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Human limbs emerge during the fourth post-conception week as mesenchymal buds, which develop into fully formed limbs over the subsequent months 1 . This process is orchestrated by numerous temporally and spatially restricted gene expression programmes, making congenital alterations in phenotype common 2 . Decades of work with model organisms have defined the fundamental mechanisms underlying vertebrate limb development, but an in-depth characterization of this process in humans has yet to be performed. Here we detail human embryonic limb development across space and time using single-cell and spatial transcriptomics. We demonstrate extensive diversification of cells from a few multipotent progenitors to myriad differentiated cell states, including several novel cell populations. We uncover two waves of human muscle development, each characterized by different cell states regulated by separate gene expression programmes, and identify musculin (MSC) as a key transcriptional repressor maintaining muscle stem cell identity. Through assembly of multiple anatomically continuous spatial transcriptomic samples using VisiumStitcher, we map cells across a sagittal section of a whole fetal hindlimb. We reveal a clear anatomical segregation between genes linked to brachydactyly and polysyndactyly, and uncover transcriptionally and spatially distinct populations of the mesenchyme in the autopod. Finally, we perform single-cell RNA sequencing on mouse embryonic limbs to facilitate cross-species developmental comparison, finding substantial homology between the two species., Competing Interests: Competing interests: In the past 3 years, S.A.T. has consulted for or been a member of scientific advisory boards at Qiagen, Sanofi, GlaxoSmithKline and ForeSite Labs. She is a consultant and equity holder for TransitionBio and EnsoCell. J.C.M has been an employee of Genentech, Inc. since September 2022. The remaining authors declare no competing interests., (© 2023. The Author(s).)

Purpose: The purpose of this study was to determine clinical importance and morphology of the fibularis longus, brevis, tertius muscles (presented as fibular muscles in this study), and prevalence of accessory fibular muscles (AFM) on fetal cadavers., Materials and Methods: In this study, 200 limbs from 100 embalmed fetuses (54 male and 46 female) were studied. Morphology of fibular muscles and the presence of AFM were observed through dissection on fetal legs bilaterally. The absence of fibularis tertius muscle (FT) and the presence of AFM were identified. Length and length of the tendon of AFM were measured. Insertion of AFM was also identified., Results: Mean values and standard deviations of all parameters according to trimesters were calculated. All parameters were increased with age during the fetal period. We determined the absence of FT; no FT was observed in 40 legs of 200 extremities (20%). The AFM was present in 7 of 200 specimens (3.5%). AFM muscles were classified into two types according to their site of origin., Conclusion: The present study has revealed the morphology of the fibular muscles and prevalence of the presence of AFM on fetal cadavers. In addition, it has revealed the morphometric development and prevalence of the absence of FT in a large series, and their clinical importance was discussed.

Objectives: Neonatal adiposity is associated with chronic metabolic sequelae such as diabetes and obesity. Identifying fetuses at risk for excess neonatal body fat may lead to research aimed at limiting nutritional excess in the prenatal period. We sought to determine whether fetal arm and leg soft tissue measurements at 28 weeks' gestation were predictive of neonatal percent body fat METHODS : In this prospective observational cohort study of singleton term pregnancies, we performed sonography at 28 and 36 weeks' gestation, including soft tissue measurements of the fetal arm and thigh (fractional limb volume and cross-sectional area). We estimated the neonatal body composition (percent body fat) using anthropometric measurements and air displacement plethysmography. We estimated Spearman correlations between sonographic findings and percent body fat and performed modeling to predict neonatal percent body fat using maternal characteristics and sonographic findings., Results: Our analysis of 44 women yielded a mean maternal age of 30 years, body mass index of 26 kg/m(2), and birth weight of 3382 g. Mean neonatal percent body fat was 8.1% by skin folds at birth and 12.2% by air displacement plethysmography 2 weeks after birth. Fractional thigh volume measurements at 28 weeks yielded the most accurate model for predicting neonatal percent body fat (R(2) = 0.697; P = .001), outperforming models that used abdominal circumference (R(2)= 0.516) and estimated fetal weight (R(2)= 0.489)., Conclusions: Soft tissue measurements of the fetal thigh at 28 weeks correlated better with neonatal percent body fat than currently used sonographic measurements. After validation in a larger cohort, our models may be useful for prenatal intervention strategies aimed at the prevention of excess fetal fat accretion and, potentially, optimization of long-term metabolic health.

