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Plastic and Reconstructive Surgery.... Apr 2024Postaxial polydactyly is a common congenital foot anomaly. However, the severity of the anomaly varies from simple cases with only soft tissue duplication to complex...
BACKGROUND
Postaxial polydactyly is a common congenital foot anomaly. However, the severity of the anomaly varies from simple cases with only soft tissue duplication to complex cases with bone and joint disorders. In our clinical practice, we found a new morphological anomaly of postaxial polydactyly. We encountered several cases of postaxial polydactyly with bone fragments located between the fourth and fifth toes. The bone fragments were independent of the joint cavity. The mechanisms underlying its development remain unknown because it is a novel disorder. In the present study, we investigated the characteristics of the excess bone to formulate an embryological hypothesis.
METHODS
We examined the frequency and trends in the occurrence of excess bone using data from photographs and radiographs of these cases. An example of a disorder similar to excess bone is mosaic-like alignment, as reported by Iba et al. We also compared the characteristics of the mosaic-like alignment with those of the excess bone. Based on these data and existing embryological knowledge, we hypothesized the origin of the excess bone.
RESULTS
Excess bone and mosaic-like alignments showed different characteristics. Therefore, both were considered completely different disorders. We hypothesized that excess bone was caused by damage to the interdigital ectoderm immediately before interdigital programmed cell death.
CONCLUSIONS
We encountered a new form of postaxial polydactyly. This can be a factor influencing the treatment strategy because it can affect alignment and stability.
PubMed: 38596575
DOI: 10.1097/GOX.0000000000005717 -
Heliyon Apr 2024gene mutations can result in various forms of polysyndactyly, such as Greig cephalopolysyndactyly syndrome (GCPS, MIM: #175700), Pallister-Hall syndrome (PHS, MIM:...
BACKGROUND
gene mutations can result in various forms of polysyndactyly, such as Greig cephalopolysyndactyly syndrome (GCPS, MIM: #175700), Pallister-Hall syndrome (PHS, MIM: #146510), and isolated polydactyly (IPD, MIM: #174200, #174700). Reports on IPD-associated mutations are rare. In this study, a novel mutation was identified in a Chinese family with IPD.
RESULTS
We report a family with six members affected by IPD. The family members demonstrated several special phenotypes, including sex differences, abnormal finger joint development, and different polydactyly types. We identified a novel frameshift variant in the gene (NM_000168.6: c.1820_1821del, NP_000159.3: p.Tyr607Cysfs*9) by whole-exome sequencing. Further analysis suggested that this mutation was the cause of polydactyly in this family.
CONCLUSIONS
The discovery of this novel frameshift variant in our study further solidifies the relationship between IPD and and expands the previously established spectrum of mutations and associated phenotypes.
PubMed: 38571622
DOI: 10.1016/j.heliyon.2024.e28638 -
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 -
International Medical Case Reports... 2024Jeune syndrome, or asphyxiating thoracic dystrophy (JATD), is a rare autosomal recessive skeletal dysplasia with heterogeneous genetic and clinical phenotypes, which...
Jeune syndrome, or asphyxiating thoracic dystrophy (JATD), is a rare autosomal recessive skeletal dysplasia with heterogeneous genetic and clinical phenotypes, which primarily affects cartilage and bone development. Herein, we report a patient with a lethal form of SRTD3 without polydactyly (JATD), which led to severe restrictive lung disease and fatal respiratory failure. A full-term boy was born to a 30-year-old mother who was known to have hypothyroidism and was on thyroxine. The parents were first-degree cousins and had one healthy older son. Fetal ultrasound showed a cephalic fetus, normal amniotic fluid and a fundal placenta. All long bones and ribs were below the 1% percentile. The femur was bowed with no fractures or signs of significant demineralization at time of imaging. Head and abdominal circumference were within normal range. An echocardiogram on the 2nd day of life showed severe pulmonary hypertension (PHTN). Nitric oxide was started due to the presence of persistent hypoxia and severe PHTN. The patient continued to require high cardiorespiratory support, but the medical condition worsened, and respiratory failure persisted. The patient died of severe respiratory failure at 16 days of life due to respiratory insufficiency secondary to a severely restricted thoracic cage. Whole-exome sequencing (WES) revealed a homozygous mutation in the DYNC2H1 (NM_001377.3) gene, namely, the c.9041G>T NP_001368.2: p.(Arg3014Ile) missense variant, which results in the substitution of the arginine codon at amino acid position 3014 with an isoleucine codon. The phenotyping of the patient's JATD and the detection of a homozygous variant in the DYNC2H1 gene confirmed the diagnosis of short-rib thoracic dysplasia-3 without polydactyly. In summary, the patient had isolated skeletal anomalies without polydactyly or other organ involvement. Additionally, the infant had severe PHTN on top of the respiratory failure, which eventually caused death. Considerably more work will need to be done to determine the clinical spectrum of JATD and understand its genetic heterogeneity.
