Treatment of congenital upper extremity problems

LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Describe the terminology and classification of congenital hand anomalies. 2. Describe the incidence and embryogenesis of some common congenital hand anomalies. 3. Discuss the general principles and goals for treatment of congenital hand anomalies. 4. Describe the management of five of the more common congenital hand anomalies (syndactyly, short digits, thumb duplication, hypoplastic thumb, and radial dysplasia). SUMMARY: Congenital hand anomalies can cause substantial emotional and functional problems. This article reviews the etiology, classification, and management of some of the more common hand anomalies. A general approach to the patient and the goals of treatment are reviewed, as is the approach to five specific congenital hand anomalies: syndactyly, short digits, thumb duplication, hypoplastic thumb, and radial dysplasia.     

Congenital constriction band syndrome. Pathophysiology and treatment.

The clinical manifestations of 88 children with congenital constriction band syndrome involvement of the hand were reviewed. Seventy-five of these children had evidence of digital or limb amputations, with 235 upper limb amputations and 138 lower limb amputations. In the hand, digital amputations were most common in the index, middle, and ring fingers, whereas in the foot, amputations of the hallux were most often noted. Band indentation was often present at multiple levels. Proximal bands may be associated with neural compression. Syndactyly was invariably associated with a proximal interdigital sinus or cleft and was frequently associated with distal amputation. Examination of a 27-week gestation stillborn specimen having manifestations of congenital constriction band syndrome demonstrated the intrauterine biologic response to band constriction. The variable clinical manifestations of congenital constriction band syndrome can best be explained as the response of the growing, embryologically defined limb to intrauterine deformation or band-induced compression and ischemia.     

Morphogenesis of the prehensile autopodium in the common chameleon (Chamaeleo Chamaeleo)

This report documents the development of the autopodium of the common chameleon (Chamaeleo chamaeleo) using light microscopy, scanning electron microscopy, and transmission electron microscopy. Three main periods were distinguished during the morphogenesis of this structure. In the first period (stages 33-35 of chameleon development) the autopodium is paddle-shaped with a prominent apical ectodermal ridge (AER) along the distal margin. During this period the AER has structural features similar to other reptilian and avian vertebrates except for the scarcity or absence of gap junctions. The second period of autopodium morphogenesis (stage 36 of chameleon development) is characterized by the formation of a central cleft which divides this structure into two digital segments. In the forelimb the autopodial cleft occupies the space between digits 3 and 4. In the hindlimb the cleft occupies the space between digits 2 and 3. Mesenchymal cell death constitutes a constant feature during cleft formation. In addition to cell death during this process, we have observed that the AER flattens out in the zone of cleft formation while in the digital portions of the autopodium it takes on a polystratified appearance. In the last period of autopodial morphogenesis (stage 37 of chameleon development) digits become free by means of interdigital mesenchymal cell death.     

Sequential changes of programmed cell death in developing fetal mouse limbs and its possible roles in limb morphogenesis

Apoptotic cell death in the developing limb of mouse fetuses was examined sequentially on days 11–15 of gestation by means of Nile blue (NB) sulfate staining with special reference to its relation to limb morphogenesis. With some exceptions, programmed cell death (PCD) in the hand and foot was observed in the mesenchyme but not in the surface ectoderm. We found that during digital formation PCD begins at the proximal portion of the interdigital mesenchyme and subsequently expands distally. Therefore, the initial PCD that occurs in the interdigital zones may determine the proximal ends of digital separation and also contribute to the demarcation between the palm (sole) and digits (toes). During digital separation, the areas of PCD in the interdigital zones were found to become larger and expand distally on day 13, which may be necessary for the separation of digits and for determining the interdigital area to disappear. PCD in presumptive phalangeal joints was also found to proceed from proximal to more distal joints. The PCD in presumptive joints may be required for the separation of phalanges and metacarpal (metatarsal) bones and for the formation of joint cavities. In addition, intense PCD was observed in the radial (tibial) and ulnar (fibular) margins of the hand and foot plates for 4–5 days. Such PCD at marginal areas seems to prevent the formation of supernumerary digits (preaxial and postaxial polydactyly) and other digital malformations. Therefore, the timing when PCD commences and ends, the sites where PCD occurs, and the intensity, duration, and proximo-distal progress of PCD appear to be genetically determined, and the elimination of unnecessary cells by PCD may be essential for normal limb morphogenesis. The present findings also suggest that the normal progress of PCD in the hand and foot plates of rodent fetuses may prevent the formation of some limb malformations such as webbing fusion of digits, polydactyly, or cleft hand/foot. © 1996 Wiley-Liss, Inc.     

