Polydactyly: phenotypes, genetics and classification

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ePolydactyly: phenotypes, genetics and classification

Author:

Sajid Malik

Author affiliation: Dr. Sajid Malik Human Genetics Program Department of Animal Sciences Quaid-i-Azam University 45320 Islamabad, Pakistan Tel.: + 92-51-9064 3158 Fax.: + 92-51-260 1176 E-mail: [email protected]

Conflict of interest: None

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/cge.12276

This article is protected by copyright. All rights reserved.

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Summary

Polydactyly is one of the most common hereditary limb malformations featuring

additional digits in hands and/or feet. It constituted the highest proportion among the

congenital limb defects in various epidemiological surveys. Polydactyly, primarily presenting

as an additional pre-axial or post-axial digit of autopod, is a highly heterogeneous condition

and depicts broad inter- and intra-familial clinical variability. There is a plethora of

polydactyly classification methods reported in the medical literature which approach the

heterogeneity in polydactyly in various ways. In this communication, well-characterized,

non-syndromic polydactylies in humans are reviewed. The cardinal features, phenotypic

variability and molecular advances of each type have been presented. Polydactyly at cellular

and developmental levels is mainly a failure in the control of digit number. Interestingly,

GLI3 and SHH (ZRS/SHH enhancer), two antagonistic factors known to modulate digit

number and identity during development, have also been implicated in polydactyly.

Mutations in GLI3 and ZRS/SHH cause overlapping polydactyly phenotypes highlighting

shared molecular cascades in the etiology of additional digits, and thus suggesting the

lumping of at least six distinct polydactyly entities. However, owing to the extreme

phenotypic and clinical heterogeneity witnessed in polydactyly a substantial genetic

heterogeneity is expected across different populations and ethnic groups.

Keywords:

polydactyly, additional digits, classification, clinical variability, genetic heterogeneity


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eIntroduction

The term “polydactyly” (Gr. Poly= many; dactylos= digit), is ascribed to a Dutch

physician Theodor Kerckring in the seventeenth century (1). Polydactyly or

polydactylism/polydactylia or bifid finger/toe or duplex or finger du-/tri-plication or

hexadactyly or hyperdactyly or hyperphalangism or intercalary digit or mirror-image

duplication or pentadactyly or polymetacarpalia or polymetatarsalia, all refer to the

occurrence of supernumerary digits or duplication of digital parts. Ambrose Parey in the

sixteenth century described this situation as “superfluous fingers” (cited in 2). Examples

range in degree from a minor cutaneous protuberance on lateral aspects of a digit to doubling

of a single phalanx, to complete duplication of a limb or part of a limb (3).

Polydactyly is the most frequently observed congenital limb anomaly noticed

immediately at birth. Its prevalence is estimated to be 0.3-3.6/1,000 in live-births and 1.6-

10.7/1,000 in general population. Males are twice as often affected as females (4,5).

Phenotypically, polydactyly is a highly heterogeneous malformation (3). Generally,

there is high predilection for the involvement of upper limbs than the lower, right hand than

the left, and left foot than the right (5,6). The duplication may involve any digit in the upper

or lower extremities. Two most common presentations are preaxial polydactyly (i.e.,

superfluous digit attached on the 1st digit), and postaxial polydactyly (i.e., extra digit along

the 5th digit) (5,3). Mesoaxial polydactylies involving 2nd, 3rd, or 4th digits are rare.

Phenotypic severity of polydactyly is defined by the extent of digit duplication and

the number of skeletal elements of the autopod involved in duplication. Morphogenetically,

polydactyly can be considered as a process of bifurcation of digit ray(s) in the longitudinal

axis progressing from distal to proximal end. The process of bifurcation occurs in numerous

grades and consequently the deformity appears in many varieties ranging from a mere


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ebroadening of a distal phalanx, to complete duplication of one or several finger/toe rays with

the involvement of carpals/tarsals (7,8).

Most of the cases encountered in the medical practice are sporadic, which usually

have unilateral presentations. Familial types are mostly bilateral and symmetrical (5,6).

Polydactyly as an isolated presentation is more frequent than syndromic appearance.

Nonetheless, polydactyly manifests itself as an integral part or a common association with

~300 well-characterized syndromic malformations (9,10,11).

