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Werner mesomelic syndrome (WMS) is an autosomal dominant disorder with unknown molecular etiology characterized by hypo- or aplasia of the tibiae in addition to the preaxial polydactyly (PPD) of the hands and feet and/or five-fingered hand with absence of thumbs. We show that point mutations of a specific nucleotide within the sonic hedgehog (SHH) regulatory region (ZRS) cause WMS. In a previously unpublished WMS family, we identified the causative G>A transition at position 404 of the ZRS, and in six affected family members of a second WMS family we found a 404G>C mutation of the ZRS. The 404G>A ZRS mutation is known as the “Cuban mutation” of PPD type II (PPD2). Interestingly, the index patient of that family had tibial hypoplasia as well. These data provide the first evidence that WMS is caused by a specific ZRS mutation, which leads to strong ectopic SHH expression. In contrast, we show that complete duplications of the ZRS region lead to type Haas polysyndactyly or triphalangeal thumb-polysyndactyly syndrome, but do not affect lower limb development. We suggest the term “ZRS-associated syndromes” and a clinical subclassification for the continuum of limb malformations caused by different molecular alterations of the ZRS. Hum Mutat 30:1–9, 2009. © 2009 Wiley-Liss, Inc.

Purpose Triphalangeal thumb is a congenital malformation characterized by an additional phalanx of the thumb. Although surgical treatment of this condition is common practice, in the past this was not generally advised. Therefore, a population with an untreated triphalangeal thumb is still present. The purpose of this study is to compare function and appearance of adults with an untreated triphalangeal thumb to a normal population. Methods Twelve adults with 23 hands with an untreated triphalangeal thumb, unilateral or bilateral, were examined using objective measurements (thumb movement, joint instability, pain, and strength) and subjective measurements (visual analog scale; Disabilities of the Arm, Shoulder, and Hand questionnaire; and Short Form 36 health survey). Results Objective measurements showed no limitations in range of motion or in grip and pinch strength. No joint instability was found in the interphalangeal joints. Five thumbs had instability in the metacarpophalangeal joint. Strength of the thumb in anteposition was diminished to 64% compared to a normal population. Opposition was diminished to 62%, and metacarpophalangeal joint flexion strength was diminished to 61%. The patients scored lower compared to a normal population for the domain of social functioning in the Medical Outcome Study 36-item short form health survey; the Disabilities of the Arm, Shoulder, and Hand questionnaire showed no differences. Visual analog scale scores for appearance of the thumb were scored low (2.2 of 10) by the adults, in contrast to visual analog scale scores for function (7.7). Conclusions The examined group of adults with an untreated triphalangeal thumb had adequate thumb movement. Thumb strength was diminished for all specific thumb functions (anteposition, opposition, and thumb flexion), as low as 55%, compared to normal controls. Self-rated scores indicate that patients perceived their functionality as good. The appearance, however, was rated much lower, implying a dislike of the thumb by the patients. This indicates that the main impact of an untreated triphalangeal thumb in daily functioning might not be the diminished function but rather the dissimilar appearance. (J Hand Surg 2010;35A:1146-1152. (C) 2010 Published by Elsevier Inc. on behalf of the American Society for Surgery of the Hand.)

Since 1977 we have operated on 13 of 15 triphalangeal thumbs in nine children (five boys, four girls). Follow-up ranged from 22 to 134 months (mean, 65 months). Total active motion averaged 63 degrees at the interphalangeal joint and 79 degrees at the metacarpophalangeal joint. There was no evidence of instability or laxity of ligaments. Reduction osteotomy was insufficient to shorten grossly long thumbs of two patients, and it was necessary to shorten the metacarpal. Premature closure of the phalangeal physis occurred in two thumbs but did not result in inadequate length; one postoperative pin-tract infection resulted in nonunion that required reoperation. This long-term experience supports reduction osteotomy for triphalangeal thumbs because it addresses the deformities and preserves both motion and stability.

A large study of limb reduction defects in British Columbia reported an incidence of 5.97 per 10,000 live births, with 75% affecting the upper limb [1]. Half the cases had associated abnormalities, mostly in the musculoskeletal system, but defects of other organ systems were also common.

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. © 2009 John Wiley & Sons A/S.

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.

Surgically resected thumbs in preaxial polydactyly were submitted to anatomic dissection to detect a triphalangeal thumb. Radiologically, two particular categories of thumbs with duplication at the metacarpophalangeal joint were seen. The surgically excised thumbs of either the radial or the ulnar member were preserved for dissection. Depending on the number of phalanges as well as on osteocartilaginous structures, the thumbs were classified into three groups. In the first group, the thumbs consisted of three phalanges but had absent joint formation between the phalanges and metacarpal. The second group consisted of three phalanges with two well-formed joints between them. The third group of thumbs also had three phalanges but had only one interphalangeal joint between them. In all three groups, morphologic features and clinical criteria are discussed.

