Does idiopathic congenital talipes equinovarus have an impact on attainment of developmental milestones? A multicentre international study.

PURPOSE: The Ponseti method is a well-established approach to treating clubfoot. Potentially, both the underlying pathology and adherence to post-correction bracing can affect lower limb function and age of independent standing and walking. This cohort study investigates the age at which infants with idiopathic clubfoot treated using the Ponseti method achieved three selected developmental milestones and whether or not this correlated with treatment compliance. METHODS: A prospectively collected database from four centres was visited. Inclusion criteria were patients with idiopathic clubfoot with no comorbidities or prior treatment. Age at attainment of independent standing, walking, nocturnal continence was compared across three groups: I) congenital talipes equinovarus (CTEV) children compliant with treatment; II) CTEV children non-compliant with treatment; and III) typically-developed siblings. Minimum follow-up was five years. RESULTS: In all, 130 patients (198 feet) fitted the inclusion criteria: 43:87 (F:M). Standing was achieved by a mean 12.0 months in group I (sd 2.50); 12.0 months (sd 2.0) in II and ten months (sd 3.0) in III. Walking was achieved by a mean 15 months (sd 4.0) in group I, 14 months (sd 1.75) in II and 12 months (sd 3) in III, respectively. Both the compliant and non-compliant CTEV children were significantly slower at achieving standing and walking compared to sibling controls (p < 0.0001). There was no significant difference between age of nocturnal continence between the three groups. CONCLUSION: Infants with idiopathic clubfoot treated according to the Ponseti method achieve independent standing and walking approximately two months later than their typically-developed siblings. The delay is not related to the use of the foot abduction brace. LEVEL OF EVIDENCE: III.

The significance of foot length at the initiation of the Ponseti method: a prospective study.

OBJECTIVES: We sought to evaluate foot length (FL) and forefoot circumference (FC) and their impact on the severity of idiopathic clubfoot (CF) and results of treatment. We hypothesized that a smaller foot size at birth that represents a lesser than term newborn may affect the response of the CF to the treatment. METHODS: We conducted a prospective study documenting FL and FC of all neonates presented with idiopathic CF. Additional demographic information was collected. Outcome measures were number of casts needed for correction, need for recasting, additional surgery and functional score. RESULTS: In all, 52 children with 73 CF with a minimum mean follow-up of two years (2.0 to 5.6; sd 1.08) were evaluated. Mean gestational age was 38.63 weeks and mean birth weight (BW) was 3184 g. The mean FL at presentation was 74 mm (5.70 to 9.00), initial Pirani score was 5.5 (2.5 to 6.0) while number of casts was 6.9 (4.0 to 11.0). The FL was significantly correlated both to initial Pirani score (r = -0.35; p < 0.01) and number of casts (r = -0.33; p < 0.05). Positive correlation was found between the number of casts to Pirani score and number of additional procedures (r = 0.39; r = 0.36; p < 0.01, respectively). A foot size of up to 8 cm, needed 7.3 casts (4 to 7) compared with a FL of 8 cm or longer who needed 4.7 casts (4 to 6; t = 7.11; p < 0.001). CONCLUSION: FL is a simple approach to identify preterm babies. It can be used as part of the initial evaluation of CF and help in predicting the course of treatment. We recommend adding FL to the existing classification. LEVEL OF EVIDENCE: I - Prognostic study.

Prolonged use of foot abduction brace reduces the rate of surgery in Ponseti-treated idiopathic club feet.

PURPOSE: There is conflicting evidence related to factors affecting the rates of recurrence of idiopathic club feet using the Ponseti method. We attempt to evaluate the predictors of success and failure in our physiotherapy-led Ponseti club foot clinic. METHODS: We evaluated 189 children with 279 club feet with a mean follow-up of 6.3 years for the following: Pirani score at presentation, number of casts for correction, indication for Achilles tenotomy, and the duration of foot abduction brace (FAB) use, in relation to outcome. Outcome measures were the need for additional surgery and functional scores. Based on the pattern and rate of ossification of the tarsal bones in idiopathic club foot, a much longer FAB weaning protocol was designed and practiced since 2000. The objective of this study was to answer the question of whether a prolonged period of FAB use reduces the need for surgery in Ponseti-treated idiopathic club foot. RESULTS: Thirty-six feet (12.9 %) underwent additional surgery. The Pirani score and the number of cast changes had no influence on the rate of surgery. The duration of FAB use had a significant effect on the outcome, i.e., the rate of surgery and functional scoring. Operated children used the FAB for 28 months versus 33 months in the non-operated group (p < 0.05). Only a minor delay in the attainment of walking age was noted (average 15 months). CONCLUSIONS: The duration of FAB treatment was found to be the most influential on the functional results and on rate of surgery. Close follow-up and longer FAB weaning program reduced the rates of recurrence.