Classification for congenital anomalies of the hand: the IFSSH classification and the JSSH modification

The purpose of a classification for clinical problems which, except for a few specialized centers, occur only sporadically is to provide a system where these cases can be stored. This should allow all involved investigators to speak the same language; so-doing syndromes can be delinated, frequencies of occurence established and results of--different--treatments compared. A classification system should be simple to use, reliable and uniformly accepted. It should allow space for adaptations and/or extensions. The IFSSH proposed a 7 categories classification based on the proposed classification of Swanson et al. in 1976. This classification, was based on, which was thought in the seventies, etiopathogenic pathways. These 7 groups are: I. Failure of formation; transverse (A), or longitudinal (B) II. Failure of differentiation III. Polydactyly IV. Overgrowth V. Undergrowth VI. Amniotic band syndrome VII. Generalized skeletal syndromes. The extended classification proposed by IFSSH was used to classify 1013 hand differences in 925 hands of 650 patients. We found associated anomalies in 26.7%. The classification was straightforward in 86%, difficult in 6.6% and not possible in 7.8%. Group II was the most numerous group including 513 anomalies. We propose to include in this group the Madelung deformity, the Kirner deformity and congenital trigger fingers and trigger thumbs. In group I the radial and ulnar deficiencies, limited to the hand without forearm deficlencies should be Included. Triphalangeal thumbs are a problem, we suggest it to be listed in group III and consider it as a duplication in length. It is not always possible to evaluate the (transverse) absence of the fingers or hand. Longitudinal deficiencies (group IIB), symbrachydactyly (group V), and amniotic bands (group IV) occasionally develop a phenotype similar to the genuine transverse deficiency (group IA). Recently, the Japanese Society for Surgery of the Hand (JSSH) (16) proposed an extension/modification of the IFSSH classification. Based on newer knowledge on teratology, symbrachydactyly in all stages were transfered to group I. Two new groups were introduced. A group "failure of finger ray induction" including typical cleft hand (IC), central polydactyly (III) and (bony) syndactyly (II)--was included. Also a group of "unclassifiable" cases was added. This Japanese proposed classification is a real improvement and most clinicians and surgeons tend to use it in the future.     

Fetal laser surgery in genetic polydactyly mice

The first digital ray of the hindlimb plate in Slc:ICR mouse fetus was irradiated with 2 watts argon laser beam for 0.3 sec after releasing from the abdominal cavity and envelop of uterine myometrium on day 13 of gestation, and then the fetuses were allowed to develop in the abdominal cavity contacting with the uterus via the placenta exo utero until term. ICR mouse fetuses which received fetal laser surgery lost their first digits completely, resulting in 4-digit hindfoot on day 18 of gestation. The homozygous Polydactyly Nagoya (Pdn/Pdn) mice exhibit 1-3 extra digits both in the fore- and hindlimbs preaxially. The extra digital rays in the left hindlimbs of Pdn/Pdn fetuses were irradiated with 2 watts argon laser beam for 0.3 sec on day 13 of gestation exo utero. The left hindlimbs of the Pdn/Pdn fetuses which received fetal laser surgery lost their preaxial extra digits on day 18 of gestation, resulting in 5 digits, though their 1st digit was triphalangia. The combination of a laser instrument with the fetoscope and/or ultrasound scanner may promote the fetal surgery of congenital anomalies in humans.     

