Polydactyly Research Articles

Polarizing activity, Sonic hedgehog, and tooth development in embryonic and postnatal mouse.

Tooth development involves reciprocal epithelial-mesenchymal interactions, polarized growth, mesenchyme condensation, and complex morphogenetic events. Because these processes bear similarities to those occurring in the developing limb, we asked whether morphogenetic signals found in the limb also occur in the developing tooth. We grafted mouse embryo tooth germs to the anterior margin of host chick embryo wing buds and determined whether the dental tissues had polarizing activity. Indeed, the grafts induced supernumerary digits. Activity of both molar and incisor tooth germs increased from bud to cap stages and was maximal at late bell stage in newborn. With further development the polarizing activity began to decrease, became undetectable in adult molar mesenchyme but persisted in incisor mesenchyme, correlating with the fact that incisors grow throughout postnatal life while molars do not. When different portions of neonatal incisors were assayed, a clear proximo-distal gradient of activity was apparent, with maximal activity restricted to the most proximal portion where undifferentiated mesenchyme and enamel organ reside. In situ hybridizations demonstrated that prior to induction of supernumerary digits, the tooth germ grafts induced expression in host tissue of Hoxd-12 and Hoxd-13. In addition, whole-mount in situ hybridizations and immunohistochemistry showed that developing tooth germs express Sonic hedgehog (Shh). Shh expression was first detected in bud stage tooth germs; at later stages Shh transcripts were prominent in enamel knot and differentiating ameloblasts at the cuspal region. We concluded that tooth germs possess polarizing activity and produce polarizing factors such as Shh. As in the limb, these factor(s) and activity probably play key roles in establishing polarity and regulating morphogenesis during early tooth development. Given its subsequent association with differentiating ameloblasts, Shh probably participates also in cytogenetic events during odontogenesis.

Central-type eight-toed polydactyly associated with ipsilateral complex renogluteal agenesis: A case report with 8 years' follow-up

At birth, a baby girl was found to have central-type eight-toed polydactyly of the left foot associated with ipsilateral nonvisualization of the kidney and atrophy of the gluteal maximum muscle. X-ray examination showed eight completely developed metatarsal and digit bones, and a chromosome study showed a normal 46,XX karyotype. She received ray amputation of the extra toes when she was 1 year old. Follow-up examination at age 9 showed unchanged renogluteal anomalies and a slightly smaller left foot. In addition, a bony defect over the posterior iliac spine and a wide femoral neck-shaft angle were found on the radiograph. Her left leg was found to be 1 cm shorter than the right, but there was no evidence of valgus or varus. Presently she can walk and run quite well, and there is no callus formation over her sole. The timing and options for excision of the supernumerary digits are discussed and this rare disease reviewed.

Molecular markers near the mouse brachymorphic (bm) gene, which affects connective tissues and bleeding time.

Several inherited skeletal/connective tissue defects are associated with hemorrhagic disorders in humans. Accordingly, three mouse mutants (brachymorphic [bm], hemimelic extra toes [Hx], and ulnaless [Ul]), with inherited skeletal abnormalities, were analyzed for hemorrhagic tendencies. All three had prolonged bleeding times. Platelet numbers, size, and function, as well as common soluble plasma clotting factors, were not measurably affected. To further define the bm mutation, its chromosomal location relative to 19 other molecular markers was determined to a high resolution in a large interspecific backcross. Several microsatellite markers were found to be very closely linked to bm and should provide useful entry points for the eventual identification of this gene by positional/candidate cloning techniques. These results suggest that inherited skeletal abnormalities and bleeding tendencies are associated more frequently in both humans and animal models than is commonly recognized. Identification of these genes may reveal novel relationships between osteogenesis and hemostasis.

Digit Induction by Hensen's Node and Notochord Involves the Expression ofshhbut NotRAR-β2

It is well established that Hensen's nodes can induce the formation of supernumerary digits after grafting into the anterior margin of the developing limb bud. The recent finding that distinct mesodermal cell populations are segregated within the node has made it possible to isolate different prospective cell types in an attempt to correlate digit-inducing ability with cell fate. We find that the prospective notochord cells contained within Hensen's node are able to induce supernumerary digits, whereas presumptive somite cells cannot. This early difference in inducing ability persists into later stages of development: epithelial somites are unable to induce while notochord from all lengths of the neuraxis continues to induce. Using probes to retinoic acid receptor-β2 and sonic hedgehog (shh) we find no evidence to support the idea that inducing tissues generate extra digits by releasing retinoic acid into adjacent limb tissue but find that the inducing ability of a tissue correlates with its expression ofshh.

