Type II Syndactyly

HAROLD E. CROSS,' DAVID B. LERBERG,1 and VICTOR A. McKuSICK'

Syndactyly, that is, webbing of adjacent digits with or without bony fusion, is a congenital malformation which occurs either as an isolated finding or as a feature of certain malformation syndromes. Several types of isolated syndactyly can be distinguished anatomically. On the basis of a study of 63 pedigrees, Bell (1953) proposed a classification of syndactyly based primarily on the localization of the webbing: type Al, in which webbing occurs between the second and third toes with no involvement of the hands; type A2, with webbing between the third and fourth fingers, frequently with duplication of the fourth finger included in the web; type B1, with webbing between the fourth and fifth toes, often associated with a supernumerary toe in the web; and type C, in which webbing occurs between three or more digits in one or more extremities. In some pedigrees, however, multiple digital anomalies were present, and these were considered combinations of the above types, such as Al with A2, or A2 with BI. After reviewing the literature and studying additional families, Temtamy (1966) concluded that at least five types of syndactyly can be distinguished: type I, in which the characteristic malformation is syndactyly of the third and fourth fingers and the second and third toes; type II, with syndactyly between the third and fourth fingers, occasional duplication of the third or fourth finger in the web, syndactyly of the fourth and fifth toes, and duplication of the fifth toe; type III, in which syndactyly involves the fourth and fifth fingers only; type IV, with complete syndactyly of all fingers; and type V, in which syndactyly is associated with metacarpal and metatarsal synostosis. Each of these types is inherited as an autosomal dominant malformation with variable expressivity and incomplete penetrance. This report describes studies of a kindred in which numerous persons had syndactyly involving the third and fourth fingers and the fourth and fifth toes, classified as "type A2 with Bi" by Bell (1953) and "type II" by Temtamy (1966). This type of syndactyly was first reported by Smith and Norwell (1894) and later by Ebstein (1896), Jacobsohn (19C9), Vogel (1913), Manson (1916), Edwards (1916), Thomsen (1927), Bonnet (1928), Schade (1937), Pipkin and Pipkin (1946), and Alvord (1947). The 14 reported pedigrees include 162 affected males and 116 affected females. Linkage studies and systematic dermatoglyphic analyses have not been reported in this type of syndactyly. Our studies were undertaken (a) to determine what dermatoglyphic changes, if any, are characteristic of type II syndactyly; (b) to search for genetic linkage of type IL syndactyly; and (c) to investigate what anatomical, dermatoglyphic, or linkage information may be useful in the identification of heterozygotes with no clinical evidence of syndactyly.

Received November 9,1967. 1 Division of Medical Genetics, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205. 368 TYPE II SYNDACTYLY 369

SUBJECTS AND METHODS No single individual served as the proband in this kindred since various affected members were brought to our attention during the course of other genetic studies being conducted in a rural community in Ohio. The pedigree (Fig. 1) was constructed through interviews with nearly half of the living members in the last four generations. Information on the first two generations was supplied by a retired schoolteacher (III-5) who is considered reliable. Individuals were examined in their homes for digital anomalies. Blood and saliva were collected from 35 persons: 28 members of the kindred in direct line of descent and seven unrelated spouses (see Fig. 1). Secretor status, blood groups, haptoglobin, and transferrin types were determined, using saliva and serum which had been packed in ice for overnight shipment to Baltimore. The ability to taste phenylthiocarbamide (PTC) was tested using paper strips impregnated with the compound. Finger, palm, and sole prints were obtained on 28 members of the kindred, using the method of Walker (1957). Dermatoglyphics were analyzed, using standard methods for determining ridge counts, aid angles, and palm and sole patterns (Cummins and Midlo, 1961). Linkage analysis was performed, using the computer-based linkage program devel- oped by Renwick and Schulze (1961).

