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American Journal of Human Genetics Jul 1994
Topics: Bone Morphogenetic Proteins; Ectoderm; Ectromelia; Embryonic Induction; Extremities; Gene Expression; Genes, Homeobox; Humans; Mesoderm; Morphogenesis; Polydactyly; Proteins; Signal Transduction
PubMed: 7912883
DOI: No ID Found -
European Journal of Human Genetics :... Mar 2022Pallister-Hall syndrome, typically caused by germline or de novo variants within the GLI3 gene, has key features of hypothalamic hamartoma and polydactyly. Recently, a...
Pallister-Hall syndrome, typically caused by germline or de novo variants within the GLI3 gene, has key features of hypothalamic hamartoma and polydactyly. Recently, a few similar cases have been described with bi-allelic SMO variants. We describe two siblings born to non-consanguineous unaffected parents presenting with hypothalamic hamartoma, post-axial polydactyly, microcephaly amongst other developmental anomalies. Previous clinical diagnostic exome analysis had excluded a pathogenic variant in GLI3. We performed exome sequencing re-analysis and identified bi-allelic SMO variants including a missense and synonymous variant in both affected siblings. We functionally characterised this synonymous variant showing it induces exon 8 skipping within the SMO transcript. Our results confirm bi-allelic SMO variants as an uncommon cause of Pallister-Hall syndrome and describe a novel exon-skipping mechanism, expanding the molecular architecture of this new clinico-molecular disorder.
Topics: Hamartoma; Humans; Hypothalamic Diseases; Pallister-Hall Syndrome; Polydactyly; Smoothened Receptor
PubMed: 35034092
DOI: 10.1038/s41431-021-01023-4 -
Developmental Dynamics : An Official... Mar 2015The vertebrate digit pattern is defined by the morphogen Sonic hedgehog (Shh), which controls the activity of Gli transcription factors. Gli1, 2 and 3 are dynamically...
BACKGROUND
The vertebrate digit pattern is defined by the morphogen Sonic hedgehog (Shh), which controls the activity of Gli transcription factors. Gli1, 2 and 3 are dynamically expressed during patterning. Downstream of Shh, their activity is regulated by Sufu and Kif7, core components of the Shh signaling cascade. The precise roles of these regulators during limb development have not been fully described. We analyze the role of Sufu and Kif7 in the limb and demonstrate that their loss has distinct and synergistic effects on Gli activity and digit pattern.
RESULTS
Using a series of mouse mutants, we show that Sufu and Kif7 are expressed throughout limb development and their deletion has distinct effects on Gli levels and limb formation. Concomitant deletion of Sufu and Kif7 results in constitutive pathway activity and severe limb truncation. This is consistent with the recently published two-population model, which suggests that precocious activation of Shh signaling inhibits organizing center formation and limb outgrowth.
CONCLUSIONS
Together, our findings demonstrate that perturbations of Sufu and Kif7 affect Gli activity and recapitulate the full spectrum of vertebrate limb defects, ranging from severe truncation to polydactyly.
Topics: Animals; Body Patterning; Hedgehog Proteins; Hindlimb; Kinesins; Mice; Mice, Knockout; Oncogene Proteins; Polydactyly; Repressor Proteins; Signal Transduction; Trans-Activators; Zinc Finger Protein GLI1
PubMed: 25581370
DOI: 10.1002/dvdy.24249 -
Genetics in Medicine : Official Journal... Apr 2020
Topics: Hedgehog Proteins; Humans; Limb Buds; Polydactyly; Thumb
PubMed: 31822852
DOI: 10.1038/s41436-019-0726-4 -
Journal of Medical Genetics Jun 2006The study of patients with rare multiple congenital anomaly syndromes can provide illuminating insights into normal development and the pathogenesis of congenital... (Review)
Review
The study of patients with rare multiple congenital anomaly syndromes can provide illuminating insights into normal development and the pathogenesis of congenital anomalies. The GLI3 gene is a particularly good example as it illuminates the phenomena of pleiotropy, phenocopies, syndrome families, and evolutionary conservation of pathogenesis, and raises questions about how diagnoses are conceptualised. These topics are reviewed in turn, in the context of the clinical and biological data derived from patients with mutations in GLI3 and experimental work in model systems.
Topics: Abnormalities, Multiple; Animals; Evolution, Molecular; Humans; Kruppel-Like Transcription Factors; Models, Animal; Mutation; Nerve Tissue Proteins; Phenotype; Polydactyly; Syndrome; Zinc Finger Protein Gli3
PubMed: 16740916
DOI: 10.1136/jmg.2004.029181 -
Journal of Medical Genetics Jan 1999Polydactyly is the most frequently observed congenital hand malformation with a prevalence between 5 and 19 per 10000 live births. It can occur as an isolated disorder,...
