Vitamin A deficiency in an infant with PAGOD syndrome

Abstract

PAGOD syndrome is a rare condition characterized by multiple congenital anomalies including pulmonary artery and lung hypoplasia, agonadism, diaphragmatic abnormalities, cardiac defects, omphalocele, and various genital anomalies. The etiology of this condition is unknown but the spectrum of birth defects is similar to the developmental anomalies observed in vitamin A deficiency animal models. We describe an infant with PAGOD syndrome phenotype. The patient had a normal male karyotype and no copy number changes were seen on chromosome genomic hybridization (CGH) microarray. Endocrine evaluation was consistent with primary hypogonadism. The testes and Müllerian structures were absent by imaging studies, raising the possibility of arrest of early gonadogenesis. The plasma free vitamin A was low, consistent with moderate to severe vitamin A deficiency; the maternal plasma vitamin A level was normal. During pregnancy maternal vitamin A is taken up by retinol binding protein 4 (RBP4) which is expressed in the embryonic visceral endoderm from pregastrulational stages. This transport is mediated via the specific membrane receptor for RBP, stimulated by retinoic acid 6 (STRA6). STRA6 is widely expressed in human organ systems including the placenta during embryonic development. Mutations in the STRA6 gene result in Matthew-Wood syndrome, which demonstrates significant phenotypic overlap with PAGOD syndrome. Sequencing of STRA6 coding regions in our patient, revealed no mutations. We present a case of PAGOD syndrome with a review of the literature, posing the hypothesis that a vitamin A metabolic defect, other than transport mediated by STRA6 receptor, might have an etiological role in the development of this multiple congenital anomalies syndrome.

The STRA6 Receptor Is Essential for Retinol-binding Protein-induced Insulin Resistance but Not for Maintaining Vitamin A Homeostasis in Tissues Other Than the Eye

“…The discrepancy between the mild symptoms displayed by humans carrying RBP mutations (20) and the severe symptoms displayed by humans suffering from Matthew-Woods syndrome (17)(18)(19) thus raise the possibility that Matthew-Woods syndrome is not caused primarily by loss of STRA6 function but involves additional genetic alterations. It is interesting to note in regard to this that no mutations in STRA6 gene were found in a patient suffering PAGOD syndrome, a multiple congenital anomalies syndrome, including defects in vitamin A homeostasis, which presents significant phenotypic overlap with Matthew-Woods syndrome (53). Our studies provide several lines of evidence that establish that, with the exception of the eye, STRA6 is not critical for maintaining ROH availability in tissues that express it.…”

Retinoic Acid and the Development of the Endoderm

“…The role of RA in lung is clearly relevant to humans because mutations in the RA pathway are associated with syndromes linked to disrupted lung development, including PAGOD syndrome [118] and Matthew Wood syndrome that results from mutations in STRA6 [119]. Later roles for RA in lung maturation have also recently been demonstrated.…”

A retinoic acid–dependent network in the foregut controls formation of the mouse lung primordium

“…There is accumulated evidence of an association between vitamin A deficiency and lung birth defects. For example, this has been recently documented in PAGOD syndrome, in which pulmonary hypoplasia is a hallmark feature (2). Moreover, mutations in STRA6, which encodes a receptor essential for cellular uptake of the retinoic acid (RA) precursor vitamin A, have been identified in patients with Matthew-Wood syndrome (3).…”