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Disorders that result from de-arrangement of growth, development and/or differentiation of the appendages (limbs and digit) are collectively called as inherited abnormalities of human appendicular skeleton. The bones of appendicular skeleton have central role in locomotion and movement. The different types of appendicular skeletal abnormalities are well described in the report of "Nosology and Classification of Genetic skeletal disorders: 2019 Revision". In the current article, we intend to present the embryology, developmental pathways, disorders and the molecular genetics of the appendicular skeletal malformations. We mainly focused on the polydactyly, syndactyly, brachydactyly, split-hand-foot malformation and clubfoot disorders. To our knowledge, only nine genes of polydactyly, five genes of split-hand-foot malformation, nine genes for syndactyly, eight genes for brachydactyly and only single gene for clubfoot have been identified to be involved in disease pathophysiology. The current molecular genetic data will help life sciences researchers working on the rare skeletal disorders. Moreover, the aim of present systematic review is to gather the published knowledge on molecular genetics of appendicular skeleton, which would help in genetic counseling and molecular diagnosis., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Pathogenic heterozygous variants in PIEZO2 typically cause distal arthrogryposis type 5 (DA5) and the closely related Gordon syndrome (GS). Only one case of PIEZO2-related Marden-Walker syndrome (MWS) has been reported to date. We report the phenotypic features of a Saudi female patient with features consistent with MWS in whom we identified a novel de novo likely pathogenic variant in PIEZO2. Our case lends support to the link between PIEZO2 and MWS., (© 2020 Wiley Periodicals LLC.)

Clubfoot and positional foot deformities (eg, pes spinatus) may have the same aspects on prenatal ultrasound (US) imaging. Nevertheless, differentiating these entities is essential because their prognoses are different. This pictorial review illustrates the US findings of clubfoot and positional foot deformities. On the basis of clinical postnatal images, we describe a prenatal US technique that could give an accurate diagnosis. In this essay, we demonstrate that when a foot malposition is suspected, a systematic analysis with 3 rigorous planes could help differentiate positional foot deformities from malformations and define their types., (© 2019 by the American Institute of Ultrasound in Medicine.)

Genetic factors underlying the human limb abnormality congenital talipes equinovarus ('clubfoot') remain incompletely understood. The spontaneous autosomal recessive mouse 'peroneal muscular atrophy' mutant (PMA) is a faithful morphological model of human clubfoot. In PMA mice, the dorsal (peroneal) branches of the sciatic nerves are absent. In this study, the primary developmental defect was identified as a reduced growth of sciatic nerve lateral motor column (LMC) neurons leading to failure to project to dorsal (peroneal) lower limb muscle blocks. The pma mutation was mapped and a candidate gene encoding LIM-domain kinase 1 ( Limk1 ) identified, which is upregulated in mutant lateral LMC motor neurons. Genetic and molecular analyses showed that the mutation acts in the EphA4-Limk1-Cfl1/cofilin-actin pathway to modulate growth cone extension/collapse. In the chicken, both experimental upregulation of Limk1 by electroporation and pharmacological inhibition of actin turnover led to defects in hindlimb spinal motor neuron growth and pathfinding, and mimicked the clubfoot phenotype. The data support a neuromuscular aetiology for clubfoot and provide a mechanistic framework to understand clubfoot in humans., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

Lymphangiomas are rare congenital malformations of the lymphatic system. Despite the benign histology, they are likely to grow rapidly and invade the surrounding tissues. In contrast to the cystic hygromas, lymphangiomas at the axillary region tend to have normal karyotype. However, associated hydrops makes the prognosis poor. Due to isolated few cases in the literature, the true incidence of foetal axillary lymphangiomas is not known. We present here a pre-natal ultrasonographic diagnosis of a 15-week foetus with rapidly growing axillary lymphangioma with ipsilateral foot abnormality which had normal karyotype.

