Ulnar dimelia - a review of 24 cases.

Ulnar dimelia is a very rare unilateral congenital upper limb anomaly (CULA) affecting the whole extremity. Treatment remains difficult because of the complexity and multi-level involvement. Twenty-four cases with duplicated ulna, absent radius and polydactyly from seven European centres were reviewed according to a structured list of parameters. At first consultation, median age 8 months (1-178), the shoulder movement was good in 17 patients or poor in six, and the median passive elbow range of motion was 20° (0°-90°). The resting wrist position was flexed in 22/24 patients. Following stretching and splinting, elbow surgery included resection of the lateral proximal ulna in 11 patients and muscle transfers in six to improve passive movement and increase active elbow motion, respectively. Tendon transfers were performed in eight wrists and a pollicization or pseudo-pollicization in 23 patients. Overall, patients demonstrate acceptable function postoperatively. Guidelines for treatment of this severe CULA are presented.Level of evidence: IV.

State of the art review: The pathogenesis and management of Madelung deformity.

Madelung deformity remains a fascinating yet unresolved challenge. There is an increasing awareness for early diagnosis by healthcare providers with improvement in diagnostic modalities, however, the exact mechanisms for the development of the deformity have still to be clarified. While some corrective procedures have been described to effectively address an established deformity, the existing literature lacks clear and evidence-based treatment guidelines on how to proceed in daily practice. This review article aims to summarize the current best evidence on this topic, including particular areas of controversy and areas with need for future research.

HOXD13-associated synpolydactyly: Extending and validating the genotypic and phenotypic spectrum with 38 new and 49 published families.

PURPOSE: HOXD13 is an important regulator of limb development. Pathogenic variants in HOXD13 cause synpolydactyly type 1 (SPD1). How different types and positions of HOXD13 variants contribute to genotype-phenotype correlations, penetrance, and expressivity of SPD1 remains elusive. Here, we present a novel cohort and a literature review to elucidate HOXD13 phenotype-genotype correlations. METHODS: Patients with limb anomalies suggestive of SPD1 were selected for analysis of HOXD13 by Sanger sequencing, repeat length analysis, and next-generation sequencing. Literature was reviewed for HOXD13 heterozygotes. Variants were annotated for phenotypic data. Severity was calculated, and cluster and decision-tree analyses were performed. RESULTS: We identified 98 affected members of 38 families featuring 11 different (likely) causative variants and 4 variants of uncertain significance. The most frequent (25/38) were alanine repeat expansions. Phenotypes ranged from unaffected heterozygotes to severe osseous synpolydactyly, with intra- and inter-familial heterogeneity and asymmetry. A literature review provided 160 evaluable affected members of 49 families with SPD1. Computer-aided analysis only corroborated a positive correlation between alanine repeat length and phenotype severity. CONCLUSION: Our findings support that HOXD13-protein condensation in addition to haploinsufficiency is the molecular pathomechanism of SPD1. Our data may, also, facilitate the interpretation of synpolydactyly radiographs by future automated tools.

Aberrant phase separation and nucleolar dysfunction in rare genetic diseases.

Thousands of genetic variants in protein-coding genes have been linked to disease. However, the functional impact of most variants is unknown as they occur within intrinsically disordered protein regions that have poorly defined functions1-3. Intrinsically disordered regions can mediate phase separation and the formation of biomolecular condensates, such as the nucleolus4,5. This suggests that mutations in disordered proteins may alter condensate properties and function6-8. Here we show that a subset of disease-associated variants in disordered regions alter phase separation, cause mispartitioning into the nucleolus and disrupt nucleolar function. We discover de novo frameshift variants in HMGB1 that cause brachyphalangy, polydactyly and tibial aplasia syndrome, a rare complex malformation syndrome. The frameshifts replace the intrinsically disordered acidic tail of HMGB1 with an arginine-rich basic tail. The mutant tail alters HMGB1 phase separation, enhances its partitioning into the nucleolus and causes nucleolar dysfunction. We built a catalogue of more than 200,000 variants in disordered carboxy-terminal tails and identified more than 600 frameshifts that create arginine-rich basic tails in transcription factors and other proteins. For 12 out of the 13 disease-associated variants tested, the mutation enhanced partitioning into the nucleolus, and several variants altered rRNA biogenesis. These data identify the cause of a rare complex syndrome and suggest that a large number of genetic variants may dysregulate nucleoli and other biomolecular condensates in humans.

