Limb Malformations Research Articles

A novel surgical correction using a combination of wave-like incision and Z-axis Z-plasty for congenital constriction band syndrome

BackgroundA congenital constriction band (CCB) is a relatively common anomaly among limb malformations. However, the number of cases treated at a given center is limited and differences in techniques used by surgeons at each facility have a significant impact on the treatment outcomes. Several surgical methods have been reported, but a standard technique that yields consistent satisfactory results is still needed. Here, we introduce a novel technique for the treatment of CCB syndrome that uses a combination of wave-like skin incision and Z-axis Z-plasty. Patients and methodsA wave-like incision was used for skin incision with the goals of achieving an accordion effect and a less noticeable post-operative scar. After the fibrous constriction band was completely excised, a Z-plasty of sufficient size in the Z-axis direction was performed on the dermis-inclusive adipose tissue. For over 10 years, this technique was applied to 11 sites in 6 patients. A retrospective study of the characteristics of these cases was performed, including age at surgery, gender, type of deformity, degree of constriction, types of examination, number of surgeries, and post-operative outcomes. ResultsIn all patients, a normal contour of the limbs was achieved and the hourglass-like deformity caused by the constriction band was satisfactorily improved. No additional corrective surgeries were needed, there was no abnormal growth of the treated limbs, and scarring was aesthetically acceptable in all cases. ConclusionThe novel technique described here uses deep subcutaneous fat to correct the hourglass-like deformity and restores a normal limb contour, while the wave-like skin incision minimizes post-operative scarring.

3D printed orthopedic prostheses for domestic and wild birds—case reports

Regardless of the species, birds are exposed to injuries that lead to amputation of part of the body structure and often euthanasia. Based on the need for new technologies that improve the quality of life of birds with locomotor problems, the present case reports aimed to describe the development of custom-made three-dimensional (3D) prostheses for domestic and wild birds that suffered amputation or malformation of the hind limb. Using the measurements of the bird, a digital model was created for 3D printing using fused deposition modeling technology (FDM) by the Brazilian company 3D Medicine. In this study we report the use of 3D prosthesis for the rehabilitation of three birds with locomotor disorders in Brazil, the animals adapted to the custom-made prosthesis with an improvement in quality of life, better distribution of body weight, locomotion, and landing. This study describes the development of 3D prostheses for birds in Brazil, the first report of this technology for these species, and the pioneering development of socket prostheses for small birds. 3D prostheses offer a high-efficiency solution to improve the quality of life of animals with amputations and malformations of the hind limbs. In addition, 3D technology provides valuable tools for veterinary medicine, developing custom-made models for the most different anatomical demands of animal patients.

The pathogenic mechanism of syndactyly type V identified in a Hoxd13Q50R knock-in mice

Syndactyly type V (SDTY5) is an autosomal dominant extremity malformation characterized by fusion of the fourth and fifth metacarpals. In the previous publication, we first identified a heterozygous missense mutation Q50R in homeobox domain (HD) of HOXD13 in a large Chinese family with SDTY5. In order to substantiate the pathogenicity of the variant and elucidate the underlying pathogenic mechanism causing limb malformation, transcription-activator-like effector nucleases (TALEN) was employed to generate a Hoxd13Q50R mutant mouse. The mutant mice exhibited obvious limb malformations including slight brachydactyly and partial syndactyly between digits 2–4 in the heterozygotes, and severe syndactyly, brachydactyly and polydactyly in homozygotes. Focusing on BMP2 and SHH/GREM1/AER-FGF epithelial mesenchymal (e-m) feedback, a crucial signal pathway for limb development, we found the ectopically expressed Shh, Grem1 and Fgf8 and down-regulated Bmp2 in the embryonic limb bud at E10.5 to E12.5. A transcriptome sequencing analysis was conducted on limb buds (LBs) at E11.5, revealing 31 genes that exhibited notable disparities in mRNA level between the Hoxd13Q50R homozygotes and the wild-type. These genes are known to be involved in various processes such as limb development, cell proliferation, migration, and apoptosis. Our findings indicate that the ectopic expression of Shh and Fgf8, in conjunction with the down-regulation of Bmp2, results in a failure of patterning along both the anterior-posterior and proximal-distal axes, as well as a decrease in interdigital programmed cell death (PCD). This cascade ultimately leads to the development of syndactyly and brachydactyly in heterozygous mice, and severe limb malformations in homozygous mice. These findings suggest that abnormal expression of SHH, FGF8, and BMP2 induced by HOXD13Q50R may be responsible for the manifestation of human SDTY5.