PubMed: 38550721
DOI: 10.2147/IMCRJ.S447466 -
Current Issues in Molecular Biology Mar 2024Bardet-Biedl syndrome (BBS), one of the most common forms of syndromic inherited retinal diseases (IRDs), is characterized by the combination of retinal degeneration...
Bardet-Biedl syndrome (BBS), one of the most common forms of syndromic inherited retinal diseases (IRDs), is characterized by the combination of retinal degeneration with additional extra-ocular manifestations, including obesity, intellectual disability, kidney disease, polydactyly and other skeletal abnormalities. We observed an Israeli patient with autosomal recessive apparently non-syndromic rod-cone dystrophy (RCD). Extra-ocular findings were limited to epilepsy and dental problems. Genetic analysis with a single molecule molecular inversion probes-based panel that targets the exons and splice sites of 113 genes associated with retinitis pigmentosa and Leber congenital amaurosis revealed a homozygous rare missense variant in the gene (c.263C>T;p.(Ser88Leu)). This variant, which affects a highly conserved amino acid, is also located in the last base of Exon 3, and predicted to be splice-altering. An in vitro minigene splice assay demonstrated that this variant leads to the partial aberrant splicing of Exon 3. Therefore, we suggest that this variant is likely hypomorphic. This is in agreement with the relatively mild phenotype observed in the patient. Hence, the findings in our study expand the phenotypic spectrum associated with variants and indicate that variants in this gene should be considered not only in BBS patients but also in individuals with non-syndromic IRD or IRD with very mild extra-ocular manifestations.
PubMed: 38534779
DOI: 10.3390/cimb46030163 -
BMC Pregnancy and Childbirth Mar 2024To describe the prevalence and epidemiology of congenital polydactyly and syndactyly in Hunan Province, China, 2016-2020.
OBJECTIVE
To describe the prevalence and epidemiology of congenital polydactyly and syndactyly in Hunan Province, China, 2016-2020.
METHODS
Data were obtained from the Birth Defects Surveillance System in Hunan Province, China, 2016-2020. Prevalence of birth defects (polydactyly or syndactyly) is the number of cases per 1000 births (unit: ‰). Prevalence and 95% confidence intervals (CI) were calculated by the log-binomial method. Chi-square trend tests (χ) were used to determine trends in prevalence by year. Crude odds ratios (ORs) were calculated to examine the association of each demographic characteristic with polydactyly and syndactyly.
RESULTS
Our study included 847,755 births, and 14,459 birth defects were identified, including 1,888 polydactyly and 626 syndactyly cases, accounting for 13.06% and 4.33% of birth defects, respectively. The prevalences of total birth defects, polydactyly, and syndactyly were 17.06‰ (95%CI: 16.78-17.33), 2.23‰ (95%CI: 2.13-2.33), and 0.74‰ (95%CI: 0.68-0.80), respectively. Most polydactyly (96.77%) and syndactyly (95.69%) were diagnosed postnatally (within 7 days). From 2016 to 2020, the prevalences of polydactyly were 1.94‰, 2.07‰, 2.20‰, 2.54‰, and 2.48‰, respectively, showing an upward trend (χ = 19.48, P < 0.01); The prevalences of syndactyly were 0.62‰, 0.66‰, 0.77‰, 0.81‰, and 0.89‰, respectively, showing an upward trend (χ = 10.81, P = 0.03). Hand polydactyly (2.26‰ vs. 1.33‰, OR = 1.69, 95%CI: 1.52-1.87) and hand syndactyly (0.43‰ vs. 0.28‰, OR = 1.42, 95%CI: 1.14-1.76) were more common in males than females. Polydactyly (2.67‰ vs. 1.93‰, OR = 1.38, 95%CI: 1.26-1.51) and syndactyly (0.91‰ vs. 0.62‰, OR = 1.47, 95%CI: 1.26-1.72) were more common in urban areas than in rural areas. Compared to maternal age 25-29, hand polydactyly was more common in maternal age < 20 (2.48‰ vs. 1.74‰, OR = 1.43, 95%CI: 1.01-2.02) or ≥ 35 (2.25‰ vs. 1.74‰, OR = 1.30, 95%CI: 1.12-1.50).
