Congenital Limb Defects Research Articles

Isolated Macrodactyly

A 5-year-old boy was brought to the outpatient department by his parents with complaints of the enlarged index finger of the left hand since birth. According to the mother, at birth, the index finger of the left hand was larger and longer than the other fingers of the same hand. The index finger grew out of proportion since then. The parents gave no history of congenital anomalies, limb defects, overgrowth syndromes, or similar complaints in any of their family members.

In ovo hyperglycemia causes congenital limb defects in chicken embryos via disruption of cell proliferation and apoptosis

While the correlation between diabetes during pregnancy and birth defects is well-established, how hyperglycemia causes developmental abnormalities remains unclear. In this study, we developed a novel “hyperglycemic” chicken embryonic model by administrating various doses of glucose to fertilized eggs at embryonic stages HH16 or HH24. When the embryos were collected at HH35, the LD50 was 1.57 g/Kg under HH16 treatment and 0.93 g/Kg under HH24 treatment, indicating that “hyperglycemic” environments can be lethal for the embryos. When exposed to a dose equal to or higher than 1 g/Kg glucose at HH16 or HH24, more than 40% of the surviving chicken embryos displayed heart defects and/or limb defects. The limb defects were associated with proliferation defects of both the wing and leg buds indicated by reduced numbers of p-H3S10 labeled cells. These limb defects were also associated with ectopic apoptosis in the leg bud and expression changes of key apoptotic genes. Furthermore, glucose treatment induced decreased expression of genes involved in Shh-signaling, chondrogenesis, and digit patterning in the limb bud. In summary, our data demonstrated that a high-glucose environment induces congenital heart and limb defects associated with disrupted cell proliferation and apoptosis, possibly through depressed Shh-signaling.

Prevalence of congenital limb defects in Uttarakhand state in India – A hospital-based retrospective cross-sectional study

BackgroundCongenital limb defects (CLD) occur when normal development of limbs is hampered during the intrauterine period. There is a paucity of literature regarding the prevalence and pattern of various congenital limb defects in India. The aim of this study is to assess the prevalence and pattern of various CLD using Swanson classification in the state of Uttarakhand, India. MethodsRetrospective study over a 6-year period was done. The prevalence of CLD was calculated by determining the live births from birth rate and total population from the 2011 census of the Government of India. ResultsA total of 316 cases with a mean age of 3.2 ± 2.3 years (1 day–12 years) were included. Radial clubhand (n = 9, prevalence = 0.4 per 10,000 live births) was the most common CLD in upper limb. Idiopathic clubfoot (CTEV) (n = 158, prevalence = 7 per 10,000 live births) was the most common CLD in lower limb. Failure of formation (n = 12) was the most common defect in the lower limb whereas failure of differentiation (n = 16) was common in the upper limb. DiscussionThis is the first study from any part of India depicting the prevalence of CLD, which can be used to formulate public health policies for early diagnosis and management of the same. ConclusionThe prevalence of CLD is 14 per 10,000 live births in Uttarakhand, India, which are comparable to various studies published from different parts of the world. Males are commonly involved with radial clubhand being common in the upper limb and CTEV being common in the lower limb.

Fetal outcomes after maternal exposure to oral antifungal agents during pregnancy: A systematic review and meta-analysis.

ObjectiveTo assess the risk of adverse fetal outcomes after exposure to oral antifungal agents during pregnancy.Search strategyPubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched up to October 2018.Selection criteriaCohort studies and case–control studies investigating fetal outcomes following maternal exposure to oral antifungal agents.Data collection and analysisTwo reviewers independently assessed studies for inclusion, assessed risk of bias, and extracted data. Pooled estimates were calculated for the frequency of adverse fetal outcomes.Main resultsOverall, eight cohort studies and one case–control study were included. The oral antifungal agents used during pregnancy were fluconazole and itraconazole. The data indicated that oral fluconazole exposure during pregnancy might slightly increase the risk of congenital heart defects and limb defects relative to the general population; oral itraconazole during pregnancy might increase the risk of eye defects. No difference was found between oral fluconazole/itraconazole exposure and non‐exposure in the risk of other birth defects, spontaneous abortion, or stillbirth.ConclusionOral fluconazole or itraconazole may not increase the risk of birth defects. Nonetheless, the risk of congenital heart defects and limb defects after fluconazole exposure and eye defects after itraconazole exposure should be cautiously investigated.

