Upper and Lower Limb Anomalies in Craniofacial Microsomia and Its Relation to the OMENS+ Classification: A Multicenter Study of 688 Patients.

BACKGROUND: Craniofacial microsomia (CFM) is characterized by several malformations related to the first and second pharyngeal arch. Patients typically present with facial asymmetry, but extracraniofacial organ systems might be involved, including limb anomalies. The purpose of this study was to analyze the occurrence of upper and lower limb anomalies in CFM patients. Furthermore, the relation between limb anomalies and the OMENS+ (orbital distortion; mandibular hypoplasia; ear anomaly; nerve involvement; soft-tissue deficiency; and associated extracraniofacial anomalies) classification was examined. METHODS: A retrospective study was conducted including patients with CFM from craniofacial units in three different countries. Patients were included when clinical and/or radiographic images were available. Demographic, radiographic, and clinical information was obtained. RESULTS: A cohort of 688 patients was available and selected for analysis. In total, 18.2% of the patients were diagnosed with at least one upper and/or lower limb anomaly. Upper and lower limb anomalies were seen in, respectively, 13.4% and 7.8% of patients. Patients with other extracraniofacial anomalies had a significantly higher risk for limb anomalies (OR, 27.98; P = 0.005). Laterality of CFM and a higher OMENS score were not associated with limb anomalies. CONCLUSIONS: More than one in six patients with craniofacial microsomia have limb anomalies. Therefore, clinical awareness for these anomalies is warranted. Examination and, if present, follow-up on limb abnormalities in patients with CFM should be implemented in the standard assessment of CFM patients. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

The unsolved problem of radial longitudinal dysplasia: how can we reliably prevent recurrence, preserve growth and optimize function?

Congenital radial longitudinal dysplasia remains an 'unsolved problem' in hand surgery. The challenges presented by the skeletal deficiency of the distal radius and soft tissue dysplasia of the severe radial longitudinal deficiency have been addressed by a number of techniques that aim to stabilize the position of the hand relative to the forearm and optimize forearm growth and hand function. Analysis of hand function and position in these children is difficult because of the abnormal 'wrist' mechanics, and the published results of the techniques used to date often lack a standardized approach and importantly the perception of function from the patient's perspective. The existing data is reviewed and compared with the results of cohorts from two major congenital upper limb centres. Soft tissue distraction prior to radialization or centralization may offer benefit in ulnar growth and forearm length but there is a need for further research into the long-term functional outcomes of the various techniques available to determine the optimal choice for these children.Level of evidence: V.

Determining the Minimally Important Change of the Michigan Hand outcomes Questionnaire in patients undergoing trigger finger release.

INTRODUCTION: The Michigan Hand outcomes Questionnaire (MHQ) is a widely used instrument to evaluate treatment results for hand conditions. Establishing the Minimally Important Change (MIC) is essential for interpreting change in outcome that is clinically relevant. PURPOSE OF THE STUDY: The purpose of this study was to determine the MIC of the MHQ total and subscale scores in patients undergoing trigger finger release. STUDY DESIGN: This is a prospective cohort study conducted between December 2011 and February 2020. METHODS: Patients completed the MHQ prior to surgery and 3 months postoperatively. The MIC of the MHQ was determined using 5 anchor-based methods (ie, 2 anchor mean change methods and 3 receiver operating characteristic methods). The median MIC value was determined to represent the triangulated MIC. RESULTS: A total of 1814 patients were included. The MIC for the MHQ total score ranged from 7.7 to 10.9, with a triangulated estimate of 9.3. The MIC estimates for 5 of 6 of the MHQ subscales ranged from 7.7 to 20.0. No MICs could be determined for the MHQ subscale "aesthetics" due to low correlations between the anchor questions and MHQ change scores. CONCLUSIONS: These MIC estimates can contribute to the interpretation of clinical outcomes following trigger finger release and for assessment of power in prospective trials.

The pZRS non-coding regulatory mutation resulting in triphalangeal thumb-polysyndactyly syndrome changes the pattern of local interactions.

