American Journal of Medical Genetics 79:9096 (1998)

Genetic Epidemiology Study of Idiopathic

Talipes Equinovarus
CarolLynn Lochmiller,1 Dennis Johnston,2 Allison Scott,3,4 Marjorie Risman,4 and
Jacqueline T. Hecht4*
1

Childrens Medical Center of Dallas, Dallas, Texas

University of Texas M.D. Anderson Cancer Center, Houston, Texas
3
Shriners Hospital for Children, Houston Unit, Houston, Texas
4
University of Texas Medical School at Houston, Houston, Texas
2

Previous genetic studies of idiopathic talipes equinovarus (ITEV) suggest an environmental and genetic component to the etiology of ITEV. The present study was undertaken to assess the role of causal factors in
the development of ITEV. A total of 285 propositi were ascertained, with detailed family history information available in 173
cases and medical records on the remaining
112 propositi. Information was collected on
specific prenatal, parental, and demographic factors. No racial heterogeneity was
noted among any of the factors. The overall
ratio of affected males to females was 2.5:1.
The incidence of twinning among all propositi was significantly increased (P = 0.006)
above the expected population frequency. A
family history of ITEV was noted in 24.4% of
all propositi studied. These findings, in addition to the detailed analysis of 53 pedigrees with ITEV history, suggest the potential role of a gene or genes operating in highrisk families to produce this foot deformity.
Am. J. Med. Genet. 79:9096, 1998.
1998 Wiley-Liss, Inc.

KEY WORDS: idiopathic talipes equinovarus; ITEV; clubfeet; genetics; Mendelian inheritance;
bone; segregation analysis;
pedigrees

INTRODUCTION
Idiopathic talipes equinovarus (ITEV) is an isolated
congenital deformity of the foot and lower leg defined
as a fixation of the foot in adduction, supination, and
varus, with concomitant soft tissue abnormalities pre*Correspondence to: Jacqueline T. Hecht, Ph.D., University of
Texas Medical School at Houston, P.O. Box 20708, Houston, TX
77225. E-mail: jhecht@ped1.med.uth.tmc.edu
Received 10 December 1997; Accepted 24 April 1998

1998 Wiley-Liss, Inc.

sent at birth [Dvaric et al., 1989]. ITEV comprises the

largest group of patients with congenital clubfeet and
must be distinguished from those cases of talipes
equinovarus for which there is a known cause or associated congenital abnormalities or which are syndromal in nature. Patients with ITEV have typical clubfeet ranging from moderate to severe, and correction
generally requires serial manipulations and castings,
followed by surgical procedures [Porter, 1995].
ITEV is one of the most common congenital defects,
with an estimated birth prevalence of 1 per 1,000 live
births [Wynne-Davies, 1972]. However, the birth
prevalence of ITEV varies greatly according to ethnic
population and gender. Most studies of ITEV have been
conducted using Caucasian patients and have shown a
range of incidences from 1 to 3 per 1,000 live births
[Cartilidge, 1984]. Chinese have been reported to have
the lowest prevalence, with 0.39 cases per 1,000 live
births, whereas Hawaiians and Maoris have the highest at of 6.5 to 7 per 1,000 births [Chung et al., 1969;
Beals, 1978]. The ratio of ITEV among males to females
is 2:1 and is consistent across ethnic groups [Chung et
al., 1969]. A bilateral deformity is seen in 50% or more
of ITEV cases, and in unilateral defects, the right side
is usually more frequently involved than the left [DeValentine and Blakeslee, 1992].
The inheritance of ITEV has not been fully elucidated, although multifactorial causation has been suggested. There is a sharp drop in ITEV prevalence between first- and second-degree relatives [Carter, 1965].
Moreover, significant variation in prevalence exists
among racial groups in Hawaii, with an increase corresponding to the proportion of Hawaiian parentage
[Stewart, 1951; Chung et al., 1969]. Evidence for genetic factors comes from the observation that concordance of ITEV among dizygotic twins is significantly
less than that of monozygotic twins [Idelberger, 1939].
Most recently, complex segregation analysis rejected
the possibility of non-Mendelian inheritance and accepted the hypothesis that a single Mendelian gene
(SMG) in combination with residual factors shared by
sibs can explain ITEV in Caucasians [Rebbeck et al.,
1993]. The present study was undertaken to define factors causing ITEV.

