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Life (Basel, Switzerland) Sep 2023Syndactyly is the most common congenital malformation of the hand, leading to the fusion of the digits and frequently affecting the ring and middle fingers. The...
Syndactyly is the most common congenital malformation of the hand, leading to the fusion of the digits and frequently affecting the ring and middle fingers. The incidence is 1 out of 2500 children, predominantly occurring in boys and Caucasians. Clinically, the malformation may present as a soft tissue or bony fusion, resulting in the union of the fingers characterised as complete or incomplete. This fusion may involve the phalanges but may also extend to the carpal/tarsal bones, even to the metacarpal or metatarsal level, rarely to the distal end of the forearm and lower leg. The malformation is mostly isolated but may occur together with other disorders or malformations such as synostosis, acro-syndactyly, cleft hand, clinodactyly, or polydactyly. Syndromic syndactyly can be observed in cases of Apert syndrome, Poland's syndrome, Pfeiffer syndrome, and many others. A girl born in June of 2019 was diagnosed with congenital malformation of the right hand at birth-affecting the right middle, ring, and little fingers, respectively. After X-ray imaging, the fusion of the third and fourth proximal phalanges to a common metacarpal was identified, forming a unique diagnosis of clino-syndactyly with metacarpal aplasia. Surgical intervention was advocated for, including a wedge osteotomy to correct the synchondrosis at the phalangeal base and a dorsal flap to close the interdigital space created during the correction of the III and IV. fingers. A trapezoid flap for the release of the syndactyly of the IV and V. fingers was applied. The paper aims to present this surgical correction and its results regarding an atypical case of syndactyly with clinodactyly and metacarpal aplasia.
PubMed: 37763346
DOI: 10.3390/life13091943 -
Molecular Genetics & Genomic Medicine Oct 2023Intronic variants outside the canonical splice site are challenging to interpret and therefore likely represent an underreported cause of human disease. Autosomal...
BACKGROUND
Intronic variants outside the canonical splice site are challenging to interpret and therefore likely represent an underreported cause of human disease. Autosomal recessive variants in DYNC2H1 are associated with short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3), a clinically heterogeneous disease generally presenting with short ribs, shortened tubular bones, narrow thorax and acetabular roof anomalies. We describe a case of SRTD3 with compound heterozygous frameshift and intronic variants and highlight the essential role of RNA sequencing (RNA-Seq) in variant interpretation.
METHODS
Following inconclusive clinical genetic testing identifying a likely pathogenic frameshift variant and an intronic variant of uncertain significance (VUS) in DYNC2H1 in trans, the family enrolled in the Care4Rare Canada research program, where RNA-Seq studies were performed.
RESULTS
The proband presented with post-axial polydactyly of all four limbs, a significantly small chest with a pectus excavatum and anterior flaring of the ribs. RNA-Seq investigations revealed a novel splice junction as a result of the intronic VUS and significantly decreased DYNC2H1 gene expression in the proband.
CONCLUSION
This case demonstrates the diagnostic utility of RNA-Seq for variant interpretation following inconclusive clinical testing, which can ultimately lead to diagnosis for patients with rare disease.
PubMed: 37489014
DOI: 10.1002/mgg3.2247 -
Animals : An Open Access Journal From... Mar 2024The Taihu Dianzi pigeon is a breed native to China, and its special piebalding, crest, and polydactyly phenotypes are the result of artificial and natural selection....
The Taihu Dianzi pigeon is a breed native to China, and its special piebalding, crest, and polydactyly phenotypes are the result of artificial and natural selection. Here, we analyzed the genetic differences among three kinds of pigeons with different phenotypes at the genomic level. A selective sweep was conducted based on the fixation index () and nucleotide diversity () ratio, and the results revealed that was related to the formation of the distinctive piebalding of the Taihu Dianzi pigeon. Combined with the results of genome-wide association studies, we identified candidate genes associated with the crest ( and ) and polydactyly ( and ). The candidate genes identified in this study and their variants may be useful for understanding the genetic mechanism underlying the special phenotypes of the Taihu Dianzi pigeon. This study provides new insights into the genetic factors that may influence the formation of the special piebalding, crest, and polydactyly characteristics in pigeons.
