J A large Turkish kindred with syndactyly type II ...jmg.bmj.com/content/jmedgenet/32/6/435.full.pdf · J MedGenet 1995;32:435-441 Alarge Turkish kindred with syndactyly type II (synpolydactyly)

J Med Genet 1995;32:435-441

A large Turkish kindred with syndactyly type II(synpolydactyly). 2 Homozygous phenotype?

A Nurten Akarsu, Okan Akhan, Bekir Sitki Sayli, Ugur Sayli, Gulay Baskaya,Mansoor Sarfarazi

Department ofMedical Biologyand Genetics,Universityof Ankara, Faculty ofMedicine, Sihhiye,Ankara, TurkeyA N AkarsuB S Sayli

Department ofRadiology, Universityof Hacettepe, Facultyof Medicine, Sihhiye,Ankara, TurkeyO Akhan

Orthopedics Clinic,Etimesgut CommunityHospital, Ankara,TurkeyU Sayli

Barbaros HealthCentre, Kayseri,TurkeyG Baskaya

Surgical ResearchCentre, Department ofSurgery, University ofConnecticut HealthCentre, Farmington,Connecticut06030-1110, USAM SarfaraziA N Akarsu

Correspondence to:Dr Sarfarazi.

Received 9 August 1994Revised version accepted forpublication 5 January 1995

AbstractSyndactyly type II (synpolydactyly (SPD))is an autosomal dominant condition withtypical abnormalities of the distal parts ofboth upper and lower limbs. We reporthere a previously undescribed phenotypicfeature ofpeople with severe hand and footdeformities who were born to two affectedparents. This is the first example of SPDsubjects manifesting a very distinctivephenotype, suggesting that they must behomozygous for this condition. The typicalcharacteristic clinical features in thesesubjects are as follows: (1) short handswith wrinkled fatty skin and short feet; (2)complete soft tissue syndactyly involvingall four limbs; (3) polydactyly of the pre-axial, mesoaxial, and postaxial digits ofthe hands; (4) loss of the normal tubularshape of the carpal, metacarpal, and pha-langeal bones, so as to give polygonalstructures; (5) loss ofthe typical structureofthe cuboid and all three cuneiform boneswhile the talus calcaneus and navicularbones remain intact; (6) large bony islandsinstead of metatarsals, most probably be-cause of cuboid-metatarsal and cunei-form-metatarsal fusions; and (7) severe

middle phalangeal hypoplasia/aplasia as

well as fusion of some phalangeal struc-tures that are associated with the loss ofnormal phalangeal pattern. We reportseven subjects with this phenotype fromthree different branches of a very largeSPD pedigree exhibiting the same pheno-type with minimal variation. In mice, thePolysyndactyly (Ps) mutation shows a pat-tern of synpolydactyly very similar to thatof human SPD, suggesting that they maywell be homologous mutations. A mo-

lecular genetic study is currently underway to determine the chromosomal loc-ation of the SPD locus in humans andto identify the corresponding homologousregion in mice.

(J Med Genet 1995;32:435-441)

Syndactyly type II (synpolydactyly, (SPD)) is a

digital malformation affecting mainly the thirdand fourth fingers of the hands and fifth toesof the feet. This condition is inherited as an

autosomal dominant trait with variable ex-

pressivity and incomplete penetrance. Homo-zygosity for SPD appears to be unknown, evenin the largest kindred reported so far.'2 In thepreceding paper we described a very large SPD

pedigree from the village ofDerbent in Turkey.3In this kindred, there are eight sets of marriagesin which both parents are affected with SPD.They produced a total of 30 offspring, ofwhom27 were affected with SPD. Seven ofthem showmore severe deformity with less phenotypicvariation than any other affected people seenin the same kindred, suggesting that they mayindeed by homozygous for this condition. Inthis paper, we present the characteristics ofthese seemingly homozygous subjects.

Materials and methodsThe family structure and results of physicalexaminations are reported in the precedingpaper and summarised on each individual ped-igree.3 The people with more severe deformitieswere shown as solid symbols and abbreviatedas "CS" below each subject in each pedigree.3The personal identification numbers (PID) ofthese people in the same pedigrees are givenin table 1 for comparison. There is a totalof seven subjects showing complete complexsyndactyly, all of whom were examined in thefield by at least one of us, and x ray films wereobtained from five willing subjects.