Most cases of the VACTERL “association” [Martinez-Frias et al., Am. J. Med. Genet. 76:291–296, 1998] are sporadic, with an empiric recurrence risk of 1% or less. Rare families with recurrence of VACTERL-H association are described with patterns consistent with single gene inheritance. Also described are occasional single anomalies of the VACTERL association in sibs or parents of affected individuals. We describe a mother and son with typical VACTERL anomalies. The patient was born by cesarean section to a 27-year-old G1 mother following an uncomplicated pregnancy. He was found to have an asymmetric crying face, preaxial polydactyly on the right, a small midmuscular ventricular septal defect with an incomplete right bundle branch block on echocardiogram, a small cleft in T3, and incomplete development of the left half of the sacrum. The kidneys were normal ultrasonographically. The patient's mother was born with an H-type tracheo-esophageal fistula, imperforate anus, rectovaginal fistula, a triphalangeal thumb, hypoplastic left kidney, and vertebral anomalies. There were no other individuals with VACTERL anomalies in the family. No families with VACTERL association in the offspring of an affected individual have been reported previously. Am. J. Med. Genet. 82:40–42, 1999. © 1999 Wiley-Liss, Inc.

Background: The Sonic hedgehog (SHH) protein produced in the zone of polarising activity (ZPA) is a major determinant of the identity and numbers of digits in early limb development. Preaxial polydactyly types II (PPD2) and III (PPD3) have been mapped to a critical region at 7q36, and subsequently shown to be caused by point mutations in the ZPA regulatory sequence (ZRS), a long range cis-regulator for the SHH gene. Triphalangeal thumb–polysyndactyly syndrome (TPTPS) and syndactyly type IV (SD4) were also mapped to the 7q36 region but pathogenic mutations in ZRS have not yet been affirmed. Methods and results: We performed linkage and haplotype analysis in six Han Chinese families with TPTPS and/or SD4, and refined the disease locus to an interval of 646 kb containing ZRS. In all families, the affected individuals heterozygous at rs10254391 (a single nucleotide polymorphism within ZRS) revealed a remarkable allele imbalance on sequence chromatogram. Using real-time quantitative polymerase chain reaction (qPCR), we identified duplication of ZRS and found that this duplication segregated with the limb phenotypes in all families but was not detected in unaffected family members or in unrelated control individuals. The duplication was also confirmed by interphase fluorescence in situ hybridisation (FISH) in an affected individual. We designed 17 additional qPCR assays and defined the minimum duplications in all six families, ranging from 131kb to 398kb. Conclusion: Both TPTPS and SD4 are due to duplications involving ZRS, the limb specific SHH enhancer. Point mutations in the ZRS and duplications encompassing the ZRS cause distinctive limb phenotypes.

Purpose Radial polydactyly is a congenital anomaly with a wide range of manifestations. Current classifications do not have the capacity to classify all different types of radial polydactyly when combined with triphalangeal components. The objective of this study was to test an adjusted classification and nomenclature that allows classification of triphalangeal components and triplication in radial polydactyly. Methods Patients from 1993 to 2006 with radial polydactyly (N = 104), a total of 121 affected hands, were identified from the hospital database. All x-rays were carefully examined and classified according to the existing classifications for radial polyclactyly and a modified classification. In the modified nomenclature, Wassel's level of duplication is preserved. Type VII and VIII are assigned for partial or complete duplication of the carpal bones according to Buck-Gramcko. Triplication and triphalangeal components can be assigned to each type of radial polydactyly by suffixes. Symphalangism, deviation, and hypoplasia can also be classified. Triplication on different levels of the thumb is classified by determining and including the different types of the original Wassel classification. Results Eighteen thumbs could not be classified according to existing classifications for radial polydactyly with triphalangeal components or triplication. Using the proposed classification, all patients could be classified. Conclusions We propose a modified classification that is a practical and utilitarian scheme for nomenclature of radial polydactyly and that may assist comparison of treatment outcomes and individual cases. Conclusions We propose a modified classification that is a practical and utilitarian scheme for nomenclature of radial polydactyly and that may assist comparison of treatment outcomes and individual cases.

A 2-week-old male is presented with the clinical findings of the autosomal dominant Townes-Brocks syndrome in an otherwise unaffected family. The patient showed the full spectrum of anomalies including imperforate anus, perineal fistula, triphalangeal thumb, preaxial polydactyly, pre-auricular tags, and microtia. As there is considerable overlap with the VACTERL association, careful examination of the parents is necessary with regard to the genetic counselling risk.

