Preaxial Polydactyly Research Articles

Genetic analysis of preaxial polydactyly: identification of novel variants and the role of ZRS duplications in a Chinese cohort of 102 cases.

Preaxial polydactyly (PPD) is a congenital limb malformation, previously reported to be caused primarily by variants in the ZRS and upstream preZRS regions. This study investigated genetic variations associated with PPD, focusing on point variants and copy number variations (CNVs) in the ZRS and preZRS regions. Comprehensive genetic analyses were conducted on 102 patients with PPD, including detailed clinical examinations and Sanger sequencing of the ZRS and preZRS regions. Additionally, real-time quantitative PCR (qPCR) was used to detect CNVs in the ZRS region. The evolutionary conservation and population frequencies of identified variants were also evaluated. Six point variants were identified, among which four are likely pathogenic novel variants: 93G > T (g.156584477G > T), 106G > A (g.156584464G > A), 278G > A (g.156584292G > A), and 409A > C (g.156585378A > C). Additionally, qPCR analysis revealed that 66.67% of patients exhibited ZRS duplications. Notably, these duplications were also present in cases with newly identified potential pathogenic point variants. These findings suggest the possible interaction of point variants in ZRS and preZRS through a common pathogenic mechanism, leading jointly to PPD. The findings expand the variant spectrum associated with non-syndromic polydactyly and highlight that, despite different classifications, anterior polydactyly caused by variants in ZRS and nearby regions may share common pathogenic mechanisms. The incorporation of various variant types in genetic screening can effectively enhance the rate of pathogenic variant detection and contribute to the cost-effectiveness of genetic testing for limb developmental defects, thereby promoting healthy births.

The Prenatal Ultrasound Diagnosis and Perinatal Outcome of Polydactyly: A Retrospective Cohort Study, 2016-2023.

To determine the significance of polydactyly identified on prenatal ultrasonography and provide a detailed analysis of characteristics and perinatal outcomes of fetal polydactyly. This is a retrospective cohort study of pregnancies with a postnatal diagnosis of fetal polydactyly between January 2016 and December 2023. The population was divided into 2 groups at postnatal diagnosis: the isolated polydactyly group and the nonisolated polydactyly group. Clinical data, prenatal ultrasonography, related genetic results, and postnatal outcomes were obtained. Our study cohort comprised 328 fetuses with polydactyly. The overall detection rate of polydactyly by prenatal ultrasound was 19.2%, and the first detection rate in the first-, second-, and third-trimester were 0.9%, 14.6%, and 3.7%, respectively. Preaxial polydactyly (PPD) of hand was the most common type and the most common type of foot polydactyly was postaxial polydactyly (PAP) both in the isolated group and in the nonisolated group; the central polydactyly is rare. Syndactyly was the most common abnormality complicated with polydactyly. Between the nonpolydactyly group, the isolatedpolydactyly group and the nonisolated polydactyly group, there was a significant difference in perinatal outcome (P < .001). The second trimester is the best gestational age for prenatal ultrasound detection of polydactyly. Polydactyly of hand was more likely PPD, while polydactyly of foot was more likely PAP. When polydactyly is detected by routine prenatal ultrasound, detailed ultrasound examination and prenatal counseling should be performed to determine the possibility of an underlying genetic syndrome.

A Novel Variant in the Cyto-Tail of SMO Gene Underlying Isolated Postaxial Polydactyly

Background: Polydactyly is one of the most common hereditary limb malformations, characterized by presence of additional digits in hands and/or feet. It is present either in isolated form or in combination with other features. Preaxial polydactyly with extra digit on the outside of the thumb or big toe, and postaxial polydactyly with extra digit on the outside of the little finger or little toe are the two main forms of polydactyly. Methods and Results: In the present study, two unrelated consanguineous families segregating PAP in an autosomal recessive manner were investigated. Whole exome sequencing, followed by segregation analysis using Sanger sequencing, revealed a homozygous missense variant [c.1792 G>A; p.(Gly598Arg); NM_005631.5] in the SMO in both families. Proteins SMO, PTCH, and GLI act as major components of the Sonic hedgehog pathway, which transmits signals to embryonic cells for cellular differentiation. Homology modeling revealed that the variant in SMO may disrupt proper protein folding and interaction with other molecules. Conclusion: Our study has revealed the second direct involvement of a sequence variant in the SMO causing isolated polydactyly. This study will highlight the importance of the inclusion of the SMO gene in screening individuals presenting polydactyly in hands and feet.