A paper published in 1925 reported that human fetuses with anencephaly have arms that are longer than normal. This finding was accepted as true through the early 1990s. An analysis of body dimensions done in 1996 and enlarged and updated here shows that the arms of human fetuses with anencephaly are appropriate for gestational age and normal in proportion to their leg lengths. A subtle difference in measurement technique was found to explain the discordant findings., ((c) 2009 Wiley-Liss, Inc.)

Background: The objective of our study was to determine differences in prenatal leg posture development between breech and cephalic-born babies., Materials and Methods: Ten healthy fetuses in breech and ten healthy fetuses in cephalic presentation were observed by means of weekly ultrasounds from 33 weeks gestational age until birth to assess leg posture., Results: The breech fetuses showed a clear preference for an extended leg position; they spent significantly more time with their knees in extension than the cephalic fetuses (p<0.001). The cephalic fetuses showed significantly more leg-crossing than the breech fetuses (p<0.01). For both findings, no significant change over time could be observed in either group., Conclusion: These findings show that the intra-uterine position does influence the fetal postural and motor development. However, it seems unlikely that intra-uterine movement restriction can solely be held accountable for the observed differences in leg position between breech and cephalic fetuses.

Objective: The purpose of this study was to establish a new reference growth chart of calf muscle biometric measurements throughout gestation in normal singleton pregnancies., Methods: A prospective cohort study was designed. One hundred pregnant women were included in the study and assessed by 3-dimensional sonography. Excluded were those with multiple pregnancies, congenital anomalies, abnormal karyotypes, and polyhydramnios or oligohydramnios. Three-dimensional multiplanar sonographic images were used to measure the calf muscles: soleus, gastrocnemius, popliteal, peroneus longus, and tibialis posterior., Results: Calf muscle widths increased with increasing gestational age (R(2) = 0.857; P < .0001), and the ratio between calf muscles and the tibia increased as well (R(2) = 0.356; P = .001)., Conclusions: The data provide a nomogram of calf width with a direct correlation between muscle growth and gestational age. This nomogram can offer a basis for normal calf development and may assist in distinguishing between different etiologies leading to clubfoot and other joint contractures associated with calf atrophy.

We report the perinatal findings of a 23 gestational-week fetus with Dandy-Walker malformation (DWM), ventriculomegaly, symmetrical transverse limb deficiencies, hypertelorism, frontal bossing, low-set ears, and a depressed nasal bridge. The karyotype was 46,XX. We believe that this combination is significant. Concomitant DWM and symmetrical distal limb deficiencies may represent a new entity that awaits more new cases for further delineation.

Amniotic band syndrome is a sporadic condition that may result in constriction bands, amputation and multiple craniofacial, visceral and body wall defects. It occurs in 1/1,200 to 1/15,000 live births. Most cases present with multiple congenital anomalies that are incompatible with life. A small group of fetuses shows isolated limb constrictions that may cause severe limb dysfunction or limb amputation if left untreated. Successful in utero surgical lyses of constriction rings have been reported. We report a case of constriction amniotic bands involving both legs and compromising blood flow to the distal extremity. The constriction ring was successfully released by a minimally invasive endoscopic surgical technique avoiding severe limb dysfunction or foot amputation., (Copyright 2006 S. Karger AG, Basel.)

As a member of the thrombospondin gene family, cartilage oligomeric protein (COMP) is found mainly in the extracellular matrix often associated with cartilage tissue. COMP exhibits a wide binding repertoire and has been shown to be involved in the regulation of chondrogenesis in vitro. Not much is known about the role of COMP in human cartilage tissue in vivo. With the help of immunohistochemistry, Western blot, in situ hybridization, and real-time reverse transcription-polymerase chain reaction, we aimed to elucidate the role of COMP in human embryonic, adult healthy, and osteoarthritis (OA) cartilage tissue. COMP is present during the earliest stages of human limb maturation and is later found in regions where the joints develop. In healthy and diseased cartilage tissue, COMP is secreted by the chondrocytes and is often associated with the collagen fibers. In late stages of OA, five times the COMP mRNA is produced by chondrocytes found in an area adjacent to the main defect than in an area with macroscopically normal appearance. The results indicate that COMP might be involved in human limb development, is upregulated in OA, and due to its wide binding repertoire, could play a role in the pathogenesis of OA as a factor secreted by chondrocytes to ameliorate the matrix breakdown.