Gait Analysis of Amputee Dogs Using a Pressure-Sensitive Walkway.

The aim of this study was to perform gait analysis using a pressure-sensitive walkway in dogs submitted to high (total) or low amputation (partial) of one forelimb or hindlimb. A total of 39 dogs met the inclusion criteria. The reasons for the amputations were motor vehicle accidents in 38 dogs and possible limb malformation in 1 dog. The amputee dogs were divided into four groups: G1 (n = 10)-high forelimb; G2 (n = 10)-low forelimb; G3 (n = 9)-high hindlimb; and G4 (n = 10)-low hindlimb. For kinetic evaluation, the dogs were walked across a pressure-sensitive walkway. In dogs with forelimb amputation, the percentage of body weight (%BW) distribution on the contralateral forelimb was 50.7% in cases of high amputation and 55.5% in cases of low amputation, while the %BW distribution on the hindlimbs, mainly in the ipsilateral hindlimb, was 27.9% in cases of high amputation and 27.1% in cases of low amputation. In cases of high amputation of the hindlimb, the %BW distribution was 71.5% on the forelimbs and 29.7% on the contralateral hindlimb, while in cases of low amputation, the distribution was mainly for the contralateral hindlimb and ipsilateral forelimb. No statistical difference was noted between the amputation levels, except for the contralateral limb in cases of low and high amputation of the hindlimbs concerning the overload percentage and %BW distribution. The amputation level of one forelimb did not influence the %BW distribution; however, in the hindlimb, this was higher for the contralateral limb in dogs submitted to high amputation.

Transcriptomic analysis reveals mitochondrial dysfunction in the pathogenesis of Nager syndrome in sf3b4-depleted zebrafish

Nager syndrome (NS) is a rare acrofacial dysostosis caused by heterozygous loss-of-function variants in the splicing factor 3B subunit 4 (SF3B4). The main clinical features of patients with NS are characterized by facial-mandibular and preaxial limb malformations. The migration and specification of neural crest cells are crucial for craniofacial development, and mitochondrial fitness appears to play a role in such processes. Here, by analyzing our previously published transcriptome dataset, we aim to investigate the potential involvement of mitochondrial components in the pathogenesis of craniofacial malformations, especially in sf3b4 mutant zebrafish. We identified that oxidative phosphorylation (OXPHOS) defects and overproduction of reactive oxygen species (ROS) due to decreased antioxidants defense activity, which leads to oxidative damage and mitochondrial dysfunction. Furthermore, our results highlight that fish lacking sf3b4 gene, primarily display defects in mitochondrial complex I. Altogether, our findings suggest that mitochondrial dysfunction may contribute to the development of the craniofacial anomalies observed in sf3b4-depleted zebrafish.

Cycasin derivative: a potential embryotoxic component of Atractylodes macrocephala rhizome for limb malformation.

The rhizome of Atractylodes macrocephala Koidz. (Asteraceae), called Atractylodes macrocephala rhizome (AMR) and known by its traditional name Bai Zhu, is a prominent Chinese herbal medicine employed for preventing miscarriage. However, our previous study revealed that high dosages of AMR administered during pregnancy could cause embryotoxicity but the specific embryotoxic components and their underlying mechanisms remain unclear. This study aimed to screen and identify the potential embryotoxic components of AMR. The AMR extracts and sub-fractions were analyzed by thin layer chromatography and subsequently screened by in vitro mouse limb bud micromass and mouse whole embryo culture bioassays. The embryotoxic fractions from AMR were further evaluated in vivo using a pregnant mouse model. The structures of the potential embryotoxic components were analyzed using matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry (MALDI-TOF/TOF-MS). In vitro and in vivo bioassays revealed that AMR glycoside-enriched sub-fractions (AMR-A-IIa and AMR-A-IIb) exhibited potential embryotoxicity. These sub-fractions, when administered to pregnant animals, increased the incidence of stillbirth and congenital limb malformations. MS spectrometry analysis identified cycasin derivatives in both sub-fractions, suggesting their possible role in the observed limb malformations. However, further experiments are necessary to validate this hypothesis and to elucidate the underlying mechanisms. Our study provides significant scientific evidence on the pharmacotoxicity of AMR, which is important for the safe clinical application of commonly used Chinese herbal medicines during pregnancy.