PubMed: 38612286
DOI: 10.3390/ani14071047 -
The Journal of Foot and Ankle Surgery :... 2024Little is known about functional outcomes in children with treated lower extremity polydactyly (LEP). No classification system has been shown to be prognostically useful...
Little is known about functional outcomes in children with treated lower extremity polydactyly (LEP). No classification system has been shown to be prognostically useful for functional outcomes. This study investigates whether children with treated LEP learn to walk at an age comparable to the population and whether the SAM (severity of syndactyly, axis deviation and metatarsal involvement) classification system is prognostically useful. In a retrospective cohort of 18 patients, we tested for associations between patient characteristics and SAM scores, age at learning to walk, and ability to fit off-the-shelf shoes. The proportion of children with treated LEP able to walk at 18 months of age was compared with the general population. We found no association between the age at which the 17 participants learned to walk and the severity of syndactyly (p = .214), axis deviation (p = .723) and metatarsal involvement (p = .781), nor between the proportion of patients able to wear off-the-shelf shoes compared to those requiring extra wide off-the-shelf shoes and the severity of syndactyly (p = 1.000), axis deviation (p = 1.000) and metatarsal involvement (p = 1.000). We found a trend between older age at surgery and the need for extra wide off-the-shelf shoes (OR = 1.008, p = .080). We found no significant difference in the proportion of children able to walk at 18 months between our patients (proportion = 1.00) and the general population (proportion = 0.95) (p = 1.000). We found no significant association between different SAM scores and functional outcomes, and none in the proportion of children able to walk at 18 months between treated LEP patients and the general population.
Topics: Child; Humans; Toes; Retrospective Studies; Foot; Polydactyly; Syndactyly
PubMed: 37951458
DOI: 10.1053/j.jfas.2023.11.004 -
Acta Medica Okayama Dec 2023A patient was born with a mass at the base of the thumb approximately 1.5 cm in diameter on the radial side of the fingers. The mass had globular swelling filled with...
A patient was born with a mass at the base of the thumb approximately 1.5 cm in diameter on the radial side of the fingers. The mass had globular swelling filled with hemorrhagic fluid and was dark red. X-rays and histology of the excised specimen suggested the diagnosis of gangrene and torsion of polydactyly. Prenatal torsion of polydactyly is not a common occurrence; moreover, prenatal torsion of polydactyly has only been found in ulnar polydactyly. Our case is a novel case of radial polydactyly that was gangrenous at birth owing to prenatal torsion. Diagnosing such a mass at the base of the thumb is important.
Topics: Infant, Newborn; Humans; Thumb; Gangrene; Polydactyly; Fingers
PubMed: 38145940
DOI: 10.18926/AMO/66158 -
Arthritis Research & Therapy Mar 2024CRISPR-Cas9-based genome engineering represents a powerful therapeutic tool for cartilage tissue engineering and for understanding molecular pathways driving cartilage...
BACKGROUND
CRISPR-Cas9-based genome engineering represents a powerful therapeutic tool for cartilage tissue engineering and for understanding molecular pathways driving cartilage diseases. However, primary chondrocytes are difficult to transfect and rapidly dedifferentiate during monolayer (2D) cell culture, making the lengthy expansion of a single-cell-derived edited clonal population not feasible. For this reason, functional genetics studies focused on cartilage and rheumatic diseases have long been carried out in cellular models that poorly recapitulate the native molecular properties of human cartilaginous tissue (e.g., cell lines, induced pluripotent stem cells). Here, we set out to develop a non-viral CRISPR-Cas9, bulk-gene editing method suitable for chondrocyte populations from different cartilaginous sources.
