World Journal of

WJ O Orthopedics
Submit a Manuscript: https://www.f6publishing.com World J Orthop 2023 January 18; 14(1): 13-22

DOI: 10.5312/wjo.v14.i1.13 ISSN 2218-5836 (online)

MINIREVIEWS

Polydactyly: Clinical and molecular manifestations

Zisis Kyriazis, Panagoula Kollia, Ioanna Grivea, Nikolaos Stefanou, Sotirios Sotiriou, Zoe H Dailiana

Specialty type: Orthopedics Zisis Kyriazis, Nikolaos Stefanou, Zoe H Dailiana, Department of Orthopaedic Surgery, Faculty of
Medicine, School of Health Sciences, University of Thessaly, Larissa 41500, Greece
Provenance and peer review:
Invited article; Externally peer Panagoula Kollia, Department of Genetics and Biotechnology, Faculty of Biology, University of
reviewed. Athens, Athens 15701, Greece

Peer-review model: Single blind Ioanna Grivea, Department of Paediatrics, Faculty of Medicine, School of Health Sciences,
University of Thessaly, Larissa 41500, Greece
Peer-review report’s scientific
quality classification Sotirios Sotiriou, Laboratory of Histology and Embryology, Faculty of Medicine, School of
Health Sciences, University of Thessaly, Larissa 41500, Greece
Grade A (Excellent): A
Grade B (Very good): B Corresponding author: Zoe H Dailiana, MD, PhD, Professor, Surgeon, Department of
Grade C (Good): 0 Orthopaedic Surgery, Faculty of Medicine, School of Health Sciences, University of Thessaly,
Grade D (Fair): 0 Biopolis, Larissa 41500, Greece. dailiana@med.uth.gr
Grade E (Poor): 0

P-Reviewer: Faillace JJ; Liao JX,

China
Abstract
Polydactyly is a malformation during the development of the human limb, which
Received: September 26, 2022 is characterized by the presence of more than the normal number of fingers or
Peer-review started: September 26, toes. It is considered to be one of the most common inherited hand disorders. It
2022 can be divided into two major groups: Non-syndromic polydactyly or syndromic
First decision: October 21, 2022 polydactyly. According to the anatomical location of the duplicated digits,
Revised: November 4, 2022 polydactyly can be generally subdivided into pre-, post-axial, and mesoaxial
Accepted: December 7, 2022 forms. Non-syndromic polydactyly is often inherited with an autosomal
Article in press: December 7, 2022 dominant trait and defects during the procedure of anterior-posterior patterning
Published online: January 18, 2023 of limb development are incriminated for the final phenotype of the malforma-
tion. There are several forms of polydactyly, including hand and foot extra digit
manifestations. The deformity affects upper limbs with a higher frequency than
the lower, and the left foot is more often involved than the right. The treatment is
always surgical. Since the clinical presentation is highly diverse, the treatment
combines single or multiple surgical operations, depending on the type of
polydactyly. The research attention that congenital limb deformities have recently
attracted has resulted in broadening the list of isolated gene mutations associated
with the disorders. Next generation sequencing technologies have contributed to
the correlation of phenotype and genetic profile of the multiple polydactyly
manifestations and have helped in early diagnosis and screening of most non-
syndromic and syndromic disorders.

Key Words: Polydactyly; Gene; Syndromic; Non-syndromic; Preaxial; Postaxial

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Kyriazis Z et al. Polydactyly: clinical and molecular manifestations

©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.

Core Tip: The molecular basis of hand and foot polydactyly, syndromic or non- syndromic, is diverse.
There are several phenotypes of the disorder which are correlated to a specific molecular profile and other
whose molecular basis is still unclear. We summarize and provide an overview of gene mutations that
cause hand and foot polydactyly as an isolated disorder or as part of a syndrome and present the clinical
manifestations that they cause.