Genetic disorders characterized by congenital patellar aplasia or hypoplasia belong to a clinically diverse and genetically heterogeneous group of lower limb malformations. Patella development involves different molecular and cellular mechanisms regulating dorso-ventral patterning, cartilage and bone formation along endochondral ossification pathways, and growth. Several human genes that are important for patella development have been uncovered by the study of human limb malformation syndromes, yet causative genes for many more such disorders await to be identified and their complex interactions in the developmental pathways deciphered. Mutant animal models of congenital patellar aplasia or hypoplasia are certainly instrumental to create more insight into this aspect of limb development. Moreover, investigation of the complete phenotype of human syndromes and animal models may reveal novel insights into the pleiotropic roles of the responsible genes in the normal developmental of other organ systems. In this review, the phenotype and gene defects of syndromes with congenital patellar aplasia or hypoplasia will be discussed, including the nail patella syndrome, small patella syndrome, isolated patella aplasia hypoplasia, Meier-Gorlin syndrome, RAPADILINO syndrome, and genitopatellar syndrome.

There are 3 groups of perforating veins of the shin: the medial, the lateral and the internal sural perforating veins. Dysfunction of these veins is one of the main factors in venous hypertension. There is a lack of data in the literature concerning perforating veins of the shin in human foetuses. The aim of this study was identification of the perforating veins of the shin in human prenatal development. The material examined included 88 human lower limbs of foetuses (21 males and 23 females) aged from 16 to 38 weeks of intra-uterine life. The perforating veins were dissected under a steromicroscope. The number of perforating veins was analysed in relation to the sex of the foetus and the side of a body. In our study perforating veins of the shin did not show sexual or syntopic dimorphism. Between 2 and 6 Cockett's perforating veins were constantly present. Of these veins 80% divided into ascending and descending branches. Fibular perforating veins were found more often (90.9%) than Boyd's perforating veins (21.6%). Between 1 and 3 fibular perforating veins were observed but in 9% of cases they were entirely absent.

Background: Severe anomalies of the forebrain together with radial limb anomalies have been reported in Steinfeld syndrome, XK aprosencephaly, and partial monosomy 13q. Steinfeld syndrome is an extremely variable autosomal dominant condition that, in severe cases, is characterized by holoprosencephaly, radial limb defects, and renal and/or cardiac defects. In mild cases there may be only thumb hypoplasia, ocular coloboma, or oral clefts. XK aprosencephaly, also called Garcia-Lurie syndrome (GLS), is a usually sporadic disorder with radial limb defects and aprosencephaly/atelencephaly. Based on two atypical sibships, autosomal recessive inheritance has been suggested. Two patients with variations of monosomy 13q have been described with atelencephaly but, generally, Steinfeld and XK aprosencephaly patients are chromosomally normal. Holoprosencephaly in 13q deletion patients appears to be due to ZIC2 mutations, but ZIC2 has not been previously tested in Steinfeld syndrome or GLS patients., Cases: We report three sporadic cases with clinical features intermediate between Steinfeld and GLS, including severe forebrain malformations and radial limb defects. All had normal karyotypes, and mutations in ZIC2 were absent in the two cases tested., Conclusions: In our cases and in the literature there is significant clinical overlap between Steinfeld syndrome and GLS. We propose these conditions may not be nosologically or etiologically distinct. The spectrum of severe forebrain anomalies in these conditions is broader than previously thought and may include some neural tube defects. Mild cases are difficult to identify and the full range of expression remains unknown. Autosomal dominant inheritance with incomplete penetrance and frequent new mutations is postulated. Thorough clinical evaluation is recommended for children with severe forebrain and radial limb defects.

This case report is of an infant of a diabetic mother who presented with lower extremity gangrene occurring in utero that necessitated a below the knee amputation at 3 hours of age. The association of venous thrombi in infants of diabetic mothers (IDMs) has been firmly established. However, in this case the thrombi were arterial and resulted in gangrene during the second trimester of gestation. The reason for the increased tendency to develop thrombi in infant of diabetic mothers has not been elucidated. We did an extensive workup of this infant to look for a cause of the arterial thrombus. The only abnormality found was in the plasminogen activity, which was significantly lower than the reference values for infants of the same gestational and chronological age. The significance of this finding on the propensity of IDMs to develop thrombi is discussed.