Etiologic Study of ITEV

SUBJECTS AND METHODS

This study is based on data collected from unrelated
families, each having at least one child under treatment for ITEV at Shriners Hospital for Children, Houston Unit, Houston, Texas. Requisites for inclusion in
this study were: (1) clinical and radiological diagnosis
of ITEV, and (2) absence of any other abnormality of
chromosomal origin, neuromuscular involvement, or
postnatal insult that could have caused the talipes
equinovarus. Methods of ascertainment employed were
personal interview and/or medical record review. Propositi and families who were interviewed personally
were contacted either during a clinic visit or by telephone.
A total of 173 propositi were included in the study on
the basis of information obtained from personal interview and medical record review, and 112 on the basis of
medical record review alone. Combined, the two data
sets comprised 285 propositi, consisting of 131 Caucasians, 111 Hispanics, 21 African Americans, and 22
individuals of an ethnic background that was not of the
above classification or was unknown. The subset of 173
propositi consisted of 99 (57.2%) Caucasian, 54 (31.2%)
Hispanic, 16 (9.3%) African American, and 4 (2.3%) individuals of other ethnicity. The mean age of all propositi at the time of the study was 7.6 years.
Detailed information on the propositus and other affected relatives was obtained and combined with previously obtained information from medical chart review so that each patient was only represented as a
single case. A family history of ITEV was defined as
having at least one affected relative at the third degree
of relation or less, in addition to the propositus.
All data were coded and entered into an Excel data
base (Microsoft Corp., 1995). Data collected only
through medical record review were cross-tabulated
with data collected by personal interview and record
review combined to ensure that the two data sets were
compatible. The data were then combined into a single
Statistica file, where the data could be analyzed in aggregate [Statsoft, Tulsa, OK, 1994]. The frequency of
each epidemiological factor was calculated for all propositi in the study with the denominator varying according to availability of the information. Statistical
analysis of the data was performed using crosstabulations, the two-tailed t-test, one-way analysis of
variance (ANOVA), Mann-Whitney test, KruskalWallis ANOVA by ranks test, and goodness-of-fit chisquare analysis as indicated [Zar, 1996].
RESULTS
Demographics
The 285 propositi consisted of 200 males and 85 females, a ratio of 2.5:1. Unilateral defects were seen in
135 propositi (47.4%) and bilateral defects in 150 cases
(52.6%). Right-sided defects (58.2%) were more common than left-sided defects (41.8%). Cross-tabulations
of demographic data showed no significant differences
among individuals of different ethnicity with respect to
gender (P 0.82) or the foot involved in the defect (P

91

0.29). There were no correlations between gender

and laterality or foot affected (P 0.53).
Twinning
Analysis of twins in this study showed 5 twins, 168
non-twins, and 112 propositi with unknown twin status. These data indicate a 2.9% twinning rate, with all
twins reportedly dizygotic and discordant for ITEV status. A significant P-value of 0.006 was obtained when
the number of twins in this study was compared with a
1.2% general population incidence of twins [Stevenson
et al., 1993]. The increase of twinning is due to the
higher frequency of dizygotic twins. There were no statistically significant differences in twinning rates
among the different ethnic groups or according to gender. An equal number of unilateral and bilateral cases
was seen among the twins. There were no significant
correlations between twinning and the foot affected,
although all cases of unilateral defects in twins were
right-sided.
Uterine Factors
A total of 16 propositi reportedly were in a breech
position at delivery, whereas 180 were not breech, and
in 89 patients, the presentation at delivery was not
known. This 8.2% frequency of breech deliveries was
not significantly higher than the 4.8% frequency of
breech births among 9,231 deliveries recorded at Herman Hospital (Houston, TX) between February 1994
and March 1996. Five patients had mothers who reported having a uterine abnormality throughout the
pregnancy of the propositus, 145 mothers reported they
did not have a uterine abnormality, and in 135 propositi, almost half, information on uterine abnormalities was unknown or unavailable. Of the five cases of
uterine abnormalities, all were reported to be fibroids.
In assessing the amniotic fluid levels in the second
trimester of pregnancy through delivery of ITEV propositi, 1 pregnancy reportedly had polyhydramnios, 6
reportedly had oligohydramnios, 67 had normal fluid
levels, and in most cases (211), information on amniotic
fluid levels was unknown. Compared with general
population frequencies of 1.6% for polyhydramnios and
5.5% oligohydramnios, there were no significant differences in the reported frequencies [Pritchard et al.,
1985]. Comparisons of breech deliveries, uterine abnormalities, and amniotic fluid levels across propositi of
different sex, ethnicity, and laterality of their defect
showed no statistically significant differences.
Gravidity
Analysis of maternal gravidity, including the ITEV
pregnancy and all previous and subsequent pregnancies, demonstrated a mean gravidity of 2.29 among 197
propositi for whom this information was given. The
mean gravidity of ITEV propositi was compared with
that of unaffected sibs (mean 2.25), and no significant differences were noted (P 0.77). Crosstabulations of gravidity with ethnicity and gender
showed no significant differences. No correlations were
seen between gravidity and laterality of the defect, ma-