Purpose Purpose This study reports the results of surgical treatment of thumb duplication in the Clinique d'Orthopédie et de Chirurgie de l'Enfant de l'Hôpital Jeanne de Flandre in Lille (France). Methods Thirty patients (33 thumbs) operated on between 1995 and 2003 are clinically reviewed. Results The mean postoperative follow-up was 3 years and 11 months. According to Wassel's classification, the series included 12 type II duplications, two type III, 14 type IV, two type V, one type VI and two type VII. The surgical approaches consisted of simple resection of the most hypoplastic thumb (16 thumbs), the Bilhaut–Cloquet procedure (ten thumbs) and resection associated with reconstructive surgery (seven thumbs). The Bilhaut–Cloquet procedure was used in three cases for treatment of type IV duplication On the basis of the Tada scoring system, we obtained 24 good results, eight fair results and one poor result. Conclusion Based on our results, we recommend that the Bilhaut–Cloquet procedure be used not only for the treatment of type II duplication when the thumbs are both hypoplastic and symmetric but also for type IV duplication with the same clinical parameters. For the other types of duplications, we consider that resection of the most hypoplastic thumb associated with reconstructive surgery is the best surgical approach. For type VII duplication, ablation of the triphalangeal thumb remains the best option. We do not recommend osteotomy at the first surgery.

Duplicated triphalangeal thumb is a surgical challenge to create a satisfactory thumb with good mobility opposition, stability, alignment and size. Some authors consider it as a thumb deletion with index duplication or preaxial polydactly due to its lack of opposition, but it does belongs to group VII of Wassel classification. The frequency of his malformation is 1/25,000. The authors report a familial serial of 10 children treated bilateraly by pollicisation with the same technique, by two senior surgeons. The mean age for surgery was 20 months and the average follow-up is 7 years and a half at the time of the study. The goal of the study is to point out the functional and cosmetic improvement, with a focus on pre- and post-surgical radiographic aspect of the trapezometacarpal joint. The results are compared with parents whose some have been operated on one side by resection of the radial component. All patients improved their pinch and mainly cosmetic appearance. An efficient opposition was achieved and is compared with non-operated parent's thumbs. The authors report 2 tourniquets incidents on the same child, a malignant hyperthermy. Wound healing was delayed in 2 cases. Author review literature to considerate other surgical methods than pollicisation in Wassel VII thumb duplication but pollicisation of the duplicated index seems the best cosmetic procedure.

Spatio-temporal expression of sonic hedgehog (SHH) is driven by a regulatory element (ZRS) that lies 1 Mb upstream from SHH. Point mutations within the highly conserved ZRS have been described in the hemimelic extra toes mouse and in four families with preaxial polydactyly [Lettice et al., 2003]. Four North American Caucasian families were identified with autosomal dominant triphalangeal thumb. DNA from 20 affected and 36 unaffected family members was evaluated by sequence analysis of a 774-bp highly conserved ZRS contained within LMBR1 intron 5. Mutations within ZRS were identified in three of four families. In pedigree A and C, a novel A/G transition was identified near the 5′ end of ZRS at bp 739 that segregated with disease or carrier status. Pedigree A, described previously [Dobbs et al., 2000], is a large family with 19 affected members who exhibit a milder phenotype, including predominantly triphalangeal thumbs and low penetrance (82%) relative to other families. Pedigree C is a small family with two affected family members with triphalangeal thumb, and one affected with both triphalangeal thumb and preaxial polydactyly. A novel C/G mutation at bp 621 was identified in pedigree B that segregated with the disease in all four affected individuals who manifested both preaxial polydactyly and triphalangeal thumb. Both mutations alter putative Cdx transcription factor binding sites. Mutations within ZRS appear to be a common cause of familial triphalangeal thumb and preaxial polydactyly. A genotype/phenotype correlate is suggested by pedigree A, whose mutation lies near the 5′ end of ZRS; this family demonstrates a higher rate of nonpenetrance and milder phenotype. However, modifier genes may be contributing to the milder phenotype in this family. © 2006 Wiley-Liss, Inc.

