Familial clubfoot with or without associated lower limb anomalies
-Rare bone disease
-Rare developmental defect during embryogenesis
Patellar dysostosis
-Rare bone disease
-Rare developmental defect during embryogenesis
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 ... 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).
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 ... 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.
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). ... 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 = ... 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).