Herein, we report on a large Polish family presenting with a classical triphalangeal thumb-polysyndactyly syndrome (TPT-PS). This rare congenital limb anomaly is generally caused by microduplications encompassing the Sonic Hedgehog (SHH) limb enhancer, termed the zone of polarizing activity (ZPA) regulatory sequence (ZRS). Recently, a pathogenic variant in the pre-ZRS (pZRS), a conserved sequence located near the ZRS, has been described in a TPT-PS Dutch family. We performed targeted ZRS sequencing, array comparative genomic hybridization, and whole-exome sequencing. Next, we sequenced the recently described pZRS region. Finally, we performed a circular chromatin conformation capture-sequencing (4C-seq) assay on skin fibroblasts of one affected family member and control samples to examine potential alterations in the SHH regulatory domain and functionally characterize the identified variant. We found that all affected individuals shared a recently identified pathogenic point mutation in the pZRS region: NC_000007.14:g.156792782C>G (GRCh38/hg38), which is the same as in the Dutch family. The results of 4C-seq experiments revealed increased interactions within the whole SHH regulatory domain (SHH-LMBR1 TAD) in the patient compared to controls. Our study expands the number of TPT-PS families carrying a pathogenic alteration of the pZRS and underlines the importance of routine pZRS sequencing in the genetic diagnostics of patients with TPT-PS or similar phenotypes. The pathogenic mutation causative for TPT-PS in our patient gave rise to increased interactions within the SHH regulatory domain in yet unknown mechanism.

Variant type and position predict two distinct limb phenotypes in patients with GLI3-mediated polydactyly syndromes.

INTRODUCTION: Pathogenic DNA variants in the GLI-Kruppel family member 3 (GLI3) gene are known to cause multiple syndromes: for example, Greig syndrome, preaxial polydactyly-type 4 (PPD4) and Pallister-Hall syndrome. Out of these, Pallister-Hall is a different entity, but the distinction between Greig syndrome and PPD4 is less evident. Using latent class analysis (LCA), our study aimed to investigate the correlation between reported limb anomalies and the reported GLI3 variants in these GLI3-mediated polydactyly syndromes. We identified two subclasses of limb anomalies that relate to the underlying variant. METHODS: Both local and published cases were included for analysis. The presence of individual limb phenotypes was dichotomised and an exploratory LCA was performed. Distribution of phenotypes and genotypes over the classes were explored and subsequently the key predictors of latent class membership were correlated to the different clustered genotypes. RESULTS: 297 cases were identified with 127 different variants in the GLI3 gene. A two-class model was fitted revealing two subgroups of patients with anterior versus posterior anomalies. Posterior anomalies were observed in cases with truncating variants in the activator domain (postaxial polydactyly; hand, OR: 12.7; foot, OR: 33.9). Multivariate analysis supports these results (Beta: 1.467, p=0.013 and Beta: 2.548, p<0.001, respectively). Corpus callosum agenesis was significantly correlated to these variants (OR: 8.8, p<0.001). CONCLUSION: There are two distinct phenotypes within the GLI3-mediated polydactyly population: anteriorly and posteriorly orientated. Variants that likely produce haploinsufficiency are associated with anterior phenotypes. Posterior phenotypes are associated with truncating variants in the activator domain. Patients with these truncating variants have a greater risk for corpus callosum anomalies.

Lateral Versus Medial Hallux Excision in Preaxial Polydactyly of the Foot.

BACKGROUND: In preaxial polydactyly of the foot, the choice for excision of the lateral or medial hallux is not straightforward, in particular with proximal phalangeal (type IV) and metatarsal (type VI) duplication, because of anatomical characteristics. We evaluated whether medial or lateral hallux excision gives better outcomes in these duplication types, to help clinical decision making. METHODS: Children with type IV or type VI duplication (n=14, age: 4.4-17.2 years), who were operatively treated by excision of the lateral or medial hallux, were assessed for foot function using plantar pressure measurements and clinical examination. Foot aesthetics were scored by the child, an expert, and 10 laypersons, and additional patient-reported outcome questionnaires were obtained. Outcomes were compared between lateral and medial excision, per duplication type. RESULTS: In type IV duplication (n=11), lateral excision showed a better distribution of peak pressure between the hallux and first metatarsal with significantly lower median first metatarsal peak pressure (P = .008). Lateral excision showed more medial hallux deviation (P = .017). Foot aesthetics were not different between excision sides. In type VI duplication (n=12), lateral excision showed a 59% higher hallux peak pressure, larger medial hallux deviation (P = .004), and more reoperations. Foot aesthetics were scored significantly better after lateral excision by experts and laypersons. CONCLUSIONS: Foot function by virtue of plantar pressure was better after lateral hallux excision in type IV and after medial hallux excision in type VI duplication. Surgeons and laypersons perceived the foot as more normal after lateral excision in type VI, whereas children reported no differences. These outcomes can be used in clinical decision making. LEVEL OF EVIDENCE: Level III, therapeutic, comparative study.

