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We present a large, ten‐generation family of 273 individuals with 84 people having preaxial polydactyly/triphalangeal thumb due to a pathogenic variant in the zone of polarizing activity regulatory sequence (ZRS) within the exon 5 of LMBR1. The causative change maps to position 396 of the ZRS, located at position c.423 + 4909C > T (chr7:156791480; hg38; LMBR1 ENST00000353442.10; rs606231153 NG_009240.2) in the intron 5 of LMBR1. The first affected individual with the disorder was traced back to mid‐1700, when some settlers and workers established in Cervera de Buitrago, a small village about 82 km North to Madrid. Clinical and radiological studies of most of the affected members have been performed for 42 years (follow‐up of the family by LFGA). Molecular studies have confirmed a pathogenic variant in the ZRS that segregates in this family. To the best of our knowledge, this is the largest family with preaxial polydactyly/triphalangeal thumb reported so far. [ABSTRACT FROM AUTHOR]

Background: Five-fingered hand (5-FH) with completely developed phalanges is a rare phenotype observed so far only in humans and characterised by three phalanges of the 1st ray. A long-lasting, debated question is if the missing element of the normal hand 1st ray is the metacarpal or the phalanx. In this study, comparative X-rays morphometry of long bones in normal and 5-FH is carried out with the aim to face this question through homology analysis of long bone segments in the transverse and longitudinal line of normal hand and 5-FH.Materials and Methods: In the normal hand X-rays (n =20) and in a 5-FH X-rays series (n = 9) the relative length of each segment on the ray total length and the index of growth rate (IGR) were assessed. The calculation of the first parameter in normal hand bi-phalangeal thumb was carried out on the 3rd ray total length in the same hand.Results: The parameters of relative length and the proximal/distal growth rate asymmetry in the post-natal period (assessed through the IGR) confirmed in 5-FH the homology of all the five segment on the transverse line. In the normal control hand, the relative length assessment methodology was biased by the missing segment of the thumb, therefore, the reference to the 3rd ray total length in the same hand (instead of the 1st), allowed the homology analysis of the thumb metacarpal and 1st phalanx with the lateral segments (2nd-5th ray) of the same hand. The 5-FH analysis was used to choose the more appropriate reference ray for the normal hand group.Conclusions: The comparative analysis of relative lengths and IGRs in the two groups suggested homology of the (anatomical) 1st metacarpal with the 2nd-5th proximal phalanges in the same hand and that of the (anatomical) 1st proximal phalanx with the 2nd-5th mid phalanges. These data suggest that the missing segment of the normal hand thumb is the metacarpal. [ABSTRACT FROM AUTHOR]

Despite being a rare congenital limb anomaly, triphalangeal thumb is a subject of research in various scientific fields, providing new insights in clinical research and evolutionary biology. The findings of triphalangeal thumb can be predictive for other congenital anomalies as part of an underlying syndrome. Furthermore, triphalangeal thumb is still being used as a model in molecular genetics to study gene regulation by long-range regulatory elements. We present a review that summarizes a number of scientifically relevant topics that involve the triphalangeal thumb phenotype. Future initiatives involving multidisciplinary teams collaborating in the field of triphalangeal thumb research can lead to a better understanding of the pathogenesis and molecular mechanisms of this condition as well as other congenital upper limb anomalies. [ABSTRACT FROM AUTHOR]

Triphalangeal thumb is a rare congenital anomaly in which the thumb has three phalanges. Clinical presentation of triphalangeal thumb can vary considerably and can be present in both hands or unilateral. The thumb can be long with a finger-like appearance. The presence of clinodactyly depends on the shape of the extra phalanx varying from wedge-shaped to rectangular. Various joints, ligaments, muscles, and tendons of the first ray can be hypoplastic or absent, with varying degrees of stiffness or instability. The aim of surgical treatment is to reconstruct or correct the anatomic anomalies to obtain greater function and a more acceptable appearance. In our series, operations varied from removal of the delta phalanx with ligament reconstruction to multiple osteotomies and rebalancing of soft tissues. Results in these often complex cases can be rewarding if the surgeon has sufficient knowledge of the underlying anatomic differences. This review summarizes our current concepts of presentation and management of the triphalangeal thumb. [ABSTRACT FROM AUTHOR]