Case histories surgical treatment of polydactyly of the little toe involving proximal and middle phalanx

Surgical Principles Removal of the hypoplastic or malpositioned supernumerary digit or digital ray which is mostly located at the tibial side of the little double toe. In case of equal sized parallel digits, the surgical method of Bilhaut-Cloquet (cit. in [1, 5]) may be applied. The adjacent digits are split in half, the parallel halves resected and bone and soft tissues of the remaining halves brought together. Lengthening of tendons and capsulo- and ligamentoplasty may be necessary. A corrective osteotomy of the little toe is rarely necessary. A remaining skin defect, after surgical correction of syndactylism of the fourth toe, may have to be covered with a full thickness skin graft.

Pedal polydactyly: An overview with case report

Polydactyly is a fairly common congenital condition of the foot, and is characterized by supernumerary digits and/or metatarsals. It may be an isolated condition or part of a congenital syndrome. Polydactyly is generally classified into three major groups: medial ray (preaxial), central ray, and lateral ray (postaxial). A review of polydactyly and an unusual case report of central ray involvement and its surgical correction are presented.

Suture Ligation of Supernumerary Digits and 'Tags': An Outmoded Practice?

Rudimentary supernumerary digits and preauricular skin are relatively common congenital abnormalities. These abnormalities can present as isolated occurrences or as part of a syndrome. Isolated polydactyly occurs in approximately 0.3 of 1000 live births in white populations and from 3.6 to 10 of 1000 live births in black populations. 1,2 Preauricular tags are also relatively common anomalies. Little attention has been paid to the treatment of these lesions, but pediatricians are commonly taught to ligate the base of these lesions with suture material as a simple, inexpensive form of removal. We recently saw a patient in whom a secondary bacterial infection developed after suture ligation of a supernumerary digit ( Figure ), prompting us to reevaluate this technique and consider the potential problems inherent in this traditional form of treatment. Suture ligation of the base of supernumerary digits and preauricular skin tags is a commonly practiced technique in pediatrics. Although documentation

Mapping of theSca1andpcdGenes on Mouse Chromosome 13 Provides Evidence That They Are Different Genes

It is well established that large chromosomal segments have remained intact during the evolution of different mammalian species. Thus, mapping information for a gene in mammalian species facilitates mapping the same gene in another mammalian species. In addition, phenotypically similar diseases that map to linkage conserved regions in two species may be caused by mutations in the same gene. Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited human disorder characterized by progressive ataxia, dysarthria, and dysmetria. SCA1 maps to the short arm of human chromosome (Chr) 6 in the 6p23-p22 region. SCA1 is caused by the expansion of an unstable CAG repeat located within the coding region of a novel protein, ataxin-1, Purkinje cell degeneration (pcd) is a recessively inherited mouse disorder characterized by a moderate ataxia, usually noted by 3-4 weeks of age. Progressive degeneration of Purkinje cells is the underlying pathogenesis in this disorder. The pcd gene was assigned to mouse Chr 13 because it showed linkage to extra toes (Xt) and pearl (pe). Some doubt about this assignment existed, however, because the calculated genetic distance between pcd and Xt was 32 cM and that between pcd and pe was 18 cM. If pcd is located inmore » Chr 13, its placement relative to Xt and pe suggests that it would be located in the region that shares linkage homology with the region that shares linkage homology with the region of human Chr 6 that contains SCA1. Here, we present data that confirm the assignment of pcd to Chr 13, map the mouse Sca1 gene to Chr 13, and eliminate Sca1 as a candidate gene for pcd. 11 refs., 1 tab.« less

A duplicated zone of polarizing activity in polydactylous mouse mutants.

The positional signaling along the anteroposterior axis of the developing vertebrate limb is provided by the zone of polarizing activity (ZPA) located at the posterior margin. Recently, it was established that the Sonic hedgehog (Shh) mediates ZPA activity. Here we report that a new mouse mutant, Recombination induced mutant 4 (Rim4), and two old mutants, Hemimelic extra toes (Hx) and Extra toes (Xt), exhibit mirror-image duplications of the skeletal pattern of the digits. In situ hybridization of the embryos of these mutants revealed ectopic expression of Shh and fibroblast growth factor-4 (Fgf-4) genes at the anterior margin of limb buds. The new mutation, Rim4, was mapped to chromosome 6 with linkage to HoxAbut segregated from HoxA. No linkage to other known polydactylous mutations was detected. In this mutant, ectopic expression of the Hoxd-11 gene, thought to be downstream of ZPA, was also observed at the anterior margin of the limb buds. All results indicate the presence of an additional ZPA at the anterior margin of limb buds in these mutants. Thus, it appears that multiple endogenous genes regulate the spatial localization of the ZPA in the developing mouse limb bud.

