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.     

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.     

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.     

Monozygotic twins with chromosome 22q11 deletion and discordant phenotype.

We report monozygotic twins concordant for 22q11.2 deletion but discordant for clinical phenotype. Both boys show the typical dysmorphic features with short palpebral fissures, square nasal tip, small mouth, and both have nasal speech, but only one twin had a heart defect. They show that the phenotypic variability seen in this microdeletion syndrome cannot be explained on the basis of genotypic differences alone.     

Craniofacial malformations: intrinsic vs extrinsic neural crest cell defects in Treacher Collins and 22q11 deletion syndromes

The craniofacial complex is anatomically the most sophisticated part of the body. It houses all the major sensory organ systems and its origins are synonymous with vertebrate evolution. Of fundamental importance to craniofacial development is a specialized population of stem and progenitor cells, known as the neural crest, which generate the majority of the bone, cartilage, connective and peripheral nerve tissue in the head. Approximately one third of all congenital abnormalities exhibit craniofacial malformations and consequently, most craniofacial anomalies are considered to arise through primary defects in neural crest cell development. Recent advances however, have challenged this classical dogma, underscoring the influence of tissues with which the neural crest cells interact as the primary origin of patterning defects in craniofacial morphogenesis. In this review we discuss these neural crest cell interactions with mesoderm, endoderm and ectoderm in the head in the context of a better understanding of craniofacial malformations such as in Treacher Collins and 22q11 deletion syndromes.     

Schizophrenic-like neurocognitive deficits in children and adolescents with 22q11 deletion syndrome.

22q11.2 Deletion Syndrome (22q11DS) is the most common genetic microdeletion syndrome affecting humans. The syndrome is associated with general cognitive impairments and specific deficits in visual-spatial ability, non-verbal reasoning, and planning skills. 22q11DS is also associated with behavioral and psychiatric abnormalities, including a markedly elevated risk for schizophrenia. Research findings indicate that people with schizophrenia, as well as those identified as schizoptypic, show specific cognitive deficits in the areas of sustained attention, executive functioning, and verbal working memory. The present study examined such schizophrenic-like cognitive deficits in children and adolescents with 22q11DS (n = 26) and controls (n = 25) using a cross-sectional design. As hypothesized, 22q11DS participants exhibited deficits in intelligence, achievement, sustained attention, executive functioning, and verbal working memory compared to controls. Furthermore, deficits in attention and executive functioning were more pronounced in the 22q11DS sample relative to general cognitive impairment. These findings suggest that the same pattern of neuropsychological impairment seen in patients with schizophrenia is present in non-psychotic children identified as at-risk for the development of schizophrenia based on a known genetic risk marker.