Am J Hum Genet 27:91-99, 1975
Polydactyly in the American Indian G. J. BINGLE'
AND
J. D. NISWANDER'
INTRODUCTION
Polydactyly is a congenital malformation with strikingly different frequencies among several racial groups. Stevenson et al. [1], using vital statistics from the World Health Organization birth centers, have noted incidences as low as 0.31 per 1,000 total single births in centers located in Alexandria, Egypt, to as high as 6.18 per 1,000 Negro births in Pretoria, Africa. Woolf and Myrianthopoulos [2] and Brehme [3] have reported incidences in American and African Negroes, respectively, which were 13 times the estimated frequency for Caucasian populations. Castilla et al. [4] have found an overall incidence similar to Caucasian populations for an ethnically heterogeneous population of South Americans. Handforth [5] has reported an incidence among Chinese male prisoners twice that of white populations. In certain instances, the difference in frequency of polydactyly between racial groups can be attributed to an increased frequency of specific types of polydactyly. The high frequency of polydactyly in American Negroes is the result of a preponderance of newborns afflicted with postaxial polydactyly type B (pedunculated postminimus) [2]. Handforth's data [5] show that among his Chinese sample, 93% of cases were preaxial type 1 involving duplication of the thumb. The contribution of monogenic expressivity to the phenotypic diversity of polydactyly is well recognized [4, 6]. Thus, Temtamy and McKusick [6] have proposed a classification of polydactyly involving not only a discrete anatomical categorization but also the specific mode of genetic transmission. Postaxial polydactyly is divided into types A and B. In type A the extra digit is well formed, articulates with the fifth or extra metacarpal, and is inherited as a dominant trait with reduced penetrance. Type B is represented by a poorly differentiated extra digit, usually just a skin tag attached to the fifth finger. The inheritance of type B is unclear [6]. Preaxial polydactyly (type 1) of the form described by Handforth [5] is sporadic and not monogenically inherited; whereas preaxial polydactyly of a triphalangeal thumb (type 2) is inherited as an autosomal dominant [7]. In the present study, part of a large study concerned with congenital malformations in American Indians, we report the incidence, sex ratio, and types of; polydactyly found in over 80 tribes and discuss various hypotheses to explain the highly variable racial incidences. Received June 17, 1974; revised August 27, 1974. Genetics and Epidemiology Section, Laboratory of Developmental Biology and Anomalies, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20014. 1
© 1975 by the American Society of Human Genetics. All rights reserved.
91
92
BINGLE AND NISWANDER PROCEDURES AND RESULTS
Copies of original handwritten newborn examination records of 44,269 American Indian and Alaskan native infants born in U.S. Public Health Service hospitals between July 1964 and June 1969 were made available for this study. These births represent approximately one-half of all Indian births occurring in the United States during this period [8]. All newborn examinations were performed by a physician at each of the hospitals during the first 48 hours of life. Because of incomplete reporting of stillborn infants, only live births were considered. Each of 44,149 records of liveborn infants were scrutinized for documentation of any indication of polydactyly. A total of 105 records were found in which the infant allegedly manifested some form of polydactyly. An attempt was made to classify each case with respect to the type of polydactyly according to the schema presented by Temtamy and McKusick [6]. Table 1 classifies the 105 cases of polydactyly by type and shows the frequency TABLE 1 TYPE, FREQUENCY, AND SEX RATIO
OF
POLYDACTYLY
Type
Postaxial: Type A .................................. Type B .................................. Unspecified ............................... Total .................................. Preaxial: ........... Type 1, thumb or big toe ....... ............. Type 2, triphalangeal ......... ............. Type 3, index finger .......... Total .................................. ........ Polydactyly with other malformations Synpolydactyly ............................. Unclassifiable ................................ Grand total ............ ..............
IN THE
AMERICAN INDIAN
No. Cases
Incidence per 1,000
5 32 10
0.11 0.73 0.23
... ...
47
1.07
1.6
11 0 0
0.25 0.00 0.00
... ... ...
11
0.25 0.18 0.06 0.84 2.40
4.5
8 3 36
105
Sex Ratio
e/l
...
... ...