Preaxial polydactyly (PPD; OMIM 603596), which is characterized as having supernumerary fingers, is an unusual congenital hand abnormality. Triphalangeal thumb (TPT; OMIM 190600) is identified by an extra phalangeal bone and is often found in association with PPD. When in combination, the disease is referred to as PPD type II (PPD II; OMIM 174500). Previous studies have demonstrated that variations in the zone of polarizing activity regulatory sequence (ZRS; chr7: 156,583,796-156,584,569; hg19) region are associated with PPD II. In this study, our patient was diagnosed with PPD II, having bilateral thumb duplication and unilateral TPT (on the right hand). Further investigation of possible causative genes identified a de novo heterozygous ZRS mutation (ZRS 428T>A). This novel mutation was neither found in 200 normal controls nor reported in online databases. Moreover, the bioinformatics program Genomic Evolutionary Rate Profiling (GERP) revealed this site (ZRS428) to be evolutionarily highly conserved, and the 428T>A point mutation was predicted to be deleterious by MutationTaster. In conclusion, the affected individual shows bilateral thumb duplication, but unilateral TPT making this case special. Thus, our findings not only further support the important role of ZRS in limb morphogenesis and expand the spectrum of ZRS mutations, but also emphasize the significance of genetic diagnosis and counseling of families with digit number and identity alterations as well. [ABSTRACT FROM AUTHOR]

The surgical strategy of treatment of the opposable triphalangeal thumb is correction of the radio-ulnar deviation, reduction of the additional length and joint stabilization. The commonest procedures are: (1) removal of the extra phalanx and stabilization of the remaining joint; and (2) a combined reduction osteotomy with resection of the distal joint followed by arthrodesis. We treated 20 patients (33 hands). In 17 hands the extra phalanx was removed, and in 16 hands we used the combined osteotomy procedure of distal joint removal and arthrodesis. None of the patients in either group had an unstable interphalangeal joint. The mean radial or ulnar deviation in the interphalangeal joint was 5° degrees and 9°, respectively. Mean active flexion in the interphalangeal joint was 35° and 46°, respectively, in the two groups. Results for both procedures are similar, for both objective measures and self-rated function and activities of daily living. Either surgical approach seems reliable.Therapeutic, Level of evidence: Level III [ABSTRACT FROM AUTHOR]

Werner mesomelia is characterized by a sequence variation in the specific region (position 404) of the enhancer ZRS of SHH. The phenotype comprises variable mesomelia, abnormalities of the thumb and great toe and supernumerary digits. We describe extensive variation in limb phenotype in a large family and report on a novel sequence variation NG_009240.1: g.106737G>T (traditional nomenclature: ZRS404G>T) in the ZRS within the LMBR1 gene. The newly recognized clinical features in this family include small thenar eminence, sandal gap, broad first metatarsals, mesoaxial polydactyly, and postaxial polydactyly. We provide information on 12 affected family members. We review the literature on how a sequence variation in ZRS may cause such diverse phenotypes. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Trichorhinophalangeal syndrome (TRP) is a group of rare genetic disorders with characteristic clinical and radiological features. In this case report we discuss the evolution of imaging features in hands in a Chinese boy diagnosed with TRP II (Langer-Giedion syndrome, LGS). This article ramifies the diagnostic value of serial hand radiograph in clinically suspected cases of TRP. [ABSTRACT FROM AUTHOR]

Radial polydactyly, the most common digital duplication in Asian and white populations, has a wide range of manifestations. Its classification is useful for planning and assessing surgical treatment. Our patient had four thumbs, duplicated radial carpal bones, and a bifurcated radius. This presentation is not covered by any of the current classifications. To the best of our knowledge, this is the first case of such characteristics reported to date. Consequently, we propose some modifications in the nomenclature and classification of radial polydactyly. [ABSTRACT FROM AUTHOR]