Identification of four highly conserved genes between breakpoint hotspots BP1 and BP2 of the Prader-Willi/Angelman syndromes deletion region that have undergone evolutionary transposition mediated by flanking duplicons.

Prader-Willi and Angelman syndromes (PWS and AS) typically result from an approximately 4-Mb deletion of human chromosome 15q11-q13, with clustered breakpoints (BP) at either of two proximal sites (BP1 and BP2) and one distal site (BP3). HERC2 and other duplicons map to these BP regions, with the 2-Mb PWS/AS imprinted domain just distal of BP2. Previously, the presence of genes and their imprinted status have not been examined between BP1 and BP2. Here, we identify two known (CYFIP1 and GCP5) and two novel (NIPA1 and NIPA2) genes in this region in human and their orthologs in mouse chromosome 7C. These genes are expressed from a broad range of tissues and are nonimprinted, as they are expressed in cells derived from normal individuals, patients with PWS or AS, and the corresponding mouse models. However, replication-timing studies in the mouse reveal that they are located in a genomic domain showing asynchronous replication, a feature typically ascribed to monoallelically expressed loci. The novel genes NIPA1 and NIPA2 each encode putative polypeptides with nine transmembrane domains, suggesting function as receptors or as transporters. Phylogenetic analyses show that NIPA1 and NIPA2 are highly conserved in vertebrate species, with ancestral members in invertebrates and plants. Intriguingly, evolutionary studies show conservation of the four-gene cassette between BP1 and BP2 in human, including NIPA1/2, CYFIP1, and GCP5, and proximity to the Herc2 gene in both mouse and Fugu. These observations support a model in which duplications of the HERC2 gene at BP3 in primates first flanked the four-gene cassette, with subsequent transposition of these four unique genes by a HERC2 duplicon-mediated process to form the BP1-BP2 region. Duplicons therefore appear to mediate genomic fluidity in both disease and evolutionary processes.

Segmental duplications: organization and impact within the current human genome project assembly.

Segmental duplications play fundamental roles in both genomic disease and gene evolution. To understand their organization within the human genome, we have developed the computational tools and methods necessary to detect identity between long stretches of genomic sequence despite the presence of high copy repeats and large insertion-deletions. Here we present our analysis of the most recent genome assembly (January 2001) in which we focus on the global organization of these segments and the role they play in the whole-genome assembly process. Initially, we considered only large recent duplication events that fell well-below levels of draft sequencing error (alignments 90%-98% similar and > or =1 kb in length). Duplications (90%-98%; > or =1 kb) comprise 3.6% of all human sequence. These duplications show clustering and up to 10-fold enrichment within pericentromeric and subtelomeric regions. In terms of assembly, duplicated sequences were found to be over-represented in unordered and unassigned contigs indicating that duplicated sequences are difficult to assign to their proper position. To assess coverage of these regions within the genome, we selected BACs containing interchromosomal duplications and characterized their duplication pattern by FISH. Only 47% (106/224) of chromosomes positive by FISH had a corresponding chromosomal position by comparison. We present data that indicate that this is attributable to misassembly, misassignment, and/or decreased sequencing coverage within duplicated regions. Surprisingly, if we consider putative duplications >98% identity, we identify 10.6% (286 Mb) of the current assembly as paralogous. The majority of these alignments, we believe, represent unmerged overlaps within unique regions. Taken together the above data indicate that segmental duplications represent a significant impediment to accurate human genome assembly, requiring the development of specialized techniques to finish these exceptional regions of the genome. The identification and characterization of these highly duplicated regions represents an important step in the complete sequencing of a human reference genome.