DiGeorge syndrome: complex pathogenesis? Maybe, maybe not

Abstract

For almost a decade, human geneticists have searched for the gene(s) responsible for the developmental defects associated with an interstitial deletion of chromosome 22 (del22q11). These defects mainly affect the cardiovascular system, thymus and parathyroids. So far, the search for the causative gene(s) has been unsuccessful, and the frustration that derives from the lack of a common region of deletion overlap (see Fig. 1 of Novelli et al.1xIndividual haploinsufficient loci and the complex phenotype of the DiGeorge syndrome. Novelli, G. et al. Mol. Med. Today. 2000; 6: 10–11Abstract | Full Text | Full Text PDF | PubMed | Scopus (10)See all References1) has sometimes driven investigators to propose complex (and even exotic) models. Whatever the reason by which non-overlapping deletions cause similar abnormalities, one thing is clear: the del22q11 region harbors one or more dosage-sensitive genes that are important for embryonic development. The heart, thymic and parathyroid (and perhaps craniofacial) abnormalities of DiGeorge syndrome (which is mainly caused by del22q11) have been attributed to a single problem: impaired development of the pharyngeal arches and arch artery derivatives2xDiGeorge’s or the III–IV pharyngeal pouch syndrome: pathology and a theory of pathogenesis. Robinson, H.B. Jr. Perspect. Pediatr. Pathol. 1975; 2: 173–206PubMedSee all References, 3xCardiovascular anomalies in DiGeorge syndrome and importance of neural crest as a possible pathogenetic factor. Van Mierop, L.H. and Kutsche, L.M. Am. J. Cardiol. 1986; 58: 133–137Abstract | Full Text PDF | PubMed | Scopus (224)See all References, 4xThe developmental field concept in pediatric pathology – especially with respect to fibular a/hypoplasia and the DiGeorge anomaly. Opitz, J.M. and Lewin, S.O. Birth Defects Orig. Artic. Ser. 1987; 23: 277–292PubMedSee all References. Although there is still no evidence that this is the case, this unifying view is reasonable and transforms the complex del22q11-associated phenotype into a conceptually ‘simple’ developmental problem.By chance or by design, some light, and a lot of excitement, is coming from mouse genetics. Two reports this year have stirred debate in the literature5xA molecular pathway revealing a genetic basis for human cardiac and craniofacial defects. Yamagishi, H. et al. Science. 1999; 283: 1158–1161Crossref | PubMed | Scopus (214)See all References, 6xCongenital heart disease in mice deficient for the DiGeorge syndrome region. Lindsay, E.A. et al. Nature. 1999; 401: 379–383PubMedSee all References, and Novelli and colleagues address both in their letter1xIndividual haploinsufficient loci and the complex phenotype of the DiGeorge syndrome. Novelli, G. et al. Mol. Med. Today. 2000; 6: 10–11Abstract | Full Text | Full Text PDF | PubMed | Scopus (10)See all