ResultsCLINICAL FINDINGSCase 1 (SPD-1, PID 43)This 30 year old female has short hands andfeet with complete soft tissue syndactyly in-volving all four extremities (fig 1A,B). Shewas born to two affected parents with typicalphenotypic expression of SPD (SPD-1, PID17 and PID 18).The upper limbs are "paw-like" and have

"cat's paw" appearance. Both hands displaycomplete soft tissue syndactyly involving allfingers, and the thumb and forefinger are ex-tremely rudimentary. The remaining digits arewithin the mass of this soft tissue. The nails ofthe first two fingers are hypoplastic, but theothers are hardly detectable within this mass.The left hand differed somewhat in that thethird finger is identifiable and there is an en-larged nail, probably representing the fourth ormore fingers. The "paw-like" appearance wasfurther aggravated by a large amount ofwrinkled and fatty skin over the dorsum andby camptodactyly of the digits (fig 1A). Palp-ation of the hands also gave the impressionthat some bones were missing under the skin.X rays of the hands showed patches of ab-

normal bone, beginning at the carpal level allthe way to the third phalanx (fig 1 C). In par-

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Akarsu, Akhan, Sayli, Sayli, Baskaya, Sarfarazi

Table 1 The corresponding personal identification numbers (PID) of homozygotes in thepreviously reported circular and individual pedigree.3

Subjects Family No in each pedigree PID numbers in pedigree

Individual Circuilar

Case 1, female SPD-1 43 VI-4Case 2, female SPD-1 74 VII-4Case 3, male SPD-1 75 VIIh5Case 4, female SPD-1 45 VI-5Case 5, female SPD-2 44 VI-34Case 6, female SPD-2 45 VI-35Case 7, female SPD-3 109 VII-14

ticular, the normal tubular shape of themetacarpals and phalanges was lost and wassubstituted by some cuboidal or polygonal bonystructures. Similarly, although to a lesser ex-tent, the carpal bones were transformed intocuboidal forms with partial fusion. Carpo-metacarpal lines were hardly identifiable. Upto six consecutive abnormal bones in two rowsreplaced the metacarpal bones (fig 1 C). Thesestructures may be tandem duplication of rudi-mentary and abnormal metacarpals.There were eight bony structures on the right

hand and seven on the left hand which replacednormal digits, so that both pre- and postaxial

polydactyly were present. The bones in thethumb formation were extremely hypoplasticand deformed with an articulation defect. Thesecond digits were similarly abnormal, in thateither the middle phalanx was absent or thepresence of the distal bone was the result offusion of the middle and distal phalanges.Middle phalangeal hypoplasia/aplasia wasnoted in all fingers as well as brachymeta-phalangism. In the postaxial region, there wasone abnormal bone on the left and two on theright, possibly representing little fingers. Inaddition to these abnormalities, the middle anddistal phalanges of the fourth and fifth fingerswere synostotic on the left side. The feet weresimilarly short and exhibited complete soft tis-sue syndactyly. The big toe was normal on bothsides, but their nails were extremely hypoplastic(fig 1B). The distance between the big toe andthe subsequent complex of toes was enlarged.The second toe was hypoplastic and was at-tached to a complex in which other toes werenot discernible individually.Xray examination of the feet showed normal

talus, calcaneus, and navicular bones, whereasall three cuneiform bones were indistinguish-

Figure 1A-D Hands and feet of case 1 (subject 43, SPD-1) with characteristic manifestation of the SPD homozygousphenotype.

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A large Turkish kindred with syndactyly type II (synpolydactyly). 2 Homozygous phenotype?

Table 2 Clinical manifestations

Physical Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7examination (Farml, PID 43) (Faml, PID 74) (Faml, PID 75) (Faml, PID 45) (Fam2, PID 44) (Fam2, PID 45) (Fam3, PID 109)

Age 30y 8y 5y l9y 8y 4y 4ySex F F M F F F FAssociated findings - - - - - - -Hands

Short hands + + + + + + +"Paw-like" appearance + + + + + + +Wrinkled and fatty + + +/- + + + +skinCamptodactyly + + + + + + +Hypoplastic nails 1st & 2nd fingers - 1st & 2nd fingers - - - -

on leftComplete syndactyly Partial in 1st & Partial in 1st & Except 1st on Partial 1st & 2nd Partial 1st & 2nd All fingers With duplicated