Increasing Sufu gene dosage reveals its unorthodox role in promoting polydactyly and medulloblastoma tumorigenesis.

Suppressor of fused (SUFU) is widely regarded as a key negative regulator of the sonic hedgehog (SHH) morphogenic pathway and a known tumor suppressor of medulloblastoma (MB). However, we report here that SUFU expression was markedly increased in 75% of specimens compiled in a tissue array comprising 49 unstratified MBs. The SUFU and GLI1 expression levels in this MB array showed strong positive correlation, which was also identified in a large public data set containing 736 MBs. We further report that increasing Sufu gene dosage in mice caused preaxial polydactyly, which was associated with the expansion of the Gli3 domain in the anterior limb bud and heightened Shh signaling responses during embryonic development. Increasing Sufu gene dosage also led to accelerated cerebellar development and, when combined with ablation of the Shh receptor encoded by Patched1 (Ptch1), promoted MB tumorigenesis. These data reveal multifaceted roles of SUFU in promoting MB tumorigenesis by enhancing SHH signaling. This revelation clarifies potentially counterintuitive clinical observation of high SUFU expression in MBs and may pave way for novel strategies to reduce or reverse MB progression.

Skeletal dysmorphology and mineralization defects in Fgf20 KO mice.

Fibroblast growth factor 20 (Fgf20), a member of the Fgf9 subfamily, was identified as an important regulator of bone differentiation and homeostasis processes. However, the role of Fgf20 in bone physiology has not been approached yet. Here we present a comprehensive bone phenotype analysis of mice with functional ablation of Fgf20. The study conducts an extensive analysis of Fgf20 knockout mice compared to controls, incorporating microCT scanning, volumetric analysis, Fgf9 subfamily expression and stimulation experiment and histological evaluation. The bone phenotype could be detected especially in the area of​ the lumbar and caudal part of the spine and in fingers. Regarding the spine, Fgf20-/- mice exhibited adhesions of the transverse process of the sixth lumbar vertebra to the pelvis as well as malformations in the distal part of their tails. Preaxial polydactyly and polysyndactyly in varying degrees of severity were also detected. High resolution microCT analysis of distal femurs and the fourth lumbar vertebra showed significant differences in structure and mineralization in both cortical and trabecular bone. These findings were histologically validated and may be associated with the expression of Fgf20 in chondrocytes and their progenitors. Moreover, histological sections demonstrated increased bone tissue formation, disruption of Fgf20-/- femur cartilage, and cellular-level alterations, particularly in osteoclasts. We also observed molar dysmorphology, including root taurodontism, and described variations in mineralization and dentin thickness. Our analysis provides evidence that Fgf20, together with other members of the Fgf9 subfamily, plays a crucial regulatory role in skeletal development and bone homeostasis.

Identification of a novel de novo PUF60 variant causing Verheij syndrome in a fetus

Verheij syndrome (VRJS) is a craniofacial spliceosomopathy with a wide phenotypic spectrum. Haploinsufficiency of the poly-uridine binding splicing factor 60 gene (PUF60) and its loss-of-function (LOF) variants are involved in VRJS. We evaluated a human fetus with congenital heart defects and preaxial polydactyly. Clinical data were obtained from the medical record. Whole-exome sequencing (WES) was used to explore the potential genetic etiology, and the detected variant verified using Sanger sequencing. Functional studies were performed to validate the pathogenic effects of the variant. Using trio-WES, we identified a novel PUF60 variant (NM_078480.2; c.1678 T > A, p.*560Argext*204) in the pedigree. Bioinformatic analyses revealed that the variant is potentially pathogenic, and functional studies indicated that it leads to degradation of the elongated protein and subsequently PUF60 LOF, producing some VRJS phenotypes. These findings confirmed the pathogenicity of the variant. This study implicates PUF60 LOF in the etiopathogenesis of VRJS. It not only expands the PUF60 variant spectrum, and also provides a basis for genetic counseling and the diagnosis of VRJS. Although trio-WES is a well-established approach for identifying the genetic etiology of rare multisystemic conditions, functional studies could aid in verifying the pathogenicity of novel variants.