Citation: Kyriazis Z, Kollia P, Grivea I, Stefanou N, Sotiriou S, Dailiana ZH. Polydactyly: Clinical and molecular
manifestations. World J Orthop 2023; 14(1): 13-22
URL: https://www.wjgnet.com/2218-5836/full/v14/i1/13.htm
DOI: https://dx.doi.org/10.5312/wjo.v14.i1.13

INTRODUCTION
Non-syndromic (Table 1) or syndromic polydactyly (Table 2) is often inherited with an autosomal
dominant trait with variable penetrance[1]. It is related with a disturbance of the anterior–posterior axial
development procedure of the limb[2] and is classified into preaxial, axial (central), and postaxial
polydactyly[3]. Preaxial polydactyly is defined as an extra digit affecting the radial/tibial digits while
postaxial involves the ulnar/peroneal digits. The rare type of axial (central) polydactyly refers to the
duplication of three central hand or foot digits. Mirror-image polydactyly and Haas-type polysyn-
dactyly are rare and distinct types, not fitting to the three categories[4].
Many specific phenotypes, including all types of hand and foot polydactyly, have been identified and
correlated to gene mutations[5].
Since polydactyly is often a part of a syndrome, the ability to identify the potential syndromes
associated with this anomaly is very important for the clinician. Additionally, it is important to
distinguish between syndromic and non-syndromic cases for reasons of genetic counselling. In this
paper, we review the recent progress in the molecular genetics, including clinical and molecular
manifestations of disorders, and present some representative syndromes including polydactyly as a
phenotype.

CLINICAL AND MOLECULAR MANIFESTATIONS OF NON-SYNDROMIC HAND AND FOOT

POLYDACTYLY
Preaxial polydactyly
The preaxial form of polydactyly is the second most common phenotype behind the postaxial with a
reported prevalence of approximately 0.8 to 2.3 in 10000 live births. It is characterized by an extra digit
on the tibial/radial side of limb (Figure 1). The following classification has been suggested:
Preaxial polydactyly type I, which is thumb polydactyly (OMIM 174400)[6]—characterized by
duplication of one or more skeletal elements of a biphalangeal thumb.
Preaxial polydactyly type II, which is polydactyly of a triphalangeal thumb (OMIM 174500).
Preaxial polydactyly type III, which is polydactyly of the index finger, characterized by the presence
of one or two triphalangeal digits (OMIM 174600).
Preaxial polydactyly type IV and syndactyly of various degrees involving the middle and ring
finger/second and third toe (OMIM 174700) or hallux polydactyly (OMIM 601759)[7].

Preaxial polydactyly type I: Thumb polydactyly is usually observed in unilateral form. In bilateral
cases, hands are more often affected and the left hand is also more often affected than the right. It
follows an autosomal dominant inheritance model[7]. However, a recent study in a Pakistani family has
revealed a rare autosomal recessive form of preaxial polydactyly, linked to a novel variant (c.1517T>A;
p. Leu506Gln) in the GLI1 gene on chromosome 12q13.3[8].
The most commonly used classification is Wassel classification which divides thumb duplication into
six subtypes according to the level and the extent of duplication (partial or complete)[9]. Hallux
polydactyly is known to exist as a predominant presentation or an isolated disorder. The incidence of
hallux duplication is 2.4/100000 as compared to thumb polydactyly incidence in South America, which
is 1.65/10000.
Preaxial type I polydactyly is caused by sequence variants in the sonic hedgehog (SHH) enhancer,
called zone of polarizing activity (ZPA) regulatory sequence (ZRS), which is regulated by LMBR1 gene.

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 Kyriazis Z et al. Polydactyly: clinical and molecular manifestations

Table 1 Mutated genes isolated in non-syndromic polydactyly

Preaxial Central Postaxial Complex

CEP290 CPLANE1 GLI3 MIPOL1

RPGRIP1 ZNF141 PITX1

TMEM216 DACH1 LMBR1

FBN1 GLI1

CEP164

MEGF8

LMBR1

ZRS

GLI3

ZNF141

STKLD1

GLI1

KIAA0586

EVC

HES1

Table 2 Mutated genes isolated in syndromic polydactyly

Syndrome Mutated gene(s)

Bardet-Biedl CCDC28B, ARL6, MKS1, BBS8, SDCCAG8, LZTFL1, WDPCP, BBS4, BBS12, TMEM67, BBS1, BBS2, BBS6, BBS10, BBS9,
BBS7, BBS5, CEP290, TRIM32, BBIP1, ALMS1, MKKS