Arthrogryposis multiplex congenita is a general term for congenital multiple joint contractures, the aetiology of which is variable. Prenatal diagnosis is usually based on the detection of diminished fetal movements and joint contractures on ultrasound. There are also reports of early diagnosis of arthrogryposis in the first and early second trimester by detection of subcutaneous oedema. We report another case of arthrogryposis multiplex congenita with increased nuchal translucency and scoliosis diagnosed by ultrasonography at 15 weeks of gestation. The pregnancy was terminated at the request of the parents. Post-mortem examination revealed that it was not associated with fetal myopathy or neuropathy. Multiple joint contractures with increased nuchal translucency without any underlying fetal neurogenic and myogenic pathology may be a distinct form of arthrogryposis multiplex congenita., (Copyright 2002 S. Karger AG, Basel)

We report five cases of a persistent sciatic artery. The lesion was unilateral in all cases. Four patients were treated by exclusion of the aneurysm with ligature of the internal iliac artery with an associated femoropopliteal bypass in two. Surgical treatment was declined by one patient. We discuss the embryology, pathology, clinical aspects and surgical procedures involved.

Three cutaneous manifestations are characteristic of Bart syndrome: congenital localized absence of skin (CLAS), mucocutaneous blistering, and nail abnormalities. Six cases of Bart syndrome are herein reported. Localized absence of skin is present at birth, particularly on the anterior aspects of the lower extremities and dorsa of the feet. Physical trauma in utero has been proposed as a mechanism to explain the denuded areas on the limbs. The recurrent, highly similar pattern of the congenital defect in regard to location and clinical appearance in our patients and in most of the reported cases strongly suggests that trauma is too simplistic an explanation. Because of the observed bilateral and symmetric distribution of denuded areas in an S-shaped broad band, their sharply demarcated borders, the involvement of the toe webs, and the frequent similar involvement of the soles, we suggest that congenital localized absence of skin in Bart syndrome may follow the lines of Blaschko.

The Polycomb group genes are involved in maintaining long term transcriptional repression of the homeotic genes in both Drosophila and mammals. The mouse eed locus encodes the highly conserved ortholog of the Drosophila ESC protein. To test the functional conservation between the two genes, eed was introduced into the fly to determine whether it could rescue the esc mutant phenotype. eed exerted a dominant negative effect on the leg transformation phenotype associated with the esc mutation. This result is interpreted in light of in vitro protein-protein binding data and in vivo polytene chromosome staining indicating the lack of significant interaction between Eed and fly E(Z), a molecular partner of ESC. genesis 26:67-76, 2000, (Copyright 2000 Wiley-Liss, Inc.)

We have isolated mammalian homologues of the Drosophila dachshund gene. Two domains of high conservation, one of which contains an alpha-helical, coiled-coil motif, show similarity to the Ski family of genes. We therefore propose that Dachshund belongs to a superfamily including these genes. Mouse Dachshund (Dach) is expressed in the eye and limb, structures affected by the Drosophila loss-of-function mutant, and rib primordia, CNS and genital eminence. Pax6 and Dach show overlapping but non-identical expression patterns. Dach expression is unaffected in smalleye mouse brain, indicating that Pax6 is not directly activating Dach. In Drosophila eye development dachshund is a component of an interacting network of proteins. Genes homologous to many of these exist in mammals; Dach joins this expanding group., (Copyright 1998 Elsevier Science Ireland Ltd. All rights reserved)

Development of paired appendages at appropriate levels along the primary body axis is a hallmark of the body plan of jawed vertebrates. Hox genes are good candidates for encoding position in lateral plate mesoderm along the body axis and thus for determining where limbs are formed. Local application of fibroblast growth factors (FGFs) to the anterior prospective flank of a chick embryo induces development of an ectopic wing, and FGF applied to posterior flank induces an ectopic leg. If particular combinations of Hox gene expression determine where wings and legs develop, then formation of additional limbs from flank should involve changes in Hox gene expression that reflect the type of limb induced. Here we show that the same population of flank cells can be induced to form either a wing or a leg, and that induction of these ectopic limbs is accompanied by specific changes in expression of three Hox genes in lateral plate mesoderm. This then reproduces, in the flank, expression patterns found at normal limb levels. Hox gene expression is reprogrammed in lateral plate mesoderm, but is unaffected in paraxial mesoderm. Independent regulation of Hox gene expression in lateral plate mesoderm may have been a key step in the evolution of paired appendages.

Embryonic chicken muscle cells (CELM) contain the calmodulin-dependent protein kinase that specifically phosphorylates eukaryotic elongation factor 2. The kinase requires Ca2+ and maximum activity in CELM was observed at 10 microM Ca2+. The ATP concentration required for half the maximum activity of CaM PKIII in CELM was calculated to be 0.15 mM. In CELM, dephosphorylation of eEF-2 was catalyzed by phosphoprotein phosphatase PP2A alone. The activity of PP2A was relatively low and the half-life of added phosphorylated eEF-2 was more than 15 min. Due to the low phosphoprotein phosphatase activity, inhibition of the PP2A activity by addition of okadaic acid had little effect on the eEF-2 phosphorylation kinetics.