Rare Occasion of Congenital Anomalies: Bilateral Syndactyly with Multiple Polydactyly of the Hands and Feet

Introduction: Upper and lower limb malformations are essential things that occur related to congenital disabilities, including syndactyly and polydactyly. It may appear in association with other birth defects as a part of a syndrome and may be present in the upper extremity or lower extremity. Cases of bilateral syndactyly with multiple polydactyly of the hands and feet are the first time in our center, and they must be promptly diagnosed and treated to avoid functional and cosmetic problems. Case presentation: A 3-month-old male toddler presented with webbed index, middle, and ring fingers with synonichia, accompanied by additional fingers on hands and feet. An x-ray examination revealed preaxial polydactyly at both hands with bifid phalanx (Wassel classification) and postaxial polydactyly type B. Duplicated postaxial metatarsal (Venn-Watson classification) and type B postaxial polydactyly also occur on both feet with webbed index and middle toe on the left foot. Direct closure was achieved with a dorsal trapezoidal and zig-zag flap to release the second and third fingers of the right hand, followed by resection of rudimentary fingers to help the child with early stages of motoric functions. Discussion: Syndactyly can cause a length difference that results in growth and functional difficulties. Surgical release of the index to middle and middle to ring fingers should be done early between 3-6 months of age and is expected to help the child grasp, write, and subsequently manipulate objects. We prioritize operating the right hand as around 90% of people prefer to use the right hand. Simple ligation was also performed to recess the rudimentary fingers on both hands and feet. It has no functional benefit and can limit function as it may get caught or make it difficult to wear shoes and gloves. We have to remind the parents that multiple surgeries may be necessary to achieve a satisfactory result and to complete the reconstruction before 24 months of age when the patterns of function of the digits are established. Conclusion: Bilateral complex syndactyly with preaxial and postaxial polydactyly on both hands and feet are distinctly uncommon entities that need multidisciplinary treatment. In this instance, the syndactyly releasing of the second and third fingers on the right hand is prioritized based on the function to be achieved, with excision of the rudimentary fingers.

Paternal age and risk for selected birth defects in a large South American sample.

The relationship between maternal age (MA) and birth defects (BD) has been extensively studied while much less research, mostly with discordant results, has focused on the risk of paternal age (PA) for BD. Furthermore, no consensus has been reached on the best way to control the association of PA with MA. The aim of the study was to evaluate the risk of PA increase, at 1-year intervals, for selected BD, especially controlling for the confounding effect of MA. The sample comprised of 27,944 liveborns presenting 1 of 18 selected isolated BD. Conditional logistic regressions were applied to evaluate the risk of advanced PA and its yearly increase, adjusting by MA and other variables. Of the 18 analyzed BD, only the risk for preaxial polydactyly (PreP) showed a significant association with increasing PA, while advanced MA was of low risk. For esophageal and anal atresia, associations with both PA and MA increases were observed. Results support the hypothesis of advanced PA as a risk factor for PreP and helps clarify the so far unexplained nonrandom association between this defect and Down syndrome.

