Prenatal diagnosis of talipes equinovarus (clubfoot)

INTRODUCTION — Clubfoot, or talipes equinovarus, refers to a complex developmental deformity of the foot/ankle in which one or both feet are excessively plantar flexed, with the forefoot swung medially and the sole facing inward (picture 1). It is a common congenital anomaly, typically discovered at the time of birth as an isolated anomaly in an otherwise normal neonate. Postnatal treatment is important to prevent potential future disability and pain.

Clubfoot can be classified as idiopathic (congenital), syndromic, or positional:

●Idiopathic (congenital) clubfoot affects the bones, muscles, tendons, and blood vessels of one or both feet. It is an isolated anomaly in an otherwise healthy newborn and the most common type of clubfoot.

●Syndromic clubfoot refers to cases associated with additional anatomic anomalies and/or chromosomal or genetic abnormalities.

●Positional clubfoot results from the fetus's position in the uterus and is often associated with a restrictive uterine environment (oligohydramnios, uterine anomalies). A positional clubfoot is flexible, rather than rigid, and can be positioned into a neutral position easily by hand.

This topic will discuss prevalence, pathogenesis, risk factors, prenatal diagnosis, and obstetric management of clubfoot, focusing on idiopathic (congenital clubfoot).

ANATOMY AND PATHOGENESIS

Normal fetal foot development — The foot sequentially assumes three different positions during embryonic and early fetal life: at the 15 mm crown-rump length (CRL) stage (approximately 8 weeks of gestation [ie, 8 weeks from the first day of the last menstrual period]), it is in a straight line with the leg; by the 30 mm CRL stage (approximately 10 weeks of gestation), it rotates to a marked equinovarus adductus position; and then by the 50 mm CRL stage (approximately 11.5 weeks), it changes to a slightly equinovarus adductus position, which remains throughout fetal life [1,2]. These positional changes result from the growth of the distal ends of the fibula and the skeletal elements of the lateral foot during the "fibular phase" of rapid growth.

Anatomy and physical findings in clubfoot — The main anatomic abnormality is a mild to severe deformity of the talus, which is small and abnormal in all of its relationships. There is subluxation of the talo-calcaneo-navicular joint with underdevelopment of the soft tissues on the medial side of the foot and, frequently, of the calf and peroneal muscles. Shortening and fibrosis in the gastrocsoleus and its tendon, as well as in the posterior tibial muscle and tendon, also occur.

On physical examination, the forefoot tends to appear wider and the heel narrower than normal. The foot is turned inward and on its side and points downward (picture 1). Bony malposition and secondary contractures cause the foot to be held in this relatively fixed position, which is resistant to realignment. The clubfoot, calf, and leg are slightly smaller and shorter than the normal limb. The components of a clubfoot are often described by the acronym CAVE, which stands for: Cavus, Adduction, Varus, Equinus.

Pathogenesis of clubfoot — Clubfoot, and other types of joint contracture, can be secondary to factors intrinsic or extrinsic to the fetus. Depending on the etiology, the prognosis varies widely. Most cases are idiopathic/isolated (80 percent), with the remainder (complex clubfoot) associated with additional structural and chromosomal or genetic anomalies (table 1).

Intrinsic causes — Over 50 syndromes include clubfoot as a frequent or occasional finding. Early fetal onset of some neurologic, muscular, skeletal, vascular, or connective tissue diseases is an intrinsic cause of clubfoot, with long-term implications for the child as well as for its siblings, especially if an underlying genetic disorder is identified. Spina bifida is the most common intrinsic cause of clubfoot.

Clubfoot has been associated with some aneuploidies, deletion syndromes, sex chromosome abnormalities, and microdeletions/duplications (see 'Fetal genetic studies' below). Despite advances in molecular genetics, a major causative gene has not been identified, and there is significant heterogeneity in clinical presentation even within familial cases [3]. Multifactorial/polygenic inheritance likely plays a role in many cases, but pedigrees with Mendelian inheritance have also been described. Pedigree analyses have suggested a single gene may be involved; recessive patterns (autosomal and X-linked) and, less commonly, variably penetrant autosomal dominant patterns have been described [4-7]. A missense mutation in PITX1 and duplications and deletions in chromosome 17q23 result in abnormalities in the PITX1-TBX4 transcriptional pathway, which is responsible for early limb development [3,8]; these genetic abnormalities have been implicated in a small proportion of familial isolated clubfoot.