METHODS
We screened electroporation and lipid nanoparticles for ribonucleoprotein (RNP) delivery in primary polydactyly chondrocytes, and optimized RNP reagents assembly. We knocked out RELA (also known as p65), a subunit of the nuclear factor kappa B (NF-κB), in polydactyly chondrocytes and further characterized knockout (KO) cells with RT-qPCR and Western Blot. We tested RELA KO in chondrocytes from diverse cartilaginous sources and characterized their phenotype with RT-qPCR. We examined the chondrogenic potential of wild-type (WT) and KO cell pellets in presence and absence of interleukin-1β (IL-1β).
RESULTS
We established electroporation as the optimal transfection technique for chondrocytes enhancing transfection and editing efficiency, while preserving high cell viability. We knocked out RELA with an unprecedented efficiency of ~90%, confirming lower inflammatory pathways activation upon IL-1β stimulation compared to unedited cells. Our protocol could be easily transferred to primary human chondrocytes harvested from osteoarthritis (OA) patients, human FE002 chondroprogenitor cells, bovine chondrocytes, and a human chondrocyte cell line, achieving comparable mean RELA KO editing levels using the same protocol. All KO pellets from primary human chondrocytes retained chondrogenic ability equivalent to WT cells, and additionally displayed enhanced matrix retention under inflamed conditions.
CONCLUSIONS
We showcased the applicability of our bulk gene editing method to develop effective autologous and allogeneic off-the-shelf gene therapies strategies and to enable functional genetics studies in human chondrocytes to unravel molecular mechanisms of cartilage diseases.
Topics: Humans; Animals; Cattle; Chondrocytes; Gene Editing; CRISPR-Cas Systems; Interleukin-1beta; Cartilage Diseases; Polydactyly
PubMed: 38468277
DOI: 10.1186/s13075-024-03294-w -
Bone Research Apr 2024Syndactyly type V (SDTY5) is an autosomal dominant extremity malformation characterized by fusion of the fourth and fifth metacarpals. In the previous publication, we...
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.
Topics: Mice; Humans; Animals; Brachydactyly; Hedgehog Proteins; Transcription Factors; Syndactyly; Limb Deformities, Congenital
PubMed: 38561387
DOI: 10.1038/s41413-024-00322-y -
Journal of Indian Association of... 2023Bardet-Biedl syndrome is an autosomal-recessive ciliopathic disorder affecting multiple organ systems. Characteristic features include progressive retinal dystrophy,...
Bardet-Biedl syndrome is an autosomal-recessive ciliopathic disorder affecting multiple organ systems. Characteristic features include progressive retinal dystrophy, obesity, polydactyly hypogonadism, mental retardation, and renal disorders. Other manifestations include congenital heart diseases, hepatic fibrosis, ataxia, and diabetes. Approximately 30% of patients with Biedl-Bardet syndrome (BBS) have hepatobiliary disorders such as periportal fibrosis, nonalcoholic fatty liver disease, and cystic dilation of the bile ducts. The association of BBS with choledochal cysts (CDC) is extremely rare. Here, we report a case of a 14-year-old boy with a novel variant of BBS and associated type IV CDC. The patient was managed surgically with CDC excision and Roux-en-Y hepaticojejunostomy.
PubMed: 38173646
DOI: 10.4103/jiaps.jiaps_124_23 -
International Journal of Molecular... Apr 2024Canine osteosarcoma (OSA) is an aggressive bone neoplasia with high metastatic potential. Metastasis is the main cause of death associated with OSA, and there is no...