2nd digits 2nd digits on right, 2nd on left digits digits on left thumb and partialright syndactyly 1st &

2nd digitsFeet

Short feet + + + + + + +Complete syndactyly + + + + All toes + +from 2nd & 5th toesHypoplastic nails + +/- + - - + +of big toeIncreased distance + + + + - - +between hallux andsubsequent complex

Table 3 X ray examination findings

X ray Case ) Case 2 Case 3 Case 4 Case S Case 6 Case 7findings (Famrn, PID 43) (Faml, PID 74) (Famrn, PID 75) (Faml, PID 45) (Fam2, PID 44) (Fam2, PID 45) (Fam3, PID 109)

HandsNormal radius/ulna + + + Not examined + + Not examinedLoss of normal tubular + + + + +shape of carpal,metacarpal, andphalangeal bonesSevere + + + + +brachymetaphalangismPreaxial polydactyly + + - + +Postaxial/mesoaxial + + + + ?polydactylyMiddle phalanx + + ? + ?hypoplasia/aplasiaTriphalangeal thumb - + -

FeetNormal tibia/fibula + + + Not examined + + Not examinedNormal talus, + + + + Navicular?calcaneus, andnavicular bonesLarge bony islands + + + + +replacing cuboid and5th metatarsalsFused metatarsals + + + + +with respectivethree cuneiformsTibial deviation of the + + + +big toeTriphalangeal hallux - + -Middle phalanx + + + i ?hypoplasiaLoss of normal + + + + +phalangeal structurefrom 2nd to 5th toes

able from the fused metatarsal bones (fig ID).The cuboid bone was completely lost and wassubstituted by a large polygonal bony structure,probably representing the cuboid as well as thefourth and fifth metatarsal bones. These bonyislands did not allow the tarsal and metatarsalbones to be distinguished. No extra digit waspresent on either side. The distal phalanx ofthebig toe was rudimentary. All of the phalangealstructures lost their normal tubular appearance,and the middle phalanges were extremely hy-poplastic or even absent on both sides. On theright, the proximal phalanges of the third andfourth toes were fused with abnormal me-tacarpal structures. There were similar findingson the left, except for the presence of a me-tatarsophalangeal fusion.There was no associated abnormality in this

person. Pedigree data in our previous workindicated that the subject belonged to a sibshipof 10, of whom nine are affected.' All of the

affected sibs showed typical features of SPD,except one (PID 45) (tables 2 and 3). Both ofthe parents were affected with typical SPD.However, the mother showed an enlarged hal-lux on the right foot, which may suggest pre-axial polydactyly. The husband (PID 44) alsohas typical features of synpolydactyly and twooffspring are affected with similar complexcomplete syndactyly.

Case 2 (SPD-1, PID 74)This 8 year old female has bilaterally shorthands with a typical "paw-like" appearance (fig2A). On her right hand, the first and seconddigits are distinguishable and there is completesoft tissue syndactyly involving the remainingdigits. On her left hand, none of the digitsexcept the thumb were discernible separatelywithin the mass. Her nails are normal and thereis camptodactyly involving all digits bilaterally.

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Figure 2A-D Hands andfeet of the second hornozygous case (subject 74, SPD-J) showing triphalangealfirst digit inboth hands and feet.

Palpation gave the impression that some bonesmay be missing under the skin, being maskedby wrinkled and fatty skin over the dorsum.

There was an increased distance between themass and the index finger.X ray examination showed normal radial and

Figure 3A-D Hands and feet of case 3 (subject 75, SPD-1).

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Figure 4A,B Hands and feet of case 4 (subject 45, SPD-1).

ulnar bones on both sides. Abnormal de-velopment has apparently started from thecarpal boundary (fig 2B). Briefly, the carpalbones have lost their normal shape and aresubstituted by bony islands. All of the carpo-metacarpal bones are replaced by polygonal orcuboid structures. Bony fusion was noted atthe carpal level bilaterally. Six bony structuresand triphalangeal thumbs constitute the fingersof both hands. Additionally, a small piece ofextra bone is present next to both thumbs.There was bony fusion between the proximal,middle, and distal phalanges on the third andfourth digits of the right hand only.