BACKGROUND At least five distinct loci have been implicated in split hand foot malformation (SHFM). Establishing genotype/phenotype correlations at the chromosomal level may elucidate responsible developmental genes and improve patient management. In our analysis of previously published genetically mapped SHFM cases, preaxial hand involvement was a significant discriminating variable, most commonly seen at the SHFM3 locus (OMIM 600095) at 10q24. Of the 47 SHFM3 patients analyzed, 15 (31.9%) had triphalangeal thumb (TPT), a limb finding not reported at any other locus. METHODS The association of TPT/split foot, in particular, prompted us to review the literature for similar cases. RESULTS We ascertained a number of unmapped familial and sporadic cases with TPT/split foot, including a group of patients with triphalangeal thumb-brachyectrodactyly syndrome. Certain trends were similar in both SHFM3 and these unmapped literature cases. With respect to gender, 7/12 (58%) of mapped SHFM3 cases with TPT/split foot were male whereas 5/12 (42%) were female, compared with 22/50 (44%) males and 28/50 (56%) females among unmapped cases (P=0.3715). Individuals in both groups usually had bilateral involvement, with 67 and 60% showing bilateral TPT among mapped and literature cases, respectively (P=0.6714). Bilateral involvement of the feet was even more striking (83% of SHFM3 patients and 96% of literature cases; P=0.0808). CONCLUSIONS Patients with TPT/split foot may in fact represent SHFM3 cases and should be evaluated for genomic rearrangements at 10q24. TPT may be identified only by radiographic analysis, emphasizing the importance of imaging these patients and their family members.

Summary Holt-Oram syndrome is a rare genetic disorder affecting the heart and upper limbs (atriodigital dysplasia). The manifestations of the limb defects may vary in severity from subtle carpal bone defects and triphalangeal thumb to digit aplasia and upper extremity phocomelia. Cardiac abnormalities include atrial and/or ventricular septal defects, anomalies in pulmonary venous return and various dysrhythmias. We present the anesthetic management of a parturient with this syndrome who underwent elective cesarean section and tubal ligation, conducted under combined spinal-epidural anesthesia with a low dose of intrathecal bupivacaine. Our goal was to avoid an excessively high sympathetic block or excessive sympathetic stimulation accompanied by potential deleterious effects on cardiac rhythm. Cardiac monitoring was continued in the postoperative period for 6 h because of the possibility of dysrhythmia.

According to the everyday use of ultrasound in the whole field of paediatric surgery we would like to define its potential role in the assessment of congenital hand malformation (CHM). We therefore tested it for several diagnoses like digitus saltans, camptodactylism, triphalangeal thumb and syndrome-associated malformations in comparison as well as in addition to clinical and x-ray findings. All soft and bony tissue details could be displayed reasonable giving the paediatric surgeon additional information. Additional information that is available at the bedside, non-invasive, less costly and does not use ionising radiation.

Preaxial polydactyly (PPD) is a common limb malformation in human. A number of polydactylous mouse mutants indicate that misexpression of Shh is a common requirement for generating extra digits. Here we identify a translocation breakpoint in a PPD patient and a transgenic insertion site in the polydactylous mouse mutant sasquatch ( Ssq ). The genetic lesions in both lie within the same respective intron of the LMBR1 / Lmbr1 gene, which resides ≈1 Mb away from Shh . Genetic analysis of Ssq reveals that the Lmbr1 gene is incidental to the phenotype and that the mutation directly interrupts a cis-acting regulator of Shh . This regulator is most likely the target for generating PPD mutations in human.

Thirty-four triphalangeal thumbs of 23 patients, who had no associated anomaly in their ipsilateral hand, were reviewed to clarify the characteristics of an isolated triphalangeal thumb and its surgical outcome. There were 13 type 1 thumbs, 21 type 2 thumbs, and no type 3 thumbs. The existence of an accessory phalanx caused ulnar bending at the interphalangeal joint. Thirteen type 1 thumbs were operated on by excising an accessory phalanx. Corrective osteotomy at the epiphysis was performed on four type 2 thumbs, and partial excision of the epiphysis was performed on 11 type 2 thumbs. At follow-up examination, the average interphalangeal joint motion was 54 degrees in type 1 thumbs and 53 degrees in type 2 thumbs. More than 10 degrees of lateral bending remained in one type 1 thumb and six type 2 thumbs. Good results were observed when an early excision of the accessory phalanx with a securing collateral ligament was performed on type 1 thumbs. For type 2 thumbs, partial excision of the epiphysis provided relatively better correction than osteotomy. For good adaptation of interphalangeal joints, surgery should be performed when the patient is between the ages of 1 and 2, when the epiphysis is visible on x-rays.

We report on a patient with Williams syndrome and a complex de novo chromosome rearrangement, including microdeletions at 7q11.23 and 7q36 and additional chromosomal material at 7q36. The nature of this additional material was elucidated by spectral karyotyping and first assigned to chromosome 22. Subsequent fluorescence in situ hybridization (FISH) experiments showed that it consisted of satellite material only. Refinement of the 7q36 breakpoint was performed with several FISH probes, showing a deletion distal to the triphalangeal thumb (TPT) region. The phenotype of the patient principally results from the microdeletion of the 7q11.23; the small deletion at 7qter and the extra satellite material may not be of clinical significance.

