Common arterial trunk, DiGeorge syndrome and microdeletion 22q11

Abstract

DiGeorge anomaly and related syndromes are frequent genetic conditions (1/4000 per live birth) characterized by conotruncal heart disease, anomalies of the face, thymic dysfunction, hypoparathyoidism and developmental delay, due to microdeletion of chromosome 22q11. Common arterial trunk (CAT) is one of the classic conotruncal defect of this syndrome; it ranges between 3 and 10% of patients and the prevalence of deletion 22q11 in a population of children with CAT is 30%. In patients with CAT and deletion 22q11 there is a prevalence of additional anomalies of the aortic arch (interruption, right sided or double aortic arch) and/or of the pulmonary arteries (discontinuity, stenosis or crossed pulmonary arteries). Severe dysplasia of the truncal valve (insufficiency and/or stenosis) can be present as well as the truncal origin from the right ventricle. These additional cardiovascular defects could complicate surgical repair. A multispecialistic approach is indicated for these patients in order to reduce mortality and mobidity.

Introduction

In 1965 Dr Angelo DiGeorge [1] reported a group of infants with congenital absence of the thymus and parathyroid glands, and defects of cellular immunity. In 1968 Strong [2], in 1976 Kinouchi et al. [3] and in 1978 Shprintzen et al. [4] described ‘new’, similar syndromes characterized by conotruncal anomalies, abnormal facies, velopharingeal insufficiency or cleft palate and learning disabilities. Although these malformations have been considered for some years as three distinct entities—DiGeorge syndrome (DGS) [1], conotruncal anomaly face syndrome [3], and velocardio-facial syndrome [2], [4]—it is evident today that there is only a single variable and a broad phenotype, due to microdeletion of the chromosomal region 22q11 (22del) [5], [6], [7].

The classic phenotype of this syndrome is characterized by conotruncal heart defects—including tetralogy of Fallot (TF), pulmonary atresia with ventricular septal defect (PAVSD), common arterial trunk (CAT), interruption of the aortic arch (IAA), transposition of the great arteries (TGA), double outlet right ventricle, and aortic arch anomalies. Additional extracardiac signs are present such as neonatal hypocalcemia, abnormal cellular immunity, cleft palate, nasal speech, developmental delay and facial dysmorphisms (i.e. short palpebral fissures, broad nasal root, lateral displacement of the inner canthi, prominent nose, low set and posteriorly rotated ears, and small mouth) (Fig. 1). The prevalence of 22del is estimated to be 1:4000 live births [8]. Recent clinical observations have further expanded the spectrum of this syndrome by including hypoplasia of depressor anguli oris muscle [9], renal anamalies [10], anal malformations [11], skeletal anomalies [12], psychosis [13], juvenile rheumatoid arthritis [14], and frontonasal malformations [15].

Since the first reports of cardiac defects to be associated with this syndrome, [16], [17], [18], [19], [20] CAT has been described to be one of the most frequent. Freedom, et al. [16] reported 4 cases amongst 11 patients affected with DGS, Conley et al. [17] found 9 of 26 children, and 7 of 35 patients were reported by Marmon et al. [19]. Similarly, autopsy studies [20] indicate CAT as one of the most frequent cardiovascular anomalies in DGS, Van Mierop et al. reporting 14 cases among 51 specimens analyzed, with further recent studies [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26] confirming these findings. Indeed, the prevalence of CAT in the large series of patients with 22del ranges between 3 and 10% [22], [24], [25], [26], whereas the prevalence of 22del in series of patients with CAT is approximately 30% [23], [27], [28]. The role of neural crest abnormalities in the pathogenesis of conotruncal malformations due to 22del is well established [8], [20], [29], [30], [31]. According to experimental embryology [29], [30], consisting of premigratory cranial neural crest ablation of the chick embryo, CAT appears to be caused by an abnormally small number of neural crest cells reaching the outflow tract of the heart resulting in the absence of aortopulmonary, truncal and infundibular septa. Evidently, the region q11 of chromosome 22 contains one or more genes contributing to the normal development, proliferation and migration of cranial neural crest cells, essential for the normal morphogenesis of the outflow tract of the heart [5], [6], [7], [8]. It has also been demonstrated that CAT may be obtained by chemical teratogen agents administered to pregnant rats [32], [33] (probably inhibiting the formation of extracellular matrix, thus interfering with normal neural crest migration), as a result of maternal diabetes, [34] or retinoic acid embryopathy [35] in humans. Furthermore, CAT is consistently present in children with CHARGE syndrome [36], [37]. Familial recurrence of CAT has been reported in the setting of DGS [38], in association with other genetic conditions [39], or in cases with complex types of CAT [40].