Variable expression of subclinical phenotypes instead of reduced penetrance in families with mild triphalangeal thumb phenotypes.

BACKGROUND: The of zone of polarizing activity regulatory sequence (ZRS) is a regulatory element residing in intron 5 of LMBR1 and regulates Sonic Hedgehog expression in the limb bud. Variants in the ZRS are generally fully penetrant and can cause triphalangeal thumb (TPT) and polydactyly in affected families. OBJECTIVE: In this report, we describe two families with mild phenotypical presentation. METHODS: We performed a field study for clinical evaluation and sequenced the ZRS for variantsusing Sanger sequencing. RESULTS: In family I, a novel 165A>G variant in the ZRS (g.156584405A>G, GRCh37/Hg19) was found. In family II, we identified a 295T>C variant in the ZRS (g.156584535T>C, GRCh37/Hg19). Family members of both families who were presumed to be unaffected shared the variant in the ZRS with affected family members, suggesting reduced penetrance of the genotype. However, clinical examination of these unaffected family members revealed minor anomalies like broad thumbs and lack of thumb opposition. As the phenotype in affected patients is remarkably mild, we suggest that these ZRS variants are minimally disruptive for Sonic Hedgehog expression and therefore can result in subclinical phenotypes. CONCLUSION: Our study underlines the importance of accurate clinical examination and appropriate genetic counselling in families with mild cases of TPT.

Congenital Forearm Pseudarthrosis, a Systematic Review for a Treatment Algorithm on a Rare Condition.

BACKGROUND: A congenital forearm pseudarthrosis is a rare condition and is strongly associated with neurofibromatosis type 1. Several surgical techniques are described in the literature, but the most optimal treatment strategy remains unclear. This systematic review aims to develop a treatment algorithm that may aid in clinical decision making. METHODS: The PROSPERO registration number for this study was CRD42018099602 and adheres to the PRISMA guidelines for systematic reviews. Embase, MEDLINE, Cochrane Central, Web of Science, and Google Scholar databases were searched for published studies reporting on congenital forearm pseudarthrosis not related to other underlying pathologies like bacterial infection or fibrous dysplasia. Results were not restricted by date or study type, only English literature was allowed. Studies were assessed for quality using the critical appraisal checklist for case reports from the Joanna Briggs Institute. Patient characteristics, underlying disease, type of surgery, union rate, and functional outcome were extracted from included studies. RESULTS: Of 829 studies identified, 47 were included in this review (17 case series and 30 case reports, a total of 84 cases). A one-bone forearm procedure showed highest union rates (92%), however, it results in loss of forearm rotation. Free vascularized fibula grafting showed high union rates (87%) and was related to good functional outcome of elbow flexion and forearm rotations. Other procedures showed disappointing outcomes. CONCLUSIONS: Congenital forearm pseudarthrosis is best treated with a free vascularized fibula grafting, a one-bone forearm procedure should be used as a salvage procedure. Evidence extracted from the case reports was sufficient to generate a treatment algorithm to be used in clinical pediatric practice. LEVEL OF EVIDENCE: Level IV-therapeutic.

Outcome of Recurrent Surgery in Dupuytren's Disease: Comparison with Initial Treatment.

