Genetic Epidemiology Study of IdiopathicTalipes Equinovarus

CarolLynn Lochmiller,1 Dennis Johnston,2 Allison Scott,3,4 Marjorie Risman,4 andJacqueline T. Hecht4*1Children’s Medical Center of Dallas, Dallas, Texas2University of Texas M.D. Anderson Cancer Center, Houston, Texas3Shriners Hospital for Children, Houston Unit, Houston, Texas4University of Texas Medical School at Houston, Houston, Texas

Previous genetic studies of idiopathic tali-pes equinovarus (ITEV) suggest an environ-mental and genetic component to the etiol-ogy of ITEV. The present study was under-taken to assess the role of causal factors inthe development of ITEV. A total of 285 pro-positi were ascertained, with detailed fam-ily history information available in 173cases and medical records on the remaining112 propositi. Information was collected onspecific prenatal, parental, and demo-graphic factors. No racial heterogeneity wasnoted among any of the factors. The overallratio of affected males to females was 2.5:1.The incidence of twinning among all pro-positi was significantly increased (P = 0.006)above the expected population frequency. Afamily history of ITEV was noted in 24.4% ofall propositi studied. These findings, in ad-dition to the detailed analysis of 53 pedi-grees with ITEV history, suggest the poten-tial role of a gene or genes operating in high-risk families to produce this foot deformity.Am. J. Med. Genet. 79:90–96, 1998.© 1998 Wiley-Liss, Inc.

KEY WORDS: idiopathic talipes equino-varus; ITEV; clubfeet; genet-ics; Mendelian inheritance;bone; segregation analysis;pedigrees

INTRODUCTIONIdiopathic talipes equinovarus (ITEV) is an isolated

congenital deformity of the foot and lower leg definedas a fixation of the foot in adduction, supination, andvarus, with concomitant soft tissue abnormalities pre-

sent at birth [Dvaric et al., 1989]. ITEV comprises thelargest group of patients with congenital clubfeet andmust be distinguished from those cases of talipesequinovarus for which there is a known cause or asso-ciated congenital abnormalities or which are syndro-mal in nature. Patients with ITEV have typical club-feet ranging from moderate to severe, and correctiongenerally 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 livebirths [Wynne-Davies, 1972]. However, the birthprevalence of ITEV varies greatly according to ethnicpopulation and gender. Most studies of ITEV have beenconducted using Caucasian patients and have shown arange of incidences from 1 to 3 per 1,000 live births[Cartilidge, 1984]. Chinese have been reported to havethe lowest prevalence, with 0.39 cases per 1,000 livebirths, whereas Hawaiians and Maoris have the high-est at of 6.5 to 7 per 1,000 births [Chung et al., 1969;Beals, 1978]. The ratio of ITEV among males to femalesis 2:1 and is consistent across ethnic groups [Chung etal., 1969]. A bilateral deformity is seen in 50% or moreof ITEV cases, and in unilateral defects, the right sideis usually more frequently involved than the left [De-Valentine and Blakeslee, 1992].

The inheritance of ITEV has not been fully eluci-dated, although multifactorial causation has been sug-gested. There is a sharp drop in ITEV prevalence be-tween first- and second-degree relatives [Carter, 1965].Moreover, significant variation in prevalence existsamong racial groups in Hawaii, with an increase cor-responding to the proportion of Hawaiian parentage[Stewart, 1951; Chung et al., 1969]. Evidence for ge-netic factors comes from the observation that concor-dance of ITEV among dizygotic twins is significantlyless than that of monozygotic twins [Idelberger, 1939].Most recently, complex segregation analysis rejectedthe possibility of non-Mendelian inheritance and ac-cepted the hypothesis that a single Mendelian gene(SMG) in combination with residual factors shared bysibs can explain ITEV in Caucasians [Rebbeck et al.,1993]. The present study was undertaken to define fac-tors causing ITEV.

*Correspondence to: Jacqueline T. Hecht, Ph.D., University ofTexas Medical School at Houston, P.O. Box 20708, Houston, TX77225. E-mail: jhecht@ped1.med.uth.tmc.edu

Received 10 December 1997; Accepted 24 April 1998

American Journal of Medical Genetics 79:90–96 (1998)

© 1998 Wiley-Liss, Inc.

