Polysyndactyly

About: Polysyndactyly is a research topic. Over the lifetime, 205 publications have been published within this topic receiving 3328 citations.

GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families

Abstract: The Greig cephalopolysyndactyly syndrome (GCPS) is an autosomal dominant disorder affecting limb and craniofacial development in humans. GCPS-affected individuals are characterized by postaxial polysyndactyly of hands, preaxial polysyndactyly of feet, macroephaly, a broad base of the nose with mild hypertelorism and a prominent forehead. The genetic locus has been pinpointed to chromosome 7p13 by three balanced translocations associated with GCPS in different families. This assignment is corroborated by the detection of two sporadic GCPS cases carrying overlapping deletions in 7p13 (ref. 7), as well as by tight linkage of GCPS to the epidermal growth factor receptor gene in 7p12-13 (ref. 8). Of the genes that map to this region, those encoding T cell receptor-gamma, interferon-beta 2, epidermal growth factor receptor, and Hox1.4, a potential candidate gene for GCPS, have been excluded from the region in which the deletions overlap. Here we show that two of the three translocations interup the GLI3 gene, a zinc-finger gene of the GLI-Kruppel family already localized to 7p13 (refs 5, 6). The breakpoints are within the first third of the coding sequence. In the third translocation, chromosome 7 is broken at about 10 kilobases downstream of the 3' end of GLI3. Our results indicate that mutations disturbing normal GLI3 expression may have a causative role in GCPS.

Abnormal development of the apical ectodermal ridge and polysyndactyly in Megf7-deficient mice.

Abstract: Megf7/Lrp4 is a member of the functionally diverse low-density lipoprotein receptor gene family, a class of ancient and highly conserved cell surface receptors with broad functions in cargo transport and cellular signaling. To gain insight into the as yet unknown biological role of Megf7/Lrp4, we have disrupted the gene in mice. Homozygous Megf7-deficient mice are growth-retarded, with fully penetrant polysyndactyly in their fore and hind limbs, and partially penetrant abnormalities of tooth development. The reason for this developmental abnormality is apparent as early as embryonic day 9.5 when the apical ectodermal ridge (AER), the principal site of Megf7 expression at the distal edge of the embryonic limb bud, forms abnormally in the absence of Megf7. Ectopic expression and aberrant signaling of several molecules involved in limb patterning, including Fgf8, Shh, Bmp2, Bmp4 and Wnt7a, as well as the Wnt- and Bmp-responsive transcription factors Lmx1b and Msx1, result in reduced apoptosis and symmetrical dorsal and ventral expansions of the AER. Abnormal signaling from the AER precedes ectopic chondrocyte condensation and subsequent fusion and duplication of digits in the Megf7 knockouts. Megf7 can antagonize canonical Wnt signaling in vitro. Taken together, these findings are consistent with a role of Megf7 as a modulator of cellular signaling pathways involving Wnts, Bmps, Fgfs and Shh. A similar autosomal recessive defect may also occur in man, where polysyndactyly, in combination with craniofacial abnormalities, is also part of a common genetic syndrome.

Congenital limb anomalies: frequency and aetiological factors: Data from the Edinburgh Register of the Newborn (1964-68)

Abstract: This paper reports a detailed follow up of 156 patients with structural upper and lower limb anomalies, obtained from the Edinburgh Register of the Newborn (a registration of 52,029 consecutive births between 1964 and 1968). At the time of this survey the patients were between 4 and 9 years of age. The Register had noted probably 96% of all children born with limb defects in Edinburgh between 1964 and 1968. It was found that the diagnosis was completely accurate in only 26% of cases, and partially so in a further 42%. The frequency of each anomaly has been noted, subdivided into isolated anomalies; those that occurred with other limb anomalies, and those that formed part of a syndrome. Syndactyly of toes, post-axial polydactyly of the fingers, polysyndactyly, and brachydactyly were found to have a genetic basis. All `absence9 defects, pre-axial polydactyly, and multiple limb deformities appeared to be sporadic. Amongst the sporadic group, the main aetiological factors noted were an excess of maternal toxaemia of pregnancy and of illegitimate children, when compared with the Register Control Data.

A specific mutation in the distant sonic hedgehog (SHH) cis-regulator (ZRS) causes Werner mesomelic syndrome (WMS) while complete ZRS duplications underlie Haas type polysyndactyly and preaxial polydactyly (PPD) with or without triphalangeal thumb.

Abstract: Werner mesomelic syndrome (WMS) is an autosomal dominant disorder with unknown molecular etiology characterized by hypo- or aplasia of the tibiae in addition to the preaxial polydactyly (PPD) of the hands and feet and/or five-fingered hand with absence of thumbs. We show that point mutations of a specific nucleotide within the sonic hedgehog (SHH) regulatory region (ZRS) cause WMS. In a previously unpublished WMS family, we identified the causative G>A transition at position 404 of the ZRS, and in six affected family members of a second WMS family we found a 404G>C mutation of the ZRS. The 404G>A ZRS mutation is known as the “Cuban mutation” of PPD type II (PPD2). Interestingly, the index patient of that family had tibial hypoplasia as well. These data provide the first evidence that WMS is caused by a specific ZRS mutation, which leads to strong ectopic SHH expression. In contrast, we show that complete duplications of the ZRS region lead to type Haas polysyndactyly or triphalangeal thumb-polysyndactyly syndrome, but do not affect lower limb development. We suggest the term “ZRS-associated syndromes” and a clinical subclassification for the continuum of limb malformations caused by different molecular alterations of the ZRS. Hum Mutat 30:1–9, 2009. © 2009 Wiley-Liss, Inc.

Craniosynostosis. II. Coronal synostosis: its familial characteristics and associated clinical findings in 109 patients lacking bilateral polysyndactyly or syndactyly.

Abstract: This paper is the second part of a survey of 370 patients with craniosynostosis. It concerns 109 patients with coronal synostosis, with or without additional suture involvement who lacked polysyndactyly or syndactyly. Bilateral and unilateral coronal synostosis occurred with approximately equal frequency and there was an excess of males in both groups. Multiple suture involvements was frequent in patients with bilateral synostosis, but was uncommon in those with unilateral involvement. Those patients with bilateral synostosis and additional suture involvement were treated later than those with isolated bilateral synostosis and a possible explanation for this finding is discussed. Forty-seven percent of patients with bilateral synostosis had additional major malformations. Cardiac malformations were significantly more frequent than would be expected by chance. Thirty-five percent of patients with unilateral involvement had major malformations. Twenty-six percent of those with bilateral and ten percent of those with unilateral synostosis were mentally retarded, but retardation was found to be associated either with increased frequency of major malformations or with a complex medical history. Mental retardation is uncommon in simple, uncomplicated coronal synostosis. Twelve of the 104 families showed a positive family history; nine with vertical and three with horizontal transmission. An admixture of unilateral and bilateral suture involvement was the rule, and families with involvement limited to unilateral synostosis did not occur. Certain patterns of characteristic familial minor malformation, particularly of the hands, allow recognition of a number of these familial cases. The recurrence risks for coronal synostosis are discussed.