Tracheobronchial anomalies in chromosome 22q11.2 microdeletion

Abstract

The 22q11.2 microdeletion syndrome consists of several manifestations including congenital heart defects (CHD), velopharyngeal insufficiency, cleft palate, thymus aplasia-hypoplasia, craniofacial anomalies, and hypoparathyroidism. These phenotypic features can occur in many combinations, and the clinical spectrum varies greatly in severity, ranging from life-threatening problems to hypernasal speech [Ryan et al., 1997]. Phenotypic variability is a striking aspect of the 22q11.2 microdeletion and to date the basis of it remains unclear [Yamagishi, 2002]. The 22q11.2 deletion syndrome encompasses the DiGeorge anomaly (DGA), velocardiofacial (VCFS) and conotruncal anomaly face syndromes (CAFS). In addition to the main clinical features several other defects have been reported with the syndrome, including learning difficulties and psychiatric disorders, eye defects, renal and urological anomalies [Wilson et al., 1993; Devriendt et al., 1996; Hong, 1998; Scambler, 2000]. The 22q11.2 microdeletion syndrome, with an incidence of 1/4,000 live births, is the most frequent interstitial deletion known in humans [Scambler, 2000]. Most of 22q11.2 microdeletions are due to ‘‘de novo’’ mutations while from 12% up to 28% are inherited [Rayan et al., 1997; Vantrappen et al., 1999]. It is suggested that it represents a ‘‘contiguous gene syndrome’’ in which many genes can be lost in several more or less visible deletions [Hall, 1993]. Isolated cases of DGA with no microdeletion (12%) may be ascribed to epigenetic factors such as alcohol or retinoic acid ingestion during pregnancy and maternal diabetes [Driscoll et al., 1993]. Structures primarily affected in 22q11.2 patients are derivatives of pharyngeal arches, pharyngeal arch arteries, and the conotruncal region of the heart (craniofacial features, thyroid, parathyroid, thymus, aortic arch, andheart outflow tract). Neural crest cells migrate in these regions during the 4th week of embryogenesis and constitute, along with paraxial mesoderm, the mesenchyme of these complex embryonic structures. Experiments of neural crest ablation on chick embryos and other animal models have shown that failure in migration/survival/differentiation of neural crest derived cells or imperfect epithelial–mesenchymal interaction in the development of pharyngeal arches, generate phenocopies of 22q11.2 deletion syndrome [Bockman et al., 1987; Frank et al., 2002; Hutson and Kirby, 2003]. Recent research found that genes mapping in the human DGA-critical region are expected to play an important function in controlling the development of neural crest derived cells or in their interaction with endodermal or mesodermal cells in the branchial arch system [Yamagishi, 2002]. In this report we describe a child who showed both 22q11.2 deletion syndrome features and two supernumerary tracheal bronchi. Bronchial branching anomalies are uncommon findings, mainly represented by supernumerary tracheal bronchus (STB) and displaced tracheal bronchus, whereas bridging bronchus, supernumerary esophageal bronchus and esophageal lung are more exceptional observations [Evans, 1990]. STB is defined as an adjunctive bronchus that originates from the tracheal lateral wall (segmentary), mostly on the right, or from the main bronchus (subsegmentary), and directs to the ipsilateral upper lobe territory [Ghaye et al., 2001]. A causal connection between 22q11.2 microdeletion and STB is plausible on the basis of the timing of embryo development. In fact the respiratory system