Developmental anomalies suggestive of the human homologue of the mouse mutant disorganization.

We describe a 21-week-old fetus with a pattern of multiple congenital anomalies suggestive of the human homologue of the mouse mutant disorganization (Ds). Manifestations included facial asymmetry, thick eye brows, micrognathia, apparently lowset ears, an enormous abdominal wall defect, severe kyphoscoliosis, camptodactyly of the fingers, complete absence of the left lower limb, and absence of the lower part of the sacrum and coccyx, as well as left side of the pelvis. There was a disorganized appearance of the right foot with supernumerary digits and appendages and talipes equinovarus. No obvious amniotic bands or oligohydramnios were noted. Similar cases in the literature are reviewed and the clinical significance to genetic counselling is emphasized.

Isolation and characterization of a cosmid contig for the GCPS gene region

The zinc finger gene GLI3 has been shown to be involved in the embryonal development of the limbs and skull. Mutations in GLI3 lead to the development of the human Greig cephalopolysyndactyly syndrome (GCPS) and the mouse mutations extra toes (Xt) and anterior digit deformity (add). The GCPS locus on human chromosome 7p13 has recently been isolated in a yeast artificial chromosome (YAC) contig. Here, we describe the establishment of a cosmid contig that was derived from two of the YAC clones, that spans 550 kb of human DNA, and that includes the GLI3 gene. In this contig, three GCPS translocation breakpoints have been mapped to distinct EcoRI fragments in the 3' half of the gene. In addition, exon-carrying fragments have been identified and the size of the GLI3 gene could be determined as at least 280 kb. The gene is flanked by a CpG island that lies on the 5' side and that is in close proximity to the first exon detected by the cloned GLI3 cDNA. Further upstream, five segments were found that have been conserved between man and mouse. In the mouse, this region has been characterized as the transgene integration site resulting in the add phenotype. Both the CpG island and the conserved regions are probable candidates for a search for GLI3 promoter and control elements.

Msx1 is close but not allelic to either Hm or Hx on mouse Chromosome 5

The Msx1 homeobox locus has been mapped in relation to the mutations hammer-toe (Hm) and hemimelic extra toes (Hx). Msx1 is expressed in the developing limb, while limb development is affected by the Hm and Hx mutations. Hm and Hx are very tightly linked loci. In interspecific crosses, the segregation of either mutation was followed in relation to polymorphic alleles of Msx1, Il6, and En2, to give a fine map around the mutant loci. Our results show that Msx1 is not allelic to either of the mutations, but is located about 3 cM from them. Il6 did not recombine with either Hm or Hx and, therefore, provides a point of access for the analysis of these mutations at the molecular level.

Ligamentary structure of the base of the nail.

The authors report the results of 115 dissections of the base of the distal phalanx of fingers and toes. In 85% of cases including hypoplastic supernumerary digits, there is a connective ligament-like structure. It is a dorsal expansion of the lateral ligament of the distal inter-phalangeal joint arising from the intermediate phalanx and ending in the matrix and the lunula. This ligament may have a role in biomechanical strains on the nail. It can explain some dystrophic nails associated with some malpositioned joints in fingers or toes.

A complex bilateral polysyndactyly disease locus maps to chromosome 7q36.

We demonstrated that the gene responsible for a congenital limb deformity (polysyndactyly) maps to chromosome 7q36 in a large family. Pre- and postaxial anomalies of the extremities are inherited in this family as an autosomal dominant trait. The disease locus is closely linked to D7S550 (maximum lod score = 6.85, theta = 0). This region is homologous to a segment of mouse chromosome 5, where the mutations hammer toe (HM) and hemimelic extra toes (HX) have been mapped. These data suggest that human chromosome 7q36 and the homologous region of mouse chromosome 5 contain genes involved in limb pattern formation.

Rudimentary Polydactyly

A case of rudimentary polydactyly on the radial aspect of the thumb of a 4-year-old male was examined. Histologic examination revealed hyperkeratosis and acanthosis in the epidermis and large numbers of nerve bundles in the dermis. With immunoperoxidase staining for S-100 protein, the nerve corpuscles were positively stained. We think that rudimentary polydactyly is a kind of congenital traumatic neuroma and that the possible cause may be intrauterine amputation.