BACKGROUND: There are multiple studies about the effectiveness of primary treatment in Dupuytren's disease. However, such studies concerning treatment effectiveness of recurrent disease are scarce. Therefore, the primary aim of this study was to compare treatment effectiveness of initial and repeated surgery in patients with Dupuytren's disease. METHODS: Patients who underwent both initial and repeated treatment were selected from a prospectively maintained database. Outcome measurements consisted of finger goniometry, the Michigan Hand Outcomes Questionnaire, and complications. Treatment effectiveness was defined as improvement in extension deficit and patient-reported hand function. In addition, measurements at intake of both treatments were compared. Subgroup analyses were performed to evaluate influence of type of surgery of initial treatment on outcomes of repeated treatment. RESULTS: One hundred fourteen patients were included in the analyses. Improvement in extension deficit and Michigan Hand Outcomes Questionnaire outcomes was equal for initial and repeated treatments. Extension deficit and Michigan Hand Outcomes Questionnaire scores were worse at intake of repeated treatment compared to these outcomes at intake of initial treatment. In addition, patients who initially underwent needle fasciotomy achieved a better contracture reduction after repeated treatment. CONCLUSIONS: This study demonstrates that treatment of recurrent Dupuytren's disease is as effective as initial treatment, despite larger extension deficit and worse self-assessed hand function before undergoing repeated treatment. Complication rates were similar for initial and repeated treatments. Furthermore, needle fasciotomy for initial treatment results in better outcomes of repeated treatment compared to patients who initially underwent limited fasciectomy. These findings can be used for a more evidence-based preoperative counseling with patients with recurrent Dupuytren's disease. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Correction: Recurrence of Dupuytren's contracture: A consensus-based definition.

[This corrects the article DOI: 10.1371/journal.pone.0164849.].

A multidisciplinary review of triphalangeal thumb.

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.

Triphalangeal thumb: clinical features and treatment.

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.

Percutaneous Aponeurotomy and Lipofilling versus Limited Fasciectomy for Dupuytren's Contracture: 5-Year Results from a Randomized Clinical Trial.

BACKGROUND: In the Dupuytren Rotterdam randomized controlled trial, percutaneous aponeurotomy with lipofilling (PALF) was as effective as limited fasciectomy in correcting primary Dupuytren's contracture after 1 year. The authors report the 5-year results of this trial, with a special focus on recurrence of contractures. METHODS: The authors invited all patients who had undergone PALF or limited fasciectomy to participate in a posttrial follow-up assessment. Thirty-one PALF patients and 21 limited fasciectomy patients were assessed by an independent examiner for the degree of contracture and whether patients had undergone a secondary procedure. The primary composite endpoint was recurrence rate, defined as either 20 degrees or greater worsening in contracture (relative to week 3) or as having undergone a secondary procedure for a new or worsening contracture. RESULTS: At 5 years, more joints in the PALF group than in the limited fasciectomy group had a recurrence (74 percent versus 39 percent; p = 0.002). When redefining recurrence as a worsening in total extension deficit of at least 30 degrees for treated digits as often reported, this was 77 percent versus 32 percent (p = 0.001). Total extension deficit was also worse for PALF-reated digits (53 degrees versus 31 degrees; p < 0.010). CONCLUSIONS: Although the authors previously reported that PALF offers a shorter convalescence and fewer long-term complications but a similar degree of contracture correction at 1-year follow-up, at 5 years, the corrections were less durable than those for limited fasciectomy. This again highlights that limited fasciectomy and different types of needle aponeurotomy have specific advantages and disadvantages to weigh by patients and clinicians. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

A point mutation in the pre-ZRS disrupts sonic hedgehog expression in the limb bud and results in triphalangeal thumb-polysyndactyly syndrome.

PURPOSE: The zone of polarizing activity regulatory sequence (ZRS) is an enhancer that regulates sonic hedgehog during embryonic limb development. Recently, mutations in a noncoding evolutionary conserved sequence 500 bp upstream of the ZRS, termed the pre-ZRS (pZRS), have been associated with polydactyly in dogs and humans. Here, we report the first case of triphalangeal thumb-polysyndactyly syndrome (TPT-PS) to be associated with mutations in this region and show via mouse enhancer assays how this mutation leads to ectopic expression throughout the developing limb bud. METHODS: We used linkage analysis, whole-exome sequencing, Sanger sequencing, fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, single-nucleotide polymorphism array, and a mouse transgenic enhancer assay. RESULTS: Ten members of a TPT-PS family were included in this study. The mutation was linked to chromosome 7q36 (LOD score 3.0). No aberrations in the ZRS could be identified. A point mutation in the pZRS (chr7:156585476G>C; GRCh37/hg19) was detected in all affected family members. Functional characterization using a mouse transgenic enhancer essay showed extended ectopic expression dispersed throughout the entire limb bud (E11.5). CONCLUSION: Our work describes the first mutation in the pZRS to be associated with TPT-PS and provides functional evidence that this mutation leads to ectopic expression of this enhancer within the developing limb.

Documenting Combined Congenital Upper Limb Anomalies Using the Oberg, Manske, and Tonkin Classification: Implications for Epidemiological Research and Outcome Comparisons.

