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Molecular Genetics & Genomic Medicine Apr 2022Polydactyly and syndactyly are congenital limb deformities, segregating in an autosomal-dominant fashion. The variants in the GLI3 gene are closely related to congenital...
BACKGROUND
Polydactyly and syndactyly are congenital limb deformities, segregating in an autosomal-dominant fashion. The variants in the GLI3 gene are closely related to congenital limb malformations. However, the causes underlying polydactyly and syndactyly are not well understood.
METHODS
We conducted a whole-exome sequencing on two four-generation Chinese families with polydactyly and syndactyly. Then c.2374C>T and c.1728C>A mutant plasmids were transfected to HEK293T cells and mice limb bud cells to explore the functional consequences of these variants. Western blot and real-time quantitative PCR were used to analyze the expression of GLI3 and Shh.
RESULTS
In these two families, the known GLI3 variant (NM_000168.6:c.2374C>T) and the novel GLI3 variant (NM_000168.6:c.1728C>A) contributed to polydactyly and syndactyly. Additionally, the GLI3 c.2374C>T mutant plasmid led to truncated GLI3 protein, and the GLI3 c.1728C>A mutant plasmid led to degraded GLI3 protein. Simultaneously, we demonstrated that the GLI3-mutant plasmids led to decreased Shh expression in mice limb bud cells.
CONCLUSION
We demonstrated that the novel GLI3 variant (c.1728C>A) and known GLI3 variant (c.2374C>T) contributed to the malformations in two four-generation pedigrees with polydactyly and syndactyly by affecting SHH signaling.
Topics: Animals; Codon, Nonsense; HEK293 Cells; Hedgehog Proteins; Humans; Limb Deformities, Congenital; Mice; Nerve Tissue Proteins; Pedigree; Polydactyly; Syndactyly; Zinc Finger Protein Gli3
PubMed: 35218158
DOI: 10.1002/mgg3.1895 -
Journal of Orthopaedic Surgery and... Aug 2021Thumb duplication is a very common congenital malformation. This study describes and compares the phenotypic manifestations of polydactyly between southwest and...
BACKGROUND
Thumb duplication is a very common congenital malformation. This study describes and compares the phenotypic manifestations of polydactyly between southwest and northeast China. However, previous studies had a limited sample size. Therefore, this study used a large sample.
METHODS
A total of 3549 well-characterized thumb duplication cases were divided into group A (southwest China) and group B (northeast China).
RESULTS
In group A and group B, the left-to-right ratio was 1:1.5 and 1:1.75, respectively, and the female-to-male ratio was 1:1.5 and 1:1.58, respectively.
CONCLUSIONS
There were no significant differences in gender distribution or the distribution of left and right polydactyly between the two groups, but the distribution of bilateral polydactyly was significantly different.
Topics: China; Female; Humans; Male; Polydactyly; Thumb
PubMed: 34372898
DOI: 10.1186/s13018-021-02567-3 -
Cureus Jan 2024Weyers acrofacial dysostosis (WAD) is a rare skeletal dysplasia, which is autosomal-dominant, and the clinical symptoms are presented as dental anomalies, polydactyly,...
Weyers acrofacial dysostosis (WAD) is a rare skeletal dysplasia, which is autosomal-dominant, and the clinical symptoms are presented as dental anomalies, polydactyly, nail dystrophy, and short physical stature. It is also termed "Curry‑Hall syndrome" and reported to be linked to genetic mutations mapped on chromosome 4p16, the region reported being commonly associated with a similar genetic syndrome, Ellis-van Creveld (EVC) syndrome. Most individuals with EVC have congenital heart abnormalities, most often atrial septal defects, unlike WAD. In this case, a 15‑year‑old girl presented with onychodystrophy and polydactyly observed in the hands and feet, microdontia, or agenesis of teeth, which were conical in shape, with a short stature. The patient had dystrophy of nails since birth, and physical growth in terms of height did not match the normal growth parameters with respect to age. The patient also had abnormal dentation with conical-shaped teeth, with the rest of the clinical presentations suggestive of WAD.
PubMed: 38420083
DOI: 10.7759/cureus.53135 -
Plastic and Reconstructive Surgery Jul 2023Surgical outcomes of duplicated thumbs differ depending on the branching type. The authors developed a new classification system and report surgical outcomes with an...
BACKGROUND
Surgical outcomes of duplicated thumbs differ depending on the branching type. The authors developed a new classification system and report surgical outcomes with an average 10.2-year follow-up.
