Central Polydactyly Research Articles

SKELETAL ABNORMALITIES IN MECKEL SYNDROME

Meckel syndrome is an autosomal recessive condition with a wide phenotypic variation. The most consistent features are cystic kidneys and intrahepatic bile duct anomalies, frequently accompanied by central nervous system (CNS) malformations and Polydactyly. Approximately one sixth of all cases also show skeletal anomalies. We present two cases, siblings bom to a consanguineous couple, in whom there was a striking curvature and shortening of the long bones in addition to cystic kidneys, CNS abnormalities, and Polydactyly. Histological examination of the long bones in the second affected sibling showed mid-diaphysial ectopic cartilaginous growth plates differentiating the long bone changes from other skeletal dysplasias with similar radiological features.

GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome.

Pallister-Hall syndrome (PHS, M146510) was first described in 1980 in six newborns. It is a pleiotropic disorder of human development that comprises hypothalamic hamartoma, central polydactyly, and other malformations. This disorder is inherited as an autosomal dominant trait and has been mapped to 7p13 (S. Kang et al. Autosomal dominant Pallister-Hall syndrome maps to 7p13. Am. J. Hum. Genet. 59, A81 (1996)), co-localizing the PHS locus and the GLI3 zinc finger transcription factor gene. Large deletions or translocations resulting in haploinsufficiency of the GLI3 gene have been associated with Greig cephalopolysyndactyly syndrome (GCPS; M175700) although no mutations have been identified in GCPS patients with normal karyotypes. Both PHS and GCPS have polysyndactyly, abnormal craniofacial features and are inherited in an autosomal dominant pattern, but they are clinically distinct. The polydactyly of GCPS is commonly preaxial and that of PHS is typically central or postaxial. No reported cases of GCPS have hypothalamic hamartoma and PHS does not cause hypertelorism or broadening of the nasal root or forehead. The co-localization of the loci for PHS and GCPS led us to investigate GLI3 as a candidate gene for PHS. Herein we report two PHS families with frameshift mutations in GLI3 that are 3' of the zinc finger-encoding domains, including one family with a de novo mutation. These data implicate mutations in GLI3 as the cause of autosomal dominant PHS, and suggest that frameshift mutations of the GLI3 transcription factor gene can alter the development of multiple organ systems in vertebrates.

Skeletal Abnormalities in Meckel Syndrome

Meckel syndrome is an autosomal recessive condition with a wide phenotypic variation. The most consistent features are cystic kidneys and intrahepatic bile duct anomalies, frequently accompanied by central nervous system (CNS) malformations and polydactyly. Approximately one sixth of all cases also show skeletal anomalies. We present two cases, siblings born to a consanguineous couple, in whom there was a striking curvature and shortening of the long bones in addition to cystic kidneys, CNS abnormalities, and polydactyly. Histological examination of the long bones in the second affected sibling showed mid-diaphysial ectopic cartilaginous growth plates differentiating the long bone changes from other skeletal dysplasias with similar radiological features.

Report from the workshop on Pallister-Hall syndrome and related phenotypes.

A one day workshop was convened on the NIH campus on March 1, 1996, in Bethesda, Maryland to discuss emerging clinical and molecular information on Pallister-Hall syndrome (PHS) and related disorders. PHS is a pleiotropic autosomal dominant disorder comprising hypothalamic hamartoma, pituitary dysfunction, central polydactyly, and visceral malformations. The goals of the meeting were to update participants in the latest clinical and research findings in the disorder, review the history and evolution of the understanding of the phenotype, determine diagnostic criteria for PHS, and make recommendations for clinical evaluation of individuals affected by PHS. (This article is a U.S. Government work and, as such, is in the public domain in the United States of America.) © 1996 Wiley-Liss, Inc.

Congenital anomalies of the hand. The Asian perspective.