Echographic Screening for Fetal Malformations at the Gynecological and Obstetric Clinic of the Aristide Le Dantec Hospital: Review from 2016 to 2018

Introduction: Congenital malformations affect around 3% to 4% of live births and 20% of stillbirths. They represent 20 to 30% of the causes of infant mortality in the countries of the European Community. It is estimated that 5 to 10% of malformations are due to exogenous or environmental causes and 12 to 30% to genetic or endogenous causes (gene mutations or chromosomal anomalies). In almost 60% of cases, the actual origin of the malformation remains unknown. Nevertheless, the origin of these anomalies is still being researched, and numerous diagnostic tools are available to practitioners to improve antenatal screening and pregnancy monitoring. However, obstetric ultrasound remains the primary tool for antenatal screening and monitoring of congenital malformations. Methodology: Our main objective was to evaluate the practice of ultrasound screening for foetal malformations at the Gynaecology and Obstetrics Clinic at Hopital Aristide Le Dantec from 1 February 2016 to 31 December 2018. We conducted a retrospective study of ultrasound screening for foetal malformations. Results: At the end of our study, 869 obstetric ultrasounds met our inclusion criteria. We had 837 singleton pregnancies (96.3%), 31 twin pregnancies (3.6%) and 1 trimellar pregnancy (0.1%). We noted 35 cases of foetal malformations, an incidence of 4.02%. All cases of malformations were diagnosed in singleton pregnancies. The average age of the patients was 29 years, with extremes of 18 and 45 years. Primiparous women were the most represented in our study (62.5%). The majority of patients were from Dakar. A history of recurrent miscarriage was found in 7 patients (20%) and there was one case of fetal death in utero during the previous pregnancy. There was no family history of malformations. Consanguinity was found in 11 cases (31.4%). Only 2 patients were found to have taken medication, one for insulin and the other for an unspecified drug. There was no evidence of toxic intake. Fetal malformations were observed in the 3rd trimester in 23 cases (42.9%). There were 11 cases in the 2nd trimester (31.4%) and only 1 case in the 1st trimester. Cranioencephalic malformations were detected in almost half of the cases (42.8%), i.e. 15 cases. There were 8 cases of polymalformative syndromes, i.e. 22.8%. Digestive malformations were represented in 3 cases, i.e. 8.6%, as were cardiac malformations in 3 cases. Pulmonary malformations and limb malformations accounted for 5.7% and 2 cases each. Renal malformations and orofacial malformations also accounted for 1 case each, 2.9% respectively. Among the 15 cases of malformations of the nervous system, ventricular dilatation ranked first with 10 cases representing 66.6%, followed by anencephaly and cystic hygroma with 2 cases each representing 13.3% and finally dolichocephaly with 1 case representing 6.7%. We found 8 different cases of polymalformative syndromes. These syndromes were labelled in 2 cases and unlabelled in the 6 others. There was 1 case of trisomy 21 and 1 case of trisomy 13. The other cases of polymalformative syndromes were not clearly labelled. A combination of cerebral, $cardiac and/or renal malformations were reported. Digestive malformations were noted in 3 cases (8.6%), including 2 dilatations of the coves (megacolon) and 1 case of omphalocele. Pericarditis, atrial septal defect and transposition of the great vessels were the cardiac malformations found in a total of 3 cases (8.6%). Two cases of achondroplasia were found in our series (5.7%). They were all associated with oligohydramnios. There were 2 cases of pulmonary hypoplasia (5.7%). These were associated with anamnios and a medullary syndrome in one of the cases. Cleft lip and palate and polycystic kidney disease were present in one case each (2.9%). The pregnancy resulted in vaginal delivery in 21 cases (60%), caesarean section in 13 cases (37.1%) and in 1 case the mode of delivery was not specified. The main indication for Caesarean section was hydrocephalus (61.5%). The anomaly and the type of malformation were announced in 85.5% of cases. A referral for fetal ultrasound was suggested in 5.7% of patients and fetal MRI in 2.9%. Concordance between antenatal and postnatal diagnosis was achieved in 18 cases (51.4%). The pregnancy resulted in vaginal delivery in 21 cases (60%), caesarean section in 13 cases (37.1%) and in 1 case the mode of delivery was not specified. The main indication for Caesarean section was hydrocephalus (61.5%). The anomaly and the type of malformation were announced in 85.5% of cases. A referral for fetal ultrasound was suggested in 5.7% of patients and fetal MRI in 2.9%. Concordance between antenatal and postnatal diagnosis was achieved in 18 cases (51.4%). Neonatal mortality accounted for 62.9% of the series, with 22 cases. Conclusion: Fetal malformations were detected with a concordance of 51.4% between antenatal and postnatal diagnosis. Neonatal mortality was high. A major preoccupation should be the strengthening of cytogenetic diagnosis and management resources, and raising awareness of the origins of congenital malformations.