To describe fetal body movements precisely and to clarify their developmental sequence in the second half of pregnancy, fetal body movements were observed in 31 normal fetuses between 20 and 41 weeks of pregnancy by using multiple ultrasonic machines. All movements of the whole trunk were able to be classified into six fundamental movements: flexion, stretch, rolling, startle, stepping, and writhing. Startle was always observed as a single movement, but others were more frequently observed as a part of combination rather than as a single movements. The incidence of flexion and stretch peaked at 28-31 weeks, whereas the incidence of startle and stepping lowered at the period. The incidence of rolling and upper half trunk movements increased at 40-41 weeks. Limb movements were frequent and did not exhibit characteristic change in the incidence. In conclusion, we classified fetal body movements into several fundamental movements instead of using the expression of "general movements" by focusing principally on movements of the trunk. In particular, some of the fundamental movements seem to appear in characteristic ways as related to gestational age. In view of that fetal behaviors are closely related to the neural activity, the present findings may contribute to an understanding of the developmental process of the central nervous system.

Wingless (Wg), a founding member of the Wingless/Int-1 (Wnt) family of secreted proteins, acts as a short-range inducer and as a long-range organizer during Drosophila development. Here, we determine the consequences of ectopically expressing (i) a wild-type form of Wg, (ii) a membrane-tethered form of Wg, and (iii) a constitutively active form of the cytosolic protein Armadillo (Arm), which normally acts to transduce Wg, and we compare them with the effects of removing endogenous Wg or Arm activity. Our results indicate that wild-type Wg acts at long range, up-regulating the transcription of particular target genes as a function of concentration and distance from secreting cells. In contrast, tethered Wg and Arm have only short-range or autonomous effects, respectively, on the transcription of these genes. We interpret these findings as evidence that Wg can act directly and at long range as a gradient morphogen during normal development.

In order to investigate the effect of the ectoderm on the pattern of mesodermal components in the chick leg, the ectoderm of the early limb bud was dorsoventrally reversed with respect to the mesoderm. The dorsoventral pattern was assessed by examination of the muscles, skeleton and epidermal differentiation. The earlier the stage at which the recombinants were made, the more complete was the reversal of the dorsoventral pattern of the limb mesoderm to conform with the ectoderm, and distal regions showed more complete reversals than proximal ones. Analysis of dorsoventral pattern along the leg shows that the dorsalization starts from the dorsal ectoderm and affects mesodermal structures in its progress to the midline and then to the ventral ectoderm. There was no strict congruence between the dorsoventral patterns of cartilage, muscle and epidermis. The results suggest that a signal from the dorsal ectoderm modifies ventral mesoderm before ventral ectoderm affects dorsal mesoderm. These observations about the way in which the mesoderm responds to ectoderm reversal suggest a new model. The model is based on two distinct signals, both initiated within the progress zone: (1) a factor made by dorsal ectoderm which specifies a dorsal state as distinct from a ventral state, and (2) a symmetrical positional signal from the apical ectodermal ridge which patterns the tissues along the dorsoventral axis.

The persistence of the sciatic artery is an unusual occurrence, with an angiographically demonstrated incidence of 0.06%. There have been 71 cases previously reported. We report an additional case in a 14-year-old boy who presented with a chief complaint of unsightly varices. The involved right limb was notably shorter than the uninvolved left lower extremity. Work-up included physical examination, duplex studies, venography, and angiography. Our patient was found to have a patent deep venous anatomy with valvular incompetency associated with complete persistence of the sciatic artery and a foreshortened right leg. He has done well with conservative treatment. The persistence of a sciatic artery has occasionally been associated with other anomalies including Mullerian and left renal agenesis, A-V fistula formation, hypertrophy or hypotrophy, multiple hemangiomata, neurofibromatosis, or anomalies of leg arteries. The literature describes three previous case reports in which patients presented with gross varicosities and were incidentally found to have persistent sciatic arteries as well as limb length discrepancies. Our patient is a fourth example of this syndrome. This pattern of physical attributes has not been previously described as a distinct entity. The association of venous incompetency, limb discrepancies, and persistence of the sciatic artery may be an incidental finding or may represent a related embryologic event. This relationship merits consideration in a young patient presenting with severe venous varicosities.