The cadherin Celsr3 regulates the directional growth and targeting of axons in the CNS, but whether it acts in collaboration with or in parallel to other guidance cues is unknown. Furthermore, the function of Celsr3 in the peripheral nervous system is still largely unexplored. Here we show that Celsr3 mediates pathfinding of motor axons innervating the hindlimb. In mice, Celsr3-deficient axons of the peroneal nerve segregate from those of the tibial nerve but fail to extend dorsally, and they stall near the branch point. Mutant axons respond to repulsive ephrinA-EphA forward signaling and glial cell-derived neurotrophic factor (GDNF). However, they are insensitive to attractive EphA-ephrinA reverse signaling. In transfected cells, Celsr3 immunoprecipitates with ephrinA2, ephrinA5, Ret, GDNF family receptor α1 (GFRα1) and Frizzled3 (Fzd3). The function of Celsr3 is Fzd3 dependent but Vangl2 independent. Our results provide evidence that the Celsr3-Fzd3 pathway interacts with EphA-ephrinA reverse signaling to guide motor axons in the hindlimb.

The 48,XXYY syndrome is a rare uncommon gonosome aneuploidy and its incidence is estimated to be 1:18,000-1:40,000. The phenotype associated with this syndrome, classically described as Klinefelter variant, is extremely variable but developmental abnormalities are always present. Ultrasound signs during pregnancy are inconsistent, and only three prenatal cases have been described in the literature. Here, we report a case of 48,XXYY syndrome identified in prenatal period because of the presence of polyhydramnios and bilateral clubfeet on second trimester ultrasound. This observation shows the importance of chromosomal prenatal diagnosis in cases with bilateral clubfeet on morphologic ultrasound. This diagnosis is essential for further characterization of the prenatal phenotype and to improving genetic counselling., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Talipes equinovarus is one of the most common congenital musculoskeletal anomalies and has a worldwide incidence of 1 in 1000 births. A genetic predisposition to talipes equinovarus is evidenced by the high concordance rate in twin studies and the increased risk to first-degree relatives. Despite the frequency of isolated talipes equinovarus and the strong evidence of a genetic basis for the disorder, few causative genes have been identified. To identify rare and/or recurrent copy number variants, we performed a genome-wide screen for deletions and duplications in 413 isolated talipes equinovarus patients using the Affymetrix 6.0 array. Segregation analysis within families and gene expression in mouse E12.5 limb buds were used to determine the significance of copy number variants. We identified 74 rare, gene-containing copy number variants that were present in talipes equinovarus probands and not present in 759 controls or in the Database of Genomic Variants. The overall frequency of copy number variants was similar between talipes equinovarus patients compared with controls. Twelve rare copy number variants segregate with talipes equinovarus in multiplex pedigrees, and contain the developmentally expressed transcription factors and transcriptional regulators PITX1, TBX4, HOXC13, UTX, CHD (chromodomain protein)1, and RIPPLY2. Although our results do not support a major role for recurrent copy number variations in the etiology of isolated talipes equinovarus, they do suggest a role for genes involved in early embryonic patterning in some families that can now be tested with large-scale sequencing methods.

Gross similarities between the external appearance of the hind limbs of the peroneal muscle atrophy (pma) mouse mutant and congenital talipes equinovarus (CTEV), a human disorder historically referred to as 'clubfoot', suggested that this mutant could be a useful model. We used micro-magnetic resonance imaging to visualize the detailed anatomy of the hind limb defect in mutant pma mice and performed 3D comparisons between mutant and wild-type hind limbs. We found that the pma foot demonstrates supination (i.e. adduction and inversion of the mid foot and fore foot together with plantar flexion of the ankle and toes) and that the tibiale and distal tarsals display 3D abnormalities in positioning. The size and shape of the tibia, fibula, tarsal and metatarsal bones are similar to the wild-type. Hypoplasia of the muscles in the antero-lateral (peroneal) compartment was also demonstrated. The resemblance of these features to those seen in CTEV suggests that the pma mouse is a possibly useful model for the human condition. To understand how the observed deformities in the pma mouse hind foot arise during embryonic development, we followed the process of foot rotation in both wild-type and pma mutant mice. Rotation of the hind foot in mouse embryos of wild-type strains (CD-1 and C57/Black) occurs from embryonic day 14.5 onwards with rotation in C57/Black taking longer. In embryos from both strains, rotation of the right hind foot more commonly precedes rotation of the left. In pma mutants, the initiation of rotation is often delayed and rotation is slower and does not reach completion. If the usefulness of the pma mutant as a model is confirmed, then these findings on pma mouse embryos, when extrapolated to humans, would support a long-standing hypothesis that CTEV is due to the failure of completion of the normal process of rotation and angulation, historically known as the 'arrested development hypothesis'.