METHODS
A total of 529 patients with 562 duplicated thumbs were reviewed. Surgical anatomies were compared with radiographs, and then a new classification system was developed based on branching level and bone shape observed on the radiograph: distal type (D-type), including Wassel types I and II; proximal type (P-type), including Wassel types Ⅲ and Ⅳ, and four subdivisions (Po, Pa, Pb, and Pc) according to bone structure; and metacarpal type (MC-type), including Wassel types V and VI. All hands were assessed using the Japanese Society for Surgery of the Hand evaluation form, and factors causing poor outcomes were analyzed.
RESULTS
There were 25% D-type, 59% P-type, and 14% MC-type hands; 2% of hands were not classified. Overall, 351 hands (63%) were directly assessed when patients reached 5 years of age. Seventeen percent of hands had fair results. Good results were achieved in 90% of D- and Po-type hands. Pa-, Pb-, Pc-, and MC-type hands had lower Japanese Society for Surgery of the Hand scores than did D- or Po-type hands. Pa- and Pb-type hands tended to develop interphalangeal joint malalignment and instability, whereas Pc- and MC-type hands developed disorders in the metacarpophalangeal joint with growth.
CONCLUSIONS
The authors' new classification system clarifies the potential pitfalls for each type of duplicated thumb. More than 90% of D- and Po-type hands obtained good results. Care should be taken with interphalangeal joint reconstruction for Pa- and Pb-type hands. Meticulous reconstruction of the metacarpophalangeal joint is essential for Pc- and MC-type hands. This analysis provides important information for surgeons and patients.
CLINICAL QUESTION/LEVEL OF EVIDENCE
Risk, IV.
Topics: Humans; Thumb; Polydactyly; Lead; Plastic Surgery Procedures; Hand Deformities; Treatment Outcome
PubMed: 36780352
DOI: 10.1097/PRS.0000000000010267 -
Journal of Human Genetics Nov 2020Meckel-Gruber syndrome (MKS) is a clinically and genetically heterogeneous ciliopathy characterized by a triad of occipital encephalocele, polycystic kidneys, and...
Meckel-Gruber syndrome (MKS) is a clinically and genetically heterogeneous ciliopathy characterized by a triad of occipital encephalocele, polycystic kidneys, and postaxial polydactyly. Pathogenesis of MKS is related to dysfunction of primary cilia. However, reports on MKS caused by Tectonic2 (TCTN2) mutations are scanty whilst. There is no direct evidence of ciliogenesis in such MKS patients. Here, we identified two novel nonsense variants of TCTN2 (c.343G > T, p.E115*; c.1540C > T, p.Q514*) in a Chinese MKS fetus. Compared to reported TCTN2-causing MKS patients, our case represented an endocardial pad defect, which was not reported previously. We also found primary cilia protruded normally from the surface of epithelial cells in the affected fetal kidney tubules compared to controls, indicating TCTN2 is not necessary for ciliogenesis in the kidney. To our knowledge, this is the first case of MKS fetus caused by TCTN2 mutations from China.
Topics: China; Ciliary Motility Disorders; Codon, Nonsense; Encephalocele; Female; Fetus; Fingers; Genetic Heterogeneity; Genetic Predisposition to Disease; Humans; Kidney; Male; Membrane Proteins; Pedigree; Polycystic Kidney Diseases; Polydactyly; Retinitis Pigmentosa; Toes
PubMed: 32655147
DOI: 10.1038/s10038-020-0804-0 -
Nagoya Journal of Medical Science Nov 2022On-top plasty may be the best option for reconstructing atypical radial polydactyly, consisting of a developed distal portion in one thumb and a developed proximal... (Review)
Review
On-top plasty may be the best option for reconstructing atypical radial polydactyly, consisting of a developed distal portion in one thumb and a developed proximal portion in the other thumb. However, it is unclear if patients can gain thumb function corresponding to the reconstructed appearance. We performed a retrospective bibliographic review to summarize the current literature and present our department's on-top plasty experiences. Over the last ten years, our department performed three on-top plasty radial polydactyly reconstructions. We surveyed the appearance and use of the reconstructed thumb and the patient's satisfaction level during postoperative follow-up. We also retrieved published case reports describing on-top plasty for polydactyly reconstruction to compare with our cases. Our patients had an acceptable thumb appearance and were satisfied with the gained function of the thumb. However, two patients required revision surgery. We found 11 studies in the literature describing on-top plasty for polydactyly treatment, four of which reported a limited range of thumb motion, but no patient or their family complained about the result. Most patients who undergo on-top plasty for radial polydactyly can expect a fair to good appearance after surgery. Although instability or limitation of the joint arc is possible, the reconstruction satisfies patients regarding function and appearance.