Based on studies using direct observation methods, type I motility, the first motility pattern to emerge in chick embryos, is characterized as random, uncoordinated movement. Yet, electromyographic (EMG) studies indicate that leg muscles are recruited in orderly patterns of alternating flexor and extensor activity during type I motility. It has been suggested that this apparent paradox may be attributable to perturbations arising during movement in ovo under buoyant conditions. It is also possible that direct observation methods are insufficient to detect the extent of coordination between body parts during type I motility. To address the apparent discrepancy between random features reported in observational studies and reliable features reported in EMG studies, embryos were video recorded continuously for 60 min at embryonic day 9 and criteria were established to obtain homogeneous samples of motility for kinematic analysis of synchronous wing and leg movements. Limited to a single camera attached to a stereomicroscope, methods were developed to correct for out-of-plane movements of the ipsilateral wing and leg. Also, amniotic fluid was extracted from the egg in some recordings to test the possibility that movement under buoyant conditions may mask coordinated movement. Extended sequences of activity were digitized and analyzed. Results indicated that within a limb (wing or leg), direction and timing of excursions at adjacent joints co-varied and limb excursions were characterized by reliable patterns of alternating flexion and extension consistent with EMG studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Ultrasound examination due to an elevated maternal serum alpha-fetoprotein level showed lower extremity asymmetry. The findings were felt to be consistent with Klippel-Trénaunay-Weber syndrome. The pregnancy was terminated based on these findings. The ultrasound findings, confirming post-mortem examination, and counselling issues are discussed.

This article's goal is to review the causes of limb rotation and arthritis and establish the correlation between the two entities. Evidence cited in this article demonstrates that malrotation is coupled with axial malalignment and both are associated with arthrosis of the hip, knee, and ankle. The clinical significance of this observation is that the prognosis of arthrosis developing in a malrotated limb may be predicted. Furthermore, the durability of an osteotomy, arthroplasty, or other surgical intervention may be limited if the intrinsic rotational deformity is not addressed.

Human leg and foot anlagen of different developmental stages were studied by means of light and scanning electron microscopy. The findings were compared with principles of human arm and hand development and results obtained experimentally from chicken limbs. The limbs studied have in common the shaping, cell differentiation, and spatial arrangement of different cells as basic processes of development. On the other hand, upper and lower limbs are very different in human and avian embryos with regard to their position, form, and function. We found that the different positions in relation to the dorsal and ventral surfaces and maintenance of the apical ectodermal ridge (AER) are important factors leading to the different orientations and forms of limbs. The unequal length of the fingers and toes might also be explained in this way. Differences in the position of the most distal muscles in the hand and foot could be a consequence of the cranio-caudal sequence of development. The factors controlling the developmental differences between arm and leg are discussed.

One hundred plantar muscles were studied and measured in fifty human fetuses from the 4th to 8th month of intra-uterine life. A reduction in the plantar muscle was observed due to slower development of the belly of muscle in relation to the tendon, which was as one to six (1:6). Mechanisms of reduction in the plantar muscle and in the long palmar muscle were compared in the study (5).

The diagnosis of limb body wall complex (LBWC) by ultrasonography does not usually present a problem. The major difficulty we found was severe oligohydramnios or a very complex relationship between the herniated viscera and the deformities. We performed fetography in a pregnant woman with fetal anterior abdominal wall defect at the 28th gestational week to show a peculiar structure of intrauterine membranes of LBWC, and we could obtain a successful prenatal diagnosis of LBWC.

The characteristics of a knemometer designed for accurate lower leg measurement in babies were assessed. Repeated measurement of a 100 mm Perspex rod gave a mean length of 99.993 mm and a mean SD of 0.058. When used to measure leg length, technical error of the measurement technique was 0.31 with a mean leg length of 98.49 mm (coefficient of variation 0.31%). Leg lengths measured at birth in 324 babies from 23 to 42 weeks' gestation gave an estimated in utero leg length velocity of 0.43 mm/day (95% confidence interval 0.41 to 0.45). Assessment of interobserver variation showed poor agreement in absolute values of leg length, although similar estimates of leg length velocity could be obtained. The neonatal knemometer allows measurements to be made in situations where conventional growth measurements are not possible. It is believed that knemometry has an important role in accurate evaluation of factors that can influence short term bone growth.

Persistent sciatic is a vascular malformation resulting in the embryo from the preferential growth of the ischiatic posterior axis remaining atrophic. We report here two cases of unilateral, complete and incompleted, persistent sciatic arteries, complicated by buttock aneurysm.