1.8
1.6
and sex ratio of polydactyly in this sample of American Indians. The overall incidence of polydactyly in this sample is 2.4 per 1,000 live births. This is nearly double the incidence reported by Woolf and Myrianthopoulos [2] for whites and Castilla et al. [4] for South Americans. Unfortunately, approximately one-third of the newborn records designating polydactyly could not be classified as to type because of an inadequate anatomical description of the anomaly. For purposes of this report, we have assumed that the distribution of specific types of the unclassifiable cases is reflected in the distribution of classifiable cases presented in table 1. The sex ratio of unclassifiable
POLYDACTYLY IN AMERICAN INDIANS
93
cases closely approximates that of postaxial polydactyly, indicating that most of the cases are of the postaxial type as would be expected. Nearly 80%o of classifiable cases of polydactyly were of the postaxial type; 11 % of all cases were associated with other minor and major malformations. With the exception of one case in which there was karyotypic evidence of trisomy D, none of the eight cases associated with other malformations could be classified as a recognizable syndrome. Postaxial type B was six times more frequent than type A. This proportion is similar to that already reported in whites [2] and in South Americans [4]. The reporting of subclassifications of preaxial polydactyly is quite variable among different studies. It is striking that in this sample all instances of preaxial polydactyly were type 1. This type, in which the defect involves duplication of the thumb or big toe, is referred to as thumb polydactyly. The toe or thumb may be seen with all degrees of differentiation. Type 1 never involves the index finger or a triphalangeal-type thumb or big toe. Three cases of type 2 syndactyly or synpolydactyly were found. In all cases the polydactyly involved a sixth toe attached to the fifth or little toe. In two cases the syndactyly was between the fourth and fifth toes; whereas in the other, the syndactyly involved the sixth or polydactylous appendage and the fifth toe. Thomsen [9] and Cross et al. [10] have reported large kindreds in which synpolydactyly was transmitted as an autosomal dominant trait. In given kindreds, polydactyly never occurs alone without syndactyly in this entity. Therefore, classification of this anomaly is with the syndactylies and not the polydactylies [6]. Castilla et al. [4] did not record a separate classification for polydactyly associated with syndactyly. Woolf and Woolf [11 ] excluded propositi with both polydactyly and syndactyly from their Utah sample but did report two kindreds in which collateral relatives of the polydactylous proband had isolated syndactyly. Woolf and Myrianthopoulos [2] reported three cases of polydactyly with associated syndactyly in their Negro sample of 25,126 births. The sex ratios (table 1) for each classification of polydactyly demonstrate an excess of affected males in this sample. The overall sex ratio was 1.6, which is significantly different from an expected ratio of 1.0 (Xe2 4.16, df - 1 P < .05). The sex ratio for the entire sample of liveborn Indians was 1.04. Both the postaxial and preaxial types have ratios demonstrating an excess of males. When tested alone, neither the postaxial nor the preaxial ratios are significantly different from 1.0 (X2 =2.12 and 3.27, df = 1). No distortion in the expected sex ratio has been reported in American Negroes or Caucasians [2]. However, a significant distortion (P < .025) in the sex ratio of preaxial type 1 was seen in South Americans [4]. Three criteria (see table 2) were employed for classification of pre- and postaxial polydactyly regarding anatomical location. Hands were preferentially affected in both preaxial type 1 polydactyly (Xc2 - 9.43, P < .005) and postaxial type B (Xc2 5.76, P < .025). Castilla et al. [4] reported a similar distribution for their South American population. Similar findings were reported for postaxial type B in both American Negro and white populations [2 ]. In the Indian population, more than onrha-Jf of all cases of type B polydactyly are bilateral, but none of the cases
BINGLE AND NISWANDER
94
TABLE 2 VARIATION IN ANATOMICAL LOCATION OF POLYDACTYLY BY TYPE POSTAXIAL
Unspecified
PREAXIAL TYPE 1
19
1
11
10
7
8
0
11
0
6
1
0
16
...............
1
4
2
Left ................ Both ............... No. affected limbs: One ................ Two ................ Three .............. Four ...............
3 1
9 19
5 3
7 5 0
4 25
4
13 15 2 2
7
11
12
2
0
10
0 1
0 0
5 10
LOCATION
Region: Hands .............. Feet ................ Both ............... Side:
Right
Type A
Type B
0 5
1
0 0
UNCLASSIFIABLE
8
of preaxial type 1 are bilateral. A similar predilection for bilateral affliction has been demonstrated for type B in Negroes but not in whites [2]. Although no family data are available from the newborn examination records, it is possible to estimate the degree of Caucasian admixture in this population from the degree of hybridization of each of the parents as indicated on the newborn record and calculate it for the proband. A close correlation between percentage Caucasian admixture as determined by B and r allele frequencies of the mothers and their stated degree of hybridization has been shown elsewhere [12]. Table 3 TABLE 3 INCIDENCE OF POLYDACTYLY AMONG OFFSPRING OF FULL-BLOODED AND NON-FULL-BLOODED INDIANS Incidence Degree of Hybridization
No. with Polydactyly
Full-blooded .69
per
1,000
2.96 1.32 2.79
Non-full-blooded .14 Unknown .22
summarizes the incidence of polydactyly in offspring of full-blooded and non-fullblooded Indians. The average degree of admixture of the non-full-blooded group was estimated to be .52. DISCUSSION
Polydactyly exhibits etiologic heterogeneity. In some part, the anatomical classification characterizes this heterogeneity. Clearly preaxial and postaxial poly-
POLYDACTYLY IN AMERICAN INDIANS
95
dactyly do not often segregate within the same family, and, to this extent, genetic heterogeneity exists [2, 6, 11 ]. Since many types of polydactyly appear to segregate in a dominant fashion and no linkage data exist, whether genetic heterogeneity operates at finer levels of subclassification (i.e., postaxial types A and B) cannot yet be determined. In population studies, evidence that the majority of cases are due to either a single dominant gene with reduced penetrance or to an additive multigenic threshold model is not compelling. The overall incidence of polydactyly has been shown to vary considerably among populations [1, 2, 4]. The incidence reported in this American Indian population is twice the Caucasian incidence, but one-sixth that of American Negroes [2]. Although the American Indian population is ethnically heterogeneous, no significant differences with regard to polydactyly exist among the five major linguistic groups [12]. Furthermore, subdivision of these data separately by tribes is impossible because of the large number of tribes comprising the population. Table 4 lists various population surveys and their estimates of overall frequencies of polydactyly. As documented, considerable variation in the type of population surveyed makes overt comparisons difficult. The incidence among 5,842 Chinese male prisoners reported by Handforth [5] is nearly the same as that of the American Indian. However, of the 26 cases described by Handforth, 25 can be classified as preaxial type 1. In contrast, of 58 readily classifiable isolated cases in this sample, only 18% were preaxial type 1. Since pedunculated postminimi are easily remedied at birth and since Handforth [5] noted the defect on consecutive routine physical examinations performed on adult male prisoners, a considerable ascertainment bias may exist in his Chinese sample. Such a sampling bias leads to the underreporting of postaxial type B polydactyly. However, in both the Indian and Chinese sample, preaxial polydactyly is far more frequent than that reported among white or black Americans [3]. Moreover, all of the Indians afflicted with preaxial type 1 polydactyly were recorded as full-blooded. This relatively high frequency of preaxial type 1 polydactyly in the American Indian and Chinese may reflect a common Mongolian origin. The incidence of polydactyly among non-full-blooded newborns, with a mean estimate of Caucasian admixture of .52, is approximately one-half the incidence of polydactyly in full-blooded Indians (see table 3). This is certainly not inconsistent with an additive multifactorial threshold model. However, it is well recognized from many documented kindreds that postaxial type A and occasionally type B appear to segregate as simple Mendelian dominant traits with variable expressivity and reduced penetrance. Castilla et al. [4] found only 36%o of 176 polydactylous probands in which a similar defect could be detected in other family members. They estimated penetrance under an autosomal dominant hypothesis as .68 for postaxial type A and .43 for postaxial type B. Concordance estimates of 42.6% between monozygous twin pairs contrasted with 5.7%o between dizygous pairs were reported by Hay and Wehrung [14]. Similar concordance rates have been reported for malformations like cleft lip with or without cleft palate in which various investigators have favored a polygenic threshold model over any single-gene hypothesis [15, 16]. Moreover, Wright has
96
BINGLE AND NISWANDER TABLE 4 COMPARISON OF POPULATION STUDIES Type of Population
No. Surveyed
Liveborn single only: Melbourne .............................. Sao Paulo ..............................