Wassel Type IV Thumb Duplication A Case Report and Literature Review

Thumb polydactyly, also known as radial polydactyly, is the prevailing manifestation of polydactyly. Its existence has been documented in the hand literature from Digby's initial description in 1645. Preaxial polydactyly, specifically bifid thumb, has been extensively observed, with a frequency ranging from 0.08 to 1.4 per 1000 live births. Traditionally, radial polydactyly is classified into three distinct categories: severe hypoplasia, partial duplication, and entire duplication, which can sometimes be mistaken for pseudo duplication. The classification system developed by Wassel has emerged as the widely accepted standard for the categorization of thumb polydactyly. The classifications of surgical treatment procedures are associated with variations. Thumb duplication is categorized as a "duplication" (group 3) in the International Federation of Societies for Surgery of the Hand (IFSSH)/Swanson classification of congenital malformations of the hand and upper limb. The objective of surgical reconstruction is to achieve a thumb that is both stable and mobile, while also possessing appropriate dimensions and form. The prevailing method of reconstruction often involves the excision of the minor digit followed by the subsequent reconstruction of the major digit. Surgical procedures aim to rectify issues pertaining to deviation, instability, and insufficient dimensions. Moreover, it is worth noting that a significant proportion of instances will necessitate an additional intervention in order to enhance the cosmetic and/or functional result.

Lower Extremity Rare Preaxial Polydactyly. A Case Report and Literature Review

The condition known as pediatric foot polydactyly can manifest itself in a broad range of malformations, from a single extra digit that is only connected to the rest of the foot by a thin band of connective tissue to intricate central foot duplications that involve the duplication of tarsal bones. The presentation of preaxial polydactyly of the foot is crucial to understand, even though it is quite uncommon. This is because in over half of the cases, several congenital malformations, such as syndactyly and atrial septum defects, have been described. The result of surgical reconstruction should be a foot that is stable, mobile, and pain-free, with five aesthetically pleasing toes. This should allow the patient to wear standard footwear and walk without experiencing any discomfort.

A novel smoothed (SMO) point mutation in congenital tibial hemimelia: a case report

BackgroundCongenital tibial hemimelia (CTH [MIM: 275220]) is a rare congenital limb deficiency that manifests as a shortened, curved, dysplastic or absent tibia with polydactyly. In previous studies, mutations of a distant sonic hedgehog (SHH) cis-regulator (ZRS) and a Shh repressor (GLI3) were identified.Case presentationHere, we admitted a 20-month-old boy who manifested with right tibial deformity, varus foot, ankle dislocation, and ipsilateral preaxial polydactyly. After genetic sequencing and data analysis, the results revealed a 443 A > G mutation in the father and a 536 C > T mutation in the mother in exon 2 of the Smoothed (SMO) gene at 7q32.1, with the coexistence of both mutant alleles in the proband/patient.ConclusionsOur report suggests that even though not previously reported, SMO mutations may be associated with limb anomalies such as tibial hemimelia via Hh signaling in humans and has implications for genetic counseling.

Distinct patterning responses of wing and leg neuromuscular systems to different preaxial polydactylies.

The tetrapod limb has long served as a paradigm to study vertebrate pattern formation and evolutionary diversification. The distal part of the limb, the so-called autopod, is of particular interest in this regard, given the numerous modifications in both its morphology and behavioral motor output. While the underlying alterations in skeletal form have received considerable attention, much less is known about the accompanying changes in the neuromuscular system. However, modifications in the skeleton need to be properly integrated with both muscle and nerve patterns, to result in a fully functional limb. This task is further complicated by the distinct embryonic origins of the three main tissue types involved-skeleton, muscles and nerves-and, accordingly, how they are patterned and connected with one another during development. To evaluate the degree of regulative crosstalk in this complex limb patterning process, here we analyze the developing limb neuromuscular system of Silkie breed chicken. These animals display a preaxial polydactyly, due to a polymorphism in the limb regulatory region of the Sonic Hedgehog gene. Using lightsheet microscopy and 3D-reconstructions, we investigate the neuromuscular patterns of extra digits in Silkie wings and legs, and compare our results to Retinoic Acid-induced polydactylies. Contrary to previous findings, Silkie autopod muscle patterns do not adjust to alterations in the underlying skeletal topology, while nerves show partial responsiveness. We discuss the implications of tissue-specific sensitivities to global limb patterning cues for our understanding of the evolution of novel forms and functions in the distal tetrapod limb.

Clinical and genetic analysis in Chinese families with synpolydactyly, and cellular localization of HOXD13 with different length of polyalanine tract.