The sibling of an affected dizygotic twin has a 2-fold increased risk of being affected (concordance rate 3 percent), while the risk in the sibling of an affected monozygotic twin is 10-fold higher (concordance rate 33 percent) [3,8].

Extrinsic causes — Extrinsic causes of clubfoot are related to factors external to the fetus that impede the normal sequential growth and position of the foot. The resulting deformation can be secondary to restriction to movement from conditions such as multiple gestation, malpresentation, uterine cavity abnormality (eg, fibroids, synechiae, amniotic bands), breech position, or oligohydramnios. In these cases, the clubfoot is usually unilateral and tends to be associated with other deformations, particularly if the cause is longstanding. For example, clubfoot from an extrinsic cause may be associated with developmental dysplasia of the hip since this condition may also be related to abnormal positioning and/or limited fetal mobility.

PREVALENCE AND EPIDEMIOLOGY — The prevalence of clubfoot is 1 to 3 per 1000 live births in White infants and appears to be stable [9,10]. Male fetuses are predominately affected, with a 2-to-1 male-to-female ratio. The birth prevalence varies among different ethnic groups; the highest rates are seen in individuals of Polynesian ancestry (7 per 1000 live births) and the lowest in Asian populations (0.57 per 1000 live births) [11].

RISK FACTORS — The major risk factors for clubfoot are:

●Family history of the anomaly

●Presence of an extrinsic condition that restricts fetal foot movement

●Presence of a fetal neuromuscular disorder

Other risk factors include maternal or paternal tobacco use, maternal obesity, early amniocentesis (before 15 weeks of gestation), maternal use of some selective serotonin reuptake inhibitors, and male sex [12,13].

PRENATAL DIAGNOSIS

Ultrasound examination — Either transabdominal or transvaginal ultrasound can be used for diagnosis. Although transvaginal ultrasound can clearly visualize the foot early in gestation, the diagnosis should not be made before 13 weeks of gestation because the characteristic plantar flexion and adduction of the foot can be a normal developmental finding [11,14-16].

Diagnostic criteria and sonographic findings — The sonographic diagnosis is based on visualization of the plantar surface of the fetal foot in the same sagittal plane as both lower extremity bones (image 1 and image 2A-C). The abnormal position should persist over time and despite motion of the foot since a fetus can temporarily turn its foot into a position simulating clubfoot. In addition, the foot should be visualized away from the uterine wall. Three-dimensional ultrasound, if available, can provide a clear image but is not essential for diagnosis (image 3).

Clubfoot is unilateral in 30 to 40 percent of cases and bilateral in 60 to 70 percent [10,17-22]. Most cases are isolated, without genetic or other structural abnormalities. (See 'Associated abnormalities' below.)

Associated abnormalities — In a series of 5458 cases of congenital clubfoot in a European registry, 82 percent were isolated clubfoot and 11 percent had associated major congenital anomalies [10]:

●246 (5 percent) had a chromosomal abnormality, most commonly trisomy 18 (n=101) or trisomy 21 (n=48).

●591 (11 percent) had nonsyndromic multiple congenital anomalies (MCA), most commonly involving the cardiovascular, central nervous, urinary, or orofacial system. Ventricular septal defects occurred in 80 cases and were the single most common abnormality in fetuses with MCA.

●144 (3 percent) had a genetic syndrome, most commonly 22q11.2 microdeletion (n=14) or Pena-Shokeir type 1 (n=13).

●9 (0.2 percent) had a teratogenic syndrome (eg, fetal alcohol syndrome).

Bilateral clubfoot does not appear to be associated with a greater risk of associated anomalies than unilateral clubfoot [19,20].

Diagnostic performance of ultrasound — Up to 80 percent of cases are detected prenatally [17,23]. Improved prenatal detection in the past 10 to 15 years is related to improvements in ultrasound equipment, increased expertise, and more frequent sonographic examination of the fetus across gestation.

Prenatal detection is higher when the clubfoot is bilateral or associated with other anomalies. As an example, in a series of children with isolated clubfoot, accurate prenatal diagnosis was twice as likely when the condition was bilateral (34/74) versus unilateral (17/73) [11]. In another study, no fetus with clubfoot was missed when there were associated congenital abnormalities [24]. (See 'Associated abnormalities' above.)

False-positive rates of 10 to 20 percent, and as high as 40 percent, have been reported for diagnosis of isolated clubfoot [11,25]. This is typically due to the ability and inclination of a normal fetus to adduct its foot.