Canine osteosarcoma (OSA) is an aggressive bone neoplasia with high metastatic potential. Metastasis is the main cause of death associated with OSA, and there is no current treatment available for metastatic disease. Proteomic analyses, including matrix-assisted laser desorption/ionisation-time of flight mass spectrometry (MALDI TOF/TOF MS), are widely used to select molecular targets and identify proteins that may play a key role in primary tumours and at various steps of the metastatic cascade. The main aim of this study was to identify proteins differently expressed in canine OSA cell lines with different malignancy phenotypes (OSCA-8 and OSCA-32) compared to canine osteoblasts (CnOb). The intermediate aim of the study was to compare canine OSA cell migration capacity and assess its correlation with the malignancy phenotypes of each cell line. Using MALDI-TOF/TOF MS analyses, we identified eight proteins that were significantly differentially expressed ( ≤ 0.05) in canine OSA cell lines compared to CnOb: cilia- and flagella-associated protein 298 (CFAP298), general transcription factor II-I (GTF2I), mirror-image polydactyly gene 1 protein (MIPOL1), alpha-2 macroglobulin (A2M), phosphoglycerate mutase 1 (PGAM1), ubiquitin (UB2L6), ectodysplasin-A receptor-associated adapter protein (EDARADD), and leucine-rich-repeat-containing protein 72 (LRRC72). Using the Simple Western technique, we confirmed high A2M expression in CnOb compared to OSCA-8 and OSCA-32 cell lines (with intermediate and low A2M expression, respectively). Then, we confirmed the role of A2M in cancer cell migration by demonstrating significantly inhibited OSA cell migration by treatment with A2M (both at 10 and 30 mM concentrations after 12 and 24 h) in a wound-healing assay. This study may be the first report indicating A2M's role in OSA cell metastasis; however, further in vitro and in vivo studies are needed to confirm its possible role as an anti-metastatic agent in this malignancy.
Topics: Animals; Dogs; Proteomics; Transcription Factors; Cell Movement; Leucine-Rich Repeat Proteins; Macroglobulins; Osteosarcoma
PubMed: 38612805
DOI: 10.3390/ijms25073989 -
Frontiers in Pediatrics 2023Birth defects (BDs) are associated with many potential risk factors, and its causes are complex.
BACKGROUND
Birth defects (BDs) are associated with many potential risk factors, and its causes are complex.
OBJECTIVES
This study aimed to explore the epidemiological characteristics of BDs in Guangxi of China and the associated risk factors of BDs.
METHODS
BDs data of perinatal infants (PIs) were obtained from the Guangxi birth defects monitoring network between 2016 and 2020. Univariate Poisson regression was used to calculate the prevalence-rate ratios (PRR) to explore the changing trends of BDs prevalence by year and the correlation between the regarding of characteristics of BDs (including infant gender, maternal age, and quarter) and BDs. Clinical characteristics of PIs with BDs and general characteristics of their mothers were documented, and Spearman correlation analysis was used to explore the potential associated risk factors of BDs.
RESULTS
Between 2016 and 2020, 44,146 PIs with BDs were monitored, with an overall BDs prevalence of 121.71 (95% CI: 120.58-122.84) per 10,000 PIs, showing a significant increase trend (PRR = 1.116, 95% CI: 1.108-1.123), especially the prevalence of congenital heart defects (CHDs) that most significantly increased (PRR = 1.300, 95% CI: 1.283-1.318). The 10 most common BDs were CHDs, polydactyly, congenital talipes equinovarus, other malformation of external ear, syndactyly, hypospadias, cleft lip with cleft palate, cleft lip, hemoglobin Bart's hydrops fetalis syndrome (BHFS), and congenital atresia of the rectum and anus. BDs were positively correlated with pregnant women's age ( = 0.732, < 0.01) and education level ( = 0.586, < 0.05) and having pre-gestational diabetes mellitus (PGDM)/gestational diabetes mellitus (GDM) ( = 0.711, < 0.01), while when the pregnant women had a family history of a dead fetus ( = -0.536, < 0.05) and a birth of a fetus with BDs ( = -0.528, < 0.05) were negatively correlated with BDs.
CONCLUSION
A significant increase in the prevalence of BDs was detected between 2016 and 2020 in Guangxi, especially the prevalence of CHDs that most significantly increased. Older maternal age, higher maternal education level, and having PGDM before pregnancy or GDM in early pregnancy were the risk factors for BDs.
PubMed: 37547102
DOI: 10.3389/fped.2023.1165477