The 22q11 deletion syndromes

DiGeorge syndrome, velocardiofacial syndrome and various other malformations have been described in association with deletions and translocations involving human chromosome 22q11. Many of the structural malformations observed are also seen in animal models of neural crest disruption suggesting that the haplo-insufficiency resulting from the deletion somehow affects this group of cells or their interactions. Over the past few years it has been shown that the deletion predisposes to a range of psychotic conditions prompting the hypothesis that the deleted region may contain a predisposition locus for psychotic illness. The DiGeorge chromosomal region has been entirely sequenced and many of the genes mapping to the deletion interval have been studied in some detail. Despite these efforts, no gene has yet been proved to play a defined role in the pathogenesis of the syndrome. Current efforts are directed at the study of engineered chromosome mouse models which offer the potential to dissect at least some of the developmental pathways disrupted in this intriguing group of malformation syndromes.     

Radial aplasia and chromosome 22q11 deletion.

We report on a neonate with deletion 22q11 (del22q11) presenting with facial dysmorphism, ocular coloboma, congenital heart defect, urogenital malformations, and unilateral radial aplasia. This malformation complex includes features frequently occurring in velocardiofacial syndrome as well as findings described in the CHARGE and VACTERL associations. To our knowledge, the present case is the first report of radial aplasia in del22q11. This observation further supports and extends the clinical variability of del22q11.     

Cortical dysgenesis in 2 patients with chromosome 22q11 deletion

Two patients with chromosome 22q11 deletion and cortical dysgenesis (gyral abnormalities) are reported in this study. One had unilateral clubfoot in addition to multiple features suggestive of the Di George syndrome (DGS), and the other presented with leg asymmetry and seizures, with subsequent recognition of the velo-cardio-facial syndrome (VCFS). In each patient, gyral abnormalities were identified in the hemisphere contralateral to the limb abnormality. A wide range of central nervous system abnormalities have been reported in DGS and VCFS, including three prior reports of gyral abnormalities (lissencephaly, microgyria). The 2 patients reported herein strengthen the association between the 22q11 deletion spectrum and cortical dysgenesis, but the underlying pathogenetic mechanism (primary neural migration vs. vascular disruption) remains unclear.     

Tricuspid atresia and 22q11 deletion

Tricuspid atresia has not been reported in 22q11 microdeletions causing DiGeorge and velo-cardio-facial syndromes. We investigated the prevalence of 22q11 hemizygosity in 26 children with tricuspid atresia. Fluorescent hybridization with the Sc11.1 probe demonstrated a 22q11 microdeletion in 2 patients, one with and another without transposition of the great arteries. Both deletion patients had minor facial anomalies characteristic of DiGeorge syndrome. The present observations suggest that tricuspid atresia should be included in the list of cardiac malformations seen in del22q11 syndromes. Am. J. Med. Genet. 72:40–42, 1997. © 1997 Wiley-Liss, Inc.     

Submicroscopic deletion in chromosome 22q11 in trizygous triplet siblings and their father Clinical variability of 22q11 deletion

A submicroscopic deletion of chromosome 22q11 was demonstrated in three triplets and in their father. Two children had the typical DiGeorge sequence with at least three of the four cardinal features: conotruncal heart disease, hypoplastic thymus and typical facial features. Hypoparathyroidism was present in one of them. The third child had features of both DiGeorge and velo-cardio-facial syndrome (VCFS). The father presented with features compatible with VCFS. This observation further illustrates the wide variability in expression of a submicroscopic deletion of 22q11, even within one family.     

Obsessive-compulsive disorder in patients with velocardiofacial (22q11 deletion) syndrome.