In the foot, the halluces were found to benormal, whereas the other toes were within themass of soft tissue (fig 2C). X ray examinationshowed normal talus, calcaneus, and navicularbones. There were large bony islands resultingfrom fusion of the cuneiform-metatarsal andcuboid-metatarsal bones (fig 2D). No extra toewas present, but all toes have lost their normalshape and the phalanges were hardly dis-cernible. A triphalangeal hallux with its tibialdeviation is the additional feature ofthis pheno-type.

Other casesThe phenotypes of cases 3 (fig 3A-D), 4 (fig4A,B), 5 (fig 5A-D), 6, and 7 are strikinglysimilar to those of the above mentioned casesand are summarised in tables 2 and 3.

PEDIGREE ANALYSISWe have identified eight marriages between twoaffected people. One of these is a marriagebetween a homozygote and a heterozygote(SPD-1 PIDs 43 and 44)3 producing two ho-mozygous offspring. In the other marriagesboth parents are heterozygotes. Eight marriages

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Figure 5A-D Hands and feet of case 5 (subject 44, SPD-2).

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Figure 6 Inheritance of the homozygous and heterozygous subjects in one branch of the SPD-2 pedigree.3 The segregation and phenotypic expression inthe hands and feet in the homozygous subjects (persons 44 and 45) are shown for comparison with their heterozygous parents and sibs. The location ofeach subject in the circular pedigree3 is indicated below each subject.

produced a total of 30 offspring, 27 affectedand three unaffected. Seven of the 27 affectedsubjects exhibited more severe features, sug-gesting homozygosity at the genetic level. Fur-thermore, despite the fact that they come fromdifferent branches of the same kindred, thereare close phenotypic similarities among them.Seven of the above mentioned eight marriageswere between two typical heterozygote SPDparents producing a grand total of 25 affected

Figure 7 Drawings of the homozygote's hands representing changes in the normal tubularformation of the bones. See text for details.

(expected n =21) and three normal (expectedn = 7) offspring. Only one marriage was notedbetween an SPD heterozygote and homozygoteproducing two affected (expected n = 2) andno normal (expected n = 0) offspring. The ob-served frequencies of a total of 27 affected andthree normal offspring in these eight matingsare well within the expected values of 23 affec-ted and seven normal offspring (x,2 = 2-98, p =0 084). Fig 6 exemplifies the "homozygousphenotype of SPD" as compared with typicalSPD ofheterozygous parents and sibs. A draw-ing of the observed characteristic features inthe hands and feet of these homozygous casesis presented in fig 7 and 8 respectively.

DiscussionTo the best of our knowledge, this work pres-ents the first cases of people with severe handand foot deformities who were born to twoparents affected with SPD. The phenotypicexpression is uniquely different from otherpatients affected with SPD (that is, hetero-zygotes) who are usually born to one affec-ted and one normal parent. So, at the genotypiclevel, the subjects presented here must be ho-mozygous for the SPD gene, representing yetanother phenotypically detectable example ofhomozygotes for a rare autosomal disorder.45The characteristic findings in these subjects

SPD-2

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Figure 8 Drawings of the homozygote's feet showing changes in the normal tubularformation of the bones. See text for details.

are: (1) short hands with wrinkled fatty skin andshort feet; (2) complete soft tissue syndactylyinvolving all four limbs; (3) polydactyly on

preaxial, mesoaxial, and postaxial areas of thehands; (4) loss of normal tubular shape ofcarpal, metacarpal, and phalangeal bones lead-ing to polygonal structures; (5) loss of typicalstructures ofthe cuboid and all three cuneiformbones, with the talus, calcaneus, and navicularbones remaining intact; (6) large bony islandsof metatarsals, most probably arising fromcuboid-metatarsal and cuneiform-metatarsalfusions; and (7) severe middle phalangealhypoplasia/aplasia, together with fusion ofsome phalangeal structures that are associatedwith the loss of the normal phalangeal pattern.There is little variation between the left andright hands (if any) as shown by x rays in-dicating a "mirror effect". On x ray ex-

amination, this phenotype can be easilydistinguished from the other types of completesyndactyly.67 Thus, this unusual phenotypemust represent homozygosity for the SPD gene.

