Clubfoot, Congenital, With Or Without Deficiency Of Long Bones And/or Mirror-Image Polydactyly

A number sign (#) is used with this entry because of evidence that congenital clubfoot with or without deficiency of long bones and/or mirror-image polydactyly can be caused by mutation in the PITX1 gene (602149) on chromosome 5q31.

Clubfoot is a congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities (Cardy et al., 2007). Clubfoot may occur in isolation or as part of a syndrome (e.g., diastrophic dysplasia, 222600). Clubfoot has been reported with deficiency of long bones and mirror-image polydactyly (Gurnett et al., 2008; Klopocki et al., 2012).

Barker et al. (2003) noted that the term 'clubfoot' has variably included both acquired and congenital talipes equinovarus, and historically has even included other conditions such as calcaneovalgus and metatarsus adductus. Moreover, within the congenital group, the distinction between syndromic and isolated subgroups has not been consistent. They concluded that it is sometimes difficult to ascertain the significance of differences between reported series.

Gurnett et al. (2008) described a 5-generation North American family of European descent segregating clubfoot. The proband had bilateral clubfoot, bilateral foot preaxial polydactyly, and right-sided tibial hemimelia. Five additional family members had clubfoot, 3 of whom had increased severity on the right. Some family members had additional lower limb malformations including patellar hypoplasia, oblique talus manifesting as pes planus, and developmental hip dysplasia. No upper extremity abnormalities or dysmorphic craniofacial features were noted.

Alvarado et al. (2011) performed an MRI of the lower limbs of a patient with unilateral clubfoot from the family originally studied by Gurnett et al. (2008), and observed a reduction in the overall size of the affected clubfoot limb, with reduced muscle and bone volumes. The limb was more severely affected below the knee. Although all muscle compartments were involved, the anterior compartment containing the tibialis anterior muscle was particularly small and partially replaced with fat. Magnetic resonance angiography demonstrated diminution of the anterior tibial and peroneal arteries on the affected limb compared with the unaffected limb.

Klopocki et al. (2012) studied 2 unrelated fetuses with microdeletions involving the PITX1 gene (602149; see MOLECULAR GENETICS). One fetus was stillborn with a prenatal diagnosis of high-degree polydactyly, hypoplasia of the corpus callosum, enlargement of the cisterna magna, and cardiomegaly; postmortem examination revealed a small median cleft palate, bilateral popliteal pterygia, and talipes equinovarus together with mirror-image polydactyly with 8 digits on each foot. The upper limbs showed no abnormalities. Dysmorphic features included low-set ears, downslanting palpebral fissures, mild hypertelorism, and a flat nasal bridge. The other fetus had a single lower leg bone on the left as well as mirror-image polydactyly of the right foot together with bilateral clubfoot; there were no abnormalities of the upper limbs.

Clubfoot appears to be multifactorial trait.

Gurnett et al. (2008) described a 5-generation family with asymmetric right-sided predominant clubfoot segregating as an autosomal dominant condition with incomplete penetrance.

Palmer (1964) suggested that 2 groups may exist: (1) a group with normal sex ratio, normal maternal age curve, recurrence risk of about 10% and probable dominant inheritance with about 40% penetrance; and (2) a group born to younger mothers with preponderance of males and no clear pattern of inheritance.

Book (1948) estimated that the risk of recurrence in subsequently born children in Caucasians is between 3 and 8% if 1 child is affected and about 10% if 1 child and 1 parent are affected.

Chung et al. (1969) performed a large-scale study of talipes equinovarus in Hawaii. They found an overall male to female sex ratio of approximately 2 to 1, no significant differences between isolated and familial cases, and no evidence of a maternal age effect. The incidence of uncomplicated TEV by major racial groups adjusted for incomplete ascertainment was highest in Hawaiians (6.81/1000 births), followed by Caucasians (1.12/1000 births) and then East Asians (0.56/1000 births).

Beals (1978) studied 50 consecutive Maori kindreds with a child with clubfoot who were treated at the same hospital in New Zealand during a 6-month period. The index patients were 31 males and 19 females. Empiric risk data indicated that if the index patient was female, the chance of subsequent children being affected was 4%, whereas if the index patient was male, the chance was 9%, and if parent and child were affected, the chance was 30%. These risks were much higher than those found in Caucasians by Book (1948) and Wynne-Davies (1964). As in Caucasians, inheritance appeared to be polygenic. The incidence of clubfoot in New Zealand Maori was estimated to be 6.5-7.0/1000 births.