This paper presents the current status of knowledge on isolated polydactyly and

covers its various aspects including approaches to polydactyly categorization, the well-

characterized phenotypes, inheritance patterns and known genetic factors for polydactyly, its

association with syndactyly, and a brief overview of two genetic factors, GLI3 and ZRS/SHH,

which cause various polydactylies.

Approaches to polydactyly classification

Being a rather common limb anomaly, the medical literature is rich in the description,

illustration and categorization of polydactyly. As in the case of syndactyly, the classification

systems proposed for polydactyly can also be lumped into three domains, depending upon the

underlying approach: 1) topographic and morpho-anatomical systems; 2) topographic but

considering familial phenotypes and inheritance patterns; and 3) embryological and

molecular approaches. A comprehensive chronological compendium of publications on

polydactyly highlighting the most significant contributions on its clinical and genetic aspects,

is presented in Table S1.

1) Topographic and morpho-anatomical systems

The conventional approach to classify extra digits is based upon the morpho-

anatomical description of the superfluous digit along the limb axis. Classically, three widely


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erecognized polydactyly types have been preaxial, mesoaxial, and postaxial (12). The medical

practitioners and surgeons consider polydactyly as a numerical, longitudinal or transverse

excess in the autopodal elements and account its various physical, anatomical and

physiological properties for classification; for instance, the size and severity, the position and

articulation within the true pentadactylous limb plan, stability and mobility, involvement of

tissue elements (i.e., skin, bone, nail, tendon), the most plausible surgical approach, and the

timing of surgery (7,8). A summary of these classification schemes is presented Table S1.

2) Topography and inheritance based approaches

A number of observations of familial polydactylies with unique segregation patterns

(i.e., transmission, penetrance, expressivity) required an alternative approach to understand

polydactyly. Thus, the Temtamy and McKusick (3) classification identified four preaxial, two

postaxial, and few high degrees/complex polydactylous entities, all of them segregating

autosomal dominantly. Goldstein et al. (13) proposed an extension to the Temtamy-

McKusick scheme by introducing subtypes (i.e., ten preaxial, nine postaxial, four high-

degrees, and seven complex types) (Table S1). Almost all of these types were suggested to

segregate in autosomal dominant fashion with variable expression and incomplete

penetrance. Castilla et al. (14) suggested that hand- and foot-postaxial polydactyly were two

different entities. Likewise, Orioli and Castilla (15) proposed that thumb and hallux

polydactylies were genetically heterogeneous (Table S1).

3) Embryological and molecular approaches

Considering the additional digit(s) as an embryological failure during limb

development has been another approach to polydactyly categorization (16). The emergence of

limb as a model of embryonic development has embarked much interest in this area and


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esuperfluous digit has been considered as a deviation from the normal anterior-posterior

developmental plan during limb morphogenesis (10). However, only a few genetic factors

have been discovered which have a potential role in the etiology of polydactyly. Talamillo et

al. (17) suggested to group polydactyly types depending upon the ectopic expression of SHH,

one of the key morphogens in limb development. Since the majority of genes involved in the

etiology of polydactyly/limb malformations remain to be identified, a molecular classification

or a unified categorization of polydactyly based upon genes and phenotypic presentation is

currently not easy.

Interestingly, the morpho-anatomical, genetic and embryological systems of

classification can be unified by the useful concept of ‘teratological sequence’ (18). All the

anatomical variations from a collection of observations can be put into a logical order, i.e.,

from very mild to very extreme phenotype, and are interpreted as orderly changes occurring

during the normal course of development with a common genetic etiology. This concept is

popular among clinicians because the extent of the pathology often determines the function of

the organ and provides a basis on which to guide treatment. This approach allows the

lumping of diverse phenotypes and helps understanding their affinities and a likely common

origin (7,19).

Recognizable phenotypes in polydactyly

In the plethora of polydactyly classifications, the Temtamy-McKusick scheme (3)

remains the most widely used among geneticists, dysmorphologists and genetic counselors.

In this scheme, the three main polydactylies with further sub-types are preaxial, postaxial,

and complex types (3). Here, by integrating the recent clinical and molecular developments in

each polydactyly, an update has been presented on this scheme (Table 1).