Multi-segment osteotomy with interlocking intramedullary nail fixation in the treatment of lower limb deformity in older children with hypophosphatemic rickets.

Malformations of the lower limbs caused by hypophosphatemic rickets in older children are mostly complex, occurring on multiple planes without a single apex and showing arcuate bending of the diaphysis combined with torsion deformity, and are difficult to correct. This study retrospectively investigated the effect of and indicators for multi-segment osteotomy with interlocking intramedullary nail fixation in the treatment of bony deformity caused by hypophosphatemic rickets. The clinical data of 21 hypophosphatemic rickets patients seen between August 2007 and March 2022 were collected. The age range of the patients at the first surgery was 11 years and 1 month old to 15 years and 3 months old, with an average age of 12 years and 8 months. There were 6 males and 15 females. All patients had abnormal alignment of their lower limbs, with 32 limbs having varus deformity and 10 limbs having valgus deformity. A total of 67 surgeries were performed across the 21 patients, including 24 cases of femoral osteotomy with antegrade intramedullary nail fixation, 6 cases of femoral osteotomy with retrograde intramedullary nail fixation, and 20 cases of tibial osteotomy with interlocking intramedullary nail fixation. A total of 34 limbs eventually underwent interlocking intramedullary nail fixation, 9 with genu valgum and 25 with genu varus. All 21 patients were followed up for a period of 14∼96 months, with an average of 42.6 months. The ends of the osteotomies achieved bony union in 4-9 months (average 6.8 months), after which normal weight-bearing walking could be resumed. No infection, vascular or neurological complications, or nonunion occurred. During postoperative follow-up, the alignment the lower limbs passed through zone 1 in 13 limbs, zone 2 in 12 limbs, and zone 3 in 5 limbs. The overall rate of an excellent effect was 83.3%. For lower limb deformity caused by hypophosphatemic rickets in older children, multi-segment osteotomy and strong fixation with interlocking intramedullary nails can achieve good correction outcomes.

Review of malformed frogs

This study reviewed the survey of malformed frogs and the probable causes of their deformities. It analysed the checklist and pattern of malformations in frogs and examined different malformations in frogs of selected articles. It also reviewed the causes of malformation in frogs of different articles. The reviewed showed that limb malformations with 22.41% was the most recorded malformations in frogs with pattern of publications revealed that there was varying trend in article publication which peaked in 2000 and 2023. Different malformations in frogs are abnormal skin, albinism, extra hindlimb, eye malformation. Others are lack of palms, appendages and appendicular, limb malformation, ectrodactyly, brachydactyly and ectrodactyly. The causes of malformations in frogs reviewed includes mutation, parasites, heavy metals, environmental stressors and ultraviolet light. The study concluded that human factors or anthropogenic activities played an important role in malformations in frogs reviewed.

Molecular signatures of angiogenesis inhibitors: a single-embryo untargeted metabolomics approach in zebrafish.

Angiogenesis is a key process in embryonic development, a disruption of this process can lead to severe developmental defects, such as limb malformations. The identification of molecular perturbations representative of antiangiogenesis in zebrafish embryo (ZFE) may guide the assessment of developmental toxicity from an endpoint- to a mechanism-based approach, thereby improving the extrapolation of findings to humans. Thus, the aim of the study was to discover molecular changes characteristic of antiangiogenesis and developmental toxicity. We exposed ZFEs to two antiangiogenic drugs (SU4312, sorafenib) and two developmental toxicants (methotrexate, rotenone) with putative antiangiogenic action. Molecular changes were measured by performing untargeted metabolomics in single embryos. The metabolome response was accompanied by the occurrence of morphological alterations. Two distinct metabolic effect patterns were observed. The first pattern comprised common effects of two specific angiogenesis inhibitors and the known teratogen methotrexate, strongly suggesting a shared mode of action of antiangiogenesis and developmental toxicity. The second pattern involved joint effects of methotrexate and rotenone, likely related to disturbances in energy metabolism. The metabolites of the first pattern, such as phosphatidylserines, pterines, retinol, or coenzyme Q precursors, represented potential links to antiangiogenesis and related developmental toxicity. The metabolic effect pattern can contribute to biomarker identification for a mechanism-based toxicological testing.