Manual digital pressures during knuckle‐walking in chimpanzees (Pan troglodytes)

Considerable attention has been given to hand morphology and function associated with knuckle‐walking in the African apes because of the implications they have for the evolution of bipedalism in early hominins. Knuckle‐walking is associated with a unique suite of musculoskeletal features of the wrist and hand, and numerous studies have hypothesized that these anatomical features are associated with the dynamics of load distribution across the digits during knuckle‐walking. We collected dynamic digital pressures on two chimpanzees during terrestrial and simulated arboreal locomotion. Comparisons were made across substrates, limb positions, hand positions, and age categories. Peak digital pressures were similar on the pole and on the ground but were distributed differently across the digits on each substrate. In young animals, pressure was equally high on digits 2–4 on the ground but higher on digits 3 and 4 on the pole. Older animals experience higher pressures on digits 2 and 3 on the ground. Hand posture (palm‐in vs. palm‐back) influenced the distribution and timing of peak pressures. Age‐related increases in body mass also result in higher overall pressures and increased variation across the digital row. In chimpanzees, digit 5 typically bears relatively little load regardless of hand position or substrate. These are the first quantitative data on digital pressures during knuckle‐walking in hominoids, and they afford the opportunity to develop hypotheses about variation among hominoids and biomechanical models of wrist and forearm loading. Am J Phys Anthropol 2009. © 2009 Wiley‐Liss, Inc.     

Busulfan-induced central polydactyly, syndactyly and cleft hand or foot: a common mechanism of disruption leads to divergent phenotypes

The prevalence of clinical phenotypes that exhibit combinations of central polydactyly, syndactyly, or cleft hand or foot is higher than would be expected for random independent mutations. We have previously demonstrated that maternal ingestion of a chemotherapeutic agent, busulfan, at embryonic day 11 (E11) induces these defects in various combinations in rat embryo limbs. In an effort to determine the mechanism by which busulfan disrupts digital development, we examined cell death by Nile Blue staining and TdT-mediated dUTP nick end labeling (TUNEL) assays; we also carried out whole mount in situ hybridization for fibroblast growth factor-8 (Fgf8), bone morphogenetic protein-4 (Bmp4), and sonic hedgehog (Shh) to examine developmental pathways linked to these defects. In busulfan-treated embryos, diffuse cell death was evident in both ectoderm and mesoderm, peaking at E13. The increased cell death leads to regression of Fgf8 in the apical ectodermal ridge (AER) and Bmp4 and Shh in the underlying mesoderm. The subsequent pattern of interdigital apoptosis and cartilage condensation was variably disrupted. These results suggest that busulfan manifests its teratogenic effects by inducing cell death of both ectoderm and mesoderm, with an associated reduction in tissue and a disruption in the generation of patterning molecules during critical periods of digit specification.     

On the symmetry of limb deficiencies among children with multiple congenital anomalies

In humans, unpaired organs are placed in a highly ordered pattern along the left-right axis. As indicated by animal studies, a cascade of signaling molecules establish left-right asymmetry in the developing embryo. Some of the same genes are involved also in limb patterning. To provide a better insight into the connection between these processes in humans, we analysed the symmetry of limb deficiencies among infants with multiple congenital anomalies. The study was based on data collected by the International Clearinghouse for Birth Defects Monitoring Systems (ICBDMS). Registries of the ICBDMS provided information on infants who, in addition to a limb deficiency, also had at least one major congenital anomaly in other organ systems. We reviewed 815 such cases of which 149 cases (18.3 %) were syndromic and 666 (81.7 %) were nonsyndromic. The comparisons were made within the associated limb deficiencies, considering the information on symmetry, using a comparison group with malformations associated not involved in the index association. Among the non-syndromic cases, the left-right distribution of limb deficiencies did not differ appreciably between limb deficiency subtypes (e.g., preaxial, transverse, longitudinal). The left-right distribution of limb anomalies did not differ among most types of non-limb anomalies, though a predominance of left-sided limb deficiencies was observed in the presence of severe genital defects - odds ratio [OR], 2.6; 95 % CI, 1.1-6.4). Limb deficiencies (LDs) were more often unilateral than bilateral when accompanied by gastroschisis (OR, 0.1) or axial skeletal defects (OR, 0.5). On the contrary, LDs were more often bilateral than unilateral when associated with cleft lip with or without cleft palate (OR, 3.9) or micrognathia (OR, 2.6). Specifically, we found an association between bilateral preaxial deficiencies and cleft lip, bilateral amelia with gastroschisis and urinary tract anomalies, and bilateral transverse deficiencies and gastroschisis and axial skeleton defects. Of 149 syndromic cases, 62 (41.6 %) were diagnosed as trisomy 18. Out of the 30 cases of trisomy 18 with known laterality, 20 cases were bilateral. In the remainder the right and left sides were equally affected. Also, in most cases (74.4 %) only the upper limbs were involved. In conclusion the left-right distribution of limb deficiencies among some non-limb anomalies may suggest a relationship between the development of the limb and the left-right axis of the embryo.     