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ePreaxial polydactylies

Temtamy and McKusick (3) identified four preaxial polydactyly types: thumb/hallux

polydactyly (type I), polydactyly of triphalangeal thumb (type II), polydactyly of index finger

(type III), and polysyndactyly or crossed polydactyly (type IV) (Table 1; Fig.1A-D).

Preaxial type I

i) Thumb polydactyly (OMIM-174400)

This is a common presentation of polydactyly in which there is a duplication of one or

more components of a biphalangeal thumb (Fig. 1A). Hands are preferentially affected, only

hands are affected in bilateral cases, and the right hand is more commonly involved than the

left (6). There is high preponderance of affected males and low frequency of familial

recurrence (15,6).

The phenotypic spectrum form milder to severe ranges as follows: broadness of the

distal phalanx (duckbill appearance) or the duplication of distal phalanx; rudimentary extra

thumb receiving no tendinous attachment and depicting hypoplasia of the thumb musculature;

distinct bifurcation of the distal two third of phalanx but with common base; rudimentary

thumb with two supernumerary phalanges which attach near the base of the proximal

phalanx, sometimes articulating with the metacarpal head; duplication of whole thumb,

comprising a metacarpal and two phalanges (3). This type may also be presented as

triplicated thumb resulting in a total of seven digits (heptadactyly or septodactyly) (20).

Familial preaxial type I segregates autosomal dominantly with reduced penetrance

(5,15). It is a genetically a heterogeneous condition. Mutations in ZRS/SHH are known to

cause one subtype of preaxial I polydactyly (21,22).


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ii) Hallucal polydactyly (OMIM-601759)

The thumb polydactyly may accompany duplication of hallux, however, hallux

polydactyly is also known to exist as an isolated entity or a predominant presentation in

families (Fig. 1A) (5). Hallux duplication is rarer as compared to thumb polydactyly

(0.024/1,000 vs. 0.165/1,000 in South America, respectively). Similar to thumb polydactyly,

hallux duplication depicted a significant excess in males, involved predominantly the right

foot, and was mainly unilateral (81.5%) (15). The molecular bases of isolated hallucal

polydactyly remain unknown. A possible causal relationship between maternal diabetes and

hallucal polydactyly with a very unusual proximal placement of the extra digit, has been

suggested (23). Duplication of hallux associated with clinodactyly has been shown to

segregate with microdeletion at chromosome 2q31.1-31.2 (24).

Preaxial type II: triphalangeal thumb polydactyly (TPT) (OMIM-174500)

The biphalangeal thumb is replaced by a triphalangeal thumb (TPT) (Fig. 1B). There

is an extra middle phalanx in the thumb and the 1st metacarpal is abnormally long and gracile

containing epiphyses at both ends (3). Alternatively, a TPT phenotype with normal first

metacarpal is usually associated with polydactyly of the thumb. The TPT is usually

opposable. In the feet there may be duplication of great toe (3). TPT is frequently bilateral

and symmetrical (25). It segregates autosomal dominantly with incomplete penetrance (3).

There is a decreased expression in females.

TPT is a rather rare type. It is also presented as a part of a broader phenotypic

spectrum. For instance, triphalangel thumb-preaxial polydactyly, triphalangeal thumb-

polysyndactyly syndrome (TPT-PS), and tibial hemimelia-polysyndactyly-triphalangeal

thumb syndrome (TH-TPTPS) (9). Isolated TPT and several of the TPT-associated limb


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eanomalies have been observed to be caused by the mutations in ZRS/SHH locus at

chromosome 7q36 (22). However, ZRS/SHH mutations account for neither all isolated TPT

families nor different types of TPT phenotypes, considering that alternative mechanisms

could still be responsible for preaxial polydactyly.

Preaxial type III: polydactyly of index fingers (OMIM-174600)

In this very rare autosomal dominant polydactyly type, there is duplication of index

finger (Fig. 1C). The thumb is replaced by one or two triphalangeal digits. There is a distal

epiphysis for the metacarpal of the accessory digit, by which this entity is separated from type

II polydactyly or TPT (3,25). There is sometimes preaxial polydactyly of first or second toes.

“Index polydactyly” is often lumped together with “central polydactyly”, but has also

been considered as a variant of thumb duplication (26). The radial-sided duplication typically

is smaller and the level of duplication may be at the metacarpal or more distal. The additional

digit typically is in significant radial deviation or angulations, and the normal digit may be

forced into a varying degree of ulnar deviation (27).

