PAGOD syndrome: Eighth case and comparison to animal models of congenital vitamin A deficiency

Abstract

We observed a 46, XY infant with atrophy of the optic nerve, complex congenital heart disease including a double outlet right ventricle, hypoplasia of the right pulmonary artery and lung, eventration of the diaphragm, and ambiguous genitalia. The baby died of cardiac arrhythmias at 204 days. The pattern of malformations was compatible with pulmonary tract and pulmonary artery, agonadism, omphalocele, diaphragmatic defect, and dextrocardia (PAGOD) syndrome. The condition may resemble the malformation complex associated with developmental deficiency of vitamin A or retinoic acid, as described in animal models.

Vitamin A deficiency in an infant with PAGOD syndrome

“…Eleven cases (9 male and 2 female) have been reported to date (Table II) [Meacham et al, 1991;Sorgo et al, 1991;Maaswinkel-Mooij and Stokvis-Brantsma, 1992;Kennerknecht et al, 1993;Oyer et al, 1994;ManouvrierHanu et al, 2000;Macayran et al, 2002;Kim et al, 2007]. All have been isolated/sporadic except for a single report of this phenotype in a set of siblings suggesting the possibility of an autosomal recessive condition [Kennerknecht et al, 1993].…”

“…The constellation of findings in PAGOD syndrome resembles the malformation complex associated with fetal deficiency of vitamin A in animal models (Table I) [Macayran et al, 2002]. Severe vitamin A deficiency (VAD) in animals results in early embryonic death, possibly due to placental insufficiency [Mendelsohn et al, 1994;Chailley-Heu et al, 1999;Morriss-Kay and Ward, 1999], while less-severe VAD results in a set of developmental malformations known as the vitamin A deficiency syndrome [Wilson et al, 1953;Morriss-Kay and Ward, 1999].…”

“…Gestational age, growth status, and maternal plasma vitamin A and RBP concentrations are the major determinants of fetal vitamin A levels [Kennerknecht et al, 1993;Tolba et al, 1998;Macayran et al, 2002]. Since all these parameters were adequate in our case, a low embryonic vitamin A level could be explained by at least two possible mechanisms: (1) a dysfunctional cell surface receptor (as with STRA6 mutations described in Matthew-Wood syndrome) [Golzio et al, 2007;Kawaguchi et al, 2007;Passuto et al, 2007], potentially resulting in defective trans-placental transfer of retinol (Table I); or (2) defective embryonic uptake (mechanism unknown), with possible involvement of RBP4 [Dancis et al, 1992;Bouillet et al, 1997;Kawaguchi et al, 2007;Niederreither and Doll e, 2008].…”

Genetics of Congenital Diaphragmatic Hernia

“…(Masturzo et al, 2001;Panda et al, 2009;van Dooren et al, 2003) CDH and eye abnormalities: microphthalmia and anophthalmia are reported in several syndromes listed above (Macayran et al, 2002;Steiner et al, 2002).…”

Gene-environment interactions in rare diseases that include common birth defects

“…It seems possible that the combined presence of both environmental and genetic disturbances in the vitamin A pathway could act in concert to greatly increase the risk for developing CDHs. Current research is exploring this pathway, and mutations that affect the vitamin A pathway are prime candidate genes for causing CDHs, especially in cases in which the phenotype resembles vitamin A deficiency in experimental animals (Macayran et al, 2002).…”