To investigate the role of gene Gli3 in idiopathic congenital talipes equinovarus (ICTEV), we constructed the Gli3 luciferase reporter gene expression vectors to analyze the promoter activity of the rat gene Gli3. The regulatory element in the promoter region of the rat Gli3 was predicted using P-Match software and further verified by ChIP experiment. Meanwhile, the correlation between the rat En1 and ICTEV was evaluated by RT-PCR, immunohistochemistry, and Western blotting analyses. The result from P-Match software prediction showed that only one of the three possible En1 binding sites in Gli3 promoter region was interacted directly with En1 in vivo, which was confirmed by ChIP analysis. The results from RT-PCR, immunohistochemistry and Western blotting analyses suggested that En1 was down-regulated in ICTEV model rats compared to the controls. Our results indicated that En1 might be the negative regulatory element in the upstream of Gli3. The low expression level of EN1 in ICTEV could contribute to the up-regulation of GLI3, which led to the genesis of ICTEV.

The Limb Morphogenetic Differentiation Scoring system introduced by Neubert and Barrach in 1977 has been used in drug testing as a measure of the degree of cartilage growth inhibition especially for forelimb in vitro. There is no scoring system to quantify the degree of hindlimb bud cartilage differentiation in vivo. A total of 60 female Sprague-Dawley rats weighing 220-250 g were assigned at random to six control groups and six experimental groups on day 0 of pregnancy. The experimental groups were treated with all-trans-retinoic acid (ATRA). A new limb morphogenetic differentiation scoring system was developed and used to quantify the degree of development of the hindlimb buds from the fetuses at embryonic days E13 to E18. The differentiation of cartilages assessed by the new scoring system showed a statistically significant difference between the experimental group and the control group from E13 to E18 (T-test, p < 0.05). Cartilage growth (the proximodistal length) in the control group increased gradually from E14, reaching its peak at E17, but in the experimental group the growth at E13, E16, E17, and E18 was significantly shorter (p < 0.05). In conclusion, the new limb morphogenetic differentiation scoring system described here can be used to quantify the degree of inhibition of the hindlimb bud development by teratogenic drugs or materials, and morphogenetic differentiation in vivo.

Mechanical characterization of human cartilage anlagen is required to effectively model congenital musculoskeletal deformities. Such modeling can effectively explore the effect of treatment procedures and potentially suggest enhanced treatment methods. Using serial MRI, we have noted shape changes of the cartilaginous hindfoot anlagen in patients with clubfoot, suggesting they are soft and deformable. We therefore determined the stress relaxation behavior of cartilage plugs obtained from third-trimester stillborn fetuses in unconfined and confined compression geometries. The material parameters determined were the aggregate modulus H(A) = 0.15 +/- 0.07 MPa, Poisson's ratio nu = 0.4 +/- 0.06, Young's modulus E(s) = 0.06 +/- 0.03 MPa, and permeability coefficients k(0) = 2.01 +/- 0.8 x 10(-14) m(4) N(-1) s(-1) and M = 4.6 +/- 1.0. As compared with adult articular cartilage, stiffness was an order of magnitude lower than the values reported in the literature, suggesting the relative softness of the tissue, and the permeability was an order of magnitude higher, indicating relative ease of flow in the tissue. Poisson's ratio also was close to the higher end of the range reported in previous studies. Such material is expected to deform and relax to larger extents. These findings are consistent with the deformability of the cartilage anlagen during manipulation and casting for treatment of clubfoot.

The pathological anatomy of idiopathic clubfoot has been investigated for more than 180 years using anatomy, computed tomography (CT), histology and microscopy. Seven idiopathic clubfeet and two normal feet of aborted fetuses were dissected in the present study, with special emphasis on the shape of the cartilage and bones. A three-dimensional (3D) micro-CT system, which generates a series of X-ray attenuation measurements, was used to produce computed reconstructed 3D data sets of each of the separated bones. Based on the micro-CT data scans a high-definition 3D colour printing system was used to make a four times enlarged clubfoot model, precisely presenting all the bony malformations. This model reflects the complexity of the anatomy of this disease and is designed to be used in the workshops of orthopaedic surgeons and physiotherapists, for training in new surgical and manipulation techniques.