Preaxial type IV: polysyndactyly, crossed polydactyly (OMIM-174700)

In this polydactyly type, the thumb shows mildest degree of duplication, being broad,

bifid or with radially deviated distal phalanx (Fig. 1D). Syndactyly of various degrees of

third-and-fourth fingers is occasionally present (3). In the feet, there is polydactyly of first toe

and the first metacarpal is short and tibially deviated. Syndactyly of second and third toe (or

all toes) is present. It is of note that this entity is distinct from synpolydactyly (OMIM-

186000), in which syndactyly is associated with additional digit within the web (28,29).


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eA term “crossed polydactyly” (CP) is usually employed for the presence of preaxial

and postaxial polydactyly with a difference in axis of the additional digits between the hands

and feet. CP type I depicts polydactyly which is postaxial in hands and preaxial in feet. In CP

type II, preaxial polydactyly of hands is combined with postaxial polydactyly of feet (Fig.

1D) (3). Molecular studies have demonstrated that CP type I is allelic to postaxial

polydactyly A/B, and mutations in GLI3 as well as ZRS/SHH are known to cause the

phenotype (30).

Postaxial polydactyly (OMIM-174200)

There is an occurrence of one or more extra ulnar or fibular digits or part of it.

Specifically for the ulnar polydactyly, two distinct entities have been recognized, i.e., types A

and B, which differ in severity, inheritance pattern and penetrance estimates (3).

i) Postaxial type A

In type A, the extra digit is rather well-formed and articulates with the fifth or an extra

meta-carpal/-tarsal (Fig. 2A) (3). Depending upon its size, the extra digit may harbor 1—3

bony elements, corresponding flexion creases and a well-developed nail. The angle-of-

articulation of postaxial digit along the 5th ray is highly variable (i.e., <30°—180°). In

majority of the cases, the additional digit remains non-functional and may pose difficulty in

daily-life activities. This type is inherited as an autosomal dominant trait with marked

penetrance (~68%) (14,31).

There is evidence of autosomal recessive type of postaxial type A (OMIM-263450)

(32). In a case-control clinical epidemiological study, Castilla et al. (33) recruited 6,586

individuals exhibiting postaxial polydactyly (types A and B as single entity). Through

complex segregation analysis, the authors obtained very high heritability value for this trait


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eand a major recessive gene effect (33). Two postaxial recessive types have been mapped to

chromosomes 13q13.3-q21.2 and 4p16.3 (ZNF141), respectively (34,35).

ii) Postaxial type B

In postaxial type B, the most abundant type of polydactyly in various populations, the

extra digit is rudimentary ranging from a minor sign of small protuberance on the ulnar

aspect of 5th finger to spine-like outgrowth, to a 2—3 cm long nubbin-like ‘pedunculated

postminimus’ which usually contains an osseous element and a nail (Fig.2B) (5). The

articulation site of this nubbin along the fifth digit is variable and is usually through a small

cutaneous bridge. The upper limbs and the left hand are preferentially affected (6). The

genetics of this type has been suggested to be more complicated, and the penetrance estimates

are ~43% (5).

Postaxial types A and B have been considered as two distinct and genetically

heterogeneous entities due to their independent occurrences and different segregation patterns

(5,3). Contrastingly however, several other reports witnessed both types in the same kindred

and/or individual (31). Mapping studies have revealed that there are at least four distinct

autosomal dominant entities (PAPA1—4), all of which exhibit phenotypes A and B,

simultaneously (Table 1). PAPA1 is known to be caused by mutations in GLI3 and ZRS/SHH

(30,21). Thus, there is so far no molecular clue that dominantly segregating phenotypes A

and B are genetically heterogeneous.

Complex and other polydactylies

This category includes polydactylies which do not fit into the familiar phenotypes of

preaxial or postaxial.


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Mirror-image polydactyly (MIP) of hands/feet: 7 fingered hand without thumb (OMIM-135750)

There is mirror duplication of posterior digits and the anterior digits are replaced by

the posterior but in reverse order, i.e., the supernumerary digits are arranged in descending

order from a single central digit (e.g.,5-4-3-2-3-4-5), with the absence of a thumb/hallux

(Fig.3A) (3). Martin et al. (36) described a family in which the affected subjects had a

complete duplication of all fingers with 9 digits on the right and 10 digits on the left, forming

a rosebud type configuration, bilaterally. MIP segregates as an autosomal dominant entity.