Sirenomelia: An anatomical assessment and genetic sex determination of two cases.

The etiology of sirenomelia is currently unknown. Data are limited in comparing external and internal abnormalities using modern imaging technologies and molecular genetic analysis. The purpose of the current study was designed to compare external and internal anatomical defects in two cases of sirenomelia and Potter's sequence. Considered rare, Potter's sequence is a fetal disorder with characteristic features of bilateral renal agenesis, obstructive uropathy, atypical facial appearance, and limb malformations. The internal and external malformations of two term fetuses with sirenomelia and Potter's sequence were compared using assessment of external features, radiography and MRI on internal structures, and molecular genetic studies on sex determination. Data reveal that both fetuses were male and manifested with an overlapping but distinct spectrum of abnormalities. Principal differences were noted in the development of the ears, brain, urogenital system, lower limbs, pelvis, and vertebral column. Defects of the axial mesoderm are likely to underlie the abnormalities seen in both fetuses. The first one, which had only caudal defects, was found to have a spectrum of abnormalities most similar to those associated with more severe forms of the small pelvic outlet syndrome, although the structure and orientation of the sacrum and iliae were different from previously reported cases. The other had both caudal and cranial defects, and was most similar to those described in the axial mesodermal dysplasia syndrome. Defects associated with sirenomelia can be evaluated with standard gross anatomy examination, radiology, MRI, and modified PCR techniques to determine anatomical abnormalities and the sex of preserved specimens, respectively. Evidence indicated that sirenomelia could be developed via various etiologies.

First Trimester Use of Buprenorphine or Methadone and the Risk of Congenital Malformations

Use of buprenorphine or methadone to treat opioid use disorder is recommended in pregnancy; however, their teratogenic potential is largely unknown. To compare the risk of congenital malformations following in utero exposure to buprenorphine vs methadone. This population-based cohort study used health care utilization data from publicly insured Medicaid beneficiaries in the US from 2000 to 2018. A total of 13 360 pregnancies with enrollment from 90 days prior to pregnancy start through 1 month after delivery and first trimester use of buprenorphine or methadone were included and linked to infants. Data were analyzed from July to December 2022. A pharmacy dispensing of buprenorphine or a code for administration of methadone in the first trimester. Primary outcomes included major malformations overall and malformations previously associated with opioids (any cardiac malformations, ventricular septal defect, secundum atrial septal defect/nonprematurity-related patent foramen ovale, neural tube defects, clubfoot, and oral clefts). Secondary outcomes included other organ system-specific malformations. Risk differences and risk ratios (RRs) were estimated comparing buprenorphine with methadone, adjusting for confounders with propensity score overlap weights. The cohort included 9514 pregnancies with first-trimester buprenorphine exposure (mean [SD] maternal age, 28.4 [4.6] years) and 3846 with methadone exposure (mean [SD] maternal age, 28.8 [4.7] years). The risk of malformations overall was 50.9 (95% CI, 46.5-55.3) per 1000 pregnancies for buprenorphine and 60.6 (95% CI, 53.0-68.1) per 1000 pregnancies for methadone. After confounding adjustment, buprenorphine was associated with a lower risk of malformations compared with methadone (RR, 0.82; 95% CI, 0.69-0.97). Risk was lower with buprenorphine for cardiac malformations (RR, 0.63; 95% CI, 0.47-0.85), including both ventricular septal defect (RR, 0.62; 95% CI, 0.39-0.98) and secundum atrial septal defect/nonprematurity-related patent foramen ovale (RR, 0.54; 95% CI, 0.30-0.97), oral clefts (RR, 0.65; 95% CI, 0.35-1.19), and clubfoot (RR, 0.55; 95% CI, 0.32-0.94). Results for neural tube defects were uncertain given low event counts. In secondary analyses, buprenorphine was associated with a decreased risk of central nervous system, urinary, and limb malformations but a greater risk of gastrointestinal malformations compared with methadone. These findings were consistent in sensitivity and bias analyses. In this cohort study, the risk of most malformations previously associated with opioid exposure was lower in buprenorphine-exposed infants compared with methadone-exposed infants, independent of measured confounders. Malformation risk is one factor that informs the individualized patient decision regarding medications for opioid use disorder in pregnancy.