CONCLUSION
In summary, we have described the prevalence and epidemiology of polydactyly and syndactyly from hospital-based surveillance in Hunan Province, China, 2016-2020. Our findings make some original contributions to the field, which may be valuable for future research.
Topics: Male; Female; Humans; Adult; Polydactyly; Syndactyly; Maternal Age; China; Prevalence; Congenital Abnormalities
PubMed: 38521899
DOI: 10.1186/s12884-024-06417-y -
Fa Yi Xue Za Zhi Feb 2024
Topics: Humans; Thumb; Polydactyly; Fractures, Bone
PubMed: 38500474
DOI: 10.12116/j.issn.1004-5619.2022.221202 -
Cureus Feb 2024This case report emphasizes the varied clinical features of Laurence-Moon-Bardet-Biedl syndrome (LMBBS) in a 10-year-old girl, presenting a rare combination of atypical...
This case report emphasizes the varied clinical features of Laurence-Moon-Bardet-Biedl syndrome (LMBBS) in a 10-year-old girl, presenting a rare combination of atypical retinitis punctata albescens, polydactyly, central obesity, and non-alcoholic fatty liver disease (NAFLD). Despite extensive management efforts, the patient's visual impairment remained unchanged, highlighting the challenging and progressive nature of LMBBS, particularly its ocular manifestations. Genetic counseling played a crucial role, stressing the significance of early genetic analysis in consanguineous marriages for anomaly detection and informed family planning. This case enhances our comprehension of LMBBS and emphasizes the necessity for ongoing research and multidisciplinary care to tackle its complexities.
PubMed: 38481887
DOI: 10.7759/cureus.54064 -
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 -
Molecular Genetics & Genomic Medicine Mar 2024Retinoblastoma (Rb) is the most common intraocular malignancy in childhood, originating from primitive retinal stem cells or cone precursor cells. It can be triggered by... (Review)
Review
BACKGROUND
Retinoblastoma (Rb) is the most common intraocular malignancy in childhood, originating from primitive retinal stem cells or cone precursor cells. It can be triggered by mutations of the RB1 gene or amplification of the MYCN gene. Rb may rarely present with polydactyly.
METHODS
We conducted karyotype analysis, copy number variation sequencing, and whole-genome sequencing on the infant proband and his family. The clinical course and laboratory results of the proband's infant were documented and collected. We also reviewed the relevant literature.
RESULTS
A 68-day-old boy presented with preaxial polydactyly and corneal edema. His intraocular pressure (IOP) was 40/19 mmHg, and color Doppler imaging revealed vitreous solid mass-occupying lesions with calcification in the right eye. Ocular CT showed flaky high-density and calcification in the right eye. This was classified as an International Retinoblastoma Staging System group E retinoblastoma with an indication for enucleation. Enucleation and orbital implantation were performed on the child's right eye. Karyotype analysis revealed an abnormal 46, XY, 15pstk+ karyotype, and the mother exhibited diploidy of the short arm of chromosome 15. The Alx-4 development factor, 13q deletion syndrome, and the PAPA2 gene have been reported as potential mechanisms for Rb combined with polydactyly.
CONCLUSION
We report the case of a baby boy with Rb and polydactyly exhibiting a 46, XY, 15pstk+ Karyotype. We discuss potential genetic factors related to both Rb and polydactyly. Furthermore, there is a need for further exploration into the impact of chromosomal polymorphisms in Rb with polydactyly.
Topics: Humans; Infant; Male; Calcinosis; DNA Copy Number Variations; Karyotype; Polydactyly; Retinal Neoplasms; Retinoblastoma
PubMed: 38465842
DOI: 10.1002/mgg3.2414