PURPOSE: Congenital upper limb anomalies (CULAs) exhibit a wide spectrum of phenotypic manifestations. To help the clinician evaluating this variety of CULAs, the Oberg, Manske, and Tonkin (OMT) classification was recently introduced. The OMT classification allows for documentation of combined hand anomalies. However, subsequent epidemiological and validation studies using the OMT scheme commonly registered only the main anomaly per arm. This study illustrates both the deficits of single diagnosis documentation as well as the merits of registering every anomaly for epidemiological research, outcome comparison, and overall applicability of the classification. METHODS: We retrospectively reviewed patients visiting the Erasmus MC - Sophia Children's Hospital between 2012 and 2014. All congenital anomalies of both limbs were classified according to the OMT scheme. The frequency of combined diagnoses as well as recurrent combinations were analyzed. The relation to the coregistered syndromes was studied. RESULTS: We included 746 patients, 79.5% of whom could be documented with a single OMT diagnosis. In 20.5%, a combination of OMT diagnoses was documented. We documented 149 different combinations: 102 were documented once, 47 were documented repeatedly (n = 196); for example, in patients with Greig syndrome. The prevalence of this syndrome was significantly higher in patients with a combination of radial polydactyly, ulnar polydactyly, and/or syndactyly (2.9% vs 33.3% and 60% in patients with 1 vs 2 and 3 diagnoses). CONCLUSIONS: Documentation of combined OMT diagnoses is required in a fifth of the patients. Not doing so will cause loss of phenotypic information and can hamper outcome comparison and epidemiological research. Documentation of combined OMT diagnoses can help to identify subgroups within a population, for example, patients with an underlying syndrome. Last, combined documentation of diagnoses improves flexibility of the classification and thereby better allows universal application. CLINICAL RELEVANCE: Consensus on the application of the OMT classification is critical to achieving the universal adoption of the system by hand surgeons and other medical professionals.

Controversies in Poland Syndrome: Alternative Diagnoses in Patients With Congenital Pectoral Muscle Deficiency.

PURPOSE: Poland syndrome was first described as a deficiency of the pectoral muscle with ipsilateral symbrachydactyly. Currently, numerous case reports describe variations of Poland syndrome in which pectoral muscle deficiency is often used as the only defining criterion. However, more syndromes can present with pectoral muscle deficiency. The aim of this review is to illustrate the diversity of the phenotypic spectrum of Poland syndrome and to create more awareness for alternative diagnoses in pectoral muscle deficiency. METHODS: A systematic literature search was performed. Articles containing phenotypical descriptions of Poland syndrome were included. Data extraction included number of patients, sex, familial occurrence, and the definition of Poland syndrome used. In addition, hand deformities, thoracic deformities, and other deformities in each patient were recorded. Alternative syndrome diagnoses were identified in patients with a combination of hand, thorax, and other deformities. RESULTS: One hundred-and-thirty-six articles were included, describing 627 patients. Ten different definitions of Poland syndrome were utilized. In 58% of the cases, an upper extremity deformity was found and 43% of the cases had an associated deformity. Classic Poland syndrome was seen in 29%. Fifty-seven percent of the patients with a pectoral malformation, a hand malformation, and another deformity had at least 1feature that matched an alternative syndrome. CONCLUSIONS: Pectoral muscle hypoplasia is not distinctive for Poland syndrome alone but is also present in syndromes with other associated anomalies with a recognized genetic cause. Therefore, in patients with an atypical phenotype, we recommend considering other diagnoses and/or syndromes before diagnosing a patient with Poland syndrome. This can prevent diagnostic and prognostic errors. CLINICAL RELEVANCE: Differentiating Poland syndrome from the alternative diagnoses has serious consequences for the patient and their family in terms of inheritance and possible related anomalies.

Preaxial polydactyly of the foot.