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.

Inter- and intra-rater reliability of the Oberg-Manske-Tonkin classification of congenital upper limb anomalies.

On two occasions, five surgeons classified a cohort of 150 consecutive patients with congenital upper limb anomalies according to the Oberg-Manske-Tonkin classification (2020 update). We estimated reliability for the main anomaly code by means of Cohen's kappa (Κ) for ten rater pairs for five common and easily distinguishable anomalies (Group 1), and for all the other anomalies (Group 2). Inter-rater reliability for all patients (n = 150) was substantial, almost perfect for Group 1 (n = 64), but only moderate for Group 2 (n = 86). Intra-rater reliability was higher for all groups. We suggest simplifications to the Oberg-Manske-Tonkin classification and highlight specific requirements for instructions to increase its reliability.Level of evidence: I.

[Differential therapeutic Approaches in congenital Malformations of the Hand]. / Differentialtherapeutische Zugänge bei kongenitalen Fehlbildungen an der Hand.

With the same clinical picture, different pathological changes must be expected in congenital malformations of the hand. Therefore, knowledge of these pathologies is crucial for planning the surgical approach. The approaches to common malformations are dealt with as examples. These include the double thumb and the syndactyly.In the case of the double thumb with an asymmetrical contour, the result is improved by augmenting parts of the redundant double thumb. In this case, a different incision is required than in simple resection.In the frequently performed syndactyly separations, there are many techniques that have been proven to achieve a good result. But only if principles such as local displacement flap plasty for commissure formation, tension-free wound closure, no longitudinal incisions and no bilateral preparation of a finger are observed here too. If it can be assumed preoperatively that a good surgical result cannot be achieved with the conventional technique of syndactyly separation, pre-treatment using an external fixator for transverse soft tissue distraction is the method of choice.The timing of surgery takes into account not to disturb the motor development of the affected person.

GLI3 variants causing isolated polysyndactyly are not restricted to the protein's C-terminal third.

Loss of function variants of GLI3 are associated with a variety of forms of polysyndactyly: Pallister-Hall syndrome (PHS), Greig-Cephalopolysyndactyly syndrome (GCPS), and isolated polysyndactyly (IPD). Variants affecting the N-terminal and C-terminal thirds of the GLI3 protein have been associated with GCPS, those within the central third with PHS. Cases of IPD have been attributed to variants affecting the C-terminal third of the GLI3 protein. In this study, we further investigate these genotype-phenotype correlations. Sequencing of GLI3 was performed in patients with clinical findings suggestive of a GLI3-associated syndrome. Additionally, we searched the literature for reported cases of either manifestation with mutations in the GLI3 gene. Here, we report 48 novel cases from 16 families with polysyndactyly in whom we found causative variants in GLI3 and a review on 314 previously reported GLI3 variants. No differences in location of variants causing either GCPS or IPD were found. Review of published data confirmed the association of PHS and variants affecting the GLI3 protein's central third. We conclude that the observed manifestations of GLI3 variants as GCPS or IPD display different phenotypic severities of the same disorder and propose a binary division of GLI3-associated disorders in either PHS or GCPS/polysyndactyly.

Genome sequencing in families with congenital limb malformations.

