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Neural tube development from the neural plate. Primary cilia are present wherever SHH is expressed )namely, the floor plate and notochord(. BMP-bone morphogenetic protein, GDF-growth and differentiation factor, WNT-wingless tumor virus protein, GLI-glioma-associated oncogene family zinc finger protein, SHH-sonic hedgehog, NOG-noggin
Source publication
Oral-facial-digital syndrome type I (OFDI) is an X-linked syndrome, which has several craniofacial and limb features; and hence, patients frequently present to craniofacial and plastic surgeons. Oral-facial-digital syndrome type I is caused by mutations in the CXORF5 gene. The gene product is one of the basal body proteins of a slim microtubule-bas...
Context in source publication
Citations
... Therefore, variants in the CS region can lead to an excess of GLI3-R in limb buds and the neural tube, which is the primary mechanism of PHS. PHS may be associated with hypothalamic hamartoma, cleft larynx, imperforate anus, and pulmonary lobation anomalies (25). In this study, the frameshift variant p.T458QfsX44 was found to be located upstream of the ZFN domain, and a premature stop codon was introduced. ...
Background
Polydactyly is a prevalent congenital anomaly with an incidence of 0.3–3.6 per 1000 live births. GLI family zinc finger 3 (GLI3) is a classical causative gene of polydactyly, and serves as a pivotal transcription factor in the hedgehog signaling pathway, regulating the development of the anterior-posterior axis in limbs.
Methods
Three pedigrees of polydactyly patients were enrolled from Hunan Province, China. Pathogenic variants were identified by whole-exome sequencing (WES) and Sanger sequencing.
Results
Three variants of GLI3 were identified in these three families, including a novel deletion variant (c.1372del, p.T458QfsX44), a novel insertion-deletion (indel) variant (c.1967_1968delinsAA, p.S656X), and a nonsense variant (c.2374C > T, p.R792X). These variants were present exclusively in patients but not in healthy individuals.
Conclusions
We identified three pathogenic GLI3 variants in polydactyly patients, broadening the genetic spectrum of GLI3 and contributing significantly to genetic counseling and diagnosis for polydactyly.
... OFD1 is necessary for maintaining the microtubule length stability of centrioles and the recruitment of IFT88 but can be prematurely truncated by mutations in the CXORF5 gene [167,168]. The clinical characteristics of the pathogenesis of OFD type I are related to abnormal Hh signal transduction, a depressed planar cell polarity pathway, and errors in cell cycle control that result from the dysfunctions of primary cilia [169]. The knockout of Ofd1 in mice to establish an animal model recapitulates the main symptoms of OFD1, but severity is enhanced [170]. ...
Bone and teeth are hard tissues. Hard tissue diseases have a serious effect on human survival and quality of life. Primary cilia are protrusions on the surfaces of cells. As antennas, they are distributed on the membrane surfaces of almost all mammalian cell types and participate in the development of organs and the maintenance of homeostasis. Mutations in cilium-related genes result in a variety of developmental and even lethal diseases. Patients with multiple ciliary gene mutations present overt changes in the skeletal system, suggesting that primary cilia are involved in hard tissue development and reconstruction. Furthermore, primary cilia act as sensors of external stimuli and regulate bone homeostasis. Specifically, substances are trafficked through primary cilia by intraflagellar transport, which affects key signaling pathways during hard tissue development. In this review, we summarize the roles of primary cilia in long bone development and remodeling from two perspectives: primary cilia signaling and sensory mechanisms. In addition, the cilium-related diseases of hard tissue and the manifestations of mutant cilia in the skeleton and teeth are described. We believe that all the findings will help with the intervention and treatment of related hard tissue genetic diseases.
... The molecular pathogenesis of OFDS type I has been presented in a simplified format using a flow chart (Figure 4). 11 Through this case report, we aim to highlight a subclinical sporadic case of OFDS type I, which lacked the easily observable phenotypic features of the syndrome and presented with few novel hitherto unreported clinical findings. To the best of our knowledge, we report the first patient of OFDS type I with midline pits in the philtrum area and a hamartomatous proliferation of tissue in the anterior maxillary alveolar gingival region showing exuberant proliferation of smooth muscle cells, blood vessels, neural tissue and cartilaginous tissue. ...
... Thus, as described in Figure 3, down regulation of the PCP pathway and abnormal functioning of the IHH pathway coupled with abnormal cycle control, may have led to the philtrum pits and hamartoma formation in our patient. 11 The cartilaginous tissue could have arisen from abnormal proliferation of the remnants of embryonic cartilage precursors from nasal and septal development in the anterior part of the maxilla. 12 While our patient had a limited expression of the conventional phenotypic features, she presented with philtrum pits and hamartomatous proliferation of soft tissues of the anterior maxillary gingiva, thus representing yet another facet in the varying phenotypic spectrum of OFDS type I. ...