RESULTS Clinical Features Twenty-seven members of the kindred are clinically affected; two others have no clinical evidence of this disorder, but both are offspring of affected individuals and both have affected children. Of the 29, six had died and 22 of the remaining 23 cases were examined, along with 16 unaffected relatives. The first individual known to manifest the anomaly (II-1) had syndactyly of both hands, but the feet were normal. Information on the immigrant couple (I-1 and I-2) is scant, but III-5 was told by his mother (II-1) that they were unaffected. Two persons (III-3 and IV-8) apparently represent "skipped generations." Avail- able evidence indicates that neither had any clinical manifestations of syndactyly, but both had affected offspring. These two matings were not consanguineous, and illegitimacy is unlikely because of the conservative religious practices of members of this community. Blood groups, available only for IV-8 and his offspring, provide no evidence of illegitimacy. III-3 is deceased, but both her feet and hands were normal. IV-8 has no clinical manifestations of syndactyly or polydactyly, although he has two affected daughers. The following analysis of clinical features is based on the 21 living members of the kindred who were examined and who manifested digital abnormalities. The anomaly is usually bilateral and is present more often in the upper extremities than in the lower. In 14 of the persons examined, both hands are involved, while in seven only one hand is involved. (In one person, VI-13, the only manifestation in the hands is bilateral fifth-finger clinodactyly, although the right foot is typically affected.) In the hands, a thick web between the third and fourth fingers usually extends the entire length of the digits, producing complete fusion. There may be a longitudinal - v

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H- H N N TYPE II SYNDACTYLY 371 dorsal groove between the two fused fingers, extending across the broad nail, giving the appearance of a double nail (Fig. 2). The webbed fingers are often inclined toward the volar and ulnar aspects of the hand, with considerable limitation to full extension. This is most marked in the older individuals. Fusion of the distal phalanges may be suspected by palpation of the web and by some decrease in flexion and extension. Bony fusion is usually limited to a portion of the distal phalanges; its extent can be determined only by radiologic examination. Partial or complete duplication of the third or fourth digit may be present in the web but again may not be detectable except by radiologic examination. IV-12, however, has a short but fully formed and func- tional extra digit on the radial side of the webbed fingers.

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_ anal,! ...... :!:. !..: -- ...... FIG. 2.-Dorsal and volar aspects of hands of III-5. The third and fourth fingers can be extended only to the degree shown. The left palm shows a simian crease, an isolated finding in this pedigree. 372 CROSS ET AL. The dorsal and volar aspects of a typical affected hand (111-5) are shown in Figure 2. This individual has nearly normal function in both hands but is limited in extension to the degree shown. The radiographic features of the same hands are shown in Figure 3. In the left hand, the metacarpals appear normal, but the proximal, middle, and distal phalanges of the fourth digit are duplicated. The proximal and possibly the distal interphalangeal joints are obliterated. The distal phalanges of the third and fourth fingers are fused. In the right hand, the middle and distal phalanges of the fourth digit are widened, suggesting that duplication has occurred. The middle and distal phalanges of the third and fourth fingers are fused. The radiographic appearance of the hands of a newborn (V-31) is shown in Figure 4. In both hands, the third metacarpal bone appears widened, distal phalanges of the

FIG. 3.-Radiographic appearance of hands in III-5 (see text for description)

FIG. 4.-Radiographic appearance of hands in a newborn (V-31) (see text for description) TYPE II SYNDACTYLY 373 third and fourth fingers are fused, and extra phalanges are present. Phalangeal duplication is also suggested by enlargement of several of the proximal phalanges in both hands. The feet are involved in 12 of the 21 persons: both feet in seven individuals and only one foot in five others. The anomaly is never present in the feet unless the hands are also affected. If only one hand is affected, either the ipsilateral foot or both feet are affected, but the contralateral foot alone is never involved.

FIG. 5.-Feet in III-5 The disorder is manifest in the feet by complete syndactyly of the fourth and fifth toes and a longitudinal groove on the dorsal aspect of the toes extending distally across the fused nails. The fifth toe may be partially or completely duplicated on the fibular side, but usually this is demonstrable only by radiologic examination. It may be suspected, however, by the abnormally broad appearance of the fused fourth and fifth toes. IV-11 had a supernumerary toe removed from the fibular side of the right foot as a child; the only manifestation at present is a short fifth toe, apparently due to short- ening of the fifth metatarsal. The clinical appearance of the feet of a typically affected individual (III-5) is shown in Figure 5, and the radiographic appearance of the same feet is shown in Figure 6. In both feet, the fifth toes are broad and appear duplicated. The left foot has an extra metatarsal. In the fifth toe of the left foot, the distal phalanx is duplicated and the proximal phalanx is partially duplicated. The distal phalanx of the fourth toe 374 CROSS ET AL. is fused with the double phalanges of the fifth toe. On the right foot, the middle and distal phalanges of the fifth toe are duplicated and the fourth distal phalanx is fused with the duplicated distal phalanx of the fifth toe. These anomalies apparently cause no discomfort to affected individuals, although shoes of extra width are required. Surgical repair has been attempted on several individuals in the first decade of life, but subsequent contractures and angulated growth of the affected fingers have resulted. No other deformities are consistently associated with the syndactyly in this kindred, although one individual (VI-9) has a minor congenital anomaly of the right pinna.