The study of neurogenetic microdeletion syndromes provides an insight into the developmental psychopathology of psychiatric disorders. The aim of the study was to evaluate the prevalence of psychiatric disorders, especially obsessive-compulsive disorder (OCD), in patients with velocardiofacial syndrome (VCFS), a 22q11 microdeletion syndrome. Forty-three subjects with VCFS of mean age 18.3 +/- 10.6 years were comprehensively assessed using semi-structured psychiatric interview and the Yale-Brown obsessive compulsive scale (Y-BOCS). Best estimate diagnoses were made on the basis of information gathered from subjects, parents, teachers, and social workers. Fourteen VCFS subjects (32.6%) met the DSM-IV criteria for OCD. OCD had an early age of onset and generally responded to fluoxetine treatment. It was not related to mental retardation. The most common obsessive-compulsive symptoms were contamination, aggression, somatic worries, hoarding, repetitive questions, and cleaning. Sixteen of the 43 patients (37.2%) had attention-deficit/hyperactivity disorder (ADHD), and 7 (16.2%) had psychotic disorder. The results of our study suggest that there is a strong association between VCFS and early-onset OCD. This finding may be significant in the understanding of the underlying genetic basis of OCD.     

Chromosome 22q11 deletion presenting as the Potter sequence.

A female fetus with the Potter sequence, caused by unilateral renal agenesis and contralateral multicystic renal dysplasia, was found to have a submicroscopic deletion in chromosome 22q11. The only associated anomaly was agenesis of the uterus and oviducts (Von Mayer-Rokitansky-Küster anomaly). The deletion was inherited from the father, who presented the typical velocardiofacial syndrome phenotype, but no urological anomalies. This observation further extends the clinical spectrum associated with a deletion in 22q11.     

Presenting symptoms in adults with the 22q11 deletion syndrome

A definitive molecular diagnosis of 22q11 Deletion Syndrome (22q11DS) even if occurring later in life, has important genetic, medical and emotional impact on the patients and their families. The aim of this study is to describe presenting symptoms and age at diagnosis in an adult 22q11DS population.A retrospective study was performed on 65 individuals diagnosed with 22q11DS at adult age. Data were collected on adults referred to the genetic clinic or actively recruited through systematic diagnostic examination in both institutions and a psychiatric unit for intellectually disabled. Presenting symptoms were categorized into seven groups: familial occurrence, intellectual disability, cardiac anomalies, palatal anomalies, facial dysmorphic features, psychiatric problems and ‘other’ (comprising all other features associated with 22q11DS). Age at diagnosis was defined as the age at which the 22q11.2 deletion was detected by fluorescence in situ hybridization or comparative genomic hybridization. Ascertainment subgroups were different in presenting symptoms and age at diagnosis. Adults were referred to the genetic clinic mainly because of familial occurrence, cardiac defects and psychiatric disorders whereas adults diagnosed in institutions for intellectually disabled presented mainly with moderate to severe intellectual disability and psychotic disorders. Adults diagnosed at the psychiatric unit for intellectually disabled had a variety of psychiatric disorders but none of them had additional physical features.This emphasizes the need to stay alert for presenting symptoms such as conotruncal heart defects or moderate to severe intellectual disability in combination with a history of psychiatric disorders, even in the absence of obvious physical features.     

Networks of attention in children with the 22q11 deletion syndrome

The 22q11 chromosomal deletion syndrome (22q11 DS) is associated with learning disabilities and a complex neuropsychological profile. Previous findings have suggested that executive attention deficits might underlie other neurocognitive anomalies. We administered the child Attention Network Test (ANT) to 52 children ages 5.0 to 11.5, 32 22q11 DS children (19 girls) and 20 controls (13 girls) and assessed the efficiency of segregated executive, orienting, and alerting networks. We hypothesized that 22q11 DS children have impaired executive network efficiency as compared to control siblings. The internal validity of the child ANT was confirmed for this population. Analysis of variance results showed significant main effects for flanker and cue types and no interaction effect in either 22q11 DS children or control siblings. Compared to control siblings, 22q11 DS children had significantly larger (less efficient) executive network scores, significantly increased errors on only incongruent trials, and a significant correlation between executive network scores and accuracy. The implications of these findings for future neurocognitive studies of 22q11 DS children are considered.