7,844 14,421
Santiago
.
...
Bogota ................................. Medellin ............................... Czechoslovakia .......................... Alexandria .............................. Hong Kong ............................. Bombay ................................ Calcutta ................................ Kuala Lumpur .......................... Singapore ............................... Mexico City ............................ Belfast ................................. Panama City ............................ Manila ................................. Cape Town ............................. Johannesburg ........................... Pretoria ................................ Madrid
.................................
Ljubljana ............................... Zagreb ................................. Liveborn single and multiple: South America ............. ............. United States (Utah), white ...... ........ United States, white ......... ............ United States, Negro ......... ............ Mexico City ............ ................ Liveborn and stillborn:
Japan
23,726 18,812 20,459 20,074 9,598 9,872 39,498 19,191
ON POLYDACTYLY
Incidence
Reference
0.38 3.62 0.80 1.54 2.05
[1] [1] [1] [1] [1] [1] [1] [1] [1] [1] [1] [1] [1] [1] [1] [1] [1] [1] [1]
0.50 0.31 0.61 0.35 0.36
15,937
0.31
39,683 24,700 28,091
0.38 1.13 0.43 3.03 0.24 0.98 1.34 6.18 0.76 0.34 0.36
15,852 29,669 3,051 11,176 10,025
19,714 8,888 8,416
185,704 59,561 24,153
[1]
[1] [1]
25,126
1.01 0.37 1.32 13.69
[4] [10] [2] [2]
14,083
0.64
[1]
63,796
0.92
[13]
................................
1,828
14.20
[3]
................................
5,842
2.40
[5]
..................................
School-age children:
Angola . Adults: Chinese .
demonstrated that postaxial polydactyly in the guinea pig is multifactorial and that the genetic component of variation may be accounted for by as few as three or four factors [17]. The polygenic threshold model has not been adequately tested in a human population. Several observations explain this omission. Polydactyly is one of the few malformations for which discrete genetic and anatomical subcategorization has been available. Once this categorization has been attempted, obtaining risk figures for an adequate sample of first-, second-, and third-degree relatives becomes difficult. (The occurrence of different anatomical types within the same family complicates the tabulation of risk figures.) The population incidence in certain groups is so high as to reduce the power of the test of significant differences in empiric risk frequencies between relatives of varying degrees of genetic relationship.
POLYDACTYLY IN AMERICAN INDIANS The high incidence of polydactyly in the American Negro has been shown to be a result of a marked increase in the relative frequency of postaxial type B [2]. Similar findings in Brazilian Negroes and African Negroes have substantiated this as a general finding [1, 3, 4]. In view of the consistency of the high frequency of postaxial type B in the Negro race over several geographically and demographically distinct populations, one can argue logically against genetic drift or common environmental factors as being significant in the maintenance of such high frequencies. One might conjecture that originally genetic drift was instrumental in establishing this high frequency of postaxial type B polydactyly in the Negro. Yet if all postaxial polydactyly were the result of a single dominant gene, any hypothesis involving genetic drift would be difficult to envision. Because of the necessity of an assumption of large interracial differences in mutation rate, Woolf and Myrianthopoulos [2] have argued against the hypothesis of autosomal dominant inheritance with complete selection against the homozygote offset by a high mutation rate to explain the high frequency of postaxial type B in Negroes. They alternatively have proposed a model in which heterozygote advantage might explain this high frequency, and also suggest that a polygenic threshold model may be as reasonable. The relative increase of preaxial type 1 polydactyly in part explains the higher frequency of polydactyly in the American Indian compared to Caucasians. An extremely high frequency of this type of polydactyly in the Chinese is inferred from the report of Handforth [5]. Because of inadequate categorization of polydactyly with respect to type, data from the World Health Organization birth record centers are not useful in determining whether this relative increase in preaxial type 1 is consistent in other Mongolian derived populations. Should subsequent studies confirm a similar high frequency of preaxial type 1 in other Mongolian derived populations, a problem in explaining this frequency will be raised as discussed previously in regard to postaxial type B in Negroes. The problem of explaining the excess of affected males in our Indian population and in the South American population [4] is complicated by the fact that no sex ratio distortion was seen in the Caucasian or Negro populations previously cited [2]. One explanation may be that this distortion is specific for type 1 preaxial polydactyly, which is only rarely seen in the Caucasian or Negro population. Support for this explanation is strengthened by the finding that in the South American population the excess of males was specifically noted only in the preaxial polydactyly class [4]. In the Indian population, the sex ratio for preaxial type 1 was 4.5. Although not significantly different from the expected ratio of 1.0, this lack of significance may be explained by the small number of cases of type 1 preaxial
polydactyly. That a significant segment of polydactyly is multifactorial in etiology is obvious from the monozygous twin concordance rate. More subtle evidence may be demonstrated from the teratogenic effects of the well publicized pharmocologic agent, thalidomide. Several of the children afflicted with limb and/or ear malformations subsequent to thalidomide ingestion by the mother during early pregnancy have
98
BINGLE AND NISWANDER
been observed to show preaxial type 1 polydactyly. This is seen as part of the limb malformation when formed digits are present (D. Poswillo, personal communication). Poswillo [18] has demonstrated that these limb defects as well as the first and second branchial arch malformations may result from embryonic hematoma formation during critical developmental time periods both in mice and the marmoset, a primate. This curious association between first and second branchial arch defects and preaxial polydactyly led us to estimate the prevalence of first and second branchial arch anomalies from our data. The overall frequency of such defects which are often characterized under the heading of microtia/anotia, otomandibular dysostosis, and mandibulofacial dysostosis was found to be 0.75 per 1,000 live births. This incidence is three times the reported incidence of 0.25 per 1,000 in Caucasians [7]. The high incidence of preaxial type 1 polydactyly and second and first branchial arch syndromes in the American Indian is noted. There were no examples of an individual affected with both polydactyly and a branchial arch anomaly. We have no explanation. There is no evidence to suggest that a pharmacologically active teratogen like thalidomide was operative in this population during the years 19641969. Preaxial and postaxial polydactyly are genetically distinct. Postaxial type B polydactyly or pedunculated postminimus may be in large part genetically determined, and the genes so responsible are more frequent in Negroes compared to Caucasians and the American Indian, whereas the genes responsible for preaxial type 1 are perhaps more common in the American Indian and Chinese and possibly other Mongolian races. There is evidence that in Indians and South Americans [4] their expression is to some extent sex limited, occurring more often in males. The number of specific genetic determinants controlling either postaxial type B or preaxial type 1 is unknown. It is difficult to clearly choose between either a single autosomal dominant gene with reduced penetrance or a multigenic threshold model involving a few major genetic factors. Moreover, the possibility that both mechanisms can operate simultaneously in a given population is not unlikely. SUMMARY