Synpolydactyly (SPD) is caused by mutations in the transcription factor gene HOXD13. Such mutations include polyalanine expansion (PAE), but further study is required for the phenotypic spectrum characteristics of HOXD13 PAE. We investigated four unrelated Chinese families with significant limb malformations. Three PAEs were found in the HOXD13 polyalanine coding region: c.172_192dup (p.Ala58_Ala64dup) in Family 1, c.169_192dup (p.Ala57_Ala64dup) in Family 2, and c.183_210dup (p.Ala62_Ala70dup) in Family 3 and Family 4. Interestingly, we identified a new manifestation of preaxial polydactyly in both hands in a pediatric patient with an expansion of seven alanines, a phenotype not previously noted in SPD patients. Comparing with the wild-type cells and mutant cells with polyalanine contractions (PACs), the HOXD13 protein with a PAE of nine-alanine or more was difficult to enter the nucleus, and easy to form inclusion bodies in the cytoplasm, and with the increase of PAE, the more inclusion bodies were formed. This study not only expanded the phenotypic spectrum of SPD, but also enriched our understanding of its pathogenic mechanisms.

A new hupehsuchian (Reptilia: Ichthyosauromorpha) from the Lower Triassic of South China with implications for the evolution of polydactyly

ABSTRACT Hupehsuchia, an enigmatic group of marine reptiles from the Lower Triassic of South China, is characterized by a suite of features including polydactyly in either or both fore and hind limbs. Particularly, one parahupehsuchine specimen shows seven-digited forelimbs and a six-digited hind limb. However, questions remain as to what sequence manus configuration evolved in hupehsuchians. Here, we describe a new hupehsuchian with seven manual digits associated with extra carpals and digits. Our new phylogeny revealed the evolutionary sequence of extra carpals, metacarpals, and phalanges in hupehsuchians through preaxial and central polydactyly and suggested that the polydactyly of the manus evolved stepwise in hupehsuchians.

Characterizing Pathogenic Enhancer Activity at Single-cell Resolution

The ZRS enhancer, a regulatory sequence found in numerous organisms, plays an important role in early embryonic limb development. ZRS controls the expression of the Sonic Hedgehog gene (Shh), and therefore early limb development in an organism as Shh has been shown to control the width of the limb bud by stimulating mesenchyme cell proliferation due to its ability to regulate the anterior-posterior length of the apical ectodermal ridge. Several transcription factors, acting as repressors or activators of the Shh gene, coordinate this limb development process in tandem with the ZRS enhancer. While the significance of normal ZRS activity is evident, this study looks deeper into the effects of pathogenic changes to the ZRS enhancer and the development of associated limb disorders such as preaxial polydactyly (PPD) by focusing on several aspects of ZRS regulation and its relation to Shh expression. This was accomplished by characterizing the expression of Shh and mCherry, an introduced luminescence gene regulated by ZRS, through single-cell RNA sequenced cells from a developing limb bud of a mouse embryo. Additionally, this study characterized specific transcription factors as potential repressors or activators of ZRS by determining TF enrichment or depletion in highly expressive Shh and mCherry cells. Classifying such TFs is vital in identifying the regulatory elements that control the formation of limb malformation disorders such as preaxial polydactyly and aid in the development of future therapeutic interventions.

A case of acrocallosal syndrome in a neonate with congenital heart abnormality

The usual features of the acrocallosal syndrome (ACLS) are agenesis of the corpus callosum, mental retardation, prominent craniofacial deformities, and specific digital abnormalities. ACLS is a rare genetic disorder which may be autosomal recessive, however it usually occurs sporadically. A 20-day-old newborn was admitted to the pediatric clinic due to the discovery of corpus callosum agenesis during pregnancy. The fetal echocardiography revealed an ASD and moderate tricuspid regurgitation (TR). During limb assessment, right foot pre-axial polydactyly was noted, and skull exam revealed anterior fontanelle enlargement. The brain MRI showed agenesis of the corpus callosum and enlarged lateral ventricles. The parents had no consanguinity and their genetic test had shown no anomalies.The neurologist decided to monitor the neurological development of the child. The current case provides additional evidence that ACLS can be associated with pre-axial polydactyly and craniofacial symptoms including enlargement of the anterior fontanelle. Second-trimester ultrasonography can detect central nervous system malformations such as ventricular enlargement and corpus callosum anomalies. Moreover, Echocardiography is recommended to check for heart abnormalities in these children.