Remote-controlled internal lengthening plate for distraction osteogenesis in pediatric patients

ABSTRACTObjectives: Limb lengthening by distraction osteogenesis is a technique widely used to treat limb length discrepancy resulting from trauma, congenital limb defects and long bone non-union. For decades, patients have resorted to the Ilizarov apparatus, prone to pin tract infections and scarring. Although implantable lengthening nails have reduced the incidence of complications, they are not applicable in pediatric patients with open growth plates. The aim of this project is to design a remote-controlled internal lengthening device suitable for implantation in children.Methods: The proposed device has the form of an internal remote-controlled telescopic lengthening plate, screwed to the lateral side of the bone with locking screws. This is appropriate for use with pediatric patients. It has been tested on an experimental bench which has the form of a vertically sliding platform, on which were stacked weights simulating soft-tissue resistance forces.Results: This internal lengthening plate generated distraction forces of up to 735 N on wooden and synthetic bones (SawbonesTM). Furthermore, it maintained a constant distraction speed over the course of the procedure for a given weight.Conclusions: This device represents a major advancement in the field of pediatric limb-lengthening, addressing a demographic gap left open by current implantable devices.

Hospital Care and Surgical Treatment of Children With Congenital Upper Limb Defects.

To evaluate hospital care of children with congenital upper limb defects. Three hundred and sixty-two children with an upper limb defect, born 1993-2005, and alive after birth admission were identified in the Finnish Register of Congenital Malformations. The data on hospital care, with focus on operative treatment, were collected from the National Hospital Discharge Register, until 31 December 2009. Mean follow-up was 10.2 years (range: 4-17 years). The results were compared with data on the whole children population (1.1 million) in Finland. Most children (321, 87%) with upper limb defects had hospital admissions: on average, one admission/year (range: 0-36), and they were treated in hospital 5 days/year (range: 0-150), which is 11-fold compared with an average child in Finland. Four surgical procedures/child were done (range: 0-45), including one hand surgical procedure. The most common procedures were orthopedic (513); gastrointestinal (263); ear, nose, and throat (143); dental (118); thoracic (48); and urologic (44). Of the 513 orthopedic procedures, 326 were directed to upper limbs, 107 to the lower limbs, and 10 to the spine. Median operation age was 2 years 7 months. Altogether, 60% of hospital admissions were non-surgical. Leading causes of non-operative hospital admissions were congenital anomalies (32%), gastroenterological problems (20%), respiratory tract conditions (13%), neurological problems (7%), perinatal conditions (5%), and infectious diseases (5%). Treatment of children with upper limb defects is teamwork between pediatric and surgical subspecialties. Burden of hospital care is 11-fold as compared with an average child.

FATCO syndrome: a case of prenatal diagnosis in the second trimester of pregnancy

A case of prenatal ultrasound diagnosis of congenital limb defect with combined features fibular aplasia, tibial campomelia, and oligosyndactyly (FATCO syndrome) at 20+4 weeks of gestation is presented. Diagnosis was completely verified macroscopically and with X-ray investigation after termination of the pregnancy at 21+4 weeks of gestation.

Rehabilitation of femoral fibular amelia: A case report

Congenital limb defects are fetal anomalies with birth. Amelia is extremely rare birth defect marked by the complete absence of or more limbs. Congenital limb defects are rare fetal anomalies with a birth prevalence of 0.55 per 1,000. Amelia is an extremely rare birth defect marked by the complete absence of one or more limbs. We report a case of fetal amelia, ultrasound findings, manifestations and the fetal outcome. We report a case of a femoral fibular amelia x-ray findings and the other outcomes.