Polydactyly has an incidence in the American Indian twice that of Caucasians. A minimum estimate of this incidence is 2.40 per 1,000 live births. Preaxial type 1 has an incidence three to four times that reported for Caucasians or Negroes. The overall sex ratio in Indians is distorted with more males affected than females. The preaxial type 1 anomaly has a strong predilection for the hands and always is unilateral in contrast to postaxial type B where more than one-half are bilateral. The evidence to date, consisting of varying incidences of specific types of polydactyly among American whites, Negroes, and Indians in varying environments, suggests different gene frequencies for polydactyly in each population. The incidence in Indians with 50% Caucasian admixture suggests that the factors controlling polydactyly are in large part genetically determined. Family studies and twin studies
POLYDACTYLY IN AMERICAN INDIANS
99
reported elsewhere offer no clear-cut genetic model which explains the highly variable gene frequencies. REFERENCES 1. STEVENSON AC, JOHNSTON HA, STEWART MIP, GOLDING DR: Congenital malformations: a report of a study of series of consecutive births in 24 centres. Bull WHO 34, suppl.: 58-62, 1966 2. WOOLF CM, MYRIANTHOPOULOS NC: Polydactyly in American Negroes and whites. Am J Hum Genet 25:397-404, 1973 3. BREHME H: Uber rudimentare polydaktylie bei Bantu-Negern. Humangenetik 15: 81-83, 1972 4. CASTILLA E, PAZ J, MUTCHINICK 0, MuNoz E, GIORGIUTTI E, GELMAN Z: Polydactyly: a genetic study in South America. Am J Hum Genet 25:405-412, 1973 5. HANDFORTH JR: Polydactyly of the hand in southern Chinese. Anat Rec 106:119-125, 1950 6. TEMTAMY S, McKusIcK V: Synopsis of hand malformations with particular emphasis on genetic factors. Birth Defects: Orig Art Ser 5(3) :125-184, 1969 7. HEFNER RA: Hereditary polydactyly. J Hered 31:25-30, 1940 8. ADAMS MS, NISWANDER JD: Health of the American Indian: congenital defects. Eugenics Quart 15:227-233, 1968 9. THOMSEN 0: Einige Eigentumlichkeiten der erblichen Poly-und Syndaktylie bei Menschen. Acta Med Scand 65:609-644, 1927 10. CROSS HE, LERBERG DB, McKuSIcK VA: Type II syndactyly. Am J Hum Genet 20:368-380, 1962 11. WOOLF CM, WOOLF RM: A genetic study of polydactyly in Utah. Am J Hum Genet 22:75-88, 1970 12. NISWANDER JD, BARROWS MV, BINGLE GJ: Congenital malformation in the American Indian. In preparation 13. NEEL JV: A study of major congenital defects in Japanese infants. Am J Hum Genet 10:398-445, 1958 14. HAY S WEHRUNG DA: Congenital malformations in twins. Am J Hum Genet 22: 662-678, 1970 15. CARTER CO: The inheritance of common congenital malformations. Prog Med Genet 4:59-84, 1965 16. CARTER CO: Genetics of common disorders. Br Med Bull 25:52-57, 1969 17. WRIGHT S: The results of crosses between inbred strains of guinea pigs, differing in number of digits. Genetics 19:537-551, 1934 18. POSWILLo D: The pathogenesis of the first and second branchial arch syndrome. Oral Surg 35:302-328, 1973
Polydactyly in the American Indian G. J. BINGLE'
AND
J. D. NISWANDER'
INTRODUCTION
Polydactyly is a congenital malformation with strikingly different frequencies among several racial groups. Stevenson et al. [1], using vital statistics from the World Health Organization birth centers, have noted incidences as low as 0.31 per 1,000 total single births in centers located in Alexandria, Egypt, to as high as 6.18 per 1,000 Negro births in Pretoria, Africa. Woolf and Myrianthopoulos [2] and Brehme [3] have reported incidences in American and African Negroes, respectively, which were 13 times the estimated frequency for Caucasian populations. Castilla et al. [4] have found an overall incidence similar to Caucasian populations for an ethnically heterogeneous population of South Americans. Handforth [5] has reported an incidence among Chinese male prisoners twice that of white populations. In certain instances, the difference in frequency of polydactyly between racial groups can be attributed to an increased frequency of specific types of polydactyly. The high frequency of polydactyly in American Negroes is the result of a preponderance of newborns afflicted with postaxial polydactyly type B (pedunculated postminimus) [2]. Handforth's data [5] show that among his Chinese sample, 93% of cases were preaxial type 1 involving duplication of the thumb. The contribution of monogenic expressivity to the phenotypic diversity of polydactyly is well recognized [4, 6]. Thus, Temtamy and McKusick [6] have proposed a classification of polydactyly involving not only a discrete anatomical categorization but also the specific mode of genetic transmission. Postaxial polydactyly is divided into types A and B. In type A the extra digit is well formed, articulates with the fifth or extra metacarpal, and is inherited as a dominant trait with reduced penetrance. Type B is represented by a poorly differentiated extra digit, usually just a skin tag attached to the fifth finger. The inheritance of type B is unclear [6]. Preaxial polydactyly (type 1) of the form described by Handforth [5] is sporadic and not monogenically inherited; whereas preaxial polydactyly of a triphalangeal thumb (type 2) is inherited as an autosomal dominant [7]. In the present study, part of a large study concerned with congenital malformations in American Indians, we report the incidence, sex ratio, and types of; polydactyly found in over 80 tribes and discuss various hypotheses to explain the highly variable racial incidences. Received June 17, 1974; revised August 27, 1974. Genetics and Epidemiology Section, Laboratory of Developmental Biology and Anomalies, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20014. 1
© 1975 by the American Society of Human Genetics. All rights reserved.
91
92
BINGLE AND NISWANDER PROCEDURES AND RESULTS
Copies of original handwritten newborn examination records of 44,269 American Indian and Alaskan native infants born in U.S. Public Health Service hospitals between July 1964 and June 1969 were made available for this study. These births represent approximately one-half of all Indian births occurring in the United States during this period [8]. All newborn examinations were performed by a physician at each of the hospitals during the first 48 hours of life. Because of incomplete reporting of stillborn infants, only live births were considered. Each of 44,149 records of liveborn infants were scrutinized for documentation of any indication of polydactyly. A total of 105 records were found in which the infant allegedly manifested some form of polydactyly. An attempt was made to classify each case with respect to the type of polydactyly according to the schema presented by Temtamy and McKusick [6]. Table 1 classifies the 105 cases of polydactyly by type and shows the frequency TABLE 1 TYPE, FREQUENCY, AND SEX RATIO
OF
POLYDACTYLY
Type
Postaxial: Type A .................................. Type B .................................. Unspecified ............................... Total .................................. Preaxial: ........... Type 1, thumb or big toe ....... ............. Type 2, triphalangeal ......... ............. Type 3, index finger .......... Total .................................. ........ Polydactyly with other malformations Synpolydactyly ............................. Unclassifiable ................................ Grand total ............ ..............
IN THE
AMERICAN INDIAN
No. Cases
Incidence per 1,000
5 32 10
0.11 0.73 0.23
... ...
47
1.07
1.6
11 0 0
0.25 0.00 0.00
... ... ...
11
0.25 0.18 0.06 0.84 2.40
4.5
8 3 36
105
Sex Ratio
e/l
...
... ...