We report on a newborn boy with a bilateral cleft of the primary palate, duplicated triphalangeal thumbs, and a patent foramen ovale. During childhood he had moderate developmental delay. Brain MRI at 4 years was normal. The concurrence of non-syndromic clefts of the lip/palate (CL/P) and duplicated thumbs with triphalangeal component has, to our knowledge, not been reported so far. In our case, array-CGH analysis documented two de novo deletions (∼1.2 Mb and ∼400 Kb) of the long arm of chromosome 4, containing four genes: platelet-derived growth factor C ( PDGFC), glycine receptor beta subunit ( GLRB), glutamate receptor ionotropic AMPA2 ( GRIA2), and F-box protein 8 gene ( FBXO8). PDGFC codes for a mesenchymal cell growth factor already known to be associated with clefts of the lip. Pdgfc−/− mice have skeletal anomalies, and facial schisis resembling human cleft/lip palate. GRIA2 codes for a ligand-activated cation channel that mediates the fast component of postsynaptic excitatory currents in neurons, and may be linked to cognitive dysfunction. FBXO8, a gene of unknown function, is a member of the F-box gene family, among which FBXW4, within the minimal duplicated region associated with human split-hand/foot malformation type 3 (SHFM type 3). The presence of overlapping deletions in patients who do not share the same phenotype of our case suggests incomplete penetrance, and a possible effect of modifier genetic factors. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Triphalangeal thumb (TPT) is congenital hand anomaly which a thumb consists of three phalanges. Thumb appearance can differ widely; the thumb can be longer than usual or it can be deviated in the radio-ulnar plane. Thumb strength and function can be significantly diminished. The goals of surgical treatment are to reduce the elongated thumb length, establish normal thumb function, maintain a stable joint and improve thumb position if necessary. In general, surgical treatment is performed for improvement of thumb function. The case presented here had a TPT with pre-axial polydactyly. The TPT was well developed but it had no movement at the proximal or distal interphalangeal joints. The rudimentary thumb had a well-developed and functioning interphalangeal (IP) joint. So as an alternative surgical technique we planned to transfer the functioning IP joint of rudimentary thumb to the TPT. [ABSTRACT FROM AUTHOR]

Strength is regarded as normal in patients with an opposable triphalangeal thumb. Our clinical impression is, however, that intrinsic musculature is probably affected in all forms of triphalangeal thumb. Therefore, we established the strength of 38 thumbs in patients with a triphalangeal thumb. Patients were excluded if the intrinsic musculature was enhanced or if osteotomies of the first metacarpal were performed. On average, strength of all thumb functions was significantly diminished, up to 63% for opposition strength. Strength of the power grip was on average 70%. As shown in this study, strength of the musculature of the thumb is affected in all types of triphalangeal thumb. Although strength of the thumb is diminished, in the investigated group it is apparently sufficient in daily life, as these individuals did not seek surgical enhancement. However, reconstructive procedures that enhance intrinsic musculature must be considered in all types of triphalangeal thumb. [ABSTRACT FROM PUBLISHER]

Limb malformations are one of the most common types of human congenital malformations. Mutations in the ZRS enhancer of Sonic Hedgehog are thought to be responsible for pre-axial polydactyly in multiple independent families. Here, we describe a large Balochi tribal family from Southern Punjab, Pakistan, with a variable set of limb malformations and a novel ZRS mutation. The family has a limb phenotype characterized by triphalangeal thumb, pre-axial polydactyly, and post-axial polydactyly. There is also a high degree of phenotypic heterogeneity with less common clinical findings in the affected family members that include osseous syndactyly of forth-fifth fingers, clinodactyly, hypoplasia of mesoaxial fingers, and bifid halluces. The presentation in most of the affected patients was bilateral and symmetrical. A heterozygous C>A mutation at position 287 of the ZRS enhancer (chr7:156,584,283; hg19) was detected in all affected subjects and is absent from four unaffected family members, 42 unrelated samples, and multiple databases of human variation. Combined, these results identify a novel ZRS287 C>A mutation which leads to a variable spectrum of limb phenotypes. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

A cis-regulatory sequence also known as zone of polarizing activity (ZPA) regulatory sequence (ZRS) located in intron 5 of LMBR1 is essential for expression of sonic hedgehog (SHH) in the developing posterior limb bud mesenchyme. Even though many point mutations causing preaxial duplication defects have been reported in ZRS, the underlying regulatory mechanism is still unknown. In this study, we analyzed the effect on transcription factor binding of a novel ZRS point mutation (463T>G) in a Pakistani family with preaxial polydactyly and triphalangeal thumb. Electrophoretical mobility shift assay demonstrated a marked difference between wild-type and the mutant probe, which uniquely bound one or several transcription factors extracted from Caco-2 cells. This finding supports a model in which ectopic anterior SHH expression in the developing limb results from abnormal binding of one or more transcription factors to the mutant sequence. [ABSTRACT FROM AUTHOR]

