Guidelines for 22q11 deletion screening of patients with conotruncal defects.

Goldmuntz et al. (1) have reported the frequency of 22q11 deletions in a prospectively ascertained sample of 251 patients with conotruncal defects. Deletions were found in 17.9% of the patients, including 50% with interrupted aortic arch (IAA), 34.3% with truncus arteriosus (TA), and 15.9% with tetralogy of Fallot (TOF). Although this study was designed to determine the frequency of deletions in patients recruited solely on the basis of cardiac findings independently from extracardiac features, the authors have recommended deletion screening of all patients with IAA, TA and TOF. Personal experience does not support these conclusions and rather suggests that general clinical evaluation, including extracardiac features, and the analysis of the anatomical subtypes of cardiac defects are mandatory for selecting patients undergoing 22q11 deletion testing. Following the first report of Goldmuntz et al. (2), who found 22q11 deletion in 29% of their patients with “nonsyndromic” conotruncal defects, careful clinical evaluation of larger series of patients has shown that one or more additional features of 22q11 deletion syndrome, including characteristic or subtle facial dysmorphisms, palatal anomalies, absent thymus, T-lymphocyte deficit, hypocalcemia or developmental disabilities, occur in deleted patients with conotruncal defect (3–9). Interestingly, 80% of the patients with “isolated” conotruncal defects in the study of Goldmuntz et al. (2) had associated extracardiac symptoms. Other investigations have corroborated these results by showing that 22q11 deletion is virtually never found in nonsyndromic patients with conotruncal defects (3,10–14). In a personal series of 204 nonsyndromic patients with conotruncal defects, we detected only one deleted patient (12). Formerly, we have shown that “isolated” cleft palate, another feature of 22q11 deletion phenotype, is never associated with 22q11 monosomy (15). It has been also shown that distinct subtypes of conotruncal defects are likely to be found in association with 22q11 deletion. For example, IAA type A and B are distinct defects, and only IAA type B is found in patients with 22q11 deletion (16,17). In addition, TA with major aortopulmonary collateral arteries, crossing pulmonary arteries and pulmonary ostial stenosis is often associated with 22q11 deletion (18). We disagree with the suggestion to perform large-scale screening of all TOF patients irrespective of their clinical phenotype (1). Tetralogy of Fallot is a heterogeneous defect, which can be either isolated or associated with genetic disorders or extracardiac malformation (3,19,20). We found 22q11 deletion in less than 10% of the patients with “classic” TOF (3,12,21), excluding children with TOF and pulmonary atresia, which are often related to 22q11 deletion (21–24). The occurrence of this deletion in onethird of our patients with TOF and pulmonary atresia has suggested the inclusion of this defect in the list of features related to 22q11 deficiency (21). Similarly, TOF with right aortic arch, absent infundibular septum and absent pulmonary valve must be included among the manifestations of 22q11 deletion syndrome (20,25). No evidence is supporting, at present, that an early detection of 22q11 deletion predicts outcome in patients with conotruncal defects (26). Therefore, we favor 22q11 deletion testing only in patients in which heart defects are associated with “classic” or “subtle” clinical anomalies falling within the phenotypic spectrum of 22q11 deletion, and in those presenting with distinct anatomic conotruncal defect subtypes. The only conotruncal defect that “per se” deserves screening for 22q11 deletion, independently from clinical phenotype, the screening for 22q11 deletion is the IAA type B, which is related to this microdeletion in about 30%–80% of the cases (16,17).