, leading to the identification of genes in the region. The gene TBX-1 has emerged as the leading cause of the major phenotypes in VCFS/DGS patients. A gene encoding for catechol-O-methyltransferase (COMT) maps to chromosome 22q11 and is considered a prime candidate for psychosis in VCFS. Although dopamine is metabolized by COMT, it is also subject to deamination by monoamine oxidase (MAO). There is speculation that blockage of one pathway allows reciprocal compensation by the other. An attractive hypothesis for causality of behavioral problems in deletion patients is that polymorphisms in COMT, MAOA, and MAOB in combination with haploinsufficiency for COMT is etiologic in VCFS.

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Medical Management of Patients with a 22q11 Deletion

Determining if the proband has a 22q11 deletion is important for appropriate genetic counseling and the organization of the most appropriate medical management for the variable features of this syndrome. The issues that need to be addressed for individuals with this syndrome are as follows:

1. FISH testing of the individualÍs parents, if possible, to identify other family members who may be at risk for having the deletion syndrome.
2. Genetic counseling for autosomal dominant inheritance of the 22q11 deletion, including its possible manifestations and the variability of these manifestations, even within families.
3. Referral to an immunologist if the proband is a child, as children with the 22q11 deletion have an increased risk of immunodeficiency, specifically in T-cell function, and any live vaccinations should be postponed until the child is immunologically competent to receive them.
4. Because of the increased risk of congenital heart defects, an echocardiogram should be arranged for all individuals identified with a 22q11 deletion.
5. Because of the increased risk of structural kidney defects associated with the deletion syndrome, it is important for all newly identified individuals with a 22q11 deletion to undergo a one-time kidney ultrasound to identify any previously unidentified defects.
6. At least annual monitoring of serum calcium, ionized calcium, parathyroid, thyroid, and platelet levels should be done to ensure early identification and treatment of any fluctuations. A referral to an endocrinologist may be indicated.
7. In the proband with speech difficulties, referral to a speech and language pathologist may be indicated for assessment of eligibility for a surgical correction of the velopharyngeal area, which, when hypotonic, often results in hypernasal speech and articulation difficulties. Speech therapy may be indicated for speech delay and other speech problems.
8. A psychiatric consultation is indicated for the symptomatic proband who has not been involved in the mental heath care system to date.
   
   

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References

Bassett, A.S. Progress on the genetics of schizophrenia. J Psychiatry Neurosci. 23, 270Æ3 (1998). Carlson, C., Papolos, D., Goldberg, R., Shprintzen, R.J., Kucherlapati, R., Morrow, B. Molecular analysis of velo-cardio-facial syndrome patients with psychiatric disorders. Am J Hum Genet 60, 851-859 (1997). Cohen, E, Chow, EWC, Weksberg, R, Bassett, AS. Phenotype of adults with the 22q11 deletion syndrome: A review. American J of Medical Genetics 86, 359-65 (1999). Goldberg, R., Motzkin, B., Marion, R., Scambler, P. J., Shprintzen, R. J. Velo-cardio-facial syndrome: a review of 120 patients. Am J Med Genet 45, 313-319 (1993). Karayiorgou, M., Morris, M., Morrow, B., Shprintzen, R.J., Goldberg, R., Borrow, J., Gos, A., Nestadt, G., Wolyniec, P., Lasseter, V., Eisen, H., Childs, B., Kazazian, H., Kucherlapati, R., Antonarakis, S., Pulver, A., Housman, D. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11.. Proc Nat Acad Sci 92, 7612-7616 (1995). Kelly, D., Goldberg, R., Wilson, D., Lindsay, E., Carey, A., Goodship, J., Burn, J., Cross, I., Shprintzen, R.J., Scambler, P. J. Confirmation that the velo-cardio-facial syndrome is associated with haplo-insufficiency of genes at chromosome 22q11. Am J Med Genet 45, 308-312 (1993). Lachman, H., Morrow, B., Shprintzen, R.J., Veit, S., Parsia, S.S., Faedda, G., Goldberg, R., Kucherlapati, R., Papolos, D. Association of codon 108/158 catechol-o-methyltransferase gene polymorphism with the psychiatric manifestations of velo-cardio-facial syndrome. Am J Med Genet 67, 468-472 (1996). Murphy, K.C., Jones, R.G., Griffiths, E., Thompson, P.W., Owen, M.J. Chromosome 22q11 deletions: An under-recognised cause of idiopathic learning disability. British J of Psychiatry 172, 180-183 (1998). Papolos, D.F., Faedda, G.L., Veit, S., Goldberg, R., Morrow, B., Kucherlapati, R., Shprintzen, R.J. 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 Psychiatr 153, 1541-1547 (1996). Pulver, A E., Nestadt, G., Goldberg, R., Shprintzen, R.J., Lamacz, M., Wolyniec, P.S., Morrow, B., Karayiogou, M., Antonarakis, S.E., Housman, D., Kucherlapati, R.J. Psychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives. Nerv. Ment. Dis. 182, 476-478 (1994). Ryan, A.K., Goodship, J.A., Wilson, D.I., et al. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: A European collaborative study. J Med Genet 34, 798-804 (1997). Scambler, P.J., Kelly, D., Lindsay, E., Williamson, R., Goldberg, R., Shprintzen, R., Wilson, D. I., Goodship, J. A., Cross, I.E., Burn, J. Velo-cardio-facial syndrome associated with chromosome 22 deletions encompassing the DiGeorge locus. Lancet 339, 1138-1139 (1992). Shprintzen, R.J.., Goldberg, R.B., Lewin, M.L., Sidoti, E.J., Berkman, M.D., Argamaso, R. V., Young, D. A new syndrome involving cleft palate, cardiac anomalies, typical facies, and learning disabilities: velo-cardio-facial syndrome. Cleft Palate J 15, 56-62 (1978). Shprintzen, R.J., Goldberg, R., Golding-Kushner, K.J., Marion, R.W. Late-onset psychosis in the velo-cardio-facial syndrome. Am J Med Genet 42, 141-142(1992). Thomas, J.A., Graham, J.M., Jr. Chromosome 22q11 deletion syndrome: An update and review for the primary pediatrician. Clinical Pediatrics: 253-266 (1997).