1.8
1.6
and sex ratio of polydactyly in this sample of American Indians. The overall incidence of polydactyly in this sample is 2.4 per 1,000 live births. This is nearly double the incidence reported by Woolf and Myrianthopoulos [2] for whites and Castilla et al. [4] for South Americans. Unfortunately, approximately one-third of the newborn records designating polydactyly could not be classified as to type because of an inadequate anatomical description of the anomaly. For purposes of this report, we have assumed that the distribution of specific types of the unclassifiable cases is reflected in the distribution of classifiable cases presented in table 1. The sex ratio of unclassifiable
POLYDACTYLY IN AMERICAN INDIANS
93
cases closely approximates that of postaxial polydactyly, indicating that most of the cases are of the postaxial type as would be expected. Nearly 80%o of classifiable cases of polydactyly were of the postaxial type; 11 % of all cases were associated with other minor and major malformations. With the exception of one case in which there was karyotypic evidence of trisomy D, none of the eight cases associated with other malformations could be classified as a recognizable syndrome. Postaxial type B was six times more frequent than type A. This proportion is similar to that already reported in whites [2] and in South Americans [4]. The reporting of subclassifications of preaxial polydactyly is quite variable among different studies. It is striking that in this sample all instances of preaxial polydactyly were type 1. This type, in which the defect involves duplication of the thumb or big toe, is referred to as thumb polydactyly. The toe or thumb may be seen with all degrees of differentiation. Type 1 never involves the index finger or a triphalangeal-type thumb or big toe. Three cases of type 2 syndactyly or synpolydactyly were found. In all cases the polydactyly involved a sixth toe attached to the fifth or little toe. In two cases the syndactyly was between the fourth and fifth toes; whereas in the other, the syndactyly involved the sixth or polydactylous appendage and the fifth toe. Thomsen [9] and Cross et al. [10] have reported large kindreds in which synpolydactyly was transmitted as an autosomal dominant trait. In given kindreds, polydactyly never occurs alone without syndactyly in this entity. Therefore, classification of this anomaly is with the syndactylies and not the polydactylies [6]. Castilla et al. [4] did not record a separate classification for polydactyly associated with syndactyly. Woolf and Woolf [11 ] excluded propositi with both polydactyly and syndactyly from their Utah sample but did report two kindreds in which collateral relatives of the polydactylous proband had isolated syndactyly. Woolf and Myrianthopoulos [2] reported three cases of polydactyly with associated syndactyly in their Negro sample of 25,126 births. The sex ratios (table 1) for each classification of polydactyly demonstrate an excess of affected males in this sample. The overall sex ratio was 1.6, which is significantly different from an expected ratio of 1.0 (Xe2 4.16, df - 1 P < .05). The sex ratio for the entire sample of liveborn Indians was 1.04. Both the postaxial and preaxial types have ratios demonstrating an excess of males. When tested alone, neither the postaxial nor the preaxial ratios are significantly different from 1.0 (X2 =2.12 and 3.27, df = 1). No distortion in the expected sex ratio has been reported in American Negroes or Caucasians [2]. However, a significant distortion (P < .025) in the sex ratio of preaxial type 1 was seen in South Americans [4]. Three criteria (see table 2) were employed for classification of pre- and postaxial polydactyly regarding anatomical location. Hands were preferentially affected in both preaxial type 1 polydactyly (Xc2 - 9.43, P < .005) and postaxial type B (Xc2 5.76, P < .025). Castilla et al. [4] reported a similar distribution for their South American population. Similar findings were reported for postaxial type B in both American Negro and white populations [2 ]. In the Indian population, more than onrha-Jf of all cases of type B polydactyly are bilateral, but none of the cases
BINGLE AND NISWANDER
94
TABLE 2 VARIATION IN ANATOMICAL LOCATION OF POLYDACTYLY BY TYPE POSTAXIAL
Unspecified
PREAXIAL TYPE 1
19
1
11
10
7
8
0
11
0
6
1
0
16
...............
1
4
2
Left ................ Both ............... No. affected limbs: One ................ Two ................ Three .............. Four ...............
3 1
9 19
5 3
7 5 0
4 25
4
13 15 2 2
7
11
12
2
0
10
0 1
0 0
5 10
LOCATION
Region: Hands .............. Feet ................ Both ............... Side:
Right
Type A
Type B
0 5
1
0 0
UNCLASSIFIABLE
8