SUBJECTS AND METHODS

This study is based on data collected from unrelatedfamilies, each having at least one child under treat-ment for ITEV at Shriners Hospital for Children, Hous-ton Unit, Houston, Texas. Requisites for inclusion inthis study were: (1) clinical and radiological diagnosisof ITEV, and (2) absence of any other abnormality ofchromosomal origin, neuromuscular involvement, orpostnatal insult that could have caused the talipesequinovarus. Methods of ascertainment employed werepersonal interview and/or medical record review. Pro-positi and families who were interviewed personallywere contacted either during a clinic visit or by tele-phone.

A total of 173 propositi were included in the study onthe basis of information obtained from personal inter-view and medical record review, and 112 on the basis ofmedical record review alone. Combined, the two datasets comprised 285 propositi, consisting of 131 Cauca-sians, 111 Hispanics, 21 African Americans, and 22individuals of an ethnic background that was not of theabove classification or was unknown. The subset of 173propositi consisted of 99 (57.2%) Caucasian, 54 (31.2%)Hispanic, 16 (9.3%) African American, and 4 (2.3%) in-dividuals of other ethnicity. The mean age of all pro-positi at the time of the study was 7.6 years.

Detailed information on the propositus and other af-fected relatives was obtained and combined with pre-viously obtained information from medical chart re-view so that each patient was only represented as asingle case. A family history of ITEV was defined ashaving at least one affected relative at the third degreeof relation or less, in addition to the propositus.

All data were coded and entered into an Excel database (Microsoft Corp., 1995). Data collected onlythrough medical record review were cross-tabulatedwith data collected by personal interview and recordreview combined to ensure that the two data sets werecompatible. The data were then combined into a singleStatistica file, where the data could be analyzed in ag-gregate [Statsoft, Tulsa, OK, 1994]. The frequency ofeach epidemiological factor was calculated for all pro-positi in the study with the denominator varying ac-cording to availability of the information. Statisticalanalysis of the data was performed using cross-tabulations, the two-tailed t-test, one-way analysis ofvariance (ANOVA), Mann-Whitney test, Kruskal-Wallis ANOVA by ranks test, and goodness-of-fit chi-square analysis as indicated [Zar, 1996].

RESULTSDemographics

The 285 propositi consisted of 200 males and 85 fe-males, a ratio of 2.5:1. Unilateral defects were seen in135 propositi (47.4%) and bilateral defects in 150 cases(52.6%). Right-sided defects (58.2%) were more com-mon than left-sided defects (41.8%). Cross-tabulationsof demographic data showed no significant differencesamong individuals of different ethnicity with respect togender (P 4 0.82) or the foot involved in the defect (P

4 0.29). There were no correlations between genderand laterality or foot affected (P 4 0.53).

Twinning

Analysis of twins in this study showed 5 twins, 168non-twins, and 112 propositi with unknown twin sta-tus. These data indicate a 2.9% twinning rate, with alltwins reportedly dizygotic and discordant for ITEV sta-tus. A significant P-value of 0.006 was obtained whenthe number of twins in this study was compared with a1.2% general population incidence of twins [Stevensonet al., 1993]. The increase of twinning is due to thehigher frequency of dizygotic twins. There were no sta-tistically significant differences in twinning ratesamong the different ethnic groups or according to gen-der. An equal number of unilateral and bilateral caseswas seen among the twins. There were no significantcorrelations between twinning and the foot affected,although all cases of unilateral defects in twins wereright-sided.

Uterine Factors

A total of 16 propositi reportedly were in a breechposition at delivery, whereas 180 were not breech, andin 89 patients, the presentation at delivery was notknown. This 8.2% frequency of breech deliveries wasnot significantly higher than the 4.8% frequency ofbreech births among 9,231 deliveries recorded at Her-man Hospital (Houston, TX) between February 1994and March 1996. Five patients had mothers who re-ported having a uterine abnormality throughout thepregnancy of the propositus, 145 mothers reported theydid not have a uterine abnormality, and in 135 pro-positi, almost half, information on uterine abnormali-ties was unknown or unavailable. Of the five cases ofuterine abnormalities, all were reported to be fibroids.