We report a 19-year-old man with congenital erythematous plaque on his left arm that was found histopathologically to be composed of respiratory mucosa. The patient had a triphalangeal thumb and polydactyly in the left hand. This is, to our knowledge, only the third case of ectopic respiratory epithelium presenting as a superficial lesion in the skin to be reported in the English literature, and the first case associated with skeletal malformation and polydactyly. (J Am Acad Dermatol 2000;43:939-42.)

The human Sonic Hedgehog gene (SHH) is one of the vertebrate homologs related to the Drosophila segment polarity gene hedgehog. The entire coding and promoter region of the SHH gene, including 2 kb 5' of the transcriptional start site has been screened for mutations in families with autosomal dominant sacral agenesis and autosomal dominant triphalangeal thumb, two conditions previously known to be linked to 7q36. We have also studied the SHH gene in five families with mirror polydactyly associated with tibial hemimelia and in 51 unrelated patients with neural tube defects. Except for two sequence variants in exon 3, no mutations were found in these disease categories. OFF

The epidemiology of preaxial limb malformations was studied in an effort to find similarities and differences between different types that could help to define suitable groups of malformations for etiologic studies. Material from three large congenital malformation registers was used, with a total of 1646 infants with such malformations among over 5 million births. We compared different types of preaxial malformations with respect to bilaterality, maternal age and parity, racial differences, sex distribution, twinning, and associated malformations. From many epidemiologic aspects, different types of preaxial malformations showed similarities, but there were some distinct differences between upper and lower limb anomalies. We conclude that in searches for etiologic factors, it may be useful to group all preaxial malformations together but to differentiate between upper and lower limb defects.

Triphalangeal thumb (TPT) is a rare congenital disorder characterised by a long, finger-like thumb with three phalanges instead of two. It can occur as an isolated defect, in association with other abnormalities of the hands and feet, or as a part of a syndrome. Sporadic cases have been described, but it is usually inherited as an autosomal dominant trait. In order to examine skeletal morphology in different phenotypic variations of this disorder, we performed metacarpophalangeal pattern profile analysis in one kindred with this disorder. A characteristic profile occurred in all affected people, based on the individual lengthening or shortening of the thumb bones. Comparison of the affected and unaffected people from this family with people with a different genetic background suggests that the described profile is specific for TPT and could be used as a helpful diagnostic tool in syndromes which include TPT.

Hereditary developmental abnormalities of the upper or lower limbs in humans are easily recognizable phenotypes that can be used in the mapping and cloning of genes involved in normal human development. We studied a large Indian pedigree (UR002) with an autosomal dominant triphalangeal thumb (TPT) and polysyndactyly (PSD). The abnormalities were present only in the upper limbs, and the phenotype was fully penetrant. The expression of the phenotype was variable and ranged from unilateral TPT to bilateral TPT, preaxial du-, tri-, or quadruplication of the thumb, or syndactyly of multiple thumbs. There were 112 affected individuals in the pedigree. Previous linkage analyses on apparently similar phenotypes have identified a locus at 7q36 [Heutink et al., 1994, Nature Genet 6:287-291; Tsukurov et al., 1994]. To map the gene responsible for the TPT-PSD in family UR002, we performed linkage analysis in DNA from 47 affected and 7 normal individuals. Marker D7S550, located at 7q36, yielded a maximum LOD score of 11.31 at theta = 0.00. Additional markers in the region also showed no recombination. These data indicate that the gene responsible for the hand abnormality in pedigree UR002 maps to the same region as that in previous pedigrees with similar phenotype. Further analyses of recombinants among all the linked families by using new polymorphic markers will narrow the critical genomic region and facilitate positional cloning of the elusive gene.

The association of vertebral, cardiac, renal, limb anomalies, anal atresia, tracheo-esophageal fistula (VACTERL) with hydrocephalus (VACTERL-H) has recently been described. Both X linked and autosomal recessive forms have been described which are mostly indistinguishable clinically. Here we report a female newborn infant with hydrocephalus detected antenatally, oesophageal atresia with tracheo-oesophageal fistula, anal atresia, renal and vertebral anomalies, and triphalangeal thumb as well as primary hypothyroidism.

We report the case of a baby girl born to consanguineous parents who died 36 hours after birth. She had multiple preauricular appendices, right radial aplasia, triphalangeal thumb and several other anomalies. Differential diagnosis included Fryns syndrome, Pallister-Killian syndrome, and hemifacial microsomia. However, since our patient had congenital diaphragmatic hernia, a rare finding in hemifacial microsomia we suggest that she had a variant form of hemifacial microsomia or an undescribed new syndrome.

textabstractTriphalangeal thumb is a developmental anomaly, sometimes dominantly transmitted, characterized by a long, finger−like thumb with three phalanges instead of two. The underlying genetic defect is unknown, but presumably involves genes that regulate the differentiation of the developing forelimb. In two large kindreds with triphalangeal thumb, evidence for linkage to the long arm of chromosome 7 was obtained with a maximum lod score of 12.61. Multipoint linkage and haplotype analysis placed the gene close to the telomere of the long arm. To our knowledge this is the first time that a human gene involved solely in the pathologic morphogenesis of the hand and feet has been localized.