STIGMA: Single-cell tissue-specific gene prioritization using machine learning

Clinical exome and genome sequencing have revolutionized the understanding of human disease genetics. Yet many genes remain functionally uncharacterized, complicating the establishment of causal disease links for genetic variants. While several scoring methods have been devised to prioritize these candidate genes, these methods fall short of capturing the expression heterogeneity across cell subpopulations within tissues. Here, we introduce single-cell tissue-specific gene prioritization using machine learning (STIGMA), an approach that leverages single-cell RNA-seq (scRNA-seq) data to prioritize candidate genes associated with rare congenital diseases. STIGMA prioritizes genes by learning the temporal dynamics of gene expression across cell types during healthy organogenesis. To assess the efficacy of our framework, we applied STIGMA to mouse limb and human fetal heart scRNA-seq datasets. In a cohort of individuals with congenital limb malformation, STIGMA prioritized 469 variants in 345 genes, with UBA2 as a notable example. For congenital heart defects, we detected 34 genes harboring nonsynonymous de novo variants (nsDNVs) in two or more individuals from a set of 7,958 individuals, including the ortholog of Prdm1, which is associated with hypoplastic left ventricle and hypoplastic aortic arch. Overall, our findings demonstrate that STIGMA effectively prioritizes tissue-specific candidate genes by utilizing single-cell transcriptome data. The ability to capture the heterogeneity of gene expression across cell populations makes STIGMA a powerful tool for the discovery of disease-associated genes and facilitates the identification of causal variants underlying human genetic disorders.

Prevalence of Congenital Anomalies of the Upper Limbs in Brazil: a descriptive cross-sectional study.

Congenital Anomalies of the Upper Limb (CAUL) are a group of structural or functional abnormalities that develop during intrauterine life and can lead to limb dysfunction. To analyze the prevalence of congenital anomalies of the upper limbs in Brazil and assess maternal and neonatal variables. A cross-sectional, descriptive study was conducted on congenital upper limb malformations among live births across Brazil. The study spanned from 2010 to 2019. Data were sourced from the Department of Informatics of the Unified Health System (DATASUS) and the Live Birth Information System (SINASC) portal. Analyses focused on the information reported in field 41 of the Live Birth Declaration Form entered into the computerized system. The most common anomaly in Brazil was supernumerary fingers, classified as ICD-Q69.0, affecting 11,708 children, with a prevalence of 4.02 per 10,000 live births. Mothers aged over 40 years had a 36% higher prevalence of having children with CAUL than mothers under 40 years old (OR = 1.36; 95% CI 1.19-1.56). Newborns weighing ≥ 2,499 g were 2.64 times more likely to have CAUL compared to those weighing ≥ 2,500 g (OR = 2.64; 95% CI 2.55-2.73). There was an observed increase in the reporting of CAUL cases over the decade studied. This trend serves as an alert for health agencies, as understanding the prevalence of CAUL and its associated factors is crucial for preventive medicine.

A Cornelia De Lange Syndrome Patient with Cleft Palate: A Case Report with Intraoral and Extraoral Findings

Objective: This case report presents the clinical and genetic findings in a one-week-old male patient with Cornelia de Lange Syndrome (CdLS) and unilateral cleft palate with a review of literature which includes case reports with cleft lip and palate. 
 Case Presentation: The patient exhibited characteristic facial dysmorphism, including a low-set hairline, long and bushy unibrow, inclined nose with anteverted nostrils, long philtrum, thin lips, and micrognathia. Upper limb malformations, genitourinary anomalies, and hirsutism were also present. The patient underwent comprehensive follow-up for five months, during which an alginate impression was taken to aid intraoral feeding, and a plaster model was prepared for the construction of an obturator, an essential component of the cleft palate management plan. The treatment plan involved multidisciplinary collaboration, including pre-surgical orthodontic preparation, evaluation of dental anomalies, surgical intervention with an oral and maxillofacial surgeon, post-operative care, and monitoring. Post-surgical orthodontic treatment and speech therapy were planned for later stages, followed by fine-tuning and a retention plan for long-term stability.
 Conclusion: CdLS is a complex genetic disorder characterized by various physical abnormalities. This case report demonstrated the management of a one-week-old male patient with CdLS and unilateral cleft palate through a comprehensive multidisciplinary approach. Early intervention, personalized treatment plans, and long-term follow-up are crucial for addressing dental and maxillofacial complications associated with cleft palate in CdLS patients. Collaborative efforts among specialists yield optimal outcomes, improving the quality of life for individuals with CdLS and cleft palate.
 Keywords: cornelia de lange, cleft palate, cleft lip

Review of Teratogenic Effects of Leflunomide, Accutane, Thalidomide, Warfarin, Tetracycline, and Angiotensin-Converting Enzyme Inhibitors.