Imperfect midtrimester prenatal diagnosis does not necessarily represent poor sensitivity of ultrasound; instead, it can be due to disease progression during the second half of pregnancy in conditions that affect fetal neuromuscular development or the progressive effect of long-term immobility on the flexibility of the joint.

PRENATAL CARE

Postdiagnostic evaluation — We suggest the following after prenatal diagnosis of clubfoot, given the common occurrence of associated abnormalities, chromosomal abnormalities, and genetic syndromes.

●Complete sonographic anatomic survey, including assessment for associated abnormalities and evaluation of fetal movement overall and specifically movement of the upper and lower extremity joints. The presence of both polyhydramnios and clubfoot suggests a central neurologic abnormality that has affected lower limb movement and swallowing.

●Evaluation of the intrauterine environment specifically looking for fetal compression or crowding by fibroids, amniotic bands, or synechiae.

●Fetal echocardiogram.

●Fetal genetic studies.

Fetal genetic studies — We agree with the Society for Maternal-Fetal Medicine regarding offering diagnostic genetic testing when a club foot is diagnosed prenatally [16]. This information is useful for reproductive decision making and counseling about postnatal prognosis. (See "Congenital cytogenetic abnormalities", section on 'Fetuses with congenital anomalies'.)

If sonographic findings are suggestive of a common aneuploidy (trisomy 18, 21, or 13), it is reasonable to perform G-banded karyotype analysis initially, and then reflex chromosomal microarray (CMA) if the results are normal; alternatively, CMA can be performed initially. Cell-free DNA screening is an option for patients who decline diagnostic evaluation, but will only identify patients at high risk of the more common aneuploidies and it is not diagnostic.  

Although the frequency of a genetic abnormality is low in cases of isolated clubfoot, there have been numerous reports of karyotypically abnormal infants who were not suspected prenatally because ultrasound failed to detect associated abnormalities that were present. In a meta-analysis of outcome of isolated fetal clubfoot (25 studies and 1567 fetuses), 7 percent (95% CI 3.4-11.7) of cases diagnosed as isolated prenatally were found to have associated anomalies at birth [26]. In addition, 3.6 percent had an abnormal karyotype. However, there is no consensus as to whether amniocentesis for fetal genetic testing should be offered when the only indication is an isolated clubfoot (unilateral or bilateral). The arguments against routine cytogenetic analysis of fetuses with isolated clubfoot are that the risks associated with amniocentesis may be greater than the risk of an abnormal karyotype, and cost. A literature review including 13 studies found 8 cases of aneuploidy among 463 cases of isolated clubfoot (1.7 percent) [27]. The karyotype abnormalities were 47 XXY (two cases), trisomy 21 (two cases), 47 XYY (two cases), trisomy 18 (one case), and 47 XXX (one case). The fact that the largest of the studies consisted of only 68 fetuses with isolated clubfoot limits our ability to make a confident assessment of the risk of karyotypic abnormalities in these cases and suggests the underlying risk of chromosomal anomalies among isolated clubfoot remains to be determined.

Though variants in PITX1 are not a common cause of isolated clubfoot, recurrent chromosome 17q23 copy number variants (CNV) involving TBX4 are responsible for approximately 5 percent of all patients with familial isolated clubfoot [28]. CMA can detect chromosome 17q23 CNV, which can be clinically significant for their possible association with both severe, treatment-refractory clubfoot and hip dysplasia.

Emerging data support use of exome sequencing for evaluation of isolated anomalies, such as clubfoot, on ultrasound [29,30]. Few data support the use of genome sequencing in isolated clubfoot as it is more time consuming, uncovers more variants of unknown significance, and is generally only available in research settings. A case report described use of whole genome sequencing to identify genetic variants in a large family with familial clubfoot [31].

Counseling — Findings on ultrasound examination and their significance should be discussed with the patient, including information on fetal genetic testing, postnatal treatment options (eg, surgical procedures, serial casting, observation), and prognosis. Referral to a genetic counselor and pediatrician or orthopedic specialist who can discuss postnatal management issues in isolated and nonisolated clubfoot can be useful.

In patients with isolated clubfoot, the severity of the abnormality and need for postnatal surgery are difficult to predict prenatally [27,32-34]. At birth, the degree of deformity is usually determined by physical examination and reported using one of several systems (eg, Dimeglio classification system, Pirani score) [35].