of preaxial type 1 are bilateral. A similar predilection for bilateral affliction has been demonstrated for type B in Negroes but not in whites [2]. Although no family data are available from the newborn examination records, it is possible to estimate the degree of Caucasian admixture in this population from the degree of hybridization of each of the parents as indicated on the newborn record and calculate it for the proband. A close correlation between percentage Caucasian admixture as determined by B and r allele frequencies of the mothers and their stated degree of hybridization has been shown elsewhere [12]. Table 3 TABLE 3 INCIDENCE OF POLYDACTYLY AMONG OFFSPRING OF FULL-BLOODED AND NON-FULL-BLOODED INDIANS Incidence Degree of Hybridization
No. with Polydactyly
Full-blooded .69
per
1,000
2.96 1.32 2.79
Non-full-blooded .14 Unknown .22
summarizes the incidence of polydactyly in offspring of full-blooded and non-fullblooded Indians. The average degree of admixture of the non-full-blooded group was estimated to be .52. DISCUSSION
Polydactyly exhibits etiologic heterogeneity. In some part, the anatomical classification characterizes this heterogeneity. Clearly preaxial and postaxial poly-
POLYDACTYLY IN AMERICAN INDIANS
95
dactyly do not often segregate within the same family, and, to this extent, genetic heterogeneity exists [2, 6, 11 ]. Since many types of polydactyly appear to segregate in a dominant fashion and no linkage data exist, whether genetic heterogeneity operates at finer levels of subclassification (i.e., postaxial types A and B) cannot yet be determined. In population studies, evidence that the majority of cases are due to either a single dominant gene with reduced penetrance or to an additive multigenic threshold model is not compelling. The overall incidence of polydactyly has been shown to vary considerably among populations [1, 2, 4]. The incidence reported in this American Indian population is twice the Caucasian incidence, but one-sixth that of American Negroes [2]. Although the American Indian population is ethnically heterogeneous, no significant differences with regard to polydactyly exist among the five major linguistic groups [12]. Furthermore, subdivision of these data separately by tribes is impossible because of the large number of tribes comprising the population. Table 4 lists various population surveys and their estimates of overall frequencies of polydactyly. As documented, considerable variation in the type of population surveyed makes overt comparisons difficult. The incidence among 5,842 Chinese male prisoners reported by Handforth [5] is nearly the same as that of the American Indian. However, of the 26 cases described by Handforth, 25 can be classified as preaxial type 1. In contrast, of 58 readily classifiable isolated cases in this sample, only 18% were preaxial type 1. Since pedunculated postminimi are easily remedied at birth and since Handforth [5] noted the defect on consecutive routine physical examinations performed on adult male prisoners, a considerable ascertainment bias may exist in his Chinese sample. Such a sampling bias leads to the underreporting of postaxial type B polydactyly. However, in both the Indian and Chinese sample, preaxial polydactyly is far more frequent than that reported among white or black Americans [3]. Moreover, all of the Indians afflicted with preaxial type 1 polydactyly were recorded as full-blooded. This relatively high frequency of preaxial type 1 polydactyly in the American Indian and Chinese may reflect a common Mongolian origin. The incidence of polydactyly among non-full-blooded newborns, with a mean estimate of Caucasian admixture of .52, is approximately one-half the incidence of polydactyly in full-blooded Indians (see table 3). This is certainly not inconsistent with an additive multifactorial threshold model. However, it is well recognized from many documented kindreds that postaxial type A and occasionally type B appear to segregate as simple Mendelian dominant traits with variable expressivity and reduced penetrance. Castilla et al. [4] found only 36%o of 176 polydactylous probands in which a similar defect could be detected in other family members. They estimated penetrance under an autosomal dominant hypothesis as .68 for postaxial type A and .43 for postaxial type B. Concordance estimates of 42.6% between monozygous twin pairs contrasted with 5.7%o between dizygous pairs were reported by Hay and Wehrung [14]. Similar concordance rates have been reported for malformations like cleft lip with or without cleft palate in which various investigators have favored a polygenic threshold model over any single-gene hypothesis [15, 16]. Moreover, Wright has
96
BINGLE AND NISWANDER TABLE 4 COMPARISON OF POPULATION STUDIES Type of Population
No. Surveyed
Liveborn single only: Melbourne .............................. Sao Paulo ..............................