McKusick-Kaufman MKKS

Carpenter P4HB, RAB23

Saethre-Chotzen TWIST1, FGFR2

Poland syndrome -

Greig cephalopolysyndactyly GLI3

Short-rib polydactyly ATD1, LBN, DYNC2H1, IFT81

Pallister-Hall GLI3

Triphalangeal thumb- LMBR1

polydactyly

Smith-Lemli-Opitz DHCR7

Mutations in CEP290, RPGRIP1, TMEM216, FBN1, CEP1, and MEGF8 genes have been isolated and
suspected to play a role in Wassel III and Wassel IV manifestations[10]. Recently, a mutation in STKLD1
gene, located on chromosome 9q34.2, was found and correlated with the disease phenotype in all
members of the studied family[11]. Another molecular study of the SHH/GLI signaling axis, identified
HES1 gene as a downstream modifier which can cause preaxial polydactyly[12].
Next generation sequence analysis in a large four-generation family with isolated preaxial
polydactyly revealed a new ZRS mutation (g.101779T>A) which can cause the disease phenotype[13].
Another recent genetic analysis of 20 Chinese patients with preaxial polydactyly identified two novel
mutations in GLI3 gene (c.G2844A) and in EVC gene (c.1409_1410del). Mutations in KIAA0586 gene,
which are related with ciliopathies (OMIM 610178), were also detected[14].

Preaxial polydactyly type II: Preaxial polydactyly type II is characterized by the presence of a usually
opposable triphalangeal thumb with or without additional duplication of one or more skeletal
components of the thumb. The thumb appearance can differ widely in shape or it can be deviated in the
radio-ulnar plane. It can also be associated with Holt-Oram syndrome and Fanconi anemia. LMBR1 and
its related pathways Wnt/Notch and Hedgehog play a significant role in the development of the disorder.
The disease gene locus was mapped to chromosome 7q36[15]. Mutations in the SHH regulatory factor

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Kyriazis Z et al. Polydactyly: clinical and molecular manifestations

Figure 1 Preaxial polydactyly. A: Preaxial/radial hand polydactyly phenotype; B: Preaxial/tibial foot polydactyly phenotype.

were also reported[16]. Two mutations, a 739A>G transition near the 5- end of the ZRS and a 621C>G
mutation in the ZRS of the LMBR1 gene, were identified[17]. Triphalangeal thumb-polysyndactyly can
manifest as a syndrome. It is an isolated limb deformity characterized by pre- and postaxial polysyn-
dactyly of hands and feet. Mutations in ZRS have been identified[18,19].

Preaxial polydactyly type III: Preaxial polydactyly type III is an autosomal dominant disorder which is
characterized by a malformation of fingers, where the thumb is replaced by one or two triphalangeal
digits with dermatoglyphic pattern specific for the index finger. It can occur unilaterally and bilaterally.
No responsible gene has been identified[20].

Preaxial polydactyly type IV: Preaxial polydactyly type IV is an autosomal dominant disorder which
can be described as mild duplication of the thumb, syndactyly that affects the third and fourth
hand/foot fingers/toes, duplication of the first or second toes, and toes syndactyly. There are patients
who have only foot malformations. GLI3 gene mutations are associated with the disorder. Genetic
analysis in two families with the phenotype were found heterozygous for p.L1216PfsX31 and p.R290X
mutations in the GLI3 gene[21].

Postaxial polydactyly
Postaxial polydactyly is a frequent congenital hand malformation characterized by fifth digit duplic-
ations in hands and/or feet (Figure 2). Its prevalence is estimated between 1/630 and 1/3300 in
Caucasian race and between 1/100 and 1/300 in Black race. Two phenotypic categories have been
described: Type A, the extra digit is well formed and articulates with the fifth or an extra metacarpal;
Type B, there is a rudimentary extra fifth digit which is usually represented by an extra skin tag. Both
types can be inherited by autosomal dominant or recessive trait[22]. There are six subcategories of type
A postaxial polydactyly.