Antenatal and intrapartum care — The prenatal diagnosis of isolated clubfoot does not alter antenatal or intrapartum maternal care. In complex cases, antenatal and intrapartum care depend on the specific fetal diagnosis and group of findings.

RECURRENCE RISK — A thorough examination of the newborn (or stillborn) is important for making a definitive diagnosis, as the presence of a syndrome will influence counseling on the child's prognosis and informs recurrence risk in future pregnancies.

●For parents without clubfoot, the overall risk of recurrent isolated clubfoot depends on the sex of the first affected child: it is 2 percent after an affected male and 5 percent after an affected female. This reflects the more common occurrence of clubfoot in males and the increased likelihood that an affected female has a genetic component.

●If both a parent and a child are affected, then the recurrence risk in a subsequent sibling can be as high as 25 percent [36]. Chromosomal microarray analysis can detect chromosome 17q23 copy number variants, which have been identified in a small proportion of cases, but may be clinically significant because of the association with both severe, treatment-refractory clubfoot and hip dysplasia [28].

Management of future pregnancies — Individuals with an affected pregnancy should receive genetic counseling and be offered ultrasound examination with thorough evaluation of the fetal feet in future pregnancies.

Preventive interventions are not available.

TREATMENT AND PROGNOSIS — There are no prenatal treatments.

Postnatal treatment is important because untreated patients can have long-term disability, deformity, and pain. Conservative interventions include physiotherapy, splinting, taping, and casting, but surgical treatment may be required. Various surgical procedures have been described; the choice depends on a variety of individual factors. Postnatal treatment is beyond the scope of this topic and is reviewed elsewhere [37-39].

Neurodevelopmental and musculoskeletal impairment are more likely with complex clubfoot. In a study of 263 treated idiopathic clubfeet in 175 patients followed to age 10 in which treatment was nonoperative in 148, extra-articular surgery in 29, and intra-articular surgery in 86, all groups showed reduced ankle plantar flexion during gait compared with controls, resulting in a deficit of 9 to 14 percent for dynamic range of motion, 13 to 20 percent for ankle moment, and 13 to 23 percent for power [40]. Patients with clubfoot took 10 percent fewer steps and had 11 percent less total ambulatory time than the controls. However, others have reported that clubfoot does not significantly impair gross motor development in five year olds [41].

SUMMARY AND RECOMMENDATIONS

●Diagnosis

•Clubfoot (talipes equinovarus) is a developmental deformity of the foot in which one or both feet are excessively plantar flexed, with the forefoot swung medially and the sole facing inward. It occurs bilaterally in 30 to 50 percent of cases. (See 'Introduction' above and 'Prevalence and epidemiology' above.)

•The sonographic diagnosis is based on visualization of the plantar surface of the fetal foot in the same sagittal plane as both lower extremity bones (image 1 and image 2A-C). (See 'Prenatal diagnosis' above.)

●Etiology – Clubfoot can be secondary to factors intrinsic or extrinsic to the fetus; most cases are idiopathic. The prognosis depends on several factors, including the severity of the abnormality and the presence of additional structural and/or chromosomal abnormalities. (See 'Pathogenesis of clubfoot' above.)

●Prenatal evaluation – We offer fetal cytogenetic studies in all cases, including isolated clubfoot, because associated abnormalities may not be detected by ultrasound and small numbers of studied cases limit the reliability of published estimates of risk. (See 'Fetal genetic studies' above.)

●Pregnancy care

•Prenatal counseling involves discussion of findings on ultrasound examination and any genetic testing and their significance, postnatal treatment options (eg, surgical procedures, serial casting, observation), and prognosis. Referral to a genetic counselor and pediatrician or orthopedic specialist who can discuss postnatal management issues can be useful. In patients with isolated clubfoot, the severity of the abnormality and need for postnatal surgery are difficult to predict prenatally. (See 'Counseling' above.)

•The antenatal diagnosis of isolated clubfoot does not alter antepartum or intrapartum maternal care. (See 'Antenatal and intrapartum care' above.)

•There is no prenatal treatment. (See 'Treatment and prognosis' above.)

●Recurrence risk – For parents without clubfoot, the overall risk of recurrent isolated clubfoot depends on the sex of the first affected child: it is 2 percent after an affected male and 5 percent after an affected female. If both a parent and a child are affected, then the recurrence risk is as high as 25 percent. (See 'Recurrence risk' above.)