Topics: Humans; Thumb; Retrospective Studies; Plastic Surgery Procedures; Polydactyly
PubMed: 36544612
DOI: 10.18999/nagjms.84.4.705 -
The Journal of Molecular Diagnostics :... Jul 2017Somatic variants have been well described in tumorigenesis; however, they are only recently appreciated in other human disorders, such as mosaic overgrowth syndromes.... (Review)
Review
Somatic variants have been well described in tumorigenesis; however, they are only recently appreciated in other human disorders, such as mosaic overgrowth syndromes. Although overgrowth is a manifestation in many genetic syndromes, not all overgrowth syndromes are inherited. Mosaic somatic variants have been lately described in several overgrowth disorders, such as Proteus syndrome, CLOVES (congenital, lipomatous, overgrowth, vascular malformations, epidermal nevi, and spinal/skeletal anomalies and/or scoliosis) syndrome, and megalencephalyepolymicrogyria-polydactyly-hydrocephalus syndrome. These syndromes are caused by somatic variants in the genes associated with the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway, resulting in a spectrum of overgrowth syndromes with overlapping features that could be difficult to distinguish based on phenotypic presentations alone. In addition, Sanger sequencing is ineffective for the detection of a causal variant because of the mosaic nature of these variants, whereas targeted next-generation sequencing technology offers a deeper sequencing coverage and allows the detection of low-level mosaicism. Recent studies have shown that the causal variants are only present in the affected tissues in most cases, and can be enriched by in vitro tissue culture. In this review, we describe several mosaic somatic overgrowth syndromes caused by variants in genes of the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin signaling pathway, their phenotypic and molecular spectrum, and the clinical utility of next-generation sequencing technology in the diagnosis of these disorders.
Topics: Animals; Clinical Trials as Topic; Female; Fingers; Genetic Testing; Genetic Variation; High-Throughput Nucleotide Sequencing; Humans; Hydrocephalus; Hypoglycemia; Limb Deformities, Congenital; Lipoma; Malformations of Cortical Development; Mosaicism; Musculoskeletal Abnormalities; Nevus; Phosphatidylinositol 3-Kinase; Polydactyly; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Vascular Malformations
PubMed: 28502730
DOI: 10.1016/j.jmoldx.2017.04.001 -
JPMA. the Journal of the Pakistan... Feb 2024Ellis-van Creveld syndrome (EVC), also known as chondroectodermal dysplasia, is a rare entity. It most commonly affects the tubular bones leading to dwarfism and a long...
Ellis-van Creveld syndrome (EVC), also known as chondroectodermal dysplasia, is a rare entity. It most commonly affects the tubular bones leading to dwarfism and a long trunk with ossification defects. Other presentations are wide hands and feet, dysplastic nails, thin hair, and cardiac malformations. An eight-year-old female patient presented to our tertiary care centre with complaints of short stature, abnormal dentition, and fatigue. The child's parents were first-degree relatives. On radiological imaging, it was revealed that the patient had postaxial polydactyly, short stature, and genu valgum deformity along with mild cardiomegaly. All these features were indicative of Ellis-van Creveld syndrome. EVC is a rare clinical syndrome with a distinctive clinical presentation. It requires comprehensive radiological investigations and the management is best done with a multidisciplinary approach.
Topics: Female; Child; Humans; Ellis-Van Creveld Syndrome; Polydactyly; Heart Defects, Congenital; Fingers
PubMed: 38419244
DOI: 10.47391/JPMA.7049 -
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 -
The Journal of Clinical Investigation Mar 2009Bardet-Biedl syndrome (BBS) is a multisystemic disorder typified by developmental and progressive degenerative defects. A combination of genetic, in vitro, and in vivo... (Review)
Review
Bardet-Biedl syndrome (BBS) is a multisystemic disorder typified by developmental and progressive degenerative defects. A combination of genetic, in vitro, and in vivo studies have highlighted ciliary dysfunction as a primary cause of BBS pathology, which has in turn contributed to the improved understanding of the functions of the primary cilium in humans and other vertebrates. Here we discuss the evidence linking the clinical BBS phenotype to ciliary defects, highlight how the genetic and cellular characteristics of BBS overlap with and inform other ciliary disorders, and explore the possible mechanistic underpinnings of ciliary dysfunction.
Topics: Animals; Bardet-Biedl Syndrome; Chromosome Mapping; Cilia; Ciliary Motility Disorders; Humans; Obesity; Phenotype; Polydactyly; Prevalence; Retinal Diseases; Vertebrates
PubMed: 19252258
DOI: 10.1172/JCI37041