During the dissection of seven club feet of foetuses, aborted between the 25th and 37th week of gestation, an additional muscle bundle was found in a right foot. This muscle arose from both heads of the gastrocnemius muscle, continued downwards onto the posterior surface of the soleus, crossed the calcaneal tendon and assumed a position on the lateral side of the calcaneal tendon. The muscle's tendon was fixed just laterally to the calcaneal tendon in the calcaneal tuberosity with some tiny fibres branching off into the superior fibular retinaculum.

Wolf-Hirschhorn (4p-) syndrome (WHS), caused by partial deletion of the short arm of chromosome 4, has been extensively described in children and young adults. Knowledge on fetuses with WHS is still limited due to the small number of published cases. We report on a fetus with prenatally diagnosed severe intrauterine growth retardation, reduced thoracal diameter, clubfeet deformity and midface hypoplasia including slight microretrognathia indicative for fetal karyotyping. Chromosome analysis after amniocentesis revealed a de novo terminal deletion of chromosome 4p [karyotype: 46,XX,del(4) (p16)] which was confirmed by FISH. Analyses of a set of polymorphic markers mapping in 4pter->4p15.3 showed absence of paternal haplotypes. These observations corroborate the preferential paternal origin of the de novo 4p deletion in WHS patients. Furthermore, the distal breakpoint could be narrowed to band 4p16.1. At autopsy, the fetus showed typical craniofacial dysmorphic signs of WHS, severe IUGR and delayed bone age. This report suggests the possibility of recognising the particular phenotype of WHS in utero by prenatal ultrasound and emphasises the importance of karyotyping fetuses with severe IUGR, especially when the amount of amniotic fluid is normal., (Copyright 2004 S. Karger AG, Basel)

Idiopathic (non-syndromic) congenital talipes equinovarus, or clubfoot, is a poorly understood but common developmental disorder of the lower limb, which affects at least 2 per 1000 Scottish births (ISD data). It is defined as a fixation of the foot in a hand-like orientation--in adduction, supination and varus--with concomitant soft tissue abnormalities. Despite advances in treatment, disability often persists. The aetiology of the condition has been little studied and is poorly understood. Neurological, muscular, bony, connective tissue and vascular mechanisms have been proposed, but the only firm evidence is that the mildest cases appear to be associated with intra-uterine posture. There is evidence for a genetic contribution to congenital talipes equinovarus aetiology. Its incidence varies with ethnic group, and we found that a family history is present in 24-50% of cases, depending on the population studied. Complex segregation analysis suggests that the most likely inheritance pattern is a single gene of major effect operating against a polygenic background. Possible mechanisms for congenital talipes equinovarus are discussed.

A congenital clubfoot is often associated with a neuromuscular disease, a chromosomal anomaly, or a syndrome. The present review will only study the idiopathic clubfoot seen in an otherwise normal child. It is considered nowadays that a clubfoot is secondary to a defect in the spontaneous "rotation-elevation" mechanism which should occur between the 9th and 10th week of fetal development. Several possible factors influence the embryonic development: genetic, neurologic, muscular, environmental, and toxic factors. Modern notions of anatomy and physiology of the foot allow a better understanding of the deformations seen in a clubfoot: calcaneo-forefoot block, talonavicular joint double "belonging", notion of "relative" hindfoot supination. The osteo-articular deformations involve mainly the talus, the calcaneus, the navicular. They are associated to articular stiffness secondary to soft tissue retractions like the posterolateral, anteromedial, and the anterolateral fibrous knots. Prenatal diagnosis can be made using the ultrasound which is usually performed at 20 weeks of gestation. Nevertheless, only the clinical exam at birth will evaluate the degree of severity of the clubfoot based upon its reducibility, the presence of skin creases, and the importance of muscular atrophy. Imaging techniques (especially standard x-ray) are useless diagnostic tools. They will be necessary for the follow-up, the evaluation of residual defects, and for the possible surgical indications. Conservative treatment is used first, and in the hands of experienced teams will give a sufficient correction in 70 to 80% of the patients. The surgical treatment is used to complete the correction obtained by conservative means. Surgical treatment will free the retracted soft tissues. Postoperatively the foot will be immobilized in the appropriate position for 2 to 3 months. Clubfoot treatments are associated with complications which have to be known to avoid them if possible and/or to be able to take the appropriate therapeutic actions when necessary. The results of clubfoot treatment are satisfactory in the majority of patients despite the treatment difficulties and the possible relapses during growth. Follow-up is mandatory until the end of growth.