92

Lochmiller et al.

ternal uterine abnormalities, breech presentation, or

oligohydramnios. A comparison of gravidity between
twins (mean 3.5) and nontwins (mean 2.21) in this
study demonstrated a significantly higher mean gravidity among the twin group (P 0.022).
Seasonal Influence
Figure 1 shows the frequency of ITEV births per
month. The greatest number of propositi were born
during July, while the lowest number of ITEV births
occurred during March. The frequency of ITEV births
was also grouped according to season, with 26.6% of
patients born between December and February, 23.8%
born between March and May, 27.7% born between
June and August, and 22.0% born between September
and November. Comparison of the frequency of births
by month and births by season between ITEV patients
and unaffected relatives demonstrated no significant
differences between the two groups (Table I). The frequency of ITEV births by month and season did not
correlate significantly with sex or ethnicity. The difference in the number of ITEV births by month according
to laterality of the defect was statistically significant (P
0.037); the significance was primarily due to the
difference between the frequency of unilateral cases
(7.1%) and bilateral cases (1.8%) in January. There
were also statistically significant differences in the
number of right-sided versus left-sided defects by
month (P 0.003), although there was no obvious pattern to explain the significant results. There was a significant excess of right-sided ITEV during February,
August, September, November, and December, and an
excess of left-sided ITEV during January, April, and
June.
Developmental Dislocated Hips
Five individuals were diagnosed with developmental
dislocated hips (DDH); 207 were not; and for 73 propositi, the information was unknown or not available at
the time of the study. The frequency of DDH did not

TABLE I. Cross-Tabulations of ITEV Propositus Births With

Other Factors
P-value
Factor
Unaffected relatives
General populationa
Gender
Ethnicityb
Laterality
Left versus right foot

Births/month

Births/season

0.185
0.466
0.396
0.099
0.037
0.003

0.155
0.603
0.708
0.342
0.075
0.177

Empirically derived number from Herman Hospital Systems, Houston,

TX, 19871995.
Includes Caucasian, African-American, and Hispanic propositi.

differ significantly with respect to gender or ethnicity

of the propositus population (P 0.66 and P 0.28).
Family History
Data collected on all propositi regarding family history of ITEV showed that 55 propositi had a family
history of ITEV, 170 had no history of ITEV, and the
family history was unknown in 60 of the 285 propositi.
Cross-tabulations of family history in all propositi by
uterine and environmental factors showed no significant differences in propositi with a positive family history and those with no family history of ITEV (Table
II). Males and females had similar frequencies of ITEV
in their family history (Table III). There was no significant preference of unilateral to bilateral cases or left
versus right feet in patients with a positive history,
although among unilateral cases, patients with rightsided defects were twice as likely to have a positive
history compared with those with left-sided defects.
The five twin propositi with information regarding
family history all reported a negative history of ITEV.
Cross-tabulations with uterine factors also showed
that these factors were not significantly associated
with family history (data not shown).
Pedigree Analysis
Family history information and pedigrees collected
through personal interview were analyzed separately

Fig. 1. Frequency of ITEV births per

month [January (J) through December (D)].

