Autosomal dominant inheritance of aplasia cutis congenita and congenital heart defect: A possible link to the Adams–Oliver syndrome^†

To the Editor:

There are numerous reported patients with aplasia cutis congenita (ACC) of the scalp and congenital heart defect (CHD) including a mother and son sharing ACC in the midline of the scalp vertex and coarctation of the aorta [Dallapiccola et al., 1992]. The boy also had bicuspid aortic valve (BAV), and parachute non-stenotic mitral valve, while the mother had BAV and duplication of the right femoral artery. Previous studies have shown the possible association between ACC of the scalp and patent ductus arteriosus [Deeken and Caplan, 1970], ventricular septal defect [Dubosson and Schneider, 1978], and aortic coarctation [Bruel et al., 1999; Heras Mulero et al., 2007] (Table I). In the article by Bruel et al. 1999], two paternal relatives of the proband displayed left-sided obstructive CHDs, including aortic coarctation and hypoplastic left ventricle, in the absence of ACC.

ACC and transverse limb malformations (syndactyly, brachydactyly, oligodactyly) are cardinal features of the Adams–Oliver syndrome (AOS) [Adams and Oliver, 1945; Kuster et al., 1988; Lin et al., 1998]. CHDs occur in 13–20% of patients with AOS, and a variety have been reported including left-sided obstructive CHDs, septal defects, conotruncal defects, and tricuspid atresia [Lin et al., 1993, 1998; Zapata et al., 1995; Swartz et al., 1999; Sankhyan et al., 2006]. However, multiple levels of left-sided obstruction characteristic of Shone's complex (parachute mitral valve, hypoplastic left ventricle, BAV, hypoplastic aortic arch) have been observed in AOS [Zapata et al., 1995; Lin et al., 1998] as well as in patients with ACC [Dallapiccola et al., 1992].

Based on these observations, we propose that a relationship between the association CHDs and ACC, and AOS should be considered, in which variability in clinical expression of AOS may include the association of CHD and ACC without limb defects. This hypothesis is substantiated by occasional examples of familial inheritance of both conditions in which some members exhibit classic AOS and other members exhibit only ACC and CHD (Table II) [Santos et al., 1989; Lin et al., 1998]. CHDs in these families have included multiple levels of left-sided obstruction, consistent with Shone's complex in some cases (Table II).

It has been hypothesized that vascular disruption could be responsible for the terminal transverse limb defects in AOS [Hoyme et al., 1982]. Over twenty years ago, altered blood hemodynamics during fetal life was postulated to be pathogenetically causative of some of the CHDs associated with AOS, including aortic coarctation, aortic stenosis, atrial septal defect, and ventricular septal defect [Clark, 1987]. More recent observations supporting the hypothesis that in utero flow disturbances contribute to the development of left-sided obstruction and ventricular hypoplasia include the prenatal finding of midgestation fetuses diagnosed with aortic valve stenosis which progresses to hypoplastic left heart at birth [Mäkikallio et al., 2006] or experimental animal studies showing that diminished flow through the left ventricle result in aortic valve anomalies and left ventricular hypoplasia [Sedmera et al., 2005; deAlmeida et al., 2007]. An early embryonic vascular abnormality has been suggested as primary event in AOS. The vascular anomaly could be caused by a presently unknown gene that may express a predisposition for a generalized vasculopathy causing disruption of blood flow manifesting in embryogenesis [Piazza et al., 2004].

Autosomal dominant inheritance has been established in most familial cases of AOS [Lin et al., 1998; Verdyck et al., 2003, 2006]. Nevertheless, autosomal recessive inheritance has also been suggested in some cases, following the observation of affected sibs born to consanguineous healthy parents [Koiffmann et al., 1988; Temtamy et al., 2007]. Seven candidate genes implicated in craniofacial, limb and vascular development have been studied in familial cases of AOS, but no disease-causing mutations have been detected up to now [Verdyck et al., 2003, 2006]. Genes known to be related with left-sided obstructive CHDs should also be considered for molecular studies in the future. In particular, the Notch signaling pathway is implicated in cardiac valve development, and heterozygous NOTCH1 mutations in humans disrupt normal development of the aortic valve and occasionally the mitral valve [Garg et al., 2005]. The severity of aortic valve disease associated with NOTCH1 mutations in humans varies from mild BAV to hypoplastic left heart syndrome, suggesting that disruption of the NOTCH signaling cascade may underlie a spectrum of left-sided obstructive CHDs.

In conclusion, variability in clinical expression is well documented in AOS, although an over-representation of left-side obstructive CHDs has been observed. Considering that no specific genetic test is available for this syndrome, we suggest that this diagnosis should be considered during evaluation of patients with the association of ACC and CHD.