A Review of the Genetics and Pathogenesis of Syndactyly in Humans and Experimental Animals: A 3-Step Pathway of Pathogenesis

Al‐Qattan, Mohammad M.

doi:10.1155/2019/9652649

Cited by 10 publications

(9 citation statements)

References 78 publications

(110 reference statements)

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“…Lower levels of BMPs, which normally positively regulate interdigital apoptosis, now leads to an overexpression of FGF8 causing increased anti-apoptotic signals in the AER. This can indirectly inhibit retinoic acid and finally repress its function in the extracellular matrix (ECM), causing perturbed ICD inducing syndactyly phenotypes [ 7 , 13 , 17 , 19 ].…”

Section: Digit Separation Interactions In Normal Vs Syndactyly Phenot...mentioning

confidence: 99%

Genetic determinants of syndactyly: perspectives on pathogenesis and diagnosis

Cassim

Hettiarachchi

Dissanayake

2022

Orphanet J Rare Dis

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The formation of the digits is a tightly regulated process. During embryogenesis, disturbance of genetic pathways in limb development could result in syndactyly; a common congenital malformation consisting of webbing in adjacent digits. Currently, there is a paucity of knowledge regarding the exact developmental mechanism leading to this condition. The best studied canonical interactions of Wingless‐type–Bone Morphogenic Protein–Fibroblast Growth Factor (WNT–BMP–FGF8), plays a role in the interdigital cell death (ICD) which is thought to be repressed in human syndactyly. Animal studies have displayed other pathways such as the Notch signaling, metalloprotease and non-canonical WNT-Planar cell polarity (PCP), to also contribute to failure of ICD, although less prominence has been given. The current diagnosis is based on a clinical evaluation followed by radiography when indicated, and surgical release of digits at 6 months of age is recommended. This review discusses the interactions repressing ICD in syndactyly, and characterizes genes associated with non-syndromic and selected syndromes involving syndactyly, according to the best studied canonical WNT-BMP-FGF interactions in humans. Additionally, the controversies regarding the current syndactyly classification and the effect of non-coding elements are evaluated, which to our knowledge has not been previously highlighted. The aim of the review is to better understand the developmental process leading to this condition.

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Section: Digit Separation Interactions In Normal Vs Syndactyly Phenot...mentioning

confidence: 99%

Genetic determinants of syndactyly: perspectives on pathogenesis and diagnosis

Cassim

Hettiarachchi

Dissanayake

2022

Orphanet J Rare Dis

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“…Genetic targets associated with syndactyly reflect the regulatory axis that globally controls limb development, but, with the exception of BMP signaling (see below), their function in interdigit remodeling lacks death specificity. Different levels of syndactyly accompanied dysregulation of each of the different steps that regulate limb outgrowth and tissue differentiation, including, (a) alterations in transcription factors modulating growth and skeletal tissue differentiation; (b) alterations in cell adhesion and extracellular matrix components; (c) dysregulation of the signaling pathways active in the interdigits; and (d) alteration of the cell degradation machinery 61 Numerous transcription factors are expressed in the interdigital regions, but none of them exhibit an exclusive expression in areas of cell death.…”

Section: Genetic Alterations and Syndactylymentioning

confidence: 99%

“…Different levels of syndactyly accompanied dysregulation of each of the different steps that regulate limb outgrowth and tissue differentiation, including, (a) alterations in transcription factors modulating growth and skeletal tissue differentiation; (b) alterations in cell adhesion and extracellular matrix components; (c) dysregulation of the signaling pathways active in the interdigits; and (d) alteration of the cell degradation machinery. 61 Numerous transcription factors are expressed in the interdigital regions, but none of them exhibit an exclusive expression in areas of cell death. Yet syndactyly is often associated with mutations of transcription factors.…”

Section: Genetic Alterations and Syndactylymentioning

confidence: 99%

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Cell death in the developing vertebrate limb: A locally regulated mechanism contributing to musculoskeletal tissue morphogenesis and differentiation

Montero

Lorda‐Diez

Sánchez-Fernández

et al. 2020

Developmental Dynamics

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Our aim is to critically review current knowledge of the function and regulation of cell death in the developing limb. We provide a detailed, but short, overview of the areas of cell death observed in the developing limb, establishing their function in morphogenesis and structural development of limb tissues. We will examine the functions of this process in the formation and growth of the limb primordia, formation of cartilaginous skeleton, formation of synovial joints, and establishment of muscle bellies, tendons, and entheses. We will analyze the plasticity of the cell death program by focusing on the developmental potential of progenitors prior to death. Considering the prolonged plasticity of progenitors to escape from the death process, we will discuss a new biological perspective that explains cell death: this process, rather than secondary to a specific genetic program, is a consequence of the tissue building strategy employed by the embryo based on the formation of scaffolds that disintegrate once their associated neighboring structures differentiate.

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“…The author has previously offered a 3-step unified pathway of pathogenesis for syndactyly [15]. In the first step, there is either the overactivation of the WNT canonical pathway or the suppression of the bone morphogenetic protein canonical pathway.…”

Section: How Does a Defective Hoxd13 Protein Cause Syndactyly?mentioning

confidence: 99%

A Review of the Phenotype of Synpolydactyly Type 1 in Homozygous Patients: Defining the Relatively Long and Medially Deviated Big Toe with/without Cupping of the Forefoot as a Pathognomonic Feature in the Phenotype

Al‐Qattan

2020

BioMed Research International

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Synpolydactyly type 1 (SPD1, OMIM 186000) is inherited as autosomal dominant and is caused by HOXD13 mutations. The condition is rare and is known for its phenotypic heterogeneity. In the homozygous state, the phenotype is generally more severe and is characterized by three main features: a more severe degree of syndactyly, a more severe degree of brachydactyly, and the frequent loss of the normal tubular shape of the metacarpals/metatarsals. Due to the phenotypic heterogeneity and the phenotypic overlap with other types of syndactyly, no pathognomonic feature has been described for the homozygous phenotype of SPD1. In the current communication, the author reviews the literature on the phenotypes of SPD1 in homozygous patients. The review documents that not all homozygous patients show a severe hand phenotype. The review also defines the “relatively long and medially deviated big toe with/without cupping of the forefoot” as a pathognomonic feature in the phenotype. Illustration of this feature is done through a demonstrative clinical report in a multigeneration family with SPD1 and HOXD13 polyalanine repeat expansion. Finally, the pathogenesis of the clinical features is reviewed.

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A Review of the Genetics and Pathogenesis of Syndactyly in Humans and Experimental Animals: A 3-Step Pathway of Pathogenesis

Cited by 10 publications

References 78 publications

Genetic determinants of syndactyly: perspectives on pathogenesis and diagnosis

Genetic determinants of syndactyly: perspectives on pathogenesis and diagnosis

Cell death in the developing vertebrate limb: A locally regulated mechanism contributing to musculoskeletal tissue morphogenesis and differentiation

A Review of the Phenotype of Synpolydactyly Type 1 in Homozygous Patients: Defining the Relatively Long and Medially Deviated Big Toe with/without Cupping of the Forefoot as a Pathognomonic Feature in the Phenotype

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