Sequential pattern of limb anomalies in Japanese monkeys on Awajishima Island

X-ray examinations of Japanese monkeys (Macaca fuscata) in two groups on Awajishima Island revealed that 11 of 46 monkeys from the Kaminada group and 5 of 37 monkeys from the Shirasaki group had limb anomalies. All the cleft hands, which comprised most of the anomalies in these Awajishima monkeys, involved reduction of one, two, or three fingers. The digital reductions showed a definite pattern: cleft hands with four, three, or two fingers lacking the digital rays III, III & IV, or II, III & IV, respectively. A similar teratological pattern has been recognized in the anomalies of other troops of Japanese monkeys. The presence of such a common teratological pattern among Japanese monkeys may be related to the high incidence of the anomalies and suggests that they may have a common etiological factor.     

Fine mapping of the split-hand/split-foot locus (SHFM3) at 10q24: evidence for anticipation and segregation distortion.

Split-hand/split-foot malformation (SHFM, ectrodactyly, or lobster-claw deformity) is a human limb malformation characterized by aberrant development of central digital rays with absence of fingers and toes, a deep median cleft, and fusion of remaining digits. SHFM is clinically heterogeneous, presenting both in an isolated form and in combination with additional abnormalities affecting the tibia and/or other organ systems, including the genitourinary, craniofacial, and ectodermal structures. Three SHFM disease loci have been genetically mapped to chromosomes 7q21 (SHFM1), Xq26 (SHFM2), and 10q24 (SHFM3). We mapped data from a large Turkish family with isolated SHFM to chromosome 10q24 and have narrowed the SHFM3 region from 9 cM to an approximately 2-cM critical interval between genetic markers D10S1147 and D10S1240. In several instances we found evidence for a more severe phenotype in offspring of a mildly affected parent, suggesting anticipation. Finally, data from this family, combined with those from six other pedigrees, mapped to 10q24, demonstrate biased transmission of SHFM3 alleles from affected fathers to offspring. The degree of this segregation distortion is obvious in male offspring and is possibly of the same magnitude for female offspring.     

Lectin teratogenesis: defects produced by concanavalin A in fetal rabbits.

Concanavalin A (con A) is teratogenic to rabbit embryos during gestational days 12--15. Intracoelomic injections of 40 microliter con A solution (4 microgram/microliter) were performed on rabbit embryos during gestational days 10--15. Control embryos received either 40 microliter of saline, sham injection or no treatment. Con A caused increased fetal resorptions on days 10 and 11, but malformation levels did not differ from controls. On days 12--15, con A produced craniofacial, trunk and limb anomalies. The highest percentage of malformation occurred on day 14. The defects were classified into four groups: (1) malformations of limbs including paw and digital dysplasias as well as fusions of the limbs to the head or body wall; (2) "closure" defects such as umbilical hernia, encephalocoele, exencephaly or ectopia cordis; (3) "contracture" defects such as club paws, extended knees, or clenched digits, which exhibited normal osseous and cartilaginous skeletons; and (4) miscellaneous, non-specific anomalies including fused or dysplastic sternebrae or ribs. Histologic analysis of selected 12-day embryos 4 to 18 hours post-injection was performed to ascertain potential sites of teratogenic action. At 12 hours ectodermal necrosis was observed in the limb buds adjacent to the apical ectodermal ridge. By 18 hours, the ectoderm had eroded, exposing the basal lamina to the amniotic fluid. Focal areas of mesenchymal necrosis were observed in association with the ectodermal erosion. The potential roles of amniocentesis and limb bud repair in the genesis of the malformations are discussed.     