Etiologic Study of ITEV

TABLE II. Cross-Tabulations of Family History in All Families
by Other Factors

TABLE III. Normalized Comparisons of Family History by

Other Factors
Frequency

Frequency

Factor
Gender
Male
Female
Ethnicity
Caucasian
African American
Hispanic
Laterality
Unilateral
Bilateral
Foot
Left
Right
Both
Twinning
Dizygotic
Singleton

Family
history
of ITEV

No family
history
of ITEV

P-value

0.167
0.077

0.554
0.203

0.504
(N 222)

0.136
0.034
0.087

0.398
0.053
0.291

0.3824
(N 206)

0.131
0.113

0.412
0.344

0.920
(N 222)

0.032
0.081
0.131

0.176
0.171
0.410

0.140
(N 222)

0
0.252

0.031
0.718

0.188
(N 163)

Factor

Family history
of ITEV (%)

No family history
of ITEV (%)

23.0
29.4

77.0
70.6

24.2
33.3
26.4

75.8
66.7
73.6

25.0
24.7

75.0
75.3

9.4
35.4
24.7

90.6
64.6
75.3

20.0
29.8

80.0
70.2

Gender
Male
Female
Ethnicity
Caucasian
African American
Hispanic
Laterality
Unilateral
Bilateral
Foot
Left
Right
Both
Twinning
Dizygotic
Singleton

from all cases of ITEV. Of the 173 on which a pedigree

was drawn, 53 (30.6%) had a significant family history
of ITEV in first-, second-, or third-degree and more distant relatives. Parent-to-child transmission was seen
in 11 of the 53 pedigrees (20.8%) with a history of
ITEV. A total of 36 of the 123 male propositi (29.3%)
and 17 of 50 females (34%) exhibited a family history,
whereas 31.3% (31/99) of Caucasians, 31.3% (5/16) of
African Americans, 29.6% (16/54) of Hispanic, and 25%
(1/4) other propositi had relatives affected with ITEV.
Among families of propositi in this group, a total of
71 relatives were reported to have ITEV. These relatives of propositi comprised 19 first-degree, 17 seconddegree, and 35 third-degree and more distant relatives
(Table IV). The number of affected relatives within a
particular pedigree ranged from 1 to 5. A detailed description of affected relatives according to sex and ethnicity is shown in Table V. No significant difference
was noted between the number of males and females in
first-, second-, and third-degree relatives (P 0.84) or
between the number of Caucasian, African-American,
and Hispanic relatives according to degree of relation
(P 0.73). When separating first-, second-, and thirddegree relatives according to the sex of the propositus,
a total of 44 affected relatives were found in families of
male propositi, whereas a total of 27 affected relatives
were seen in families of female propositi. No significant
difference was noted among the distribution of first-,
second-, and third-degree relatives between male and
female propositi (P 0.34).

Calculations of absolute risk for developing ITEV in

the families studied were calculated for first- and second-degree relatives based on a ratio of affected individuals to the total number individuals in a particular
category. The overall risk based on information from
all 173 families shows that first-degree relatives had
an absolute risk of 3.6%, whereas second-degree relatives had a lower risk of 0.9% (Table VI). Analysis of
risk based on gender showed that first-degree males
had a higher risk compared with first-degree females,
although the risk for second-degree males and females
decreased to a similar value. According to ethnicity,
first-degree African Americans had the highest absolute risk; however, this may be related to small sample
size of this ethnic group.
To assess specifically the risk of malformation in individuals within those families with multiple affected
individuals, absolute risks were also calculated as the
ratio of the number of affected individuals to the total
number of relatives within the pedigrees having a positive family history (Table VII). The risk was highest
among first-degree male relatives of female propositi,
with a risk of 17.2%; male relatives of male propositi
were also at a similarly high risk of 15.7%. The risk to
all first-degree relatives of female propositi (12.1%)
was slightly higher than the risk to relatives of male
propositi (11.3%) (Table VII). However, regardless of
propositus gender, overall risk to first-degree male
relatives (16.7%) was substantially higher than the
risk to first-degree female relatives (6.1%) (Table VII).

TABLE IV. Relatives of Caucasian, African American, and Hispanic Propositi

Affected relatives
Relation
First degree
Second degree
Third and greater degree
Total

93

Total relatives

Male

Female

Total

Male

Female

Total

13
8
23
44

6
9
12
27

19
17
35
71

263
975
83
1321

264
990
92
1346

527
1965
175*
2667

*Includes only sibs of affected third-degree and more distant relatives.