FiG. 6.-Radiographic appearance of feet in III-5 (see text for description) Radiologic examination of both hands and feet in the living, clinically unaffected heterozygote (IV-8) revealed no abnormalities. Dermatoglyphics Palmar patterns satisfactory for complete dermatoglyphic analysis were obtained in 25 affected adult hands, and all lack either one or both of the b and c triradii (Table 1). In eight persons with unilaterally affected upper limbs, only one (VI-11) clinically normal hand shows a missing triradius. In the absence of a triradius, the volar surface of the web presents transverse alignment of ridges extending from the base of the fused digits to the distal interphalangeal joint (Fig. 7). At this joint the ridges are interrupted by the apical patterns on the TABLE 1 DERMATOGLYPHIC CHARACTERISTICS OF CASES WITH TYPE Il SYNDACTYLY

AFFECTED HANDS ABSENT TRIRADIUS aid ANGLE AFFECTED FEET PATIENT Left Right Left Right Left Right Left Ri xht I- -I--I- III-5 ...... + 59.5 69.0 + + IV-3 ...... 46.5 46.0 O 0 IV-7 ...... + + + + 54.5 56.0 O O IV-8* ...... 0 0 0 49.0 48.0 O 0 IV-9 ...... + + + 84.0 + + IV-11...... O O IV-12 ...... ++ + + + 48.0 39.0 + 0 V-2...... + 0 0 40.0 O 0 V-3...... + 80.0 73.0 O + V-14...... + 43.0 42.0 O + V-15...... + 48.0 52.0 O 0 V-19...... 0 72.0 57.0 O 0 V-27...... + + + 48.0 53.0 + + V-30...... 84.0 97.0 + + V-31...... + + + 63.0 + + V-32...... + 0 54.0 55.5 + + VI-6...... +t 42.0 44.0 + + VI-7...... 42.0 38.5 O + VI-9...... + O 0 VI-11...... 53.5 51.0 O 0 VI-13...... +t 0 + VI-14...... 0 + +

* No clinical evidence of syndactyly, but mother and two daughters affected. t Bilateral fifth-finger clinodactyly is the only abnormality in the hands.

A B FIG. 7.-Diagrams of the palmar dermatoglyphic patterns in (A) typically affected and (B) normal hands. Note the absence of a fingerprint pattern in the fourth finger of the affected hand, the lack of both the b and c digital triradii, and the transverse alignment of ridges on the fused fingers. 376 CROSS ET AL. fused distal phalanges. No consistent apical patterns are present. In some hands, one half of the fused distal phalanges has a distinct ridge pattern (whorl, loop, or arch) whereas the other half, corresponding to the second digit, has no recognizable pattern. In others, both halves have patterns, while in still others neither half has a recognizable pattern. Affected palms also show a large atd angle (Table 1). The mean atd angle is 55.4° in 12 affected right hands and 60.7° in 13 affected left hands (excluding the hands of IV-8, a nonmanifesting heterozygote). The mean angle is 58.10 for all affected hands. This is significantly increased (P < .0025) compared with the mean angle of 480 for the general population (Penrose, 1954). The clinically unaffected hands of unilaterally TABLE 2 A PRIORI ANALYSIS OF TYPE II SYNDACTYLY CASES

NUMBER AFFECTED SIZE OF No. OF VARIANCE SIBSHIP SIBSHIPS VARIANCE Observed Expected

3 ...... 2 4 3.430 0.979 4 .3 6 6.402 2.347 5 .2 8 5.162 2.164 6 .2 5 6.094 2.758 10 .1 3 5.005 2.478