Clubfoot (talipes equinovarus) is a common orthopaedic malformation that can be accurately diagnosed prenatally. The study was conducted to investigate possible in utero visualization of transient and late-onset clubfoot. Early (13-16 weeks' gestation) prenatal transvaginal sonographic diagnosis of clubfoot deformity was made in 36 cases during the study period. Only those cases where follow-up examination revealed different sonographic findings were considered. The results showed that seven cases of transient (as well as relapsing) clubfoot were identified. In 4 of 7 cases, the clubfoot resolved (all after more than 10 min of observation) during the same examination. In the fifth and sixth cases, it initially resolved, later reappearing in follow-up examinations (20 and 22 weeks' gestation). In the seventh case, the clubfoot persisted for two consecutive examinations (2 weeks apart each) and later disappeared. In addition, six late-onset (22-24 weeks' gestation) clubfoot cases were identified during the study period. Although infrequent, in utero clubfoot can be both a transient and a late-onset phenomenon. Over- and under-diagnosis are potential hazards in these situations.

The medical records of 330 children who were born with uncomplicated congenital clubfoot were reviewed retrospectively. To determine their months of conception, the duration of gestation was extrapolated and those which were less than 40 weeks were noted. The years of conception for the studied children were from 1956 to 1994. Months of the year were ascribed angle values and the distribution of conceptions per month were grouped in radial manner. Using a circular analysis for variance a lack of uniform circular distribution was found for the grouped months of conception. There is a significant seasonal variation in the data. The mean month of conception was June. This finding is at variance with the peak months of conception for the population of the United States for the years 1989 through 1993. The theory that congenital clubfoot is caused by an intrauterine Enterovirus may be supported by this data. The summer and fall peak of Enterovirus infections in temperate climates coincide with the stage of embryologic development (> 8 weeks) which would allow an anterior horn cell lesion to lead to a deformity such as congenital club foot.

We studied 16 club feet and 27 normal feet from spontaneously aborted human fetuses in the second trimester of gestation and measured the length of the spring ligament, and the declination angle and size of the talus. We also studied the cellular characteristics of the spring ligament and the immunohistochemical features of the medial ankle ligaments using monoclonal antibodies against type-III collagen, desmin, vimentin, and smooth muscle actin. Histomorphometric results indicated that the talar deformity was not the primary lesion. Histological and immunohistochemical findings showed that the cells and collagen fibres of the medial ankle ligaments of club feet appeared to be the site of the earliest changes, in that they had lost their spatial orientation and had contracted. In severe club feet before the third trimester of gestation, myofibroblast-like cells seemed to create a disorder of the ligaments resembling fibromatosis. This led to contraction and resulted in typical club-foot deformity.

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.

Clubfoot, a relatively frequent congenital malformation, may be associated with several genetic syndromes or other malformations, or may appear as an isolated idiopathic anomaly. We describe the intrauterine development of clubfeet subsequent and in parallel to fetal hydrocephalus formation, as followed by serial transvaginal sonographic scans at 11-16 weeks' gestation. The possibility of a causal relationship between the central nervous system malformation and the clubfeet is suggested. To the best of our knowledge, this is the first description of the dynamic, in vivo fetal development of hydrocephalus and clubfeet at 11-16 weeks' gestation.

The operative treatment of congenital club foot deformity in childhood consists of a release of soft tissues which are retracted in fibrous "knots" at the hindfoot and midtarsus. This release is more or less extensive, depending on the importance of the contracture and allows reduction of the triple deformity i.e. varus and equinus of the hindfoot and adduction at the midtarsus. Surgery is performed preferably before walking commences in order to take advantage of the functional self-treatment by bearing weight after removal of the cast. During the last several years, the different operative procedures employed for release have gained in precision and efficiency by addressing the deformity at their precise location. The difficult aim of the surgical procedure is to avoid insufficient release causing pseudo-recurrencies or overcorrection.