Prevalence and Patterns of Congenital Limb Defects in the North of Iran (2007-2011)

Background: Congenital limb defects (CLDs) are the leading cause of disability across the world.CLDsvary depending on the anatomical location, type, and cause of anomaly. The present study aimed to evaluate the prevalence and patterns of CLDs in the North of Iran. Methods: This descriptive-analytical, hospital-based study was conducted in three hospitals in Gorgan, the capital of Golestan Province in the north of Iran. Samples included 32,895 newborns with CLDs, and stillborn neonates were excluded from the study. Data analysis was performed in SPSS version 16 using Chi-square at the significance level of ≤0.05. Results: Overall prevalence ofCLDs was three cases per 1,000 live births, and the rate was estimated at 3.17 and 2.82 cases per 1,000 live births in male and female infants, respectively. In addition, the prevalence of upper- and lower-limb anomalies was 1.03 and 1.91 cases per 1,000 live births, respectively. In terms ofethnicity, the prevalence of CLDs among the native Fars, Turkmen, and Sistani populations was 3.86, 2.02, and 3.85 cases per 1,000 live births, respectively. Clubfoot was the most common type of CLDs, and the most prevalent type of the associated malformationswas gastrointestinal anomalies. Conclusion: According to the results, the prevalence of CLDs in the north of Iran was similar to European countries (2.11-3.18 cases per 1,000 live births), while it was lower compared to the other regions in Iran (5.8 cases per 1,000 live births).

Clinical profile of congenital limb anomalies in neonates

Background: Reported birth prevalence of congenital limb defects vary from country to country. Epidemiological studies permit the timely detection of trends in congenital limb anomalies and the associations with other birth defects. The objective of this study was to know the prevalence and the variety of congenital limb anomalies and their association with other anomalies.Methods: A prospective observational study in which all newborns reported to the neonatal department were surveyed to find out the incidence, diversity and association of limb anomalies. Age of the mother, risk factors and other demographic data of the newborns was analyzed. Babies born less than 28 weeks were excluded from the study.Results: The prevalence was 6.34 per thousand live births. The majority of the neonates were term babies and female. 28 % of the babies were born out of consanguineous marriage. The mean age of the mother was 25. Median parity was 1. 9.52 % of the babies had a history of anomaly in the sibling. 4.76 % had a history of still birth. The most common congenital anomaly was congenital talipo equino varus. The other congenital limb anomalies observed were polydactyly, syndactyly, bifid thumb and absence of the radius. There were multiple congenital anomalies in 28.57 % of the babies.Conclusions: The study has given us an insight into the variety of congenital limb malformations and also into the possible etiological factors. A study done on a larger population would probably help us assess the incidence and pattern of occurrence of limb anomalies and help us counsel the parents.

Regulatory integration of Hox factor activity with T-box factors in limb development.

In tetrapods, Tbx4, Tbx5 and Hox cluster genes are crucial for forelimb and hindlimb development and mutations in these genes are responsible for congenital limb defects. The molecular basis of their integrated mechanisms of action in the context of limb development remains poorly understood. We studied Tbx4 and Hoxc10 owing to their overlapping loss-of-function phenotypes and colocalized expression in mouse hindlimb buds. We report an extensive overlap between Tbx4 and Hoxc10 genome occupancy and their putative target genes. Tbx4 and Hoxc10 interact directly with each other, have the ability to bind to a previously unrecognized T-box-Hox composite DNA motif and show synergistic activity when acting on reporter genes. Pitx1, the master regulator for hindlimb specification, also shows extensive genomic colocalization with Tbx4 and Hoxc10. Genome occupancy by Tbx4 in hindlimb buds is similar to Tbx5 occupancy in forelimbs. By contrast, another Hox factor, Hoxd13, also interacts with Tbx4/Tbx5 but antagonizes Tbx4/Tbx5-dependent transcriptional activity. Collectively, the modulation of Tbx-dependent activity by Hox factors acting on common DNA targets may integrate different developmental processes for the balanced formation of proportionate limbs.

Mutations in HODX13 and ZRS/LMBR1 Genes and Chromosomal Abnormalities Cause Congenital Limb Defects

Mutations in HODX13 and ZRS/LMBR1 Genes and Chromosomal Abnormalities Cause Congenital Limb Defects

Sonic Hedgehog Signaling in Limb Development.