The extensive clinical and genetic heterogeneity of congenital limb malformation calls for comprehensive genome-wide analysis of genetic variation. Genome sequencing (GS) has the potential to identify all genetic variants. Here we aim to determine the diagnostic potential of GS as a comprehensive one-test-for-all strategy in a cohort of undiagnosed patients with congenital limb malformations. We collected 69 cases (64 trios, 1 duo, 5 singletons) with congenital limb malformations with no molecular diagnosis after standard clinical genetic testing and performed genome sequencing. We also developed a framework to identify potential noncoding pathogenic variants. We identified likely pathogenic/disease-associated variants in 12 cases (17.4%) including four in known disease genes, and one repeat expansion in HOXD13. In three unrelated cases with ectrodactyly, we identified likely pathogenic variants in UBA2, establishing it as a novel disease gene. In addition, we found two complex structural variants (3%). We also identified likely causative variants in three novel high confidence candidate genes. We were not able to identify any noncoding variants. GS is a powerful strategy to identify all types of genomic variants associated with congenital limb malformation, including repeat expansions and complex structural variants missed by standard diagnostic approaches. In this cohort, no causative noncoding SNVs could be identified.

Severe congenital contractural arachnodactyly caused by biallelic pathogenic variants in FBN2.

Fibrillin-2, encoded by FBN2, plays an important role in the early process of elastic fiber assembly. To date, heterozygous pathogenic variants in FBN2 have been shown to cause congenital contractural arachnodactyly (CCA; Beals-Hecht syndrome). Classical CCA is characterized by long and slender fingers and toes, ear deformities, joint contractures at birth, clubfeet, muscular hypoplasia and often tall stature. In individuals with a severe CCA form, different cardiovascular or gastrointestinal anomalies have been described. Here, we report on a 15-year-old girl with a severe form of CCA and novel biallelic variants in FBN2. The girl inherited the missense variant c.3563G > T/p.(Gly1188Val) from her unaffected father and the nonsense variant c.6831C > A/p.(Cys2277*) from her healthy mother. We could detect only a small amount of FBN2 transcripts harboring the nonsense variant in leukocyte-derived mRNA from the patient and mother suggesting nonsense-mediated mRNA decay. As the father did not show any clinical signs of CCA we hypothesize the missense variant c.3563G > T to be a hypomorphic allele. Taken together, our data suggests that severe CCA can be inherited in an autosomal-recessive manner by compound heterozygosity of a hypomorphic and a null allele of the FBN2 gene.

Variable pulmonary manifestations in Chitayat syndrome: Six additional affected individuals.

Hand hyperphalangism leading to shortened index fingers with ulnar deviation, hallux valgus, mild facial dysmorphism and respiratory compromise requiring assisted ventilation are the key features of Chitayat syndrome. This condition results from the recurrent heterozygous missense variant NM_006494.2:c.266A>G; p.(Tyr89Cys) in ERF on chromosome 19q13.2, encoding the ETS2 repressor factor (ERF) protein. The pathomechanism of Chitayat syndrome is unknown. To date, seven individuals with Chitayat syndrome and the recurrent pathogenic ERF variant have been reported in the literature. Here, we describe six additional individuals, among them only one presenting with a history of assisted ventilation, and the remaining presenting with variable pulmonary phenotypes, including one individual without any obvious pulmonary manifestations. Our findings widen the phenotype spectrum caused by the recurrent pathogenic variant in ERF, underline Chitayat syndrome as a cause of isolated skeletal malformations and therefore contribute to the improvement of diagnostic strategies in individuals with hand hyperphalangism.

Hi-C Identifies Complex Genomic Rearrangements and TAD-Shuffling in Developmental Diseases.