The development of the human foot from the eighth to the twenty-first intrauterine week was studied in 147 specimens. The results documented a stage of "physiologic club foot" characterized by a medial deviation and plantigrade orientation of talar neck and head during the ninth week. At the same time, the calcaneus assumes a position of varus with the forefoot in adduction. By the eleventh week, the foot assumes a normal position. All findings during the stage of physiologic club foot closely resemble those of the intrinsic type of club foot.

Patients with resistant clubfeet were reviewed in their second and third decades. For comparison, normal embryological and fetal feet, untreated clubfeet, a recurrent clubfoot, and an amputated foot were dissected. In no child with a resistant clubfoot was the bone architecture normal. In untreated and recurrent clubfeet we found the lateral malleolus to be directed posteriorly, the head of the talus pointed laterally, and the navicular subluxated medially toward the medial malleolus. An operative technique to restore normal alignment of the talus in the ankle mortice, of the navicular and talus, and of the talus and os calcis is described.

During embryonic development the foot passes consecutively into three different positions: (1) when the embryo is in the 15-mm stage the foot is in a straight line with the leg (initial position); (2) by 30 mm the foot passes to a marked equinovarus-adductus position (embryonic position); and (3) finally, by 50 mm, the foot changes to a slightly equinovarus adductus position (fetal position). The morphologic and structural changes of the foot from the initial to the embryonic position result from the growth of the distal ends of the fibula and of the skeletal elements of the lateral foot during the "fibular phase" of rapid growth (from 21 to 30 mm). The changes from the embryonic to the fetal position are due to the growth of the distal ends of the tibia and of the skeletal rays of the medial foot during the "tibial phase" of rapid growth. Many known noxious industrial chemicals (and probably many more yet to be recognized) have antimitotic and antimetabolic action. Depending on the characteristics of the chemical, some produce permanent arrest and therefore congenital malformation, while others cause temporary growth arrest, e.g., Harris transverse lines, which is frequently unnoticed. Finally, some substances, e.g., glucocorticoids, cause a growth delay. Depending on the developmental stage of the embryo and the duration of the action of the noxious substance, growth arrest of the foot occurs in an attitude close to the embryonic position. If it occurs at the end of the fibular phase and during the first half of the tibial phase, the foot will remain in a permanent and marked equinovarus-adductus position, and a severe clubfoot will result. When a noxious chemical acts only during the last half of the tibial phase, a mild, flexible clubfoot will result because by this stage most parts of the embryonic components have been corrected. If it occurs at the end of the tibial phase, a simple metatarsus adductus deformity will persist. As soon as the growth arrest phase ends, all of the skeletal elements begin to grow again, but only from a later point in development. If the growth disturbance occupies the entire tibial phase, neither the tibia nor the skeletal elements of the foot would be able to complete a rapid growth spurt, since by that stage the moment genetically programmed for such growth has already passed. The morphology of the deformities existing in the clubfoot corresponds to the morphologic program of the embryonic foot.(ABSTRACT TRUNCATED AT 400 WORDS)

It is demonstrated, using the Couette viscometer method, that talpid-3 mutant chick wing mesenchyme cells are more adhesive to one another than are normal cells. The relation of this to differences in the size and shape, and the internal architecture, of aggregates produced in rotation cultures of these cells was investigated. Sequences of sections through aggregates in all stages of formation, from 2-cell aggregates up to those with large cell numbers, were prepared. These confirm the theoretically predicted relationships among adhering cells which would produce the observed small, spherical talpid-3 aggregates and the larger, unevenly shaped normal aggregates. The cell contacts are further analysed with electron micrographs.

Eighteen cases of congenital clubfoot were diagnosed sonographically between 16 and 38 weeks. The method of diagnosis, associated anomalies, karyotypes, and obstetric outcomes are described. Fifteen of the 18 fetuses had other major congenital anomalies, and of these, four had abnormal karyotypes. Only three had uncomplicated clubfoot as the only abnormality. Because of the significant incidence of abnormal karyotypes in our series, confirmed in other reported cases, identification of a clubfoot on prenatal sonography may be considered an indication for amniocentesis, particularly when other anomalies are present.

Empirical testing has not revealed an indisputable cause of clubfoot. Evidence put forward for intrauterine moulding as a cause of idiopathic clubfoot does not stand up to scrutiny. The hypothesis that a regional growth disturbance is the cause of clubfoot would explain clinical and existing research data.