Isolated MIP is very rare, while it is normally observed as a part of Laurin-Sandrow

syndrome (OMIM-135750), which is characterized by the duplication of ulna and/or fibula,

agenesis of radius and/or tibia, duplication of middle, ring and little fingers, and absence of

thumbs. The recurrent involvement of tubular bones of upper and lower limbs has lead to a

suggestion of three heritable types of MIP: 1) tibial defect with preaxial polydactyly is a rare,

autosomal dominant trait with variable penetrance and expressivity; 2) agenesis of the tibia

and mirror foot; and 3) ulnar and fibular dimelia (3).

One type of MIP phenotype is caused by mutations in MIPOL1 localized at

chromosome14q13 (37). Additionally, MIP with lower-limb malformations are caused by

mutations in PITX1 (38).

Haas type: extra digital ray with extensive syndactyly (OMIM-186200)

Haas type polysyndactyly manifests itself as complete cutaneous fusion of all fingers

accompanied by the presence of extra pre- or postaxial ray(s) in the web (Fig. 3B) (39).

Owing to an extensive syndactyly the flexion of fingers is limited and the union of

contiguous fingers gives the hand a cup-shaped appearance.


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eHaas type anomaly is usually classified as type IV syndactyly (29). Genetic

heterogeneity has been witnessed in Haas polysyndactyly and mutations in GLI3 and

ZRS/SHH are known to cause this anomaly (30,21).

Central polydactyly

Central polydactyly, also referred as “hidden” duplications may present as a mass of

tissue in the mid part of the hand, with obvious syndactyly and even synonychia. However,

not all central types are hidden (Fig.3C). Central polydactyly like duplications of index

finger, usually is inherited autosomal dominantly (27). The anomaly is often bilateral,

although contralateral hand deformities of different types (central cleft or complex

syndactyly) also can manifest. The ring digit is duplicated most frequently, followed by the

long ray, both of which are more common than index digit duplications (3).

Palmer/ventral and dorsal polydactyly

A very rare and unusual presentation of polydactyly is a supernumerary digit arising

from the dorsum (or ventrum) of the autopod. It may be presented as a minor skin appendage

or a partially developed digit ray, or a fully developed digit with/without nail and inserted

into the autopod/palm as a peg (Fig.3D). Depending upon the extent of growth, articulation

and musculature, the accessory digit could be mobile and active. In the hand, a palmer/ventral

origin of a mobile accessory digit is reported (40). Likewise, an accessory digit originating

from the dorsam of foot has been described (41). Embryologically, this accessory digit

appears to deviate from the anterio-posterior axis of digital alignment in the limb field,

splaying from the dorsal (or ventral) surface of the autopod.


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eSyndactyly as a part of polydactyly

Certain digit webbing patterns have been customarily observed with polydactylies. In

fact, the relationship of polydactyly and syndactyly is so intimate that it may pose a challenge

in their categorization. For instance, syndactyly is a key feature of preaxial polydactyly type

IV (3). In TPT-polydactyly, webbing between 1st-2nd and 3rd-5th fingers may accompany. In

more extreme TPT types (i.e., TPT with absent tibiae), syndactyly is more extensive

mimicking Haas polydactyly (9). In isolated preaxial polydactyly of feet, there is a fusion of

digit proper and additional toe. Polydactylies with combined preaxial and postaxial types may

also be presented with syndactyly, and there is usually a fusion of 4th-5th fingers and toes

(13). In postaxial type A, partial cutaneous syndactyly involving digits 4th-5th (or 5th-6th)

fingers and 2nd-3rd (or 5th-6th) in toes is a frequent finding (13,5). Syndactyly is particularly

accompanying recessive type A (32). Complete syndactyly resulting in cup shaped hand is

commonly observed in mirror-image polydactyly (3).

Two candidates, GLI3 and SHH enhancer ZRS/SHH lump six distinct polydactyly types

On the basis of their etiologies, several researchers have appreciated two main

preaxial polydactylies. In the first type, the additional digit results from the duplication of a

thumb, while in the second type the superfluous thumb materializes from variable splitting of

the single thumb (42). In the case of postaxial polydactyly, there may also be two different

underlying mechanisms: first, the additional digit may arise from the mass of superfluous

cells in the limb field; and second, environmental/stochastic factors trigger the formation of

additional digit (17).