Postaxial polydactyly type A1: In postaxial polydactyly type A1, the extra digit is well-formed and
articulates with the fifth or a sixth metacarpal/metatarsal. Genetic analysis in an Indian family resulted
in the identification of association of GLI3 gene mutations with the phenotype[23]. It was mapped to
7pl5-q11.23. Mutation in the C- and the N-terminal or the zinc finger domain of the GLI3 gene causes
isolated postaxial polydactyly type A1 and is also linked to Greig cephalopolysyndactyly syndrome,
while a mutation in the post-zinc finger region is incriminated for Pallister–Hall syndrome[24]. A recent
genetic study in a Chinese family with isolated postaxial polydactyly revealed a new mutation of GLI3
(c.1180C>TT, p.P394fs18x)[25]. A DACH1 gene mutation was identified in a patient with bilateral
postaxial polydactyly who was subjected to whole exome sequencing[26]. New mutations of the GLI1
gene have been incriminated for postaxial polydactyly according to a novel study which aims to help in
prevention of the disorder[27].

Postaxial polydactyly type A2: It consists of Type A polydactyly phenotypes with an extra digit well-
formed. A genetic study of an Indian kindred revealed disease gene locus of postaxial polydactyly type
A2 (OMIM 602085) which was mapped to 13q21-q32[28]. The underlying gene for the disorder has not
been identified.

Postaxial polydactyly type A3: It manifests with polydactyly phenotypes Type A/B in hands and feet.
Genetic analysis of a Chinese family discovered incomplete penetrance of the phenotype and identified
the disease gene locus which was mapped to 19p13.2-p13.1[29]. There is not an identified gene
responsible for the disorder.

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 Kyriazis Z et al. Polydactyly: clinical and molecular manifestations

Figure 2 Postaxial polydactyly. A: Postaxial/ulnar hand polydactyly phenotype; B: Postaxial/fibular foot polydactyly phenotype.

Postaxial polydactyly type A4: It is characterized by polydactyly phenotypes Type A/B in hands and
feet and two to three finger/toe syndactyly. The disease locus (OMIM 608562) was mapped to 7q21-q34
by genetic analysis in a Dutch family with an autosomal dominant inheritance of the phenotype[30].
Until now there is no candidate gene for this manifestation.

Postaxial polydactyly type A5: It is characterized by polydactyly of hands and feet, minor syndactyly,
and five to six metacarpal synostoses. Two Indian families and a Sicilian family were identified to have
this type of autosomal recessive postaxial polydactyly[31]. Postaxial polydactyly type A5 (OMIM 263450
) was mapped to 13q13.3- 13q21.2 region. The underlying gene for this phenotype has not yet been
identified.

Postaxial polydactyly type A6: The phenotype is characterized by an extra functionally developed digit
in hands and/or feet. Mutations in the ZNF141 gene are considered to cause postaxial polydactyly type
A6 (OMIM 615226). Exome sequencing in a Pakistani family resulted in showing autosomal recessive
inheritance of A6 phenotype. The ZNF141 gene consists of four exons[32]. The final protein is expressed
in many different tissues and it is still unclear whether it plays a role in embryogenesis[33].

Postaxial polydactyly type B: It is the most common type of polydactyly. There is a vestigial nonfunc-
tional, partially formed, ulnar (or fibular) digit with no bony attachments, attached by a narrow
neurovascular pedicle to the lateral aspect of the hand or foot[25]. GLI3 gene mutations are associated
with this often manifestation.

Central polydactyly
Central polydactyly (OMIM 174200) is a very rare phenotype which is characterized by duplication of
one of the three middle digits of the hand and foot. It can be an isolated defect or can be accompanied
with other anomalies. The most often manifestation of hand central polydactyly is duplication of the
fourth digit[3]. Foot central polydactyly is very rare and the second toe is most commonly duplicated
[34]. Central polydactyly is related to split-foot malformation with mesoaxial polydactyly and
Holzgreve syndrome. CPLANE1 is the only known gene which is associated with central polydactyly.

Complex types
Mirror image polydactyly: This rare non-syndromic limb malformation (OMIM 135750) presents with
mirror-image hand or foot polydactyly. The malformation can be unilateral, bilateral, and very rarely
tetramelic. It can be associated with other congenital anomalies or can present isolated. MIPOL1 and
PITX1 gene mutations have been identified and incriminated for this disorder. A recent German study
in a patient with the phenotype showed a heterozygous deletion of 4.9 Mb on 5q31 including PITX1[35].