The gene encoding the secreted protein Sonic hedgehog (Shh) is expressed in the polarizing region (or zone of polarizing activity), a small group of mesenchyme cells at the posterior margin of the vertebrate limb bud. Detailed analyses have revealed that Shh has the properties of the long sought after polarizing region morphogen that specifies positional values across the antero-posterior axis (e.g., thumb to little finger axis) of the limb. Shh has also been shown to control the width of the limb bud by stimulating mesenchyme cell proliferation and by regulating the antero-posterior length of the apical ectodermal ridge, the signaling region required for limb bud outgrowth and the laying down of structures along the proximo-distal axis (e.g., shoulder to digits axis) of the limb. It has been shown that Shh signaling can specify antero-posterior positional values in limb buds in both a concentration- (paracrine) and time-dependent (autocrine) fashion. Currently there are several models for how Shh specifies positional values over time in the limb buds of chick and mouse embryos and how this is integrated with growth. Extensive work has elucidated downstream transcriptional targets of Shh signaling. Nevertheless, it remains unclear how antero-posterior positional values are encoded and then interpreted to give the particular structure appropriate to that position, for example, the type of digit. A distant cis-regulatory enhancer controls limb-bud-specific expression of Shh and the discovery of increasing numbers of interacting transcription factors indicate complex spatiotemporal regulation. Altered Shh signaling is implicated in clinical conditions with congenital limb defects and in the evolution of the morphological diversity of vertebrate limbs.

Adams-Olıver syndrome: A case report

Background: Adams-Oliver Syndrome has been described by Adams and Oliver in 1945. Original definition, along with aplasia cutis congenital syndrome and limb defects, has neurological and cardiological problems. In the first description, genetic defect passes variable autosomal dominant pattern. Afterwards the autosomal recessive and sporadic cases were published. Case Report: 11-year old male patient complained of mobile teeth admitted to our clinic. He was noted to have characteristic view with distal-phalanx and nail hypoplasia of his hand and feet with occipital scalp defect. We consulted to genetics because of these findings and learned that he has the Adams-Oliver Syndrome. The patient has some orofacial manifestations including high-narrow palate, fissured tongue, crowding, dysmorphic facial features, facial asymmetry, deep-philtrum, delayed eruption, class III malocclusion. The extraction of mobile deciduous teeth, restoration of caries and also oral hygiene motivation was made. Then, the patient was referred to orthodontics. Conclusions: Adams-Oliver syndrome represents are rare congenital alteration, insufficiently documented in scientific literature. This shows the need to document news cases.

Prevalence of congenital limb defects: Data from birth defects registries in three provinces in Southern Thailand.

This is the first population-based study in Thailand on the prevalence of congenital limb defects (CLD). Data were obtained from recently established birth defects registries in three southern Thailand provinces during 2009-2013. Entries in the birth defects registries included live births, stillbirths after 24 weeks gestational age, and terminations of pregnancy following a prenatal diagnosis of fetal anomaly. The total of 186 393 births recorded included 424 CLD cases, giving an average prevalence of 2.27 per 1000 births (95% CI, 2.05-2.49). The most common CLD was talipes equinovarus (44.1%), followed by polydactyly (13.9%) and syndactyly (9.4%). The prevalence significantly increased with maternal age from 1.81 in mothers aged <30 years to 2.75 in mothers 30 to < 35 years, and to 2.94 in mothers ≥35 years (P = 0.004). Overall 9.4% of the CLDs were syndromic CLD, again with significantly greater percentages in pregnant women aged ≥35 years than the non-syndromic CLD (32.5% vs 17.5% respectively, P = 0.03). In conclusion, the overall prevalence of CLD in the 3 southern Thailand provinces examined was 2.27 per 1000 births, and syndromic CLD was significantly higher in pregnant women aged ≥35 years than younger pregnant women.

Prenatal exposure to environmental factors and congenital limb defects.

Limb congenital defects afflict approximately 0.6:1000 live births. In addition to genetic factors, prenatal exposure to drugs and environmental toxicants, represents a major contributing factor to limb defects. Examples of well-recognized limb teratogenic agents include thalidomide, warfarin, valproic acid, misoprostol, and phenytoin. While the mechanism by which these agents cause dymorphogenesis is increasingly clear, prediction of the limb teratogenicity of many thousands of as yet uncharacterized environmental factors (pollutants) remains inexact. This is limited by the insufficiencies of currently available models. Specifically, in vivo approaches using guideline animal models have inherently deficient predictive power due to genomic and anatomic differences that complicate mechanistic comparisons. On the other hand, in vitro two-dimensional (2D) cell cultures, while accessible for cellular and molecular experimentation, do not reflect the three-dimensional (3D) morphogenetic events in vivo nor systemic influences. More robust and accessible models based on human cells that accurately replicate specific processes of embryonic limb development are needed to enhance limb teratogenesis prediction and to permit mechanistic analysis of the adverse outcome pathways. Recent advances in elucidating mechanisms of normal development will aid in the development of process-specific 3D cell cultures within specialized bioreactors to support multicellular microtissues or organoid constructs that will lead to increased understanding of cell functions, cell-to-cell signaling, pathway networks, and mechanisms of toxicity. The promise is prompting researchers to look to such 3D microphysiological systems to help sort out complex and often subtle interactions relevant to developmental malformations that would not be evident by standard 2D cell culture testing. Birth Defects Research (Part C) 108:243-273, 2016. © 2016 Wiley Periodicals, Inc.