The current molecular data including mapping and mutation studies suggest that

several clinically discrete polydactylies have common genetic bases. Mutations in two


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edifferent factors, i.e., GLI3 and SHH enhancer ZRS/SHH, cause at least six polydactylies, i.e.,

PPD1, PPD2, TPT-PS, PPD4, PAPA1, Haas type (Table 1;Fig.4). This finding demonstrates

not only the vital role of these genetic factors in the control of digit number but also the

intimate functional crosstalk between GLI3 and SHH during limb development.

In order to understand the etiology of polydactyly, it is imperative to understand the

key events taking place during limb development and digit morphogenesis and the role of

Shh and Gli3 elucidated by studies on animal models. In humans, embryogenesis of limb

occurs between 4-8 weeks of gestation. The limb bud grows as a bulge of cells from lateral

plate mesoderm covered by a sheath of cells of ectodermal origin. Specific signal centers

develop in the growing limb field which guide patterning and anterior/posterior identity, i.e.,

digit morphogenesis and determination of digit number and identity (reviewed in 17).

Sonic hedgehog (Shh) is one of three signal centers in the growing limb and it

operates from the posterior end (Shh-end or zone of polarizing activity) of the limb bud (Fig.

4A). Shh signaling is pivotal in determining digit number and identity. In a mouse limb, a

specific gradient of Shh patterns anterior digits and the length of time that proliferating region

cells are exposed to direct Shh signaling patterns the posterior digits (43). Gli3 protein an

antagonist of Shh, expresses at the anterior end (i.e., opposite to Shh-end) (Fig. 4B). The Gli3

itself is a downstream mediator of the Shh pathway and this pathway includes several genes

that cause abnormal human phenotypes when mutated (e.g., PTC1, CBP, Smo, Twist, GLI1,

dHand) (reviewed in 44). Gli3 has a dual function: the full-length GLI3 acts as an activator

(GLI3A) of Shh pathway while its truncated version GLI3R, acts as Shh repressor (45). A

proper balance between the GLI3A and the GLI3R specifies limb digit number and identity

(Fig. 4B,C).


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eThe formation of correct number of digital rays correlates with the size of the digital

plate in the autopodium which depends on the amount of tissue available. SHH, by

influencing the rate of proliferation of cells in the limb plate, influences the amount of tissue

available in the autopodium (17). Furthermore, ectopic origin of extra digit in the growing

limb plate is also possible by minor disturbances by external or stochastic factors during digit

morphogenesis. During digit morphogenesis, the digits become demarcated and form the

digital rays that are separated by the flattened interdigital tissue. The digits will form in the

digital rays and the interdigital tissue will disappear through apoptosis. The simple generation

of a wound or minor physical disturbance in the interdigital tissue is sufficient to activate the

chondrogenic phenotype resulting in an extra digit (17). This may at least partly explain why

the majority of polydactyly cases are sporadic, isolated and with no evidence of further

transmission in family.

The variety of limb phenotypes caused by the mutations in GLI3 or ZRS/SHH reflects

the complexity of their interaction as well as the extraordinary importance of the pathway in

controlling the number of digits. However, among the intricacies of polydactyly lies genetic

heterogeneity. There are many polydactyly phenotypes both preaxial and postaxial, which are

not associated to mutations in GLI3 or ZRS/SHH (46). Owing to the broad phenotypic

variability witnessed particularly in preaxial type I and postaxial A and/or B, a substantial

underlying genetic heterogeneity is expected across different populations and ethnic groups.

The clue that many genetic factors involved in the etiology of polydactyly/limb

malformations still remain to be identified is also gleaned from the enormous number of

anomalies/syndromes in which polydactyly accompanies (11). The development of

innovative methods should allow the dissection of stochastic factors responsible for a copious

number of sporadic polydactylies.


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eAcknowledgements:

I am very grateful to Prof. Drs. Mahmud Ahmad and Karl-Heinz Grzeschik for their

useful comments on the earlier versions of the manuscript. The study was supported by HEC-

Pakistan and PSF-Islamabad.