The clinical features of opposable triphalangeal thumb were examined in 15 patients (23 hands). Triphalangeal thumb appeared as an isolated anomaly in 16 hands and in combination with cleft hand in 7 hands. Polydactylous changes in the distal phalanx were frequently observed in these hands and in the opposite thumbs in unilaterally affected cases. Opposable triphalangeal thumb seemed to have formed as a result of incomplete fusion of the duplicated distal phalanges or fusion of the thumb and index finger. Twelve hands in ten patients were treated surgically and followed for an average of 6.5 years. Nine hands were treated by removal of the accessory phalanx, and good results were obtained in all except one. Removal of the accessory phalanx seems to be a simple and reliable treatment for opposable triphalangeal thumb in young children.

A 5-year-old girl with Klippel-Feil anomaly and bimanual polydactyly of triphalangeal thumb is described. The main findings include--in addition to the classical congenital fusion of cervical vertebrae and the clinical triad of short neck, limitation of head and neck movement and low-set posterior hairline--several associated abnormalities: scoliosis, spina bifida occulta, absence of ribs, conductive hearing loss, mirror movements, unilateral renal ectopia with dilation of the collecting system, and microtia. The hand malformation appears to represent a previously unreported defect associated with Klippel-Feil anomaly.

To date, the contribution of disrupted potentially cis-regulatory conserved non-coding sequences (CNCs) to human disease is most likely underestimated, as no systematic screens for putative deleterious variations in CNCs have been conducted. As a model for monogenic disease we studied the involvement of genetic changes of CNCs in the cis-regulatory domain of FOXL2 in blepharophimosis syndrome (BPES). Fifty-seven molecularly unsolved BPES patients underwent high-resolution copy number screening and targeted sequencing of CNCs. Apart from three larger distant deletions, a de novo deletion as small as 7.4 kb was found at 283 kb 5′ to FOXL2. The deletion appeared to be triggered by an H-DNA-induced double-stranded break (DSB). In addition, it disrupts a novel long non-coding RNA (ncRNA) PISRT1 and 8 CNCs. The regulatory potential of the deleted CNCs was substantiated by in vitro luciferase assays. Interestingly, Chromosome Conformation Capture (3C) of a 625 kb region surrounding FOXL2 in expressing cellular systems revealed physical interactions of three upstream fragments and the FOXL2 core promoter. Importantly, one of these contains the 7.4 kb deleted fragment. Overall, this study revealed the smallest distant deletion causing monogenic disease and impacts upon the concept of mutation screening in human disease and developmental disorders in particular., Author Summary Long-range genetic control is an inherent feature of genes harbouring a highly complex spatiotemporal expression pattern, requiring a combined action of multiple cis-regulatory elements such as promoters, enhancers, and silencers. Consequently, disruption of the long-range genetic control of a target gene by genomic rearrangements of regulatory elements may lead to aberrant gene transcription and disease. To date, the contribution of mutated regulatory elements to human disease has not been studied frequently. Here, we explored the contribution of genetic changes in potentially cis-regulatory elements of the FOXL2 gene in blepharophimosis syndrome (BPES), a developmental monogenic condition of the eyelids and ovaries. We identified a de novo very subtle deletion of 7.4 kb causing BPES. Moreover, we studied the functional capacities and chromosome conformation of the deleted region in FOXL2 expressing cellular systems. Interestingly, the chromosome conformation analysis demonstrated the close proximity of the 7.4 kb deleted fragment and two other conserved regions with the FOXL2 core promoter, and the necessity of their integrity for correct FOXL2 expression. Finally, our study revealed the smallest distant deletion causing monogenic disease and emphasized the importance of mutation screening of cis-regulatory elements in human genetic disease.

We report a case of Klinefelter's syndrome owing to maternal meiotic error associated with triphalangeal thumb and delta phalanx bilaterally. There are no previous reports of similar cases and triphalangism with delta phalanx abnormalities of both thumbs might therefore be considered a further, but rare, manifestation of this aneuploidy.