Haas-type polysyndactyly: Haas-type polysyndactyly (OMIM 186200) is characterized by complete

cutaneous syndactyly of all hand fingers and occasionally foot toes are affected. It frequently presents
with polydactyly with six digits and six metacarpals. It is inherited with an autosomal dominant trait. It
is usually classified as syndactyly type IV. The locus for Haas-type polysyndactyly was mapped on 7q36
by linkage and haplotype analysis of a Chinese family[36]. Mutations of the ZRS region of LMBR1 gene
and other ZRS point mutations were found in families presenting with the clinical sings of Haas-type
polysyndactyly according to two recent studies[37,38].

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CLINICAL AND MOLECULAR MANIFESTATIONS OF SYNDROMIC HAND AND FOOT

POLYDACTYLY
Bardet-Biedl syndrome
Bardet-Biedl syndrome (OMIM 209900) is an autosomal or digenic recessive disorder which can present
with vision loss, obesity, hand and/or foot polydactyly, intellectual disabilities, and hypogonadism.
Mutations in at least 20 genes have been identified and associated with the syndrome[39]: CCDC28B,
ARL6, MKS1, BBS8, SDCCAG8, LZTFL1, WDPCP, BBS4, BBS12, TMEM67, BBS1, BBS2, BBS6, BBS10,
BBS9, BBS4, BBS7, CEP290, TRIM32, BBIP1, IFT27, and IFT172genes are examples of them. A recent
study in four Iranian children with a clinical diagnosis of Bardet-Biedl syndrome identified in three
children one previously reported mutation in BBS12 gene (c.265-266delTT, p.L89fs) and two newly
detected mutations in MKKS (c.1196T>G, p.L399X) and BBS7 gene (c.1636C>T, p.Q546X). A new
mutation in ALMS1 gene was isolated in the other child[40].

McKusick-Kaufman syndrome
McKusick-Kaufman syndrome’s phenotype (OMIM 236700) consists of the following features:
Genitourinary malformations (hydrometrocolpos, glanular hypospadias, and prominent scrotal raphe),
postaxial hand and/or foot polydactyly, and rarely cardiac defects. MKKS gene mutations are
associated with McKusick-Kaufman syndrome and they are inherited with an autosomal recessive trait
[41].

Carpenter syndrome
Carpenter syndrome (OMIM 201000) is characterized by craniosynostosis, involving a pointed head
(acrocephaly), syndactyly of certain fingers or toes, and polydactyly. It appears most commonly with
foot polydactyly, rarely hand polydactyly and hand or toe cutaneous syndactyly. RAB23 gene mutations
are associated with the syndrome, which appears with autosomal recessive inheritance[42]. Recent
molecular studies have identified two new mutations in RAB23 gene (NM_001278668:c.T416C:p.Leu139-
Pro and NM_016277.5:c.398+1G>A)[43] and a new mutation in P4HB gene [44].

Saethre-Chotzen syndrome
Saethre-Chotzen syndrome’s phenotype (OMIM 101400) is characterized by premature closure of cranial
sutures, hand syndactyly, and foot polydactyly. Foot polydactyly most often involves the first toe.
TWIST1 and FGFR2 gene mutations are usually incriminated and inherited with an autosomal dominant
trait[45].

Poland syndrome
Poland syndrome (OMIM 173800) involves underdeveloped pectoralis muscles on one side of chest wall
and ipsilateral hand abnormalities, including short fingers and syndactyly (symbrachydactyly);
however, there are rare cases of preaxial polydactyly manifestations in the literature[46]. Most cases of
Poland syndrome are not related with a family history, and they are sporadic. Rarely it is inherited with
an autosomal dominant trait through generations in families. There are no isolated gene mutations
correlated with Poland syndrome.

Greig cephalopolysyndactyly syndrome

Greig cephalopolysyndactyly (OMIM 175700) syndrome is an autosomal dominant syndrome, which
presents with hypertelorism, macrocephaly, and polydactyly. The polydactyly is most commonly
preaxial of the feet and postaxial in the hands. Greig cephalopolysyndactyly is associated with GLI3
mutations[47]. Recently, molecular studies have broadened the spectrum of known GLI3 mutations
correlated with the syndrome[48,49].