Teratogenic agents have been shown to have drastic and detrimental effects on fetuses if exposed to the agent during uterine life. The most sensitive time for a developing fetus is during the first trimester, and teratogenic exposure during this time can lead to severe deformities in the fetus. The Food and Drug Administration has categorized teratogenic agents based on the severity of their effecton the fetus; these categories include A, B, C, D, and X. Category A is the safest, with the most dangerous, and highly contraindicated in pregnant patients being Category X. This review article will discuss the teratogenic agents leflunomide, isotretinoin, thalidomide, warfarin, tetracycline, and angiotensinogen-converting enzyme inhibitors. Leflunomide can cause cranioschisis, exencephaly, and vertebral, head, and limb malformations. Isotretinoin's main teratogenic effects include central nervous system malformations, hydrocephalus, eye abnormalities, cardiac septal defects, thymus abnormalities, spontaneous abortions, and external ear abnormalities. Thalidomide has been shown to cause limb deformities, bowel atresia, and heart defects when the embryo is exposed to the agent during development.Warfarin can lead to spontaneous abortion and intrauterine death, as well as nasal hypoplasia, hypoplasia of extremities, cardiac defects, scoliosis, and mental retardation when exposed in utero. Tetracycline's teratogenic effects include gastrointestinal distress, esophageal ulceration and strictures, teeth discoloration, hepatotoxicity, and calcifications. Angiotensinogen-converting enzyme inhibitors can cause skull hyperplasia, anuria, hypotension, renal failure, lung hypoplasia, skeletal deformation, oligohydramnios, and fetal death. Teratogenic effects can be avoided if the pregnant patient is educated on the teratogenic effects of these agents.

Perinatal Prognosis of Pregnancies with Single Umbilical Artery in a Romanian Third-Level Unit.

Objectives: Single umbilical artery (SUA) is considered the most common abnormality of the umbilical artery. The objective of the study was to evaluate the perinatal prognosis of fetuses with SUA and to describe the associated malformations. The significance of the study is represented by examining whether our findings are in correlation with data already described.Methods: We performed a prospective cohort study on singleton pregnancies complicated with SUA. The study population was composed of women with singleton pregnancies who were examined at the Department of Obstetrics and Gynecology of the Târgu Mures County Emergency Clinical Hospital between 2012 and 2021.Results: The incidence of SUA in the study population was 0.48%. C-section was performed in 40 cases with SUA and in 5258 cases with no SUA (RR:1.56, P<0.05.) From the total number of 2249 premature deliveries, 23 newborns were diagnosed with SUA (RR:2.12, P<0.05.) From the total number of 869 deliveries with low birth weight (LBW) newborns, 13 were associated with SUA (RR: 3.12, P<0.05.) There were 206 pregnancies noted with antenatal fetal demise after 24 weeks of gestation, and only 2 of them were with SUA (RR:2.01, P>0.05.) Fetal and neonatal malformations were described in 290 cases, and 28 were associated with SUA (R:21.96, P<0.05.) In 57 of 85 cases (67.05%), we found iSUA, and 28 newborns (32.95%) had minor, major, or other associated pathologies. We found two cases of trisomy 18 and one case with trisomy 13 associated with SUA. Investigating the malformations associated with SUA, the most common were cardiac and great vessels malformations (12), followed by limb malformations (8), urogenital malformations (7), digestive tract malformations (7), central nervous system malformations (4), and in one case we found cleft palate.Conclusions: Perinatal prognosis regarding SUA is significantly poorer than in cases without this pathology. One-third of fetuses with SUA were associated with fetal anomalies. The most common pathologies associated with SUA were cardiovascular, limb, urogenital, and digestive system malformations. Our data are similar to those described in other studies; therefore, we conclude, we can implement the general recommendations in our region regarding counselling patients.

Early detection and risk factors of congenital hip dislocation in Morocco.