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eLegends to Figures:

Fig. 1

Schematic diagrams of autopods showing preaxial polydactylies. Black filled elements depict the affected/polydactylous digits. Digital elements with amorphous borders symbolize dysplastic/hypoplastic bones. Shaded digits represent syndactyly.


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eFig. 2

Schematic diagrams of autopods depicting postaxial polydactylies. Black filled elements depict the affected/polydactylous digits. Digital elements with amorphous borders symbolize dysplastic/hypoplastic bones.


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eFig. 3

Schematic diagrams of autopods showing complex and other polydactylies. Black filled elements depict the affected/polydactylous digits. Digital elements with amorphous borders symbolize dysplastic/hypoplastic bones. Shaded digits represent syndactyly.


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eFig. 4 Schematic depicting the growing limb bud (A) with five digits precursor zones materializing

through the SHH-GLI3 antagonism along the antero-posterior developmental axis. Shh is turned on in the posterior through the early expression of Hoxd genes and dHAND (shown in the pathway) (B). Expression domains of SHH at the posterior axis and GLI3 at the anterior axis, shown as gradients. (C). Schematics of limb depicting various polydactylies which could be identified as preaxial, mesoaxial or postaxial types. Mutations in GLI3 and ZRS/SHH cause both preaxial and postaxial polydactylies.


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e Table 1: Well-characterized polydactyly types: cardinal features, inheritance and mapped loci/genes.

OMIM Type; Symbol Description Inheritance Locus; Gene174400 Preaxial I; PPD1 Polydactyly of biphalangeal thumb/hallux; hypoplasia of thumb musculature, radial

deviation of thumb terminal phalanx AD, reduced penetrance

7q36; ZRS/SHH

601759 Preaxial hallucal polydactyly

Preaxial hallucal polydactyly, proximal placement of extra digit ?

174500 Preaxial II; PPD2; TPT-PS

Triphalangeal thumb (TPT); duplication of distal thumb phalanx, opposable/nonopposable TPT, duplication of great toes. Other phenotypes: TPT-polysyndactyly syndrome (TPT-PS; webbing of 3-4-5; pre-, post-axial polysyndactyly of toes); tibial hemimelia-TPTPS; complex polysyndactyly (TPT-pre-, post-axial polydactyly, syndactyly)

AD, nearly complete penetrance

7q36; ZRS/SHH

174600 Preaxial III; PPD3

Duplication of index fingers; thumb replaced by one or two triphalangeal digits, distal epiphyses present for metacarpals of accessory digits; occasional polydactyly of 1st or 2nd toes

AD

174700 Preaxial IV; PPD4; Crossed polydactyly

Polysyndactyly; mild thumb duplication, dysplastic distal thumb phalanges with a central hole; syndactyly of 3-4 fingers; 1st or 2nd toe duplication, syndactyly of all toes, Crossed type I (postaxial polydactyly in hands and preaxial in feet); Crossed type II (preaxial polydactyly in hands and postaxial in feet)

AD 7p14.1; GLI3; 7q36; ZRS/SHH

174200 Postaxial A1 (types A/B); PAPA1

Polydactyly of 5th finger/toe; Type A: well-formed articulating extra digit containing 1-3 phalanges; Type B: minor protuberance, a knob like pedunculated postminimi

AD 7p14.1; GLI3; 7q36; ZRS/SHH

602085 Postaxial A2; PAPA2

Phenotypes A, extra digit is well-formed AD 13q21-32


Phenotypes A/B in hands and feet AD 19p13.1-13.2


Phenotypes A/B in hands and feet; 2-3 syndactyly AD 7q21-q34

263450 Postaxial A

In hands and feet; minor syndactyly, 5-6 metacarpal synostosis AR 13q13.3-q21.2

Postaxial A Functionally developed digit in hands and/or feet AR 4p16.3; ZNF141


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135750 Mirror image polydactyly

Mirror duplication of posterior digits, the supernumerary digits are arranged in descending order or size from a single central digit, absence of a thumb/hallux

AD

14q13; MIPOL. 5q31.1; PITX1

186200 Haas type Complete cutaneous fusion of all fingers with additional digit ray in the web AD 7p14.1; GLI3; 7q36; ZRS/SHH

AD=autosomal dominant; AR=autosomal recessive


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Polydactyly: phenotypes, genetics and classification