Background and purpose - Preaxial polydactyly of the foot is a rare malformation and clinicians are often unfamiliar with the associated malformations and syndromes. In order to give guidelines for diagnostics and referral to a clinical geneticist, we provide an overview of the presentation using a literature review and our own patient population. Patients and methods - The literature review was based on the Human Phenotype Ontology (HPO) project. From the HPO dataset, all phenotypes describing preaxial polydactyly were obtained and related diseases were identified and selected. An overview was generated in a heatmap, in which the phenotypic contribution of 12 anatomical groups to each disease is displayed. Clinical cases were obtained from our hospital database and were reviewed in terms of phenotype, genotype, heredity, and diagnosed syndromes. Results - From the HPO dataset, 21 diseases were related to preaxial polydactyly of the foot. The anatomical groups with the highest phenotypic contribution were lower limb, upper limb, and craniofacial. From our clinical database, we included 76 patients with 9 different diseases, of which 27 had a GLI3 mutation. Lower limb malformations (n = 55), upper limb malformations (n = 59), and craniofacial malformations (n = 32) were most frequently observed. Malformations in other anatomical groups were observed in 27 patients. Interpretation - Preaxial polydactyly of the foot often presents with other upper and lower limb malformations. In patients with isolated preaxial polydactyly of the foot, referral to a clinical geneticist is not mandatory. In patients with additional malformations, consultation with a clinical geneticist is recommended. When additional limb malformations are present, analysis of GLI3 is most feasible.

Intrafamilial variability of the triphalangeal thumb phenotype in a Dutch population: Evidence for phenotypic progression over generations?

Triphalangeal thumbs (TPTs) are regularly caused by mutations in the ZRS in LMBR1. Phenotypic variability can be present in TPT-families. However, recent observations suggest an increased occurrence of severe phenotypes in the Dutch TPT-population. Therefore, the aim of this study is to investigate the progression of the clinical severity of TPT-phenotype through generations. Index patients from a Dutch TPT-population were identified. A 105C>G mutation in the ZRS has previously been confirmed in this population. Questionnaires regarding family occurrence and phenotypes were distributed. Subsequently, families were visited to validate the phenotype. Both occurrence and inheritance patterns of the TPT-phenotype were analyzed through multiple generations. One hundred seventy patients with TPT were identified from 11 families. When considering all 132 segregations (parent-to-child transmission), 54% of the segregations produced a stable phenotype, 38% produced a more severe phenotype while only 8% of the phenotype was less severe when compared to the affected parents. Overall, 71% of the index patients had a more severe phenotype compared to their great-grandparent. Although all family members share an identical mutation in the ZRS (105C>G), it does not explain the wide phenotypic range of anomalies. Our observational study provides better estimations for counseling and provides new insights in the long-range regulation of SHH by the ZRS-enhancer. In the current study, we provide evidence that the assumed variability in TPT-phenotype is not random, but in fact it is more likely that the expression becomes more severe in the next generation. Therefore, we observe a pattern that resembles phenotypic anticipation in TPT-families.

Identification of Associated Genes and Diseases in Patients With Congenital Upper-Limb Anomalies: A Novel Application of the OMT Classification.

PURPOSE: Congenital upper-limb anomalies (CULA) can present as a part of a syndrome or association. There is a wide spectrum of CULA, each of which might be related to different diseases. The structure provided by the Oberg, Manske, and Tonkin (OMT) classification could aid in differential diagnosis formulation in patients with CULA. The aims of this study were to review the Human Phenotype Ontology (HPO) project database for diseases and causative genes related to the CULA described in the OMT classification and to develop a methodology for differential diagnosis formulation based on the observed congenital anomalies, CulaPhen. METHODS: We reviewed the HPO database for all diseases, including causative genes related to CULA. All CULA were classified according to the OMT classification; associated non-hand phenotypes were classified into 12 anatomical groups. We analyzed the contribution of each anatomical group to a given disease and developed a tool for differential diagnosis formulation based on these contributions. We compared our results with cases from the literature and with a current HPO tool, Phenomizer. RESULTS: In total, 514 hand phenotypes were obtained, 384 of which could be classified in the OMT classification. A total of 1,403 diseases could be related to those CULA. A comparison with 10 recently published cases with CULA revealed that the presented phenotype matched the descriptions in our dataset. The differential diagnosis produced using our methodology was more accurate than Phenomizer in 4 of 5 examples. CONCLUSIONS: The OMT classification can be used to describe hand anomalies that may present in over 1,400 diseases. CulaPhen was developed to provide a (hand) phenotype-based differential diagnosis. Differential diagnosis formulation based on the proposed system outperforms the system in current use. CLINICAL RELEVANCE: This study illustrates that the OMT diagnoses, either individually or combined, can be cross-referenced with different diseases and syndromes. Therefore, use of the OMT classification can aid differential diagnosis formulation for CULA patients.