Congenital dislocation of the hip is a malformation of the lower limbs that could be complicated by a disabling physical handicap with long-term psychological and social repercussions if detected late. This study aims to describe the screening for congenital hip dislocation and to investigate the association between the occurrence of this anomaly and possible risk factors in Morocco. The study was based on the exploitation of the records of children treated at the trauma and orthopedics department of the Mohammed VI University Hospital in Marrakech, Morocco. It concerned 160 cases with a 5-year follow-up from January 2016 to March 2021. The results of the study showed that 56.7% of the affected children had a bilateral dislocation and 25.8% of the cases had a left-sided dislocation. The malformation occurred more frequently in females 69.2%. A familial disposition to the malformation was found in about 22% of the cases. The diagnosis was late (at walking age) in 61% of children following the onset of lameness with or without pain in 91% of children. In 41.87% of the hips, the reduction was surgical, with 28% failure dominated by acetabular dysplasia in 11%. The risk factors for congenital hip dislocation identified in our setting were dominated by sex, primiparity, consanguineous marriage, and the presence of a family history of dislocation. Communication of risk factors specific to our setting to healthcare personnel will allow them to guide the diagnosis and increase vigilance in the at-risk population for management that prevents the development of complications.

Rare Occasion of Congenital Anomalies: Bilateral Syndactyly with Multiple Polydactyly of the Hands and Feet

Introduction: Upper and lower limb malformations are essential things that occur related to congenital disabilities, including syndactyly and polydactyly. It may appear in association with other birth defects as a part of a syndrome and may be present in the upper extremity or lower extremity. Cases of bilateral syndactyly with multiple polydactyly of the hands and feet are the first time in our center, and they must be promptly diagnosed and treated to avoid functional and cosmetic problems. Case presentation: A 3-month-old male toddler presented with webbed index, middle, and ring fingers with synonichia, accompanied by additional fingers on hands and feet. An x-ray examination revealed preaxial polydactyly at both hands with bifid phalanx (Wassel classification) and postaxial polydactyly type B. Duplicated postaxial metatarsal (Venn-Watson classification) and type B postaxial polydactyly also occur on both feet with webbed index and middle toe on the left foot. Direct closure was achieved with a dorsal trapezoidal and zig-zag flap to release the second and third fingers of the right hand, followed by resection of rudimentary fingers to help the child with early stages of motoric functions. Discussion: Syndactyly can cause a length difference that results in growth and functional difficulties. Surgical release of the index to middle and middle to ring fingers should be done early between 3-6 months of age and is expected to help the child grasp, write, and subsequently manipulate objects. We prioritize operating the right hand as around 90% of people prefer to use the right hand. Simple ligation was also performed to recess the rudimentary fingers on both hands and feet. It has no functional benefit and can limit function as it may get caught or make it difficult to wear shoes and gloves. We have to remind the parents that multiple surgeries may be necessary to achieve a satisfactory result and to complete the reconstruction before 24 months of age when the patterns of function of the digits are established. Conclusion: Bilateral complex syndactyly with preaxial and postaxial polydactyly on both hands and feet are distinctly uncommon entities that need multidisciplinary treatment. In this instance, the syndactyly releasing of the second and third fingers on the right hand is prioritized based on the function to be achieved, with excision of the rudimentary fingers.

Molecular characterization of 13 patients with PIK3CA-related overgrowth spectrum using a targeted deep sequencing approach.

Activating variants in the PIK3CA gene cause a heterogeneous spectrum of disorders that involve congenital or early-onset segmental/focal overgrowth, now referred to as PIK3CA-related overgrowth spectrum (PROS). Historically, the clinical diagnoses of patients with PROS included a range of distinct syndromes, including CLOVES syndrome, dysplastic megalencephaly, hemimegalencephaly, focal cortical dysplasia, Klippel-Trenaunay syndrome, CLAPO syndrome, fibroadipose hyperplasia or overgrowth, hemihyperplasia multiple lipomatosis, and megalencephaly capillary malformation-polymicrogyria (MCAP) syndrome. MCAP is a sporadic overgrowth disorder that exhibits core features of progressive megalencephaly, vascular malformations, distal limb malformations, cortical brain malformations, and connective tissue dysplasia. In 2012, our research group contributed to the identification of predominantly mosaic, gain-of-function variants in PIK3CA as an underlying genetic cause of the syndrome. Mosaic variants are technically more difficult to detect and require implementation of more sensitive sequencing technologies and less stringent variant calling algorithms. In this study, we demonstrated the utility of deep sequencing using the Illumina TruSight Oncology 500 (TSO500) sequencing panel in identifying variants with low allele fractions in a series of patients with PROS and suspected mosaicism: pathogenic, mosaic PIK3CA variants were identified in all 13 individuals, including 6 positive controls. This study highlights the importance of screening for low-level mosaic variants in PROS patients. The use of targeted panels with deep sequencing in clinical genetic testing laboratories would improve diagnostic yield and accuracy within this patient population.