Wang et al. (1988) used updated data on families with clubfoot originally reported by Palmer (1964) and concluded that the segregation pattern in these families is best explained by assuming the action of a major gene with additional contribution of multifactorial inheritance. The mixed model suggested that the major gene behaves largely as a dominant.

Chapman et al. (2000) analyzed the role of major gene and multifactorial inheritance in the etiology of clubfoot in the New Zealand Polynesian population by studying 287 clubfoot families. Using the computer program POINTER, they showed that the best genetic model for clubfoot in this population is a single dominant gene with a penetrance of 33% and a predicted gene frequency of 0.9%.

Reviews

Dietz (2002) reviewed the genetics of idiopathic clubfoot.

In affected members of a 5-generation family segregating clubfoot and various other lower extremity anomalies but without upper extremity abnormalities or dysmorphic craniofacial features, Gurnett et al. (2008) identified a missense mutation in the PITX1 gene (602149.0001).

Alvarado et al. (2011) screened 40 probands with isolated clubfoot who had at least 1 affected first-degree relative for genomic copy-number variations (CNVs), and identified a 241-kb microdeletion on chromosome 5q31 in 1 proband. The microdeletion (chr5:134,222,383-134,463,022, NCBI36) encompassed 4 genes, of which PITX1 was the only one that did not overlap a CNV previously observed in healthy individuals from the UCSC Database of Genomic Variants. The microdeletion, which was verified by quantitative PCR, was also present in the proband's affected mother and grandmother, and was not found in 700 controls. All 3 affected individuals had bilateral clubfoot and short stature (height more than 2 SD below the mean), but did not display any of the other features previously reported with PITX1 mutation, including tibial hemimelia, preaxial polydactyly, patellar hypoplasia, or developmental hip dysplasia. Alvarado et al. (2011) noted that isolated clubfoot has also been associated with deletions or duplications (see 613355 and 613618, respectively) involving the TBX4 gene (601719), which is a transcriptional target of PITX1.

In 2 unrelated fetuses with bilateral clubfoot and mirror-image polydactyly but no upper extremity anomalies, Klopocki et al. (2012) identified heterozygous deletions on chromosome 5q31 that encompassed the PITX1 gene, a de novo 5.7-Mb deletion (chr5:132,560,606-138,352,212, NCBI36) and a 4.9-Mb deletion (chr5:133,200,000-138,080,000, NCBI36), respectively. The authors then sequenced the PITX1 gene in 8 individuals with isolated higher-degree polydactyly and/or tibial hemimelia but normally developed upper extremities, and identified heterozygosity for a 35-bp deletion in exon 3 of the PITX1 gene (602149.0002) in an infant with bilateral preaxial polydactyly, talipes equinovarus, and right tibial hemimelia. Klopocki et al. (2012) concluded that mutations in PITX1 can cause a broad spectrum of isolated lower-limb malformations, including clubfoot, deficiency of long bones, and mirror-image polydactyly.

Kancherla et al. (2010) estimated the incidence of isolated clubfoot to be 11.4 per 10,000 livebirths in Iowa. Increased prevalence odds ratios (POR) were found for male sex (POR = 1.8) and maternal smoking during pregnancy (POR = 1.5). Low birth weight showed an increased POR for females (POR = 3.2), but not males (POR = 0.9).

Alvarado et al. (2011) generated Pitx1 +/- mice and observed clubfoot-like abnormalities in 20 of 225 Pitx1 +/- mice, for a penetrance of 8.9%. Clubfoot was unilateral in 16 of the 20 affected mice, with the right and left limbs equally affected. Peroneal artery hypoplasia occurred in the clubfoot limb and corresponded spatially with small lateral muscle compartments. Tibial and fibular bone volumes were also reduced. Skeletal muscle gene expression was significantly reduced in Pitx1 -/- hindlimb buds at embryonic day 12.5 compared to wildtype, suggesting that muscle hypoplasia was due to abnormal early muscle development and not disuse atrophy. Alvarado et al. (2011) concluded that PITX1 haploinsufficiency may cause a developmental field defect preferentially affecting the lateral lower leg.