Anatomical features associated with preaxial duplication (pd): a recessive mutation in the rat

Preaxial polydactyly of the fore- and hindlimbs was found in Wistar-derived rats in 1978. Genetic analysis indicated that the polydactyly was due to the effects of an autosomal recessive gene (gene symbol; pd). Polydactylous homozygous rats had two or three pollices (six or seven digits) in the forelimbs and one to three preaxial extra digits (six to eight digits) in the hindlimbs. Skeletal examination revealed the presence of the extra carpal, metacarpal, and phalangeal bones that seemed to be complete or incomplete duplication of the navicular, greater multangular, first metacarpal, and phalanges of digit I in the forelimbs. In the hindlimbs, extra tarsal, metatarsal, and phalangeal bones were also observed preaxially. These extra elements seemed to be mirror-image duplications of the talus, navicular, second cuneiform, third cuneiform, cuboid, and metatarsals and phalanges of digits II-V with the absence of the first cuneiform, tibiale, first metatarsal, and phalanges of digit I. In addition, morphological changes were observed in the humerus, radius, and ulna in the forelimbs and femur, tibia, and fibula in the hindlimbs. Especially in the radius and tibia, thickening and bifurcation were found, indicating incomplete duplication of these bones. Based on these findings, the limb anomaly was classified as preaxial carpometacarpal/tarsometatarsal-type polydactyly with incomplete duplication of the radius and tibia. The mutant rats had other associated anomalies such as accessory spleens and cryptorchism. The males are sterile, whereas the females breed normally.     

Familial clustering of a rare syndrome

Ectrodactyly, ectodermal dysplasia and cleft palate syndrome is a rare autosomal dominant multiple congenital anomaly syndrome with variable expressivity and reduced penetration. The cardinal features are cleft palate/lip, lobster hand deformity, sparse hypopigmented hair, dry scaly skin, and lacrimal and urogenital anomalies. A neonate presented to us with typical features, his mother and other two siblings were also affected.     

Potential teratogenicity of gonadotropin treatment for ovulation induction in the mouse offspring

The teratogenic effects of induced ovulation were studied in mice by using three different doses of pregnant mare's serum (PMS)/human chorionic gonadotropin (HCG) (2.5, 5, or 10 IU) at two different stages of the estrous cycle. The PMS/HCG treatment induced high incidences of external congenital anomalies in the offspring in a dose-dependent manner. This was especially so when the treatment was "out of phase" to the naturally occurring ovulation schedule. The predominant malformations were open eyelids and cleft palate. The problems of extrapolating these findings to humans are discussed.     

Studies of the development of congenital anomalies in rats. III. Effects of inhibition of mitochondrial energy systems on embryonic development.

Pregnant rats were treated with various inhibitors of mitochondrial oxidative energy metabolism and with lowered oxygen tension, and the embryo fetuses examined for the occurrence of congenital malformations and for changes in enzymatic activities. Treatment with all agents tested resulted in the production of skeletal anomalies. Sodium phenobarbital was the most teratogenic of the drugs tested and produced a high incidence of malformations which included cleft palate, tail anomalies, spinal retroflexion, domed head, and facial hypoplasia. Diphenylhydantoin produced a low incidence of syndactyly and oligodactyly. In addition to its effects on fetal growth and development chloramphenicol appeared to interfere with implantation. Tissue preparations from embryos exposed to sodium phenobarbital and chloramphenicol showed markedly lowered levels of DPNH oxidase activity. Cytochrome oxidase activity was also markedly lowered in the preparations from chloramphenicol-exposed embryos. Enzyme activities in preparations from embryos exposed to malonate and diphenylhydantoin appeared unaffected, although the drugs are strong inhibitors of electron transport in vitro; the lack of apparent effect may be due to the fact that both drugs do not bind to the enzyme preparations and were diluted 100- to 200-fold during preparation and assay of the tissue homogenates.     

The association of split hand foot malformation (SHFM) and congenital heart defects