Three cases of a complex malformation of the hand involving syndactyly, polydactyly, and hypoplastic triphalangeal thumb are presented. In all three patients, six metacarpal bones and hypoplasticity of the thenar muscles were present. In one patient, both hands, except the most radial digits of the left hand, were completely fused by soft webs as reported by Haas and Ofodile. In two other patients, the extent of the webs differed from Haas's case, but one of them was similar to Ofodile's first case. In all instances the supernumerary digit had a triphalangeal configuration and the thenar muscles were hypoplastic, often associated with some degree of webbing.

The combination of Moebius and Poland anomalies is rarely described in the literature. Some authors believe that this association is an independent syndrome, while others propose that Poland, Moebius and Poland-Moebius are a spectrum of the same condition. Here we report a family where a child has Poland-Moebius syndrome and an aunt is affected with Poland anomaly. This probably represents the second report of possible autosomal dominant transmission of Poland-Moebius syndrome. The presence of contralateral triphalangeal thumb in the proband and in other members of the family can be explained by chance alone or, alternatively, by a pleiotropic expression of this gene.

The biennial meeting of the Scandinavian Society for Surgery of the Hand was held May 15 and 16, 1981, in Gothenburg , Sweden . The Society was founded in 1951 as the first Hand Society in Europe . The founder, DR. ERIK MOBERG, was honored at this 30th Anniversay Meeting . DR. MOBERG presented scientific papers and also reviewed the development of the Society and the field of hand surgery in Scandinavia. The ERIK MOBERG lecture , "Observations on the joints of the hand, " was given by MR. K. KUSCZYNSKI, Edinburgh. DR. SVANTE EDSHAGE, Gothenburg , Sweden, was elected President and DR. TORE HAGA, Bergen , Norway, was elected Secretary-Treasurer for 1982. Following is a condensation of papers presented at the meeting. Giant cell reparative granuloma-Unusual location to the bone of the hand. K. BERTHEUSSEN and S. HOLCK, Copenhagen , Denmark, presented a case of giant cell reparative granuloma, localized within the bones of the hand and mimicking a giant cell tumor (osteoclastoma). A review of the literature had failed to disclose any previous reports of this disorder outside the skull and facial bones. Angiomatosis osteohypotrophica. l. NIECHAJEV, Malmo, Sweden, reported a syndrome consisting of congenital hemangiomas with arteriovenous fistulae involving the soft tissues and bones, with shortening of the involved extremity . He had studied seven patients clinically and radiologically and suggested the name angiomatosis osteohypotrophica. Angioma, varicose veins, and/or arteriovenous fistulae with an increase in limb length has been widely known since the beginning of this century as Klippel-Trenaunay syndrome. Although DR. NIECHAJEV'S patients presented all other features of that syndrome, thinning and shortening of the long bones occurred, resulting in an overall reduction of limb length. Intraosseous hemangiomas of the metacarpal or metatarsal bones was a common characteristic finding. The influence of arteriovenous fistulae on the skeletal growth was discussed. Small finger tendon anomaly. T. BARFRED, Odense, Denmark, described two cases with tendon-slip from extensor carpi ulnaris to the small finger extensor tendons. One of the patients, unable to play her violin professionally , was cured by resection of the tendonslip. Deltaphalanx in thumbs. A. W EILB Y, Copenhagen, Denmark, discussed delta phalanges in thumbs . He stated that those cases where it occurs in biphalangeal thumbs should be treated early with osteotomy to gain length. When this condition occurs as a middle phalanx in a triphalangeal thumb , the bone should be excised, and reconstruction of the joint ligament and extensor aponeurosis should be performed. The results of treatment in the two different types was illustrated, and the problems of frequently accompanying deformities in bilateral triphalangeal thumbs was discussed. Closed compartment syndrome in the first dorsal interosseous muscle. P. FORSSBLAD, CH SOLLERMAN, and A. BACH, Gothenburg, Sweden, stated that closed compartment syndrome in the legs with exerciseinduced pain probably has an analogy in the upper extremity , although it is not reported . Writer's cramp is considered to be a behavioral disorder because of lack of organic explanation . However, there is evidence in some cases that this disorder may be caused by an overuse reaction in the compartment of the first dorsal interosseous muscle and the thumb adductor. These muscles especially take part in performing a pinch grip. Since 1978, three cases of writer's cramp have been treated by a plain incision of the fascia overlying the first interosseous muscle, with prompt relief. This would indicate that a compartment syndrome could be the explanation for many cases of writer's cramp. Reconstruction of the median nerve in children. M. VASTAMAKI , Helsinki, Finland , presented five cases of reconstruction of the median nerve in children. All the injuries were in the wrist area. Operative delay was from 1 to 17 months, with an average of 7 months . The sural nerve was used as a graft with 3 to 5 strands, and the length of the graft was 3 to 13 em, with an average of 5 cm. The follow-up time was 3 to 8 years. The two-point discrimination was 3 to 7 mm in those four patients who had been followed longest; all the patients, even the fifth patient with two-point discrimination of 8 to 12 mm, reported sensibility to be normal.