Robinow syndrome

Fourteen cases of Robinow syndrome are described with special emphasis on dermatoglyphics and hand malformations (split hands were detected in two, ectrodactyly with nail hypoplasia in one and hypoplastic extra middle finger in another one). Dermatoglyphic studies were performed on ten cases. Increased whorl patterns of the finger tips and a single large palmar hypothenar whorl pattern associated with distally displaced axial triradii were detected. These have not previously been described.

Stability of positional identity of axolotl blastema cells in vitro.

Previous grafting experiments have demonstrated that cells from non-contiguous positions within developing and regenerating limbs differ in a property referred to as positional identity. The goal of this study was to determine how long the positional identity of axolotl limb blastema cells is stable during culture in vitro. We have developed an assay for posterior positional properties such that blastema cells can be cultured and then grafted into anterior positions in host blastemas, to determine if they can stimulate supernumerary digit formation. We report that posterior blastema cells are able to maintain their positional identities for at least a week in culture. In addition, we observed that blastema cells are able to rapidly degrade collagenous substrates in vitro, a property that apparently distinguishes them from limb cells of other vertebrates. These results provide information regarding the time boundaries within which the positional properties of blastema cells can be studied and manipulated in vitro.

Gli, a zinc finger transcription factor and oncogene, is expressed during normal mouse development

The oncogene GLI is amplified and expressed in some cases of human malignant glioma and undifferentiated childhood sarcoma and is the prototype for a gene family characterized by a highly conserved set of five tandem zinc fingers and a consensus cysteine-histidine link. This zinc finger motif has been shown to bind DNA with sequence specificity and may mediate transcriptional regulation. Since GLI is expressed in embryonal carcinoma cell lines but not in most normal adult tissues and shows significant sequence similarity within its zinc finger domain to cubitus interruptus dominant (ciD), a Drosophila segmentation gene known to be important in the morphogenesis of the posterior portion of each larval segment, we established the temporal and tissue expression patterns of the mouse homologue of human GLI in day 10 through 18 mouse embryos with Northern blotting, reverse transcriptase coupled PCR, and in situ hybridization. gli transcripts were demonstrated on days 10 through 18 of mouse embryonic development as well as in normal adult uterus, brain, testis, and limb. Tissue expression of gli during gestation was demonstrated in Meckel's precartilage mesenchyme, the basis occipitus, rib mesenchymal condensations, primordial vertebral bodies, digital mesenchymal condensations in forefoot and hindfoot plates, the ependymal layer of the spinal cord, and the mesoderm of the gastrointestinal tract. Expression persisted throughout gestation in developing bone and cartilage of the extremities, the ribs, and the vertebral bodies, as well as the gastrointestinal tract mesoderm. These findings support a role for gli family genes in normal craniofacial and digital development in mammals first suggested by the demonstration of translocation breakpoints within the GLI3 gene in families with the Greig cephalopolysyndactylyl syndrome and subsequently by reduced gli3 expression in the mouse mutant extra toes. It is surprising that a single gene would be expressed in such a wide range of mesenchymal structures.

Heterotopic Finger Transfer in Ulnar Ray Deficiency Associated with Contralateral Postaxial Polydactyly: A Case Report

A case of type-I ulnar ray deficiency, combined with postaxial polydactyly of the opposite hand, is described. Heterotopic transfer of the supernumerary finger was performed, in order to improve function in the defective hand and to treat the hexadactyly of the other hand. A combination of these malformations has apparently not previously been reported in the literature.

Measuring radiation exposure during percutaneous drainages: can shoulder dosemeters be used to estimate finger doses?

Some previous studies have shown remarkably high finger doses to radiologists performing percutaneous drainage under fluoroscopy. To assess the possible need for extra finger dosemeters in addition to the general dosemeter, radiologists' and assistants' radiation exposure at both shoulders and at the third fingers of both hands were recorded using thermoluminescent dosemeters during 27 interventional drainage procedures. Under couch screening was used. Mean dose rates were calculated by dividing the doses by the screening time. The dose rates for the sites measured were correlated with each other. The radiologists' bilateral finger dose rates did not correlate with each other; nor did dose rates between the left shoulder and the right hand. The radiologists' dose rates at both shoulders, however, correlated with each other, as did the shoulder dose rates with the dose rates at the ispilateral hand. The right shoulder dose rates correlated with the left hand dose rates. The assistants' dose rates at the places of measurement all showed significant correlations with each other. It is therefore concluded that radiologists involved in percutaneous drainages should use finger dosemeters on both hands; for assistants this may not be necessary.