7,844 14,421
Santiago
.
...
Bogota ................................. Medellin ............................... Czechoslovakia .......................... Alexandria .............................. Hong Kong ............................. Bombay ................................ Calcutta ................................ Kuala Lumpur .......................... Singapore ............................... Mexico City ............................ Belfast ................................. Panama City ............................ Manila ................................. Cape Town ............................. Johannesburg ........................... Pretoria ................................ Madrid
.................................
Ljubljana ............................... Zagreb ................................. Liveborn single and multiple: South America ............. ............. United States (Utah), white ...... ........ United States, white ......... ............ United States, Negro ......... ............ Mexico City ............ ................ Liveborn and stillborn:
Japan
23,726 18,812 20,459 20,074 9,598 9,872 39,498 19,191
ON POLYDACTYLY
Incidence
Reference
0.38 3.62 0.80 1.54 2.05
[1] [1] [1] [1] [1] [1] [1] [1] [1] [1] [1] [1] [1] [1] [1] [1] [1] [1] [1]
0.50 0.31 0.61 0.35 0.36
15,937
0.31
39,683 24,700 28,091
0.38 1.13 0.43 3.03 0.24 0.98 1.34 6.18 0.76 0.34 0.36
15,852 29,669 3,051 11,176 10,025
19,714 8,888 8,416
185,704 59,561 24,153
[1]
[1] [1]
25,126
1.01 0.37 1.32 13.69
[4] [10] [2] [2]
14,083
0.64
[1]
63,796
0.92
[13]
................................
1,828
14.20
[3]
................................
5,842
2.40
[5]
..................................
School-age children:
Angola . Adults: Chinese .
demonstrated that postaxial polydactyly in the guinea pig is multifactorial and that the genetic component of variation may be accounted for by as few as three or four factors [17]. The polygenic threshold model has not been adequately tested in a human population. Several observations explain this omission. Polydactyly is one of the few malformations for which discrete genetic and anatomical subcategorization has been available. Once this categorization has been attempted, obtaining risk figures for an adequate sample of first-, second-, and third-degree relatives becomes difficult. (The occurrence of different anatomical types within the same family complicates the tabulation of risk figures.) The population incidence in certain groups is so high as to reduce the power of the test of significant differences in empiric risk frequencies between relatives of varying degrees of genetic relationship.
POLYDACTYLY IN AMERICAN INDIANS The high incidence of polydactyly in the American Negro has been shown to be a result of a marked increase in the relative frequency of postaxial type B [2]. Similar findings in Brazilian Negroes and African Negroes have substantiated this as a general finding [1, 3, 4]. In view of the consistency of the high frequency of postaxial type B in the Negro race over several geographically and demographically distinct populations, one can argue logically against genetic drift or common environmental factors as being significant in the maintenance of such high frequencies. One might conjecture that originally genetic drift was instrumental in establishing this high frequency of postaxial type B polydactyly in the Negro. Yet if all postaxial polydactyly were the result of a single dominant gene, any hypothesis involving genetic drift would be difficult to envision. Because of the necessity of an assumption of large interracial differences in mutation rate, Woolf and Myrianthopoulos [2] have argued against the hypothesis of autosomal dominant inheritance with complete selection against the homozygote offset by a high mutation rate to explain the high frequency of postaxial type B in Negroes. They alternatively have proposed a model in which heterozygote advantage might explain this high frequency, and also suggest that a polygenic threshold model may be as reasonable. The relative increase of preaxial type 1 polydactyly in part explains the higher frequency of polydactyly in the American Indian compared to Caucasians. An extremely high frequency of this type of polydactyly in the Chinese is inferred from the report of Handforth [5]. Because of inadequate categorization of polydactyly with respect to type, data from the World Health Organization birth record centers are not useful in determining whether this relative increase in preaxial type 1 is consistent in other Mongolian derived populations. Should subsequent studies confirm a similar high frequency of preaxial type 1 in other Mongolian derived populations, a problem in explaining this frequency will be raised as discussed previously in regard to postaxial type B in Negroes. The problem of explaining the excess of affected males in our Indian population and in the South American population [4] is complicated by the fact that no sex ratio distortion was seen in the Caucasian or Negro populations previously cited [2]. One explanation may be that this distortion is specific for type 1 preaxial polydactyly, which is only rarely seen in the Caucasian or Negro population. Support for this explanation is strengthened by the finding that in the South American population the excess of males was specifically noted only in the preaxial polydactyly class [4]. In the Indian population, the sex ratio for preaxial type 1 was 4.5. Although not significantly different from the expected ratio of 1.0, this lack of significance may be explained by the small number of cases of type 1 preaxial