Total.10 26 26.093 10.726 SD=3. 275 affected individuals have a mean angle of only 47.3°. Similarly, the aid angles for the right and left hands of the nonmanifesting heterozygote (IV-8) are 480 and 490, respectively. Sole and hallucal patterns show no significant deviation from normal. Formal Genetics Complete ascertainment has probably been achieved in this study, since syndactyly is an easily observable trait and every clinically affected individual in the pedigree is known. From Table 2 it can be seen that the number of observed individuals agrees closely with the number expected on the basis of a presumed autosomal dominant mutation after correction of bias using the a priori method (Li, 1961). Additional support for dominant inheritance is obtained by noting the nearly equal number of affected and unaffected offspring (26 and 25, respectively) of affected parents (count- ing twin births as one and considering the nonmanifesting heterozygotes 111-3 and IV-8 to be affected). These results are in agreement with previous reports (Gates, 1946; Bell, 1953) on this type of syndactyly. However, incomplete penetrance of the disorder is indicated by the two cases of unaffected parents (III-3 and IV-8) with affected offspring. The over-all sex ratio of 17 affected females to 12 affected males among the offspring at risk is not significantly different from 1:1 (X[l1 = 0.552 [with Yates's correction applied]; .50 > P > .25). TYPE II SYNDACTYLY 377 To test for linkage of Type II syndactyly with known autosomal markers, the computer program of Renwick and Schulze (1961) was used to calculate the lod scores over a range of recombination fractions, 0. The lod scores are given in Table 3, together with an estimate of the average likelihood ratios and probabilities of linkage over the full range of possible values of 0 (see Smith, 1959; Renwick and Lawler, 1963). No measurable linkage was detected between the locus for syndactyly and the loci for secretor status; PTC tasting; ABO, MN, P, Rh, K, Le, Fy, and Jk blood groups; transferrins; or haptoglobins. The probability of linkage with one of these markers (.487) is about evenly distributed, except for the most likely locus, that for haptoglobins, which has a probability of .138, taking into account certain prior considera- tions, such as number of autosomes.

DISCUSSION Syndactyly, next to polydactyly the most common congenital malformation affect- ing the hand (Skoog, 1965), is clearly an etiologically heterogeneous disorder. It may appear as an isolated phenomenon or in association with other congenital anomalies, such as cleft lip and palate (Fuhrmann and Vogel, 1960); ipsilateral absence of the sternal head of the pectoralis major muscle (Poland, 1841); acrocephaly (Apert, 19C6). The individuals reported here have one of the rarer types of isolated syndactyly. In addition to fusion of the fingers, there is frequently a duplication of the phalanges in the web, resulting in a malformation that is more accurately termed "synpoly- dactyly." If the criteria set by Bell (1953) and Temtamy (1966) are followed, there are only 14 previously reported pedigrees of this condition. Some of these kindreds have been of Danish, German, French, and English extraction. The immigrant couple (I-1 and 1-2) of the family reported here came from Switzerland, but no other families of known Swiss extraction have been reported. Available evidence is consistent with the hypothesis that the mutation responsible for the disorder in this kindred occurred in one of the members of the immigrant couple. Incomplete penetrance and variable expressivity have been noted in other kindreds. In several pedigrees (Smith and Norwell, 1894; Jacobsohn, 1909; Alvord, 1947), individuals with no clinical evidence of the disorder have had affected offspring. Two instances of this also occur in our kindred (111-3 and IV-8). "Skipped generations" or nonmanifesting heterozygotes, however, may have a minor expression of the trait, which, if detectable, could serve as a basis for genetic counseling. This study failed to detect clinical, dermatoglyphic, or radiologic abnormalities in an individual (IV-8) who is known to carry the trait. It is likely that a search for an abnormality nearer to the site of primary gene action will be necessary to detect such heterozygotes since, for example, dermatoglyphic changes are probably as far removed from the primary gene effect as is syndactyly (Temtamy, 1966) and therefore would not be expected to show complete penetrance. Observations on syndactyly of the foot (Cummins and Sicomo, 1923) suggest that the mutant gene may have a gradation of manifestations from actual digital union to a minor expression of syndactyly expressed as an alteration of the distal plantar dermatoglyphics. These signs have their parallel in the palm (Cummins and Midlo, 0 H... If) 0 _ C., 1- 000. .. m ... --0 C) t

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SUMMARY A kindred is described in which 27 individuals were affected with type II syndactyly. Genetic analysis is consistent with autosomal dominant inheritance. Der- matoglyphic analysis demonstrated that all affected hands lacked the b and/or c digital triradius and that the mean of the aid angles for the affected hands was significantly greater than the aid angle found in normal populations. No measurable linkage was found between the syndactyly locus and 12 marker loci.

ACKNOWLEDGMENT The computer calculations of linkage were performed by Dr. James H. Renwick, using facilities supported in part by U.S. Public Health Service research grant GM 10189. Part of the computations were done in the Computing Center of the Johns Hopkins Medical 380 CROSS ET AL. Institutions, which is supported by research grant FR-00004 from the National Institutes of Health and by educational contributions from the International Business Machines Corporation. We are indebted to Dr. Wilma Bias of the Immunogenetics Laboratory, Baltimore City Hospitals, for blood-group determinations and serum protein typing.

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