We report a new case of persistent sciatic artery. An 18-year-old girl was hospitalized with ischemia of the left foot. An arteriogram demonstrated a sciatic artery completely persistent. The superficial femoral artery was hypoplasic. A left femoro-popliteal by pass with saphenous vein graft was practised. After the operation, the patient did well and had no complications. We present this observation with a literature review about clinical arteriographic and surgical aspects of this vascular structure and its complications.

The congenital etiology of many malformations of the lower extremities is undisputed. This study uses cryomicrotomy of the knees and legs of midterm fetuses to establish the best anatomical representations of lower extremity parts, as they are developing, in a partially microscopic form. Adequate treatment plans of congenital defects require a knowledge of the normal status of development, and this investigation provides these data in a unique way. A comprehensive review of current therapeutic philosophies is related to morphology, which is discussed in light of the various congenital abnormalities of the knee and leg.

The talpid2 (ta2) chick mutant has wide, polydactylous wings and legs. Talpid2 limb cartilages have abnormal morphology and a very subtle anteroposterior polarity. Specifically, posterior ta2 limb structures are identifiable, while more anterior cartilages are less distinctive. Here, we investigate the development of anteroposterior limb pattern in the ta2 embryo. We show that ta2 posterior limb bud mesoderm is capable of respecifying the anteroposterior axis of a normal wing. However, the average duplication obtained after grafting a ta2 polarizing region was significantly less than the average duplication formed after a graft of normal wing bud polarizing zone. Thus, polarizing activity appears to be weak in ta2. Grafts of normal polarizing zone to the posterior edge of ta2 wing buds had no effect on the ta2 phenotype. This result suggests that a weakly functioning polarizing signal does not account for the altered anteroposterior polarity in ta2 limbs, and that normal polarizing zone activity is not sufficient for formation of normal limb bud cartilages. We demonstrated that transmission of a polarizing signal through the ta2 limb mesoderm was normal. In addition, ta2 anterior border mesoderm had no polarizing activity. We also assessed the ability of ta2 limb bud mesoderm to respond to a polarizing signal. Either normal polarizing zone tissue or a bead containing retinoic acid was placed at the anterior edge of ta2 wing buds at stages 18-23. Both polarizing zone and retinoic acid caused respecification of the ta2 wing anteroposterior axis. The result was that a ta2 ulna replaced the radius, and the most posterior digit was duplicated anteriorly. Limb cartilages with normal morphology never formed. When a bead containing retinoic acid was placed at the posterior edge of ta2 wing buds, there was no effect on anteroposterior pattern. However, beads with retinoic acid always caused a reduction in the number of ta2 wing digits which formed, whether the beads were placed at the anterior or posterior edge of the developing ta2 limb.

In the malformation analysis of 445 patients ascertained only for a sacrococcygeal malformation, a new phenotype, the sacrococcygeal dysgenesis association (SDA), was delineated in 34%. In addition, sirenomelia patients were found in 12%, the VATER association in 27%, and 27% could not be classified. Heterogeneity in the patients with sacrococcygeal malformations was identified by the differences found in their associated malformations. SDA patients have a relatively small average number (3.3) of anomalies per patient as compared with 9.3 in sirenomelia and 6.2 in VATER patients. SDA abnormalities occurred to a significant degree only in 6 of 20 designated malformation categories (vertebral, rib, pelvic, lower limb, central nervous system [CNS], renal) in contrast to 17 in VATER and 18 in sirenomelia patients. The SDA vertebral malformation pattern also differed from that of VATER/sirenomelia patients as did the high sacrococcygeal agenesis:dysgenesis ratio and low thoracolumbar vertebrae and/or rib hypersegmentations. Most significantly, SDA patients had a large number of CNS anomalies and CNS-related dysfunctions of the urinary and distal intestinal tracts but no anatomic urinary or intestinal tract malformations. This contrasted sharply with the markedly increased occurrences of anatomic abnormalities in these body regions of the sirenomelia and VATER patients. Demographic data such as patient survival, twinning and, particularly, the high (28%) incidence of maternal diabetes in the SDA further support its differentiation from VATER/sirenomelia patients.

The assessment of fetal growth is crucial in twin gestations, since the information gained often has an impact on pregnancy management. The measurement of the fetal anatomy by ultrasound enables us to follow the growth and development of the fetus. However, the pattern of fetal growth in twin gestations has not yet been precisely characterized in prospective studies. In this light, we initiated a prospective longitudinal study and sonographically examined 35 patients with twin gestations every 3 weeks from the 15th week until delivery. Multiple biometric parameters were measured, including the femur length, humerus length, ulna length, and tibia length. The results of our study showed that growth of these long bones was not significantly different between twins A and B throughout gestation and that the growth velocity between twins and singletons was not significantly different. The incremental growth, although significantly less in twins than in singletons, was so small that it was judged not to be of clinical importance to warrant the generation of separate nomograms for the evaluation of growth in twin gestations.