In assessing the amniotic fluid levels in the secondtrimester of pregnancy through delivery of ITEV pro-positi, 1 pregnancy reportedly had polyhydramnios, 6reportedly had oligohydramnios, 67 had normal fluidlevels, and in most cases (211), information on amnioticfluid levels was unknown. Compared with generalpopulation frequencies of 1.6% for polyhydramnios and5.5% oligohydramnios, there were no significant differ-ences in the reported frequencies [Pritchard et al.,1985]. Comparisons of breech deliveries, uterine abnor-malities, and amniotic fluid levels across propositi ofdifferent sex, ethnicity, and laterality of their defectshowed no statistically significant differences.

Gravidity

Analysis of maternal gravidity, including the ITEVpregnancy and all previous and subsequent pregnan-cies, demonstrated a mean gravidity of 2.29 among 197propositi for whom this information was given. Themean gravidity of ITEV propositi was compared withthat of unaffected sibs (mean 4 2.25), and no signifi-cant differences were noted (P 4 0.77). Cross-tabulations of gravidity with ethnicity and gendershowed no significant differences. No correlations wereseen between gravidity and laterality of the defect, ma-

Etiologic Study of ITEV 91

ternal uterine abnormalities, breech presentation, oroligohydramnios. A comparison of gravidity betweentwins (mean 4 3.5) and nontwins (mean 4 2.21) in thisstudy demonstrated a significantly higher mean gra-vidity among the twin group (P 4 0.022).

Seasonal Influence

Figure 1 shows the frequency of ITEV births permonth. The greatest number of propositi were bornduring July, while the lowest number of ITEV birthsoccurred during March. The frequency of ITEV birthswas also grouped according to season, with 26.6% ofpatients born between December and February, 23.8%born between March and May, 27.7% born betweenJune and August, and 22.0% born between Septemberand November. Comparison of the frequency of birthsby month and births by season between ITEV patientsand unaffected relatives demonstrated no significantdifferences between the two groups (Table I). The fre-quency of ITEV births by month and season did notcorrelate significantly with sex or ethnicity. The differ-ence in the number of ITEV births by month accordingto laterality of the defect was statistically significant (P4 0.037); the significance was primarily due to thedifference between the frequency of unilateral cases(7.1%) and bilateral cases (1.8%) in January. Therewere also statistically significant differences in thenumber of right-sided versus left-sided defects bymonth (P 4 0.003), although there was no obvious pat-tern to explain the significant results. There was a sig-nificant excess of right-sided ITEV during February,August, September, November, and December, and anexcess of left-sided ITEV during January, April, andJune.

Developmental Dislocated Hips

Five individuals were diagnosed with developmentaldislocated hips (DDH); 207 were not; and for 73 pro-positi, the information was unknown or not available atthe time of the study. The frequency of DDH did not

differ significantly with respect to gender or ethnicityof the propositus population (P 4 0.66 and P 4 0.28).

Family History

Data collected on all propositi regarding family his-tory of ITEV showed that 55 propositi had a familyhistory of ITEV, 170 had no history of ITEV, and thefamily history was unknown in 60 of the 285 propositi.Cross-tabulations of family history in all propositi byuterine and environmental factors showed no signifi-cant differences in propositi with a positive family his-tory and those with no family history of ITEV (TableII). Males and females had similar frequencies of ITEVin their family history (Table III). There was no signifi-cant preference of unilateral to bilateral cases or leftversus right feet in patients with a positive history,although among unilateral cases, patients with right-sided defects were twice as likely to have a positivehistory compared with those with left-sided defects.The five twin propositi with information regardingfamily history all reported a negative history of ITEV.Cross-tabulations with uterine factors also showedthat these factors were not significantly associatedwith family history (data not shown).

Pedigree Analysis

Family history information and pedigrees collectedthrough personal interview were analyzed separately

Fig. 1. Frequency of ITEV births permonth [January (J) through December (D)].

TABLE I. Cross-Tabulations of ITEV Propositus Births WithOther Factors

Factor

P-value

Births/month Births/season

Unaffected relatives 0.185 0.155General populationa 0.466 0.603Gender 0.396 0.708Ethnicityb 0.099 0.342Laterality 0.037 0.075Left versus right foot 0.003 0.177

aEmpirically derived number from Herman Hospital Systems, Houston,TX, 1987–1995.bIncludes Caucasian, African-American, and Hispanic propositi.