In mice, syn/polydactyly results from a num-

ber of distinct mutations.8 In addition to thesemutations, Johnson9 described another mutantgene which is designated polysyndactyly (Ps).The characteristic features of this mutation are

the most similar to those described in our

patient population, as originally suggested byWinter.'0 However, homozygous mice die ator before birth. Embryological studies in themouse showed that cell death of interdigitalareas is almost totally absent in fore- and hind-feet in Ps/Ps mutants, chondrification is poor,

and up to six metatarsals can be seen.9 Thus,phenotypically, the Ps mutation could be thecounterpart of the human SPD mutation inmice. No homology is known between the Pslocus and its counterpart in humans. However,the two flanking loci to the Ps locus on mouse

chromosome 4 (Pgm-2 and C8b) do showhomology with the region lp36-p22 in hu-

mans, '0 providing an excellent candidate re-gion for synpolydactyly. However, a geneticlinkage study of DNA markers selected fromthe entire short arm ofchromosome 1 produceda negative lod score in the Derbent kindred.These preliminary linkage studies showed thateither the mouse Ps mutation is not the coun-terpart of SPD in humans or the precise ho-mologous region of the Ps locus in the mouseis not the corresponding region of 1p36-p22in humans.From an embryological point of view, the

differentiation of specific cell types and struc-tures suggest that limb buds have positionalinformation which must relate to the proxi-modistal, anteroposterior (preaxial-postaxial),and dorsoventral axes." 12 In this particularphenotype, while the thumb and hallux aresituated on the preaxial side of the limb and thefifth digit on the postaxial side, the formation ofa correct number of digits and a correct patternofformation is likely to be defective. The typicalSPD phenotype (heterozygous) shows at leasta normal pattern formation on positional in-formation. Thus, it is classified as "increasednumber of digits on the mesoaxial line withnormal pattern formation" according to thenewly devised classification of Winter andTickle.'2 Speculatively, to have such a normalpattern of formation (that is, heterozygousSPD), it seems likely that at least one copy ofa normal gene is essential. Positional mappingof the putative gene, mutation identification,and cloning of the eventual molecular defectwill solve the synpolydactyly puzzle. Studiesare currently under way in our laboratory toidentify the chromosomal location of the SPDlocus.

We would like to thank the Turkish Ministry of Health, Divisionof Basic Health Services for providing many facilities includingx rays and transport to and from the village of Derbent. Wewould also like to thank Dr P Erdogdu from the TurkishMinistry of Health for her participation in ascertaining the SPDkindred. We are equally grateful to the proband and her familyfor travelling from remote areas in order to participate in thisstudy. The authors also express their deepest appreciation toother affected people and their families for participating in thestudy. This work is supported by an intermural Faculty ResearchProgram from the University of Connecticut Health Center.The work described here was originally presented for fulfilmentof a PhD degree (A N Akarsu).

1 Thomsen 0. Einige Eigentuemlichkeiten der erblichen Poly-und Syndactylie bei Menschen. Acta Med Scand 1927;65:609-44.

2 Cross HE, Lerberg DB, McKusick VA. Type II syndactyly.AmJtHum Genet 1968;20:368-80.

3 Sayli BS, Akarsu AN, Sayli U, Akhan 0, Ceylaner S,Sarfarazi M. A large Turkish kindred with syndactyly typeII (synpolydactyly). 1 Field investigation, clinical andpedigree data. J Med Genet 1995;32:421-34.

4 Hulten MA, Honeyman MM, Mayne AJ, Tarlow MS.Homozygosity in piebald trait. J Med Genet 1987;24:568-71.

5 Pauli RM. Dominance and homozygosity in man. Am JMed Genet 1983;16:455-8.

6 McKusick VA. Mendelian inheritance in man. 10th ed. Bal-timore: The Johns Hopkins University Press, 1992.

7 Temtamy SA, McKusick VA. The genetics of hand mal-formations. In: Birth defects: original article series. VolumeXIV (3). New York: Alan R Liss, 1978.

8 Lyon MF, Searle AG. Genetic variants and strains of thelaboratory mouse. 2nd ed. Oxford: Oxford University Press,1989.

9 Johnson DR. Polysyndactyly, a new mutant gene in themouse. Jf Embryol Exp Morphol 1969;21:285-94.

10 Winter RM. Malformation syndromes: a review of mouse/human homology. J Med Genet 1988;25:480-7.

11 Moore KL. The developing human. 4th ed. Philadelphia:Saunders International Edition, 1988.

12 Winter RM. Tickle C. Syndactylies and polydactylies: em-bryological overview and suggested classifications. Eur JHum Genet 1993;1:96-104.

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