To have a better understanding of teratogenic mechanisms of congenital absence of digits, ulnar and radial deficiencies, cleft hand, and symbrachydactyly were analyzed in clinical cases. The same anomalies were induced in rat fetuses by busulfan, and their characteristics were investigated. The formation process of longitudinal deficiency also was observed histologically. There seemed to be 4 teratogenic mechanisms of congenital absence of digits. Ulnar and radial deficiencies have the same clinical features, and the cause of these deficiencies is related closely to a deficit of mesenchymal cells in the limb bud caused by the impairment before the formation of the limb bud. Cleft hand, central polydactyly, and osseous syndactyly were induced by the same treatment at the same developmental stage in rats. Cleft hand formation process from osseous syndactylies and central polydactylies was supposed. The teratogenic mechanism of cleft hand seemed to be failure of induction of digital rays in the hand plate. The sequence of anomalies from brachysyndactyly, or the atypical cleft hand, to the transverse deficiency can be regarded as equivalent to the category of bony dysplasia of the hand. Congenital constriction ring syndrome does appear after the formation of the digital rays.

A BRIEF REVIEW AND A PROPOSAL FOR THE CLASSIFICATION OF THE CONGENITAL ANOMALIES OF THE UPPER LIMB: My Proposal for the Classification of Congenital Upper Limb Anomalies

The evaluation of the international classification of congenital anomalies of the upper limb in the past 25 years is described. Syndactyly, cleft hand, and central polydactyly have the same embryological defect. Triphalangeal thumb and five fingered hand are unclassifiable, while camplodactyly, clinodactyly and haemangioma should not be grouped under “failure of differentiation of parts”. A new approach in classification is suggested.

Radial clubhand and contralateral duplicated thumb

Although radial deficiencies and radial polydactyly are frequently encountered congenital anomalies, they do not commonly occur together. In contrast to central polydactyly and central deficiency. which are closely associated clinically’ and in experimental studies,2 the concomitant association of radial deficiency and radial polydactyly is rare. Although the two conditions have occurred separately in different members of the same family and in successive generations, 3.4 there are only two previous case report+ in the English literature of a hypoplastic thumb and a contralateral duplicated thumb occurring in the same infant; one was thought to be due to untreated maternal diabetes during pregnancy,5 and no cases demonstrated radius hypoplasia.

Clinical and Experimental Studies on Teratogenic Mechanisms of Congenital Absence of Digits in Longitudinal Deficiencies*

ABSTRACT: In order to clarify teratogenic mechanisms of congenital absence of the digits in longitudinal deficiencies, ulnar deficiency, radial deficiency, central polydactyly, osseous syndactyly and cleft hand (central deficiency) were analyzed. Then, the same anomalies induced in rat fetuses with myleran were analyzed. In ulnar and radial deficiencies, the more severe was the degree of finger deficit, the more severe was the arrest of the forearm bone. The critical periods of these anomalies were earlier than those of other anomalies. Ulnar deficiencies were induced only in Gun: Wistar rats and radial deficiencies only in WKAH/Hkm rats. A genetic factor may influence the teratogenesis of ulnar and radial deficiencies. From histological analysis of tibial deficiency, it may be suggested that the cause of absence of digits in longitudinal deficiency is closely related to a deficit of mesenchymal cells. The analysis of skeletal changes of central polydactylies, osseous syndactylies and cleft hands suggested that there seemed to be the cleft hand formation process from osseous syndactylies and central polydactylies. These anomalies were often observed in both hands in various combinations. They could be induced by the same treatment at the same developmental stage in rats. The teratogenic mechanism of cleft hand seemed to be failure of induction of digital rays in the hand plate.

The treatment of metacarpal synostosis

One hundred nine patients with metacarpal synostosis were examined to determine the best treatment for this condition. The fourth and fifth metacarpals are most frequently affected, and bilateral involvement occurs often. Many anomalies are associated with synostosis, as well as many syndromes such as Apert's syndrome, central polydactyly, syndactyly, and partial absence of the hand. An osteotomy to split and separate the synostosis, a bone graft to lengthen the fifth metacarpal, collateral ligament reconstruction, and tendon transposition of the extensor digiti minimi quinti all appear to be valuable for the treatment of this rare congenital anomaly.