92 Lochmiller et al.

from all cases of ITEV. Of the 173 on which a pedigreewas drawn, 53 (30.6%) had a significant family historyof ITEV in first-, second-, or third-degree and more dis-tant relatives. Parent-to-child transmission was seenin 11 of the 53 pedigrees (20.8%) with a history ofITEV. 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) ofAfrican 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 of71 relatives were reported to have ITEV. These rela-tives of propositi comprised 19 first-degree, 17 second-degree, and 35 third-degree and more distant relatives(Table IV). The number of affected relatives within aparticular pedigree ranged from 1 to 5. A detailed de-scription of affected relatives according to sex and eth-nicity is shown in Table V. No significant differencewas noted between the number of males and females infirst-, second-, and third-degree relatives (P 4 0.84) orbetween the number of Caucasian, African-American,and Hispanic relatives according to degree of relation(P 4 0.73). When separating first-, second-, and third-degree relatives according to the sex of the propositus,a total of 44 affected relatives were found in families ofmale propositi, whereas a total of 27 affected relativeswere seen in families of female propositi. No significantdifference was noted among the distribution of first-,second-, and third-degree relatives between male andfemale propositi (P 4 0.34).

Calculations of absolute risk for developing ITEV inthe families studied were calculated for first- and sec-ond-degree relatives based on a ratio of affected indi-viduals to the total number individuals in a particularcategory. The overall risk based on information fromall 173 families shows that first-degree relatives hadan absolute risk of 3.6%, whereas second-degree rela-tives had a lower risk of 0.9% (Table VI). Analysis ofrisk based on gender showed that first-degree maleshad a higher risk compared with first-degree females,although the risk for second-degree males and femalesdecreased to a similar value. According to ethnicity,first-degree African Americans had the highest abso-lute risk; however, this may be related to small samplesize of this ethnic group.

To assess specifically the risk of malformation in in-dividuals within those families with multiple affectedindividuals, absolute risks were also calculated as theratio of the number of affected individuals to the totalnumber of relatives within the pedigrees having a posi-tive family history (Table VII). The risk was highestamong first-degree male relatives of female propositi,with a risk of 17.2%; male relatives of male propositiwere also at a similarly high risk of 15.7%. The risk toall first-degree relatives of female propositi (12.1%)was slightly higher than the risk to relatives of malepropositi (11.3%) (Table VII). However, regardless ofpropositus gender, overall risk to first-degree malerelatives (16.7%) was substantially higher than therisk to first-degree female relatives (6.1%) (Table VII).

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

Factor

Frequency

P-value

Familyhistoryof ITEV

No familyhistoryof ITEV

GenderMale 0.167 0.554 0.504Female 0.077 0.203 (N 4 222)

EthnicityCaucasian 0.136 0.398 0.3824African American 0.034 0.053 (N 4 206)Hispanic 0.087 0.291

LateralityUnilateral 0.131 0.412 0.920Bilateral 0.113 0.344 (N 4 222)

FootLeft 0.032 0.176 0.140Right 0.081 0.171 (N 4 222)Both 0.131 0.410

TwinningDizygotic 0 0.031 0.188Singleton 0.252 0.718 (N 4 163)

TABLE III. Normalized Comparisons of Family History byOther Factors

Factor

Frequency

Family historyof ITEV (%)

No family historyof ITEV (%)

GenderMale 23.0 77.0Female 29.4 70.6

EthnicityCaucasian 24.2 75.8African American 33.3 66.7Hispanic 26.4 73.6

LateralityUnilateral 25.0 75.0Bilateral 24.7 75.3

FootLeft 9.4 90.6Right 35.4 64.6Both 24.7 75.3

TwinningDizygotic 20.0 80.0Singleton 29.8 70.2

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

Relation

Affected relatives Total relatives

Male Female Total Male Female Total

First degree 13 6 19 263 264 527Second degree 8 9 17 975 990 1965Third and greater degree 23 12 35 83 92 175*Total 44 27 71 1321 1346 2667

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

Etiologic Study of ITEV 93

Among second-degree relatives, the risks to male andfemale relatives were similar.