Polydactyly: A Review.

Polydactyly, also known as hyperdactyly, is a common congenital limb defect, which can present with various morphologic phenotypes. Apart from cosmetic and functional impairments, it can be the first indication of an underlying syndrome in the newborn. Usually, it follows an autosomal dominant pattern of inheritance with defects occurring in the anteroposterior patterning of limb development. Although many mutations have been discovered, teratogens have also been implicated in leading to this anomaly, thus making it of multifactorial origin. There are three polydactyly subtypes (radial, ulnar, and central), and treatment options depend on the underlying feature.

Frequency of hospitalization in patients diagnosed with congenital talipes equinovarus (CTEV)

Abstract Introduction. Congenital talipes equinovarus (CTEV), also called clubfoot is the second after congenital dysplasia of the hip (CDH) most frequently occurring congenital limb defect. In Europe the deformity affects 1-2 newborns in 1000 live births. Aim. The aim of the study was to determine frequency of the deformity among other reasons for hospitalization, as well as depicting the profile of patients treated for clubfoot. Material and methods. Study method was the analysis of medical documentation from two Orthopaedic Wards of Prof. Antoni Gębala Children’s Hospital of Lublin. Medical records of patients treated for congenital talipes equinovarus (IDC 10-Q66.0) between 2008 and 2013 were the study material. Results. Results of the study show that in the analyzed period of time 310 children were hospitalized for clubfoot in hospotal. 39.35% (n=122) of the total number of patients were girls and 60.65% (n=188) were boys. The average age of patients was 3.69 years, (Me=1.09 years). Average age of girls was 4.17 (Me=1.35 years) and boys 3.89 (Me=0.83 years). The most numerous group consisted of infants up to 1 year (n=154; 49.68%). Conclusions. Clubfoot affects boys twice as often as girls. Moreover, in the examined hospital the average length of stay for patients with clubfoot has decreased. The research reveals that the average hospitalization length in children with congenital talipes equinovarus is systematically decreasing. The study shows that the number of patients being admitted to the Children’s Orthopedics Institute of the Hospital is increasing while the number of patients with clubfoot remains on the same level.

Prevalence and pattern of congenital limb defects in north of Iran

Prevalence and pattern of congenital limb defects in north of Iran

Epidemiological study of congenital limb defects in individuals or families from the interior Sindh region of Pakistan

Background: Congenital limb defects (CLDs) are a significant cause of morbidity and depending upon the severity, result in varying degrees of disability. Data on CLDs is scarce for South Asian populations. Objective: To obtain insight into the spectrum of CLDs in the population of the interior Sindh region Pakistan. Methods: A cross-sectional study was conducted in seven districts of interior Sindh and individuals or families were recruited from various hospitals and through door-to-door surveys. Results: We recruited 165 independent individuals or families with certain type of CLDs during 2010–2013. The CLDs were categorized into 10 broad categories, and the five major types witnessed were: polydactyly, syndactyly, reduction deformities, musculoskeletal defects, and brachydactyly. CLDs depicted great phenotypic variability, but collectively, upper limbs were more commonly involved than lower limbs, right arms more than the left, left legs more than the right, and distal limb segments more than proximal segments. The pattern of malformations was not different between Muslims and Hindus. Conclusions: These data established detailed distributions of CLDs across the vital sociodemographic attributes of the studied population, and are helpful in quantifying the impact of CLDs on the study population. Future molecular analyses of this cohort are anticipated to improve the clinical classifications and would also be of tremendous help to the affected individuals or families in risk estimation and genetic counseling.