Polydactyly is the most frequently observed congenital hand malformation with a prevalence between 5 and 19 per 10000 live births. It can occur as an isolated disorder, in association with other hand/foot malformations, or as a part of a syndrome, and is usually inherited as an autosomal dominant trait. According to its anatomical location, polydactyly can be generally subdivided into pre- and postaxial forms. Recently, a gene responsible for preaxial polydactyly types II and III, as well as complex polysyndactyly, has been localised to chromosome 7q36. In order to facilitate the search for the underlying genetic defect, we ascertained 12 additional families of different ethnic origin affected with preaxial polydactyly. Eleven of the kindreds investigated could be linked to chromosome 7q36, enabling us to refine the critical region for the preaxial polydactyly gene to a region of 1.9 cM. Our findings also indicate that radial and tibial dysplasia/aplasia can be associated with preaxial polydactyly on chromosome 7q36. Combining our results with other studies suggests that all non-syndromic preaxial polydactylies associated with triphalangism of the thumb are caused by a single genetic locus, but that there is genetic heterogeneity for preaxial polydactyly associated with duplications of biphalangeal thumbs. Comparison of the phenotypic and genetic findings of different forms of preaxial polydactyly is an important step in analysing and understanding the aetiology and pathogenesis of these limb malformations.
Topics: Animals; Chromosome Mapping; Chromosomes, Human, Pair 7; Haplotypes; Humans; Mice; Microsatellite Repeats; Pedigree; Phenotype; Polydactyly; Radiography; Recombination, Genetic
PubMed: 9950363
DOI: No ID Found -
Parasites & Vectors Jul 2020Cases of polydactyly in natural populations of amphibians have attracted great interest from biologists. At the end of the 1940s, the French biologist Jean Rostand...
BACKGROUND
Cases of polydactyly in natural populations of amphibians have attracted great interest from biologists. At the end of the 1940s, the French biologist Jean Rostand discovered a polymorphic syndrome in some water frog (Anura: Pelophylax) populations that included polydactyly and some severe morphological anomalies (he called it 'anomaly P'). The cause of this anomaly remains unknown for 70 years. In a previous study, we obtained anomaly P in the laboratory in tadpoles of water frogs that developed together with molluscs Planorbarius corneus (Mollusca: Gastropoda) collected in the field. We thus proposed the 'trematode hypothesis', according to which the infectious agent responsible for anomaly P is a trematode species.
METHODS
Metacercariae from tadpoles with anomaly P were identified using ITS2 gene sequencing as Strigea robusta (Trematoda: Strigeidae). To verify teratogenic features of the species, cercariae of S. robusta were tested for the possibility to cause anomalies. Identification of cercariae species was made using morphological and molecular methods (sequencing of ITS2 and 28S rRNA). The tadpoles were exposed to parasites at four doses of cercariae (control, low, medium and high) and divided into two groups: "early" (at 25-27 Gosner stages) and "late" (at 29-34 Gosner stages) exposure.
RESULTS
A total of 58 (72.5%) tadpoles survived until metamorphosis under the dose-dependent experiment with the trematode S. robusta. Differences in the survival rates were observed between the exposed and unexposed tadpoles both in the group of "early" tadpoles and "late" tadpoles. The exposure of tadpoles to the cercariae of S. robusta induced anomaly P in 82% of surviving tadpoles. The severe forms developed only in "early" stages under all doses of cercariae exposure. Polydactyly predominantly developed in the "late" stages; under a light exposure dose, polydactyly also developed in "early" tadpoles. Laboratory-hatched tadpoles reared together with infected snails had different rates of survival and complexity of deformations associated with the period of coexistence.
CONCLUSIONS
The experiments with direct cercariae exposure provide compelling evidence that S. robusta leads to anomaly P in tadpoles of water frogs. The manifestation of anomaly P turned out to be dependent on the stage of development, cercariae dose, and the location of the cysts.
Topics: Animals; Forelimb; Gastropoda; Genes, Helminth; Larva; Life Cycle Stages; Pathology, Molecular; Polydactyly; Ranidae; Toes; Trematoda
PubMed: 32727553
DOI: 10.1186/s13071-020-04256-2 -
Nature Communications Jul 2022Sonic hedgehog (Shh) is essential for limb development, and the mechanisms that govern the propagation and maintenance of its expression has been well studied; however,...
Sonic hedgehog (Shh) is essential for limb development, and the mechanisms that govern the propagation and maintenance of its expression has been well studied; however, the mechanisms that govern the initiation of Shh expression are incomplete. Here we report that ETV2 initiates Shh expression by changing the chromatin status of the developmental limb enhancer, ZRS. Etv2 expression precedes Shh in limb buds, and Etv2 inactivation prevents the opening of limb chromatin, including the ZRS, resulting in an absence of Shh expression. Etv2 overexpression in limb buds causes nucleosomal displacement at the ZRS, ectopic Shh expression, and polydactyly. Areas of nucleosome displacement coincide with ETS binding site clusters. ETV2 also functions as a transcriptional activator of ZRS and is antagonized by ETV4/5 repressors. Known human polydactyl mutations introduce novel ETV2 binding sites in the ZRS, suggesting that ETV2 dosage regulates ZRS activation. These studies identify ETV2 as a pioneer transcription factor (TF) regulating the onset of Shh expression, having both a chromatin regulatory role and a transcriptional activation role.