Cleft Feet

The authors studied 45 cleft feet from among their patients and 128 from the literature with regard to their roentgenographic morphology. An increasing degree of malformation was found, from deepening of a central interdigital commissure to a monodactylous cleft foot. These observations resulted in a classification of six groups based on the number of metatarsal bones. Types I and II are cleft feet with minor deficiencies, both having five metatarsals. The metatarsals are all normal in Type I and partially hypoplastic in Type II. As the degree of malformation increases, only four metatarsals in Type III, three metatarsals in Type IV, and two metatarsals in Type V can be identified. Type VI represents the monodactylous cleft foot. Of the 173 feet studied, 166 could be assigned to one of these types. Two additional forms were also found: four cleft feet with central polydactyly are described as polydactylous type, and three monodactylous feet with lower-leg diastasis or tibial aplasia or both are described as diastatic type. According to the distribution of syndactylies, synostoses, and aplasias, it became evident that cleft formation begins at the second or third ray. It then proceeds in a longitudinal direction from distal to proximal as well as in a transverse direction from tibial to fibular, while the first ray remains intact. The first ray is only missing in the monodactylous cleft foot, which possesses only the fifth ray. The defects are always larger distally than proximally. Synostoses are found only at the margin of the cleft. Cross-bones are rare and usually occur in mild cases of the deformity. Another rare feature is polydactyly.(ABSTRACT TRUNCATED AT 250 WORDS)

Teratogenic relationship between polydactyly, syndactyly and cleft hand

Several investigators have suggested that polydactyly, syndactyly and cleft hand might have arisen from a common teratogenic mechanism. To confirm this hypothesis, 75 hands with these anomalies were analysed. Advanced cases with central polydactyly or osseous syndactyly in which the fusion area extends as far as the proximal phalanx and metacarpus are identical to typical cleft hand. The author has induced the same deformities using myleran in rat foetuses. The clinical features of these anomalies in rats were the same as those in clinical cases and the critical periods of these anomalies were also the same. The findings suggest that these hand anomalies may appear in human beings when the same teratogenic factor acts on the embryo at the same developmental period and that they should belong to the same teratogenic entity.

Teratogenic Relationship between Polydactyly, Syndactyly and Cleft Hand

Several investigators have suggested that polydactyly, syndactyly and cleft hand might have arisen from a common teratogenic mechanism. To confirm this hypothesis, 75 hands with these anomalies were analysed. Advanced cases with central polydactyly or osseous syndactyly in which the fusion area extends as far as the proximal phalanx and metacarpus are identical to typical cleft hand. The author has induced the same deformities using myleran in rat foetuses. The clinical features of these anomalies in rats were the same as those in clinical cases and the critical periods of these anomalies were also the same. The findings suggest that these hand anomalies may appear in human beings when the same teratogenic factor acts on the embryo at the same developmental period and that they should belong to the same teratogenic entity.

TERATOGENIC MECHANISM OF DRUG-INDUCED ANOMALIES OF EXTREMITIES IN RATS

In order to clarify the teratogenic mechanism of oligodactyly, we have carried out some experimental studies in rats. In this paper we report the results and discuss the teratogenic mechanism of the anomalies of the extremities. 1. Ulnar ray deficiency, cleft hand, central ray polydactyly, and central ray syndactyly were induced in W: Gun rats, and radial ray deficiency was induced only in W KAH/H km rats. The features of these anomalies in rats were the same as in humans. The critical periods of ulnar ray deficiency and radial ray deficiency seemed to be earlier than those of central polydactyly, syndactyly, and cleft hand. The critical period of cleft hand was identical to those of central polydactyly and central syndactyly, and advanced cases of central polydactyly or syndactyly in which the fusion area extended as far as the proximal phalanx and metacarpus, became identical to the cleft hand. These findings suggest that radial and ulnar ray deficiencies belong to longitudinal ray deficiency, and the central polydactyly, syndactyly, and cleft hand might be formed by the same teratogenic mechanism, that is, failure of separation of finger ray. 2. DNA synthesis and cell condensation in the developing hand plate of normal and preaxial oligodactylic rats treated with myleran on the day of 12.0th gestation were examined using a BrdU/anti-BrdU immunohistochemical study. DAN-synthesizing cells were distributed uniformly in the mesenchyme of the hand on day 12.0 in normal rat embryos. From day 13.0. these cells were distributed in the interdigital mesenchymal areas, leaving rare labeled cells in the sites of cell condensation. When the labeled mesenchymal cells were followed from day 12.0 until day 14.0, they were found to be concentrated in the digital rays. We concluded that cell migration rather than cell proliferation in the digital-ray area could be an initial step in digital-ray formation. In the oligodactylic hand plate, mesenchymal cell condensation was delayed and preaxial digital rays were not formed. On day 13.0 the number of DNA-synthesizing cells was much less than normal in all areas of the hand plate, and cell necrosis of the epidermis and mesenchyme near the epidermis was prominent. On day 14.0, DNA-synthesizing cells decreased in the epidermis rather than in the mesenchyme. From these results, we conclude that the mechanism of this oligodactyly could involve a mesenchymal cell deficit and restriction of migration.