From the literature we found reports of 105 patients whom we judged had a triangular deformity of one of the bones of the hand or foot. We found 49 patients of our own with 84 delta-shaped phalanges limited strictly to the hand. This represents an incidence of 3.5 percent of our congenital abnormalities of the upper extremity. The deformity is associated with many abnormalities; syndactyly, Polydactyly, symphalangism, triphalangeal thumb, cleft hand, and hypoplastic hand are the most frequent. Triangular deformity of the bone of the index finger usually is associated with Apert's syndrome. Triangular deformity of the proximal phalanx of the ring finger often is found with central Polydactyly. Our average follow-up time on these 49 patients was 14 years, giving us a chance to establish some guidelines and general rules about the natural history and treatment of the delta bone.

Polydactyly associated with triphalangeal thumb is not rare, as among the records of 1,269 patients with congenital deformation of the upper extremity at the University of Iowa there were 21 patients with 32 hands with such involvement. More detailed classification based on Wassel's work was made. Treatment should be early, with removal of the radial digit if equal in size, excision of all accessory parts including delta bone when present, reconstruction of joint ligaments or joint fusion and osteotomy for correction of deviations. Care should be taken to avoid leaving a narrow first web space.

Hamatologische Erscheinungen sind heute bei zwei Syndromen bekannt, deren wesentliches Merkmal Knochenfehlbildungen sind: der Fanconi-Anamie und der kongenitalen Thrombocytopenie mit Radiusaplasie. Ein weniger bekanntes Syndrom, von dem seit 1969 4 Falle mitgeteilt wurden, ist gekennzeichnet durch die Syntropie von dreigliedrigem Daumen und hypoplastischer Anamie. Als weitere Misbildungen werden dabei eine Hypoplasie des Radius, ein angeborener Herzfehler und orale Spaltbildungen beobachtet. Da das Syndrom bisher nur bei Knaben gefunden wurde, ist eine recessive, x-chromosomale Vererbung moglich. 3 der beobachteten Patienten zeigten eine Besserung der Anamie nach Gabe von Prednisolon. Die hamatologischen und knochernen Veranderungen bei einem weiteren Fall dieses seltenen Syndroms werden beschrieben.

We describe two daughters of a nonconsanguineous couple. Both had facial and skeletal anomalies, but in quantitatively and qualitatively different ways. In one patient signs of mandibulofacial dysostosis are associated with anomalies of the radial rays of both arms. In the other, cleft lip and cleft palate are associated with hypoplastic thumbs. Clinical and genetical aspects of present case are discussed.

Clinodactyly in 10 fingers (9 patients) with longitudinally bracketed diaphysis (LBD) was treated surgically with various methods. In 4 cases with LBD in the middle phalanx of a triphalangeal thumb this phalanx was removed and the ligaments reconstructed. In the other 6 digits the LBD was in the base phalanx of a thumb or in the middle phalanx of some other digit. One of these was treated in infancy with transverse resection of the bracket. In 3 cases (4 digits) wedge osteotomy with reversal of the wedge was carried out. In the remaining case simple osteotomy was performed and a wedge-shaped bonegraft was interposed in the space created. Treatment in the last-mentioned case was unsuccessful because postoperatively the graft slipped out of position, but in all other cases the results achieved appear satisfactory.

1. The pedigree of a family in which lobster claw foot and triphalangeal thumb occurred together is presented. The affected members of two generations are described. The clinical appearances and radiological abnormalities are described in detail. Results of surgical treatment of the forefoot cleft are presented. 2. Lobster clawing of the foot is discussed with particular reference to associated hand and finger abnormalities. Triphalangeal thumb is discussed. The current and probably acceptable theory of the etiology of duplication is expanded. A hypothesis is formulated of excessive activity at the pre-and post-axial borders of the distal limb bud, followed by variable resorption, to explain not only the cause of lobster claw foot but also its occurrence in association with triphalangeal thumb.

Two families with the Holt-Oram syndrome are described. These families demonstrate a wide variety of thumbs including a “fingerized” hypoplastic thumb, a triphalangeal thumb, a long clumsy-appearing thumb, and a normal thumb. Three of the patients studied had an atrial septal defect. Three affected patients do not have heart disease but do have an abnormal thumb. The cardiac defect in 1 is uncertain. These families are reported on to emphasize that the thumb may be normal or long rather than hypoplastic. Diagnosis of the Holt-Oram syndrome thus offers the excitement of making a cardiovascular diagnosis merely by looking at the hand as well as the discovery of a surgically curable lesion.