We describe for the first time the successful organ culture, in a serum-free chemically defined medium, of hind limb buds from stage 54/55 Xenopus laevis tadpoles in which 2 x 10(-9) M triiodothyronine (T3) precociously induces morphogenesis to give rise to morphologically normal limbs within 7 days. It was important to retain the mesenchymal tissue joining the two limb buds in order to obtain limb development in culture. T3 added to tail explants from the same larvae, cultured in parallel with limb buds, induced regression and cell loss at rates comparable to those seen during T3-induced metamorphosis in intact tadpoles. We also demonstrate for the first time that 0.2 units of prolactin (PRL) added at the same time as 2 x 10(-9) M T3 totally blocked both limb development and tail regression over 8 days in culture. When added after T3 had initiated its metamorphic action. PRL arrested further morphogenesis and regression of these two tissues, respectively. Retinoic acid at 10(-7) M had only a marginal effect. Histological examination showed that T3 added to limb buds produced normal chondrogenesis and osteogenesis in vitro as well as skin, muscle, and digit formation, while it produced a rapid and marked histolysis of fin and connective tissue of the tail. The ease of hormonally manipulating both morphogenesis and cell death in culture in opposite directions offers a simple, effective model system for molecular analysis of mechanisms underlying hormone-regulated postembryonic developmental processes.

The authors provide a comprehensive review of the nature, origins, and natural history of torsion of the lower extremity. Norms for children and adults are discussed, along with implications for treatment.

Expression of the muscle-specific integral membrane protein H36 and the intermediate filament protein desmin, detected by immunofluorescence, was used to identify cells at distinct stages in the skeletal myogenic lineage. These proteins were coordinately expressed in cultures of rat hindlimb myoblasts from 17- and 19-day fetuses and newborn pups, and in satellite cells from juveniles. Both H36+ and desmin+ cells were present in cultures from 13.5- and 15-day embryonic hindlimbs, but desmin expression was more prevalent: H36-/desmin+ myoblasts predominate during this early stage of development. H36 was not detected in Day 12 embryo hindlimb bud cells in vivo nor in cultures soon after plating. Initially, only 1% of the Day 12 limb bud cells expressed desmin. When these cells were serially passaged every 3-4 days, cells with all three possible myogenic phenotypes developed: that is, H36+/desmin-, H36+/desmin+, and H36-/desmin+ cells. There was a progressive increase in the frequency of H36+ cells, with 75% of cells positive by passage 6 (Day 27 in vitro). The maximum frequency of cells that expressed desmin occurred in passage 5 (Day 23 in vitro). These results demonstrate that precursors to the cells that express H36 and desmin are present in the 12-day embryo hindlimb bud and that the transition from H36-/desmin- precursors to cells with a myogenic phenotype can occur in vitro. MyoD1 and myogenin were not detected in these cells, suggesting that the initial expression of H36 and desmin in the myogenic lineage may precede and/or is independent of these regulatory proteins. The conversion of precursor cells in the 12-day limb bud to a more advanced stage of development serves to define additional cells in the myogenic lineage. The ability to monitor in vitro these stages of development affords the opportunity to study how they are regulated.

A number of seemingly unrelated congenital deformities of the lower limb have been presented which include clubfoot, fibular deficiency, tibial aplasia, and diplopodia. Although the bony morphology in these limbs is quite different, they all share a strikingly similar arterial pattern, that being deficiency or absence of the anterior tibial artery, and of its derivative, the dorsal pedis artery. Since all of these diverse conditions share a similar aberrant arterial pattern, we suspect that the arterial changes are important in the pathogenesis of those conditions. Study of the soft tissue anatomy of these specimens suggests that the etiologic teratogenic event occurred early in embryonic development. In those limbs that contain the remnant of a missing structure, it is concluded that injury occurred after the mesenchyme was instructed to form that structure. These are termed "post-specification" defects. In those circumstances where limb duplication occurs, the injury affected the signal before instruction of mesenchyme to develop into a specific structure was completed and these abnormalities are termed "pre-specification" malformations. The musculotendenous and neurologic abnormalities seem to be reactive to the pre-existing bony pattern.