polydactyly. That a significant segment of polydactyly is multifactorial in etiology is obvious from the monozygous twin concordance rate. More subtle evidence may be demonstrated from the teratogenic effects of the well publicized pharmocologic agent, thalidomide. Several of the children afflicted with limb and/or ear malformations subsequent to thalidomide ingestion by the mother during early pregnancy have
98
BINGLE AND NISWANDER
been observed to show preaxial type 1 polydactyly. This is seen as part of the limb malformation when formed digits are present (D. Poswillo, personal communication). Poswillo [18] has demonstrated that these limb defects as well as the first and second branchial arch malformations may result from embryonic hematoma formation during critical developmental time periods both in mice and the marmoset, a primate. This curious association between first and second branchial arch defects and preaxial polydactyly led us to estimate the prevalence of first and second branchial arch anomalies from our data. The overall frequency of such defects which are often characterized under the heading of microtia/anotia, otomandibular dysostosis, and mandibulofacial dysostosis was found to be 0.75 per 1,000 live births. This incidence is three times the reported incidence of 0.25 per 1,000 in Caucasians [7]. The high incidence of preaxial type 1 polydactyly and second and first branchial arch syndromes in the American Indian is noted. There were no examples of an individual affected with both polydactyly and a branchial arch anomaly. We have no explanation. There is no evidence to suggest that a pharmacologically active teratogen like thalidomide was operative in this population during the years 19641969. Preaxial and postaxial polydactyly are genetically distinct. Postaxial type B polydactyly or pedunculated postminimus may be in large part genetically determined, and the genes so responsible are more frequent in Negroes compared to Caucasians and the American Indian, whereas the genes responsible for preaxial type 1 are perhaps more common in the American Indian and Chinese and possibly other Mongolian races. There is evidence that in Indians and South Americans [4] their expression is to some extent sex limited, occurring more often in males. The number of specific genetic determinants controlling either postaxial type B or preaxial type 1 is unknown. It is difficult to clearly choose between either a single autosomal dominant gene with reduced penetrance or a multigenic threshold model involving a few major genetic factors. Moreover, the possibility that both mechanisms can operate simultaneously in a given population is not unlikely. SUMMARY
Polydactyly has an incidence in the American Indian twice that of Caucasians. A minimum estimate of this incidence is 2.40 per 1,000 live births. Preaxial type 1 has an incidence three to four times that reported for Caucasians or Negroes. The overall sex ratio in Indians is distorted with more males affected than females. The preaxial type 1 anomaly has a strong predilection for the hands and always is unilateral in contrast to postaxial type B where more than one-half are bilateral. The evidence to date, consisting of varying incidences of specific types of polydactyly among American whites, Negroes, and Indians in varying environments, suggests different gene frequencies for polydactyly in each population. The incidence in Indians with 50% Caucasian admixture suggests that the factors controlling polydactyly are in large part genetically determined. Family studies and twin studies
POLYDACTYLY IN AMERICAN INDIANS
99
reported elsewhere offer no clear-cut genetic model which explains the highly variable gene frequencies. REFERENCES 1. STEVENSON AC, JOHNSTON HA, STEWART MIP, GOLDING DR: Congenital malformations: a report of a study of series of consecutive births in 24 centres. Bull WHO 34, suppl.: 58-62, 1966 2. WOOLF CM, MYRIANTHOPOULOS NC: Polydactyly in American Negroes and whites. Am J Hum Genet 25:397-404, 1973 3. BREHME H: Uber rudimentare polydaktylie bei Bantu-Negern. Humangenetik 15: 81-83, 1972 4. CASTILLA E, PAZ J, MUTCHINICK 0, MuNoz E, GIORGIUTTI E, GELMAN Z: Polydactyly: a genetic study in South America. Am J Hum Genet 25:405-412, 1973 5. HANDFORTH JR: Polydactyly of the hand in southern Chinese. Anat Rec 106:119-125, 1950 6. TEMTAMY S, McKusIcK V: Synopsis of hand malformations with particular emphasis on genetic factors. Birth Defects: Orig Art Ser 5(3) :125-184, 1969 7. HEFNER RA: Hereditary polydactyly. J Hered 31:25-30, 1940 8. ADAMS MS, NISWANDER JD: Health of the American Indian: congenital defects. Eugenics Quart 15:227-233, 1968 9. THOMSEN 0: Einige Eigentumlichkeiten der erblichen Poly-und Syndaktylie bei Menschen. Acta Med Scand 65:609-644, 1927 10. CROSS HE, LERBERG DB, McKuSIcK VA: Type II syndactyly. Am J Hum Genet 20:368-380, 1962 11. WOOLF CM, WOOLF RM: A genetic study of polydactyly in Utah. Am J Hum Genet 22:75-88, 1970 12. NISWANDER JD, BARROWS MV, BINGLE GJ: Congenital malformation in the American Indian. In preparation 13. NEEL JV: A study of major congenital defects in Japanese infants. Am J Hum Genet 10:398-445, 1958 14. HAY S WEHRUNG DA: Congenital malformations in twins. Am J Hum Genet 22: 662-678, 1970 15. CARTER CO: The inheritance of common congenital malformations. Prog Med Genet 4:59-84, 1965 16. CARTER CO: Genetics of common disorders. Br Med Bull 25:52-57, 1969 17. WRIGHT S: The results of crosses between inbred strains of guinea pigs, differing in number of digits. Genetics 19:537-551, 1934 18. POSWILLo D: The pathogenesis of the first and second branchial arch syndrome. Oral Surg 35:302-328, 1973