Current concepts in the management of the duplicated thumb

Preaxial polydactyly is a common congenital anomaly of the hand presenting at birth. Surgical treatment is aimed at creating a functional thumb capable of normal grip and pinch strength with acceptable aesthetics. Each case is unique and presents individual challenges to the hand surgeon. The aim of this review is to provide a synopsis of current knowledge and recommended surgical techniques for the duplicated thumb.

A review of polydactyly and its inheritance: Connecting the dots

This study collects what is known about the inheritance underpinnings of syndromic and non-syndromic polydactylies and highlights dactyly presentations with unknown genetic roots. This review summarizes the current information and genetics-enhanced understanding of polydactyly. There is a frequency of 0.37 to 1.2 per 1000 live births for polydactyly, which is also known as hyperdactyly. It is characterized by the presence of extra fingers. Polydactyly is caused by a failure in limb development, specifically the patterning of the developing limb bud. The phenotypic and genetic variability of polydactyly makes its etiology difficult to understand. Pre-axial polydactyly, central polydactyly (axial), and postaxial polydactyly are all examples of non-syndromic polydactyly (ulnar). An autosomal dominant disorder with varying penetrance that is mostly passed down via limb development patterning abnormalities. A comprehensive search of MEDLINE/PubMed and other databases was followed by an evaluation of the relevant papers, with a particular focus on those published between 2000 and 2022. Of 747 published article related to Polydactyly from MEDLINE/PubMed search, 43 were from the last 10 years and were the focus of this review. Polydactyly is one of the most frequent congenital hand malformations. PAP is more common than PPD, whereas central polydactyly is very uncommon.

Meckel Syndrome: A Clinical and Molecular Overview

AbstractMeckel syndrome (MKS) is a lethal, autosomal recessive, congenital syndrome caused by mutations in genes that encode proteins structurally or functionally related to the primary cilium. MKS is a malformative syndrome, most commonly characterized by occipital meningoencephalocele, polycystic kidney disease, liver fibrosis, and post- and (occasionally) preaxial polydactyly. To date, more than 10 genes are known to constitute the molecular background of MKS, displaying genetic heterogeneity. Individuals with MKS may resemble some phenotypic features of Joubert syndrome and related disorders, thus making diagnostic setting quite challenging. Here, we systematically reviewed the main clinical and genetic characteristics of MKS and its role among ciliopathies.

Tissue-specific requirement of sodium channel and clathrin linker 1 (Sclt1) for ciliogenesis during limb development.

Primary cilia have essential roles as signaling centers during development and adult homeostasis. Disruption of ciliary structure or function causes congenital human disorders called ciliopathies. Centriolar distal appendage (DAP) proteins are important for anchoring cilia to the membrane. However, the exact functions of DAP during in vivo ciliogenesis and animal development remain poorly understood. Here, we showed that the DAP component sodium channel and clathrin linker 1 (Sclt1) mutant mice had abnormal craniofacial and limb development with postnatal lethality. In mutant embryos, most of the affected tissues had defects in DAP recruitment to the basal body and docking to the membrane that resulted in reduced ciliogenesis and disrupted hedgehog (Hh) signaling in limb bud mesenchymal cells. However, limb digit formation and ciliogenesis in Sclt1 mutant mice were differentially affected between the fore- and hindlimb buds. The forelimbs developed normally in Sclt1 mutants, but the hindlimbs had preaxial polydactyly. Heterozygous loss of Cep83, another core DAP component, in Sclt1 mutant mice, caused forelimb and hindlimb polydactyly. These findings revealed the tissue-specific differential requirement of DAPs. Taken together, these results indicated that during limb development the ciliary base components, DAPs, play an essential role in ciliogenesis and Hh signaling in vivo in a position-dependent manner.