Matthew‐Wood syndrome: Report of two new cases supporting autosomal recessive inheritance and exclusion of FGF10 and FGFR2

Abstract

We describe two fetal cases of microphthalmia/anophthalmia, pulmonary agenesis, and diaphragmatic defect. This rare association is known as Matthew-Wood syndrome (MWS; MIM 601186) or by the acronym "PMD" (Pulmonary agenesis, Microphthalmia, Diaphragmatic defect). Fewer than ten pre- and perinatal diagnoses of Matthew-Wood syndrome have been described to date. The cause is unknown, and the mode of transmission remains unclear. Most cases have been reported as isolated and sporadic, although recurrence among sibs has been observed once. Our two cases both occurred in consanguineous families, further supporting autosomal recessive transmission. In addition, in one family at least one of the elder sibs presented an evocatively similar phenotype. The spatiotemporal expression pattern of the FGF10 and FGFR2 genes in human embryos and the reported phenotypes of knockout mice for these genes spurred us to examine their coding sequences in our two cases of MWS. While in our patients, no causative sequence variations were identified in FGF10 or FGFR2, this cognate ligand-receptor pair and its downstream effectors remain functional candidates for MWS and similar associations of congenital ocular, diaphragmatic and pulmonary malformations.

ISL1 Directly Regulates FGF10 Transcription during Human Cardiac Outflow Formation

“…Recent results from our and other groups have demonstrated the expression of both FGF10 and ISL1 in a region probably corresponding to a second heart field in human embryos at appropriate and similar stages of morphogenesis [11], [37]. A non-exhaustive bioinformatics analysis of the FGF10 locus to search for putative highly conserved ISL1 consensus binding sites with the sequence YTAATGR, using rVista 2.0 (http://rvista.dcode.org) [39] and the ECR browser (http://ecrbrowser.dcode.org) [40], identified two candidate regions conserved among therian mammals (Fig.…”

“…Based on the murine phenotypes of Fgf10 and Fgfr2-IIIb knockouts and their expression patterns [3], [19], we had previously found very similar expression during normal human embryonic development; however, sequencing of both FGF10 and FGFR2-IIIb in human fetuses exhibiting great vessel defects that resembled those in knockout mice, among other symptoms, did not demonstrate coding mutations [37]. The responsible gene turned out to encode a protein, STRA6, necessary to bring vitamin A into cells, a first step in transcriptional regulation through retinoic acid receptor binding [63], [64].…”

Humans, Mice, and Mechanisms of Intestinal Atresias: A Window into Understanding Early Intestinal Development

“…Encouragingly, work in humans has demonstrated that mutations in the Fgfr2 coding region are associated with duodenal stenosis. 65 Work in mice has demonstrated that mutations in a number of members of the Hedgehog signaling pathway genes ( Gli-1, Gli-2, Gli-3, Ihh , and Foxf1 ) do not result in intestinal atresias but in some cases can cause variations in imperforate anus. 63,66 These results suggest that formation of atresias may require disruptions of other signaling cascades in addition to the Hedgehog pathway.…”

Two novel STRA6 mutations in a patient with anophthalmia and diaphragmatic eventration

“…These two malformations have been described together with pulmonary agenesis in the Matthew-Wood syndrome [MWS; OMIM 601186; Berkenstadt et al, 1999]. P ulmonary hypoplasia/agenesis, D iaphragmatic hernia/eventration, A nophthalmia/microphthalmia, and C ardiac defects, or PDAC syndrome, overlaps with MWS [for selected recent reports, see Ceylaner et al, 2006; Li et al, 2006; Chitayat et al, 2007; Martinovic-Bouriel et al, 2007]. Recently mutations in the STRA6 gene were identified in a phenotype that overlaps with both MWS and PDAC [Golzio et al, 2007; Pasutto et al, 2007], with clinical features of affected families comprising pulmonary agenesis, diaphragmatic defects, anophthalmia or severe microphthalmia, cardiac defects, pancreatic malformations and intrauterine growth retardation.…”