DISCUSSION

Development of ITEV has been suggested to haveboth a genetic and environmental component. The sig-nificantly increased frequency of dizygotic twins amongpropositi of this study suggests that twinning poten-tially influences the development of ITEV. In twinpregnancies, mobility of the fetuses can be restricted byvirtue of sharing a uterine environment; hence, an in-crease in twinning among ITEV patients provides sup-port for Hippocrates’ ancient contention that clubfootmay result from the continued maintenance of the footin a certain position [Hippocrates, 1939]. Twinning ac-counts for only a very small portion of patients in thissample, suggesting the possibility of multifactorial in-heritance, with twinning as only a potential part of thecause of ITEV in some instances. Interestingly, none ofthe six cases of dizygotic twins had a family history ofITEV. Previous studies have not found an associationbetween ITEV and twinning [Wynne-Davies, 1972;Litchblau, 1972].

Seasonal variation in the incidence of ITEV birthshas been postulated to indicate a seasonal influence inITEV etiology [Pryor et al., 1991]. The lack of signifi-cant variation in the incidence of ITEV births accord-ing to months or seasons in the present study arguesagainst the previously reported finding of consistentpeaks of ITEV births during the winter months of De-cember through February [Pryor et al., 1991]. The pre-sent study not only failed to find an association of ITEVbirths during the winter months, but the highest peak

was noted during the middle of the summer, in July.The lack of seasonal variation is consistent with astudy by Wynne-Davies et al. [1982] that detected nodifference in the ratio of ITEV births in the wintermonths of October through March to the summermonths of April through September. The higher inci-dence of ITEV births during July in the present studyis mostly likely due to random variation. However, left-sided defects, which are overall less common thanright-sided defects, account for nearly 75% of the uni-lateral defects during the peak month. This may sug-gest that the left fetal foot could be more susceptiblethan the right foot to an unknown seasonal factor. Fur-ther investigation would be required to tease out anypotential importance to the significant variation in lat-erality of the defect according to birth month.

Carter postulated that breech positioning duringpregnancy is likely an important influence in clubfootcausation, yet the results of the present study do notsupport this theory [Carter, 1965]. In agreement withChung and Myrianthopoulos [1968], neither position-ing in utero nor amniotic fluid levels were found to beassociated with ITEV in this study. However, the verysmall number of mothers (n 4 74) reporting informa-tion on amniotic fluid levels does not allow the possibleassociation with amniotic fluid levels to be excluded.The role of maternal gravity on ITEV development wasalso found to be insignificant according to the compari-son of ITEV propositi and their unaffected sibs; hence,the potential for a primigravid uterus contributing tothe cause of ITEV could not be shown [Palmer, 1964].

DDH has been suggested to be related to ITEV; thetheory behind this suggests that ITEV is one disorderof a much larger group of connective tissue defects thatare all related pathogenetically [Wynne-Davies et al.,1982]. Although the frequency of DDH has been evalu-ated in other groups of ITEV patients, no definitiveassociation was found. A study by Chung et al. [1969]found a total of 12 DDH patients among 801 ITEV pro-positi, which is comparable to the 5 cases among 209propositi in the present study. The general populationbirth prevalence of DDH is reported be 1 per 1,000[Record and Edwards, 1958]. There are many factorsthat can influence the reported prevalence of thesimple, isolated form of DDH, such as age at examina-tion, ethnic group, mode of ascertainment, and exper-tise of the examiner. It is not possible to discern fromthis study whether DDH is related to ITEV, leaving the

TABLE VI. Absolute Risk for Relatives of Propositi

Relative group

Degree of relation

Firstn (%)

Secondn (%)

All affected relatives 19/527 (3.6) 17/1865 (0.9)Gender

Male 13/263 (4.9) 8/875 (0.9)Female 6/264 (2.3) 9/990 (0.9)

EthnicityCaucasian 10/292 (3.4) 11/869 (1.3)African American 2/43 (4.7) 2/169 (1.2)Hispanic 7/173 (4.0) 4/746 (0.5)

TABLE V. Summary of Affected Relatives According to Gender and Ethnicity of the Propositus

Relatives by degree of relation to propositus

First Second Third and greater

TotalMale Female Male Female Male Female

GenderMale 8 4 6 7 16 7 48Female 5 2 2 2 7 5 23

EthnicityCaucasian 7 3 6 5 14 7 42African American 1 1 1 1 1 0 5Hispanic 5 2 1 3 8 5 24

94 Lochmiller et al.

potential for a common pathogenetic pathway to re-main speculative.