The carpal bones in congenital hand anomalies: A radiographic study in patients older than ten years

Abnormalities of the carpal bones in 192 anomalous hands of 154 patients older than 10 years were examined. Judging from the time of appearance of the pisiform, there was no delay of carpal bone maturation in these anomalies. There were differences between the carpal bones of three distinct groups: which included central polydactyly, syndactyly, and typical cleft hand; the group which included radial and ulnar deficiency, and the group which included symbrachydactyly and transverse defect. This suggests that there were differences between these groups in the timing and degree of injury to the limb bud or the hand plate in the course of development. It is thought that the first group originates from maldistribution of mesenchymal tissue of the limb bud (or of the apical ectodermal ridge), the second group from defects of that tissue, and the last group from defects of the mesenchymal tissue of the hand plate.

A Clinical and Experimental Study on Longitudinal Deficiencies in Lower Limbs in Relation to Pathogenesis of Cleft Foot

Abstract In order to determine whether cleft foot is caused by the same mechanism as tibial and fibular ray deficiencies, clinical cases of these anomalies and those in rat fetuses induced by myleran were analyzed. In tibial and fibular ray deficiencies, arrest of tibia or fibula was closely related to the missing of toes and tibial and fibular ray deficiencies can be accepted as an occurrence of so called longitudinal deficiency. On the other hand, cleft feet were frequently associated with central Polydactyly and syndactyly. In our experimental study, the critical period of formation of cleft foot was different from that of tibial ray deficiency, but it was similar to those of central Polydactyly and syndactyly. It seems that cleft foot is caused by the abnormal induction of toe rays as in cleft hand and does not belong to the same group as tibial and fibular ray deficiencies.

Polydactyly of the hands and feet

Polydactyly of the hand, of the foot, and of the hand combined with the foot were studied. As noted in previous reports of polydactyly, inherited cases represent about 10% of polydactyly of the hand or foot, and unilateral involvement is more common than bilateral. In 495 cases of polydactyly 27 patients had polydactyly of the hands and feet. The extra digits in 21 of those 27 were in the same digital rays of the hand and foot. There were 14 inherited cases (51.9%) and most were an autosomal dominant, but some were an autosomal recessive. Both hand and/or feet were involved in 22 cases. Most cases of preaxial polydactyly of the hand combined with central polydactyly of the foot were sporadic and unilateral. All cases of both preaxial and postaxial (polyaxial) polydactyly were inherited and bilateral. Two pairs of sisters had the same clinical features. The parent (mother or father) also had the same deformities in the inherited cases.

Central polydactyly—A review of twelve cases and their surgical treatment

Central polydactyly—A review of twelve cases and their surgical treatment

Cleft hand and central polydactyly in identical twins: A case report

Four hands of a pair of identical twins demonstrated manifestations of both cleft hand deformity and central polydactyly, supporting the concept that a common etiological mechanism is involved in the development of these anomalies.

Central polydactyly—A review of 12 cases and their surgical treatment

Twelve patients with central polydactyly of the index, long, or ring fingers are reviewed. Surgical reconstruction of a five-digit hand was carried out in 10 patients. Review after an average of 40 months' follow-up showed that from both a functional and cosmetic viewpoint the results were unsatisfactory. Despite these findings all parents were satisfied with the five-digit hand because it corresponds with cultural and religious norms of Japanese society.

Congenital central ray deficiency in the hand—A survey of 59 cases and subclassification

Eighty-nine hands were studied in 59 patients with central ray deficiency. A subclassification into two subgroups was established based on the clinical and radiological findings-subgroup I: typical type and subgroup II: (atypical type) with type a, syndactylous type, and type b, polydactylous type. In subgroup I, the sequential severity of deficiency ranged from a partial defect of phalanges of the middle finger to a monodigit hand. The central digital elements were fused to adjacent digital rays in subgroup II-type a. Supernumerary bony elements were seen in subgroup II-type b. The close relationship between central ray deficiency, syndactyly, and polydactyly was discussed from the standpoint of development of the hand. The classification of central ray deficiency into the longitudinal deficiency category of the International Classification of Congenital Limb Malformations was recommended.