Oro-facial-digital syndrome is a group of rare heterogeneous hereditary disorders characterized by abnormalities of the oral cavity, face and digits, along with varying degrees of mental retardation. Currently, Oro-facial-digital syndrome has been classified into 14 types and two additional unclassified variants have been proposed. Amongst the various variants described, Oro-facial-digital syndrome type I is the most common. We report an interesting subclinical sporadic case of Oro-facial-digital syndrome type I in a 21-year-old female patient. Interestingly, our patient presented with a few novel hitherto unreported clinical findings like midline pits in the philtrum area and a hamartomatous proliferation of tissue in the anterior maxillary alveolar gingival region. This case report highlights the importance of prudent histopathological-clinical correlation, which can direct the flow of clinical investigations leading to the detection and diagnosis of unsuspected conditions as learned in this case. We would also like to emphasize that comprehensive examination of new born for structural abnormalities of the orofacial region is crucial to early diagnosis of syndromes and subsequent referral for further evaluation and management.
... This syndrome is X-linked dominant and primarily lethal in male embryos. The incidence is estimated at 1:50000 live births and is caused by a mutation in the OFD1 gene (CXORF5 gene) [60], coding for a centrosomal protein located at the basal body of the primary cilium. This leads to abnormal Hedgehof signal transduction and errors in cell cycle control. ...
... This leads to abnormal Hedgehof signal transduction and errors in cell cycle control. [60] Phenotypically these patients may present with congenital heart defects, median cleft palate, cleft lip, lingual hamartomas, hypertelorism, short palpebral fissures, pseudocleft of the upper lip, low set ears, postaxial polydactyly, pre-axial polydactyly of the feet, also an array of other possible signs including microphthalmia and hydrocephalus. Only five live born male patients have been mentioned in the literature. ...
... This was thought to be important for the clinician since intellectual disability, arching of the eyebrows, and hirsutism are features of both RSTS and Cornelia de Lang syndromes. Similarly, a microform median upper lip cleft, a bifid tongue, and brachydactyly are characteristic features of oro-facio-digital syndrome Type 1 (OFD1, OMIM 311200) [18]. Hence, our case shows that patients with RSTS Type 1 may have features that overlap with those of OFD1. ...
Background
Rubinstein-Taybi syndrome (RSTS) Type 1 (OMIM 180849) is characterized by three main features: intellectual disability; broad and frequently angulated thumbs and halluces; and characteristic facial dysmorphism.
Case presentation
We report on a Saudi boy with RSTS Type 1 and the following distinct features: a midline notch of the upper lip, a bifid tip of the tongue, a midline groove of the lower lip, plump fingers with broad / flat fingertips, and brachydactyly. The child was found to be heterozygous in the CREBBP gene for a sequence variant designated c.4963del, which is predicted to result in premature protein termination p.Leu1655Cysfs*89. The child and his father were also found to be heterozygous in the EP300 gene for a sequence variant designated c.586A > G, which is predicted to result in the amino-acid substitution p.Ile196Val.
Conclusion
Our report expands the clinical spectrum of RSTS to include several distinct facial and limb features. The variant of the CREBBP gene is known to be causative of RSTS Type 1. The variant in the EP300 gene is benign since the father carried the same variant and exhibited no abnormalities. However, functional studies are required to investigate if this benign EP300 variant influences the phenotype in the presence of disease-causing CREBBP gene mutations.
... Ciliopathies are a group of syndromes caused by genetic mutations encoding proteins related to the formation or function of the embryonic primary cilium [1]. The primary cilium is composed of three parts: a basal body (attached to the actin network of the cell), an axoneme (projecting microtubules) and a ciliary membrane (covering the axoneme) [2]. The primary cilium is the site of hedgehog signal transduction which includes Sonic hedgehog (involved in limb patterning and the pathogenesis of ulnar polydactyly) and Indian hedgehog (involved in the coordination of chondrocyte proliferation and differentiation) [2,3]. ...
... The primary cilium is composed of three parts: a basal body (attached to the actin network of the cell), an axoneme (projecting microtubules) and a ciliary membrane (covering the axoneme) [2]. The primary cilium is the site of hedgehog signal transduction which includes Sonic hedgehog (involved in limb patterning and the pathogenesis of ulnar polydactyly) and Indian hedgehog (involved in the coordination of chondrocyte proliferation and differentiation) [2,3]. ...