94

Lochmiller et al.
TABLE V. Summary of Affected Relatives According to Gender and Ethnicity of the Propositus
Relatives by degree of relation to propositus
First

Gender
Male
Female
Ethnicity
Caucasian
African American
Hispanic

Second

Male

Female

Male

Female

Male

Female

Total

8
5

4
2

6
2

7
2

16
7

7
5

48
23

7
1
5

3
1
2

6
1
1

5
1
3

14
1
8

7
0
5

42
5
24

Among second-degree relatives, the risks to male and

female relatives were similar.
DISCUSSION
Development of ITEV has been suggested to have
both a genetic and environmental component. The significantly increased frequency of dizygotic twins among
propositi of this study suggests that twinning potentially influences the development of ITEV. In twin
pregnancies, mobility of the fetuses can be restricted by
virtue of sharing a uterine environment; hence, an increase in twinning among ITEV patients provides support for Hippocrates ancient contention that clubfoot
may result from the continued maintenance of the foot
in a certain position [Hippocrates, 1939]. Twinning accounts for only a very small portion of patients in this
sample, suggesting the possibility of multifactorial inheritance, with twinning as only a potential part of the
cause of ITEV in some instances. Interestingly, none of
the six cases of dizygotic twins had a family history of
ITEV. Previous studies have not found an association
between ITEV and twinning [Wynne-Davies, 1972;
Litchblau, 1972].
Seasonal variation in the incidence of ITEV births
has been postulated to indicate a seasonal influence in
ITEV etiology [Pryor et al., 1991]. The lack of significant variation in the incidence of ITEV births according to months or seasons in the present study argues
against the previously reported finding of consistent
peaks of ITEV births during the winter months of December through February [Pryor et al., 1991]. The present study not only failed to find an association of ITEV
births during the winter months, but the highest peak
TABLE VI. Absolute Risk for Relatives of Propositi
Degree of relation
Relative group
All affected relatives
Gender
Male
Female
Ethnicity
Caucasian
African American
Hispanic

Third and greater

First
n (%)

Second
n (%)

19/527 (3.6)

17/1865 (0.9)

13/263 (4.9)
6/264 (2.3)

8/875 (0.9)
9/990 (0.9)

10/292 (3.4)
2/43 (4.7)
7/173 (4.0)

11/869 (1.3)
2/169 (1.2)
4/746 (0.5)

was noted during the middle of the summer, in July.

The lack of seasonal variation is consistent with a
study by Wynne-Davies et al. [1982] that detected no
difference in the ratio of ITEV births in the winter
months of October through March to the summer
months of April through September. The higher incidence of ITEV births during July in the present study
is mostly likely due to random variation. However, leftsided defects, which are overall less common than
right-sided defects, account for nearly 75% of the unilateral defects during the peak month. This may suggest that the left fetal foot could be more susceptible
than the right foot to an unknown seasonal factor. Further investigation would be required to tease out any
potential importance to the significant variation in laterality of the defect according to birth month.
Carter postulated that breech positioning during
pregnancy is likely an important influence in clubfoot
causation, yet the results of the present study do not
support this theory [Carter, 1965]. In agreement with
Chung and Myrianthopoulos [1968], neither positioning in utero nor amniotic fluid levels were found to be
associated with ITEV in this study. However, the very
small number of mothers (n 74) reporting information on amniotic fluid levels does not allow the possible
association with amniotic fluid levels to be excluded.
The role of maternal gravity on ITEV development was
also found to be insignificant according to the comparison of ITEV propositi and their unaffected sibs; hence,
the potential for a primigravid uterus contributing to
the cause of ITEV could not be shown [Palmer, 1964].
DDH has been suggested to be related to ITEV; the
theory behind this suggests that ITEV is one disorder
of a much larger group of connective tissue defects that
are all related pathogenetically [Wynne-Davies et al.,
1982]. Although the frequency of DDH has been evaluated in other groups of ITEV patients, no definitive
association was found. A study by Chung et al. [1969]
found a total of 12 DDH patients among 801 ITEV propositi, which is comparable to the 5 cases among 209
propositi in the present study. The general population
birth prevalence of DDH is reported be 1 per 1,000
[Record and Edwards, 1958]. There are many factors
that can influence the reported prevalence of the
simple, isolated form of DDH, such as age at examination, ethnic group, mode of ascertainment, and expertise of the examiner. It is not possible to discern from
this study whether DDH is related to ITEV, leaving the