BACKGROUND: Split hand foot malformation (SHFM) (cleft hand, central ray deficiency) is a highly variable malformation that shows genetic heterogeneity with at least five loci mapped to date. SHFM occurs as an isolated finding or in association with other anomalies, including congenital heart defects (CHDs). METHODS: In total 48 SHFM1, 52 SHFM3, 48 SHFM4, 21 SHFM5, and four chromosome 8 patients were evaluated. In addition, we performed a literature review to identify “unmapped” SHFM patients with CHD to evaluate the various etiologies of this combination of findings. The London Dysmorphology Database also served as a resource to identify syndromes with this combination of phenotypic findings. Only patients presenting with both SHFM and CHD were included in the analysis. Classification of CHD among mapped and unmapped SHFM patients was performed utilizing the revised Clark classification. A closer inspection of the types of CHD found in this patient group was performed in order to investigate possible pathogenetic mechanisms. RESULTS: CHDs were found in 10% of SHFM1 patients, 47% of SHFM5 patients, but were not reported in SHFM2, SHFM4 patients, or patients mapped to chromosome 8. Forty‐two syndromic cases and 15 cases of unrecognized syndromes were identified. CONCLUSIONS: The higher frequency of heart defects seen in SHFM1 and SHFM5 of the mapped patient group raises the question as to whether common mechanisms/genetic players are involved. Candidate genes for SHFM1 and SHFM5 include members of the DLX homeobox gene family. Birth Defects Research (Part A), 2008. © 2008 Wiley‐Liss, Inc.     

The absence of cell death during development of free digits in amphibians

Massive cellular death occurs in the interdigital regions of developing limbs of free-digited birds and mammals. This mesodermal degeneration occurs at the same time that digits become free. The present study of digit formation in amphibians, using vital staining and histological and autoradiographic techniques, demonstrates the absence of zones of interdigital degeneration during the formation of free digits. Furthermore, no other areas of predictable cell death occur during amphibian limb development, a situation quite unlike the case for avian limb development where predictable zones of degeneration occur in the mesoderm along the pre- and postaxial borders of the developing wing and leg. Thus, zones of cell death are not a part of amphibian limb morphogenesis. Analysis of the labeling index of the developing free-digited forelimb of Xenopus laevis reveals that during stage 52 the interdigital and digital labeling indexes are the same. The change in the ratio of interdigital labeling index to the digital labeling index in the forelimb suggests that during subsequent development the interdigital labeling index decreases while the digital labeling index is maintained. In comparison, the same analysis indicates that the interdigital labeling index of the webbed hindlimb increases when compared to the digital labeling index, which stays the same from early to late stages. It is proposed that free digits develop in Xenopus laevis forelimb as a result of a decrease in the proliferation rate of the interdigital region as compared to the digital region, which remains unchanged. Conversely, webbed digits develop in the hindlimb as a result of an interdigital rate at least equal to the digital rate.     

Development of limbs in urodeles and the origin of tetrapod limbs

On the basis of studies on serial sections of larval Ranodon sibiricus limbs and published data, the hypothesis of the origin of tetrapod limbs from the biserial archipterygium is proposed. The mesomeres of the central axis of the biserial fin correspond (in proximodistal direction) to the humerus, ulna, ulnare, all carpalia distalia, metacarpale 1, and phalanges of the first digit in the forelimb of caudate amphibians and to the femur, fibula, fibulare, tarsalia distalia, metatarsale 1, and phalanges of the first digit in the hind limb. The preaxial elements of the zygopodium and autopodium, which are positioned proximal to the digital arch, correspond to the preaxial rays of the biserial fin, and digits 2–5 correspond to its postaxial rays. As the fin transformed into the limb, the central axis curved preaxially, forming the digital arch and resulting in partial reduction and fusion of preaxial rays.     

Unilateral bowing of long bones and multiple congenital anomalies in a child born to a mother with gestational diabetes

We report on a new-born girl with multiple congenital anomalies consisting of major skeletal anomalies restricted to the left side, cleft palate, ventricular and atrial septal defect, retromicrognathia, short neck, dysplastic low-set ears and large birth weight. The left-side bony anomalies include shortening and bowing of the femur and tibia, hypoplasia of the fibula, hip dislocation, clubfoot and mild shortening of the long tubular bones in the left arm with elbow dislocation. The pregnancy was complicated by insulin-dependent gestational diabetes mellitus in the mother. The radiographic features were not consistent with the diagnosis of campomelic dysplasia, kyphomelic dysplasia or other skeletal dysplasias characterized by bowing and shortening of the long bones. To our knowledge, the multiple congenital anomalies, including major skeletal malformations, present in our case have never been simultaneously reported until now. A maternal diabetes syndrome in this infant is probable. The occurrence of major congenital malformations in offspring of women with gestational diabetes is reviewed and discussed. We provide evidence that gestational diabetes mellitus could be teratogenic. We recommend a careful diabetic control in every woman with a history of gestational diabetes.