Pallister-Hall syndrome
Pallister-Hall syndrome (OMIM 146510) is a rare disorder which affects many parts of the body. Very
often manifestation of the syndrome is postaxial polydactyly and cutaneous syndactyly of hands and
toes. GLI3 gene mutations are considered responsible for this autosomal dominant disorder[50].

Short-rib polydactyly
Jeune syndrome, Ellis-van Creveld syndrome, Saldino-Noonan syndrome, and Majewski syndrome are
called short-rib polydactyly syndromes (OMIM 613091). They belong to a group of lethal congenital
disorders characterized by shortening of the ribs and long bones, hand and/ or foot polydactyly, and a
range of extraskeletal phenotypes. ATD1 gene is considered to be responsible for Jeune syndrome. LBN
gene mutations cause Ellis-van Creveld syndrome and individuals carrying DYNC2H1 gene mutations
can present with Saldino-Noonan and Majewski syndromes. Novel exome sequencing studies have
isolated two new mutations in DYNC2H1 gene (c.8077G>T and c.11741_11742delTT) and a new
mutation in IFT81 gene, causing malformation of the cilia[51,52]. Short-rib polydactyly syndromes are

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 Kyriazis Z et al. Polydactyly: clinical and molecular manifestations

usually inherited with an autosomal recessive trait[53].

Triphalangeal thumb-polydactyly syndrome

Triphalangeal thumb-polydactyly syndrome (OMIM 173800) consists of triphalangeal thumbs, pre- or
post-axial polydactyly, and syndactyly. LMBR1 gene is considered to be responsible for this
manifestation. It is inherited with an autosomal dominant genetic trait. Typically, the syndrome
presents with duplicated triphalangeal thumbs and typical phenotypic findings include duplicated
triphalangeal thumbs and syndactyly between middle, ring, or little finger[54].

Smith-Lemli-Opitz syndrome
Smith-Lemli-Opitz syndrome (OMIM 173800) is a multi-malformation syndrome. The responsible gene
for this syndrome is considered to be DHCR7 gene and it is inherited with an autosomal recessive
pattern[55]. Its phenotype contains foot syndactyly (usually of 2nd and 3rd toes) and postaxial hand
polydactyly.

CONCLUSION
Genetic mechanisms which combine epigenetic and environmental factors play a significant role in foot
and hand polydactyly manifestations[56]. Proper genotype-phenotype correlations might help in future
genetic testing and enhance our knowledge about identified diseases and their associated genes. Recent
genetic analysis techniques of extra foot or hand digit formation highlight the existence of nongradual
transitions in phenotypes, suggesting a distinction between continuous and discontinuous variation in
evolution. Genome sequencing will probably lead to the discovery of a number of new gene mutations
responsible for non-syndromic or syndromic polydactyly. Clinical manifestation and genetic profile
correlation of polydactyly types will be further established by use of bioinformatics analysis of gene
mutations. Progress of prenatal diagnosis, which is still mostly postnatal, prenatal operative treatment
planning, and potential future gene modification treatment will be enhanced and unknown molecular
background of diseases, which is to date unclear, will be elucidated.

FOOTNOTES
Author contributions: Kyriazis Z wrote the paper and participated in the collection of the data; Dailiana ZH, Kollia P,
and Grivea I participated in the conception of the study, and interpretation and collection of the literature data;
Stefanou N and Sotiriou S participated in the collection of the literature data; all authors have read and approved the
final manuscript.

Conflict-of-interest statement: The authors have no conflict of interest to disclose.

Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by
external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-
NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license
their derivative works on different terms, provided the original work is properly cited and the use is non-
commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

Country/Territory of origin: Greece

ORCID number: Zisis Kyriazis 0000-0003-2465-8774; Panagoula Kollia 0000-0002-0635-3996; Ioanna Grivea 0000-0002-
9221-5628; Nikolaos Stefanou 0000-0002-6784-6022; Sotirios Sotiriou 0000-0002-9466-6086; Zoe H Dailiana 0000-0003-3890-
0832.

S-Editor: Chang KL
L-Editor: Wang TQ
P-Editor: Chang KL

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