Abnormal function in the triphalangeal thumb is partly due to its extra length, which is due not only to the extra phalanx, but also to differences in the length of the first metacarpal. This study investigated whether the additional length of the first metacarpal is influenced by the growth plate location alone, or also by the type of triphalangeal thumb. Fifty-nine hands in 37 patients with triphalangeal thumbs were examined for thumb type (delta 31, trapezoid nine and full type 19), growth plate location and relative length of the first metacarpal. The first metacarpals in all three types of triphalangeal thumbs were significantly longer than in the normal population. The length of the first metacarpal was related to the site of the growth plate. The type of triphalangeal thumb did not affect the length. These findings suggest that a corrective procedure on the first metacarpal should be considered in all types of triphalangeal thumbs. [ABSTRACT FROM PUBLISHER]

Preaxial polydactyly is a common limb malformation in humans with variable clinical expression. Different types of triphalangeal thumb-preaxial polydactyly phenotypes were mapped to the chromosome 7q36 region. We studied a large Turkish family of 69 individuals, of whom 22 individuals were affected. In all, 11 affected family members were clinically and radiologically evaluated. All affected individuals had a triphalangeal thumb and a preaxial (hypoplastic) extra digit bilaterally, with minimal intrafamilial variation. No feet involvement was observed. Linkage and haplotype analyses using 20 informative meioses confirmed the 7q36 region contained the LIMBR1 gene. Maximum logarithm of the odds (LOD) scores were obtained with DNA markers D7S550 and D7S2423. We have further identified a novel C to T alteration at position 4909 bp in the critical zone of polarizing activity regulatory sequence (ZRS) region, in the intron 5, of the LMBR1 gene. One affected male with homozygous status and no phenotypic difference from affected family members with heterozygous status represented the first homozygote case of the triphalangeal thumb-preaxial polydactyly phenotype. [ABSTRACT FROM AUTHOR]

Split hand foot malformation (SHFM) is genetically heterogeneous with five loci mapped to date. Highly variable in presentation, it can occur as an isolated finding or with other anomalies. The genetic heterogeneity and clinical variability make genetic counselling of SHFM families challenging. By establishing genotype/phenotype correlations, one can provide insight into responsible developmental genes and help to direct mapping efforts and target genetic testing, ultimately providing more accurate information for family members. Preaxial involvement of the upper extremities was a significant discriminating limb-specific variable in our analysis of genetically mapped SHFM cases. This finding, which was originally identified through descriptive epidemiology, was subsequently confirmed by discriminant function analysis (p < 0.0001) to be a significant locus discriminator. Preaxial involvement of the upper extremities was most commonly seen at the SHFM3 locus mapped to chromosome 10q24 (OMIM 600095) and consisted of proximally placed thumbs and/or triphalangeal thumbs (TPT), preaxial polydactyly and/or absence of the first ray. These patients' feet, however, tended to show a classical central longitudinal deficiency without a significant preaxial component. This article discusses this discrepant clefting pattern between the upper and lower extremities and proposes potential mechanisms. [ABSTRACT FROM AUTHOR]

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Copyright of Zeitschrift für Kinderheilkunde is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The triphalangeal thumb–brachyectrodactyly syndrome is a very rare autosomal dominant disorder of unknown etiology characterized by an unusual pattern of limb malformations: triphalangeal thumbs and brachyectrodactyly in the hands, and ectrodactyly in the feet. In a previous report, we described the clinical and radiographical features of three related subjects with the disease and suggest that due to the unusual combination of limb defects and to its phenotypic similarity with the limb malformative pattern induced by disrupting the Hoxd13 gene in mouse, the triphalangeal thumb–brachyectrodactyly syndrome might be caused by mutations in a HOX gene. After sequencing the entire coding region of HOXD13 and the highly conserved homeodomain encoding region of HOXA13, we do not detect any deleterious mutation in any of the patients excluding that alterations at these sequences are responsible for the disease. Mutations in regulatory regions of these genes or in other genes involved in limb development might be responsible for the disease. [Copyright &y& Elsevier]

An adult with delta-phalanges of both thumbs was treated with removal of the supernumerary phalanx on one side and wedge osteotomy of the proximal phalanx on the other. The results show that wedge osteotomy of the proximal phalanx is the treatment of choice for this type of congenital deformity in adults. [ABSTRACT FROM AUTHOR]