Introduction:
Ellis-van Creveld (EVC) syndrome is one of the rarest ciliopathy syndromes. It is caused by mutations of the EVC and EVC2 genes which encode the EVC proteins present in the basal body of the primary cilium.
Presentation of cases:
We report on a Saudi family with two affected children. Gene analysis revealed a homozygous c.2T >A in exon 1 of the EVC gene. The most interesting finding in our patients was the wide - spread cone-shaped epiphyses in the hands and feet.
Discussion:
Although cone-shaped epiphyses is a known feature of EVC syndrome, it usually limited to the middle or proximal phalanges. The wide-spread cone-shaped epiphyses seen in our patients have not been previously reported.
Conclusion:
EVC syndrome is very rare in the Middle East. We report on the first Saudi family with EVC syndrome confirmed by gene analysis. The most unique finding in our patients was the wide-spread cone-shaped epiphyses in the hands and feet. The abnormality is probably related to abnormal Indian hedgehog signaling in the primary cilium.
Metodología:
la revisión bibliográfica se realizó en bases de datos académicas PubMed, LILACS, OVID-MEDLINE usando lenguaje normalizado con términos DECS-LILACS: exposición a riesgos ambientales, fisura del paladar, labio leporino, genética, medicina de precisión y síndrome; se aplicaron filtros de búsqueda propios de las bases de datos, tipos de textos científicos e información relevante para la investigación. De acuerdo con los resultados de la búsqueda bibliográfica se encontró que la etiología de las fisuras es multifactorial y se asocia a factores genéticos y ambientales. La identificación de diversos genes relacionados con estas malformaciones ha permitido reconocer oportunamente cuándo una fisura es sindrómica o no sindrómica, lo que lleva a entender la interacción gen por gen, a identificar variantes funcionales y a comprender su importancia etiológica.
Conclusiones:
el estudio y el conocimiento acerca de los mecanismos moleculares que se encuentran involucrados en la formación de las fisuras labiopalatinas ha tomado fuerza gracias al entendimiento del genoma humano y al desarrollo de herramientas modernas de biología molecular que permiten identificar gran cantidad de datos de secuencia, haciendo que los genes candidatos aumenten constantemente. Esto permitirá un manejo oportuno de la enfermedad, la identificación del riesgo de ocurrencia y un tratamiento especializado mediante la medicina de precisión.
Development requires cell proliferation, differentiation and spatial organization of daughter cells to occur in a highly controlled manner. The mode of cell division, the extent of proliferation and the spatial distribution of mitosis allow the formation of tissues of the right size and with the correct structural organization. All these aspects depend on cell cycle duration, correct chromosome segregation and spindle orientation. The centrosome, which is the main microtubule-organizing centre (MTOC) of animal cells, contributes to all these processes. As one of the most structurally complex organs in our body, the brain is particularly susceptible to centrosome dysfunction. Autosomal recessive primary microcephaly (MCPH), primordial dwarfism disease Seckel syndrome (SCKS) and microcephalic osteodysplastic primordial dwarfism type II (MOPD-II) are often connected to mutations in centrosomal genes. In this chapter, we discuss the consequences of centrosome dysfunction during development and how they can contribute to the etiology of human diseases.
Varadi syndrome is a subtype of orofaciodigital syndrome (OFDS) that combines the typical features of OFDS and the posterior fossa features of Joubert syndrome. The only gene known to be mutated in Varadi syndrome is C5ORF42. In this report, we describe the phenotype of a patient with Varadi syndrome who is homozygous for a previously reported mutation in TCTN1 (NM_001082538.2:c.342-2A>G, p.Gly115Lysfs*8) and suggest that allelic disorders linked to TCTN1 include Varadi syndrome, in addition to Joubert syndrome and Meckel-Gruber syndrome.
GLI3 mutations are known to be associated with nine syndromes/conditions in which polydactyly is a feature. In this review, the embryology, pathogenesis, and animal models of GLI3-related polydactyly are discussed first. This is followed by a detailed review of the genotype-phenotype correlations. Based on our review of the literature and our clinical experiences, we recommend viewing GLI3-related syndromes/conditions as four separate entities; each characterized by a specific pattern of polydactyly. These four entities are: the preaxial polydactyly type IV-Greig-acrocallosal spectrum, postaxial polydactyly types A/B, Pallister-Hall syndrome (PHS), and oral-facial-digital overlap syndrome. We also provide illustrative clinical examples from our practice including a family with a novel GLI3 mutation causing PHS. The review also introduces the term 'Forme Fruste' preaxial polydactyly and gives several conclusions/recommendations including the recommendation to revise the current criteria for the clinical diagnosis of PHS.