Etiologic Study of ITEV

95

TABLE VII. Absolute Risk in Families With a Family History of ITEV

Affected relatives
First degree
Propositi
Male
Female
Total

Second degree

Male (%)

Female (%)

Total (%)

Male (%)

Female (%)

Total (%)

8/51 (15.7)
5/29 (17.2)
13/80 (16.7)

4/55 (7.3)
2/29 (6.9)
6/84 (6.1)

12/106 (11.3)
7/58 (12.1)
19/164 (11.3)

6/225 (2.7)
2/106 (1.9)
8/331 (2.7)

7/203 (3.4)
2/110 (1.8)
9/313 (2.9)

13/428 (3.0)
4/226 (1.8)
17/654 (2.6)

potential for a common pathogenetic pathway to remain speculative.

The high frequency of all propositi (24.4%) with a
family history of ITEV suggests that genetic factors
play an important role in the cause of the deformity.
Previous studies have attempted to separate ITEV patients into two categories based on family history,
claiming that different causal factors were responsible
in each group [Palmer, 1964]. Because there were no
statistically significant differences between propositi
with a positive and a negative history for all of the
factors studied in this investigation, there is no evidence to support this contention.
Direct analysis of the pedigrees obtained during personal interviews provides the most reliable data on
family history. The analysis of these pedigrees shows a
family history of ITEV in 30.6% of 173 propositi, again
suggesting that there is an important genetic component in the cause of ITEV. This frequency is higher
than the 14% reported by Rebbeck et al. in 1993, which
included fourth-degree affected relatives as well. Because we observed no differences between the races for
all of the factors in this study, all pedigrees were analyzed together. The number of affected relatives within
a given pedigree ranged from 0 to 5, although the average number of affected relatives when including the
propositus was 2.4. The range of affected relatives suggests that some families could be at higher risk for
developing ITEV than other families. Families with
multiple affected relatives were targeted specifically
and studied separately from families with a negative
history, with the thought that potential genetic mechanisms could be more easily assessed in this manner.
The presence of all patterns of parent-to-child transmission in ITEV families discounts X-linked inheritance. Parent-to-child transmission is seen in 11 of the
53 pedigrees (20.8%) studied, suggesting that a major
dominantly acting gene could be causing ITEV in onefifth of familial cases. These findings agree with the
previously suggested single-gene explanation for Caucasian ITEV causation that is supported by segregation
studies [Rebbeck et al., 1993]. These findings are also
compatible with a multigenic model including major
gene effects that was reported by Wang et al. in 1988.
The absolute risks among affected pedigrees could
also suggest a multifactorial model of inheritance, because there is a sharp drop in the percentage of seconddegree affected relatives (2.9%) in comparison with
first-degree relatives (11.3%). However, according to
the multifactorial threshold model, males are presumed to have a lower threshold for ITEV development. In turn, male relatives of female propositi would
be expected have a significantly higher risk than male

relatives of male propositi. By comparison, the risk to

first-degree male relatives in this study appears to be
independent of the sex of the propositus. In seconddegree relatives, more relatives of male propositi
(3.0%) are affected than female relatives (1.8%). Collectively, these findings suggest that the risks to males
and females in this selected group are not related to
threshold effects, given that sex of the propositus does
not significantly change the absolute risk within a family. Indeed, complex segregation analysis suggests that
our data are compatible with a major locus additive
model (de Andrade et al., 1998). To our knowledge, this
is the first study that has attempted to define further
the environmental and genetic etiology of ITEV among
African-American and Hispanic propositi, in addition
to Caucasian propositi. Although no significant differences were noted between the ethnic groups, the study
demonstrates a limited role of twinning and suggests a
potentially significant role of genetic factors in ITEV
causation in all propositi studied. Although definitive
conclusions cannot be drawn regarding the genetic
mechanisms involved in idiopathic clubfoot development, this study has set the stage for future research.
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