The high frequency of all propositi (24.4%) with afamily history of ITEV suggests that genetic factorsplay an important role in the cause of the deformity.Previous studies have attempted to separate ITEV pa-tients into two categories based on family history,claiming that different causal factors were responsiblein each group [Palmer, 1964]. Because there were nostatistically significant differences between propositiwith a positive and a negative history for all of thefactors studied in this investigation, there is no evi-dence to support this contention.

Direct analysis of the pedigrees obtained during per-sonal interviews provides the most reliable data onfamily history. The analysis of these pedigrees shows afamily history of ITEV in 30.6% of 173 propositi, againsuggesting that there is an important genetic compo-nent in the cause of ITEV. This frequency is higherthan the 14% reported by Rebbeck et al. in 1993, whichincluded fourth-degree affected relatives as well. Be-cause we observed no differences between the races forall of the factors in this study, all pedigrees were ana-lyzed together. The number of affected relatives withina given pedigree ranged from 0 to 5, although the av-erage number of affected relatives when including thepropositus was 2.4. The range of affected relatives sug-gests that some families could be at higher risk fordeveloping ITEV than other families. Families withmultiple affected relatives were targeted specificallyand studied separately from families with a negativehistory, with the thought that potential genetic mecha-nisms could be more easily assessed in this manner.The presence of all patterns of parent-to-child trans-mission in ITEV families discounts X-linked inheri-tance. Parent-to-child transmission is seen in 11 of the53 pedigrees (20.8%) studied, suggesting that a majordominantly acting gene could be causing ITEV in one-fifth of familial cases. These findings agree with thepreviously suggested single-gene explanation for Cau-casian ITEV causation that is supported by segregationstudies [Rebbeck et al., 1993]. These findings are alsocompatible with a multigenic model including majorgene effects that was reported by Wang et al. in 1988.

The absolute risks among affected pedigrees couldalso suggest a multifactorial model of inheritance, be-cause there is a sharp drop in the percentage of second-degree affected relatives (2.9%) in comparison withfirst-degree relatives (11.3%). However, according tothe multifactorial threshold model, males are pre-sumed to have a lower threshold for ITEV develop-ment. In turn, male relatives of female propositi wouldbe expected have a significantly higher risk than male

relatives of male propositi. By comparison, the risk tofirst-degree male relatives in this study appears to beindependent of the sex of the propositus. In second-degree relatives, more relatives of male propositi(3.0%) are affected than female relatives (1.8%). Col-lectively, these findings suggest that the risks to malesand females in this selected group are not related tothreshold effects, given that sex of the propositus doesnot significantly change the absolute risk within a fam-ily. Indeed, complex segregation analysis suggests thatour data are compatible with a major locus additivemodel (de Andrade et al., 1998). To our knowledge, thisis the first study that has attempted to define furtherthe environmental and genetic etiology of ITEV amongAfrican-American and Hispanic propositi, in additionto Caucasian propositi. Although no significant differ-ences were noted between the ethnic groups, the studydemonstrates a limited role of twinning and suggests apotentially significant role of genetic factors in ITEVcausation in all propositi studied. Although definitiveconclusions cannot be drawn regarding the geneticmechanisms involved in idiopathic clubfoot develop-ment, this study has set the stage for future research.

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

Affected relatives

Propositi

First degree Second degree

Male (%) Female (%) Total (%) Male (%) Female (%) Total (%)

Male 8/51 (15.7) 4/55 (7.3) 12/106 (11.3) 6/225 (2.7) 7/203 (3.4) 13/428 (3.0)Female 5/29 (17.2) 2/29 (6.9) 7/58 (12.1) 2/106 (1.9) 2/110 (1.8) 4/226 (1.8)Total 13/80 (16.7) 6/84 (6.1) 19/164 (11.3) 8/331 (2.7) 9/313 (2.9) 17/654 (2.6)

Etiologic Study of ITEV 95

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96 Lochmiller et al.