Topics: Animals; Chromatin; Enhancer Elements, Genetic; Gene Expression Regulation, Developmental; Hedgehog Proteins; Humans; Limb Buds; Mice; Polydactyly; Transcription Factors
PubMed: 35864091
DOI: 10.1038/s41467-022-31848-6 -
Orphanet Journal of Rare Diseases Jan 2012Oral-Facial-Digital Syndrome type VI (OFD VI) represents a rare phenotypic subtype of Joubert syndrome and related disorders (JSRD). In the original report polydactyly,...
Oral-Facial-Digital Syndrome type VI (OFD VI) represents a rare phenotypic subtype of Joubert syndrome and related disorders (JSRD). In the original report polydactyly, oral findings, intellectual disability, and absence of the cerebellar vermis at post-mortem characterized the syndrome. Subsequently, the molar tooth sign (MTS) has been found in patients with OFD VI, prompting the inclusion of OFD VI in JSRD. We studied the clinical, neurodevelopmental, neuroimaging, and genetic findings in a cohort of 16 patients with OFD VI. We derived the following inclusion criteria from the literature: 1) MTS and one oral finding and polydactyly, or 2) MTS and more than one typical oral finding. The OFD VI neuroimaging pattern was found to be more severe than in other JSRD subgroups and includes severe hypoplasia of the cerebellar vermis, hypoplastic and dysplastic cerebellar hemispheres, marked enlargement of the posterior fossa, increased retrocerebellar collection of cerebrospinal fluid, abnormal brainstem, and frequently supratentorial abnormalities that occasionally include characteristic hypothalamic hamartomas. Additionally, two new JSRD neuroimaging findings (ascending superior cerebellar peduncles and fused thalami) have been identified. Tongue hamartomas, additional frenula, upper lip notch, and mesoaxial polydactyly are specific findings in OFD VI, while cleft lip/palate and other types of polydactyly of hands and feet are not specific. Involvement of other organs may include ocular findings, particularly colobomas. The majority of the patients have absent motor development and profound cognitive impairment. In OFD VI, normal cognitive functions are possible, but exceptional. Sequencing of known JSRD genes in most patients failed to detect pathogenetic mutations, therefore the genetic basis of OFD VI remains unknown. Compared with other JSRD subgroups, the neurological findings and impairment of motor development and cognitive functions in OFD VI are significantly worse, suggesting a correlation with the more severe neuroimaging findings. Based on the literature and this study we suggest as diagnostic criteria for OFD VI: MTS and one or more of the following: 1) tongue hamartoma(s) and/or additional frenula and/or upper lip notch; 2) mesoaxial polydactyly of one or more hands or feet; 3) hypothalamic hamartoma.
Topics: Abnormalities, Multiple; Adolescent; Adult; Cerebellar Diseases; Cerebellum; Child; Child, Preschool; Eye Abnormalities; Female; Humans; Infant; Infant, Newborn; Kidney Diseases, Cystic; Magnetic Resonance Imaging; Male; Neuroimaging; Orofaciodigital Syndromes; Phenotype; Polydactyly; Retina; Young Adult
PubMed: 22236771
DOI: 10.1186/1750-1172-7-4 -
Hand (New York, N.Y.) Nov 2022Surgical excision for postaxial polydactyly type B is advocated to avoid long-term complications. Excision with local anesthesia (LA) in infancy represents a safe and...
BACKGROUND
Surgical excision for postaxial polydactyly type B is advocated to avoid long-term complications. Excision with local anesthesia (LA) in infancy represents a safe and effective treatment for this condition, although general anesthesia (GA) is employed by many surgeons. We present a comparison of surgical outcomes, cost, and time between LA and GA to support widespread change in management.
METHODS
A retrospective review of patients under 12 months of age undergoing surgical polydactyly excision by a single surgeon was performed. Anesthesia type, patient demographics, and complications were recorded. Comparisons were made between LA and GA groups on procedure cost, operating time, length of stay (LOS), and time from procedure end to discharge. Stepwise forward regression was used to identify the best model for predicting total costs.
RESULTS
Ninety-one infants with a mean age of 3 months (±1.9) were examined; 51 (56%) underwent LA alone, 40 (44%) underwent GA. Mean operating time was 11.53 ± 4.36 minutes, with no difference observed between anesthesia groups ( = .39). LA infants had a significantly shorter LOS (2.5 vs 3.5 hours; < .05), quicker postoperative discharge (32 vs 65 minutes, < .05), and fewer overall expenses, 2803 vs 6067 U.S. dollars (USD), < .05. Two minor surgical complications (1 in each group) were reported.
CONCLUSIONS
This study demonstrates significantly decreased cost, LOS, and time to discharge using LA alone for surgical excision of postaxial polydactyly type B. Results suggest the approach is quick, economical, and avoids the risks of GA in early infancy.
Topics: Infant; Humans; Anesthesia, Local; Polydactyly; Toes; Anesthesia, General
PubMed: 33631987
DOI: 10.1177/1558944721994255