Genome-wide analysis methods, such as array comparative genomic hybridization (CGH) and whole-genome sequencing (WGS), have greatly advanced the identification of structural variants (SVs) in the human genome. However, even with standard high-throughput sequencing techniques, complex rearrangements with multiple breakpoints are often difficult to resolve, and predicting their effects on gene expression and phenotype remains a challenge. Here, we address these problems by using high-throughput chromosome conformation capture (Hi-C) generated from cultured cells of nine individuals with developmental disorders (DDs). Three individuals had previously been identified as harboring duplications at the SOX9 locus and six had been identified with translocations. Hi-C resolved the positions of the duplications and was instructive in interpreting their distinct pathogenic effects, including the formation of new topologically associating domains (neo-TADs). Hi-C was very sensitive in detecting translocations, and it revealed previously unrecognized complex rearrangements at the breakpoints. In several cases, we observed the formation of fused-TADs promoting ectopic enhancer-promoter interactions that were likely to be involved in the disease pathology. In summary, we show that Hi-C is a sensible method for the detection of complex SVs in a clinical setting. The results help interpret the possible pathogenic effects of the SVs in individuals with DDs.

[The interdisciplinary Microsurgeon - Results of the Consensus Workshop of the German Speaking Society for Microsurgery of Peripheral Nerves and Vessels]. / Der interdisziplinäre Mikrochirurg ­ Ergebnisse des Konsensus-Workshops der Deutschsprachigen Arbeitsgemeinschaft für Mikrochirurgie der peripheren Nerven und Gefäße am Beispiel unterschiedlicher Board-Formate.

Plastic and reconstructive surgery is characterized by a high degree of interdisciplinarity. Although Plastic surgery offers a wide range of reliable surgical treatment options independent departments for plastic and reconstructive surgery are not present in every university clinic or leading hospital in Germany. However, the ongoing improvements especially in the field of reconstructive microsurgery enabled and enhanced the treatment of complex defects in order to restore function as well as cosmetic outcome. Knowing the fact that patients are usually referred from other medical disciplines that are familiar with the development and treatment of the primary disease, creation of an interdisciplinary reconstructive treatment plan is crucial to guarantee best patient care. Thus, one of the future major challenges in plastic surgery will be the establishment of multidisciplinary boards in order to strengthen the role of plastic surgery within the medical system with the overall aim to solve complex reconstructive cases. During the 39th annual meeting of the German Speaking Society for Microsurgery of Peripheral Nerves and Vessels a workshop titled "The interdisciplinary microsurgeon" addressed this topic. In the present article we will highlight the consented results of the workshop and provide pitfalls and pearls concerning the implementation process of different multidisciplinary boards based on representative examples.

Noncoding copy-number variations are associated with congenital limb malformation.

PurposeCopy-number variants (CNVs) are generally interpreted by linking the effects of gene dosage with phenotypes. The clinical interpretation of noncoding CNVs remains challenging. We investigated the percentage of disease-associated CNVs in patients with congenital limb malformations that affect noncoding cis-regulatory sequences versus genes sensitive to gene dosage effects.MethodsWe applied high-resolution copy-number analysis to 340 unrelated individuals with isolated limb malformation. To investigate novel candidate CNVs, we re-engineered human CNVs in mice using clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing.ResultsOf the individuals studied, 10% harbored CNVs segregating with the phenotype in the affected families. We identified 31 CNVs previously associated with congenital limb malformations and four novel candidate CNVs. Most of the disease-associated CNVs (57%) affected the noncoding cis-regulatory genome, while only 43% included a known disease gene and were likely to result from gene dosage effects. In transgenic mice harboring four novel candidate CNVs, we observed altered gene expression in all cases, indicating that the CNVs had a regulatory effect either by changing the enhancer dosage or altering the topological associating domain architecture of the genome.ConclusionOur findings suggest that CNVs affecting noncoding regulatory elements are a major cause of congenital limb malformations.

A Matched Comparative Study of the Bilhaut Procedure Versus Resection and Reconstruction for Treatment of Radial Polydactyly Types II and IV.

PURPOSE: To compare outcomes of the Bilhaut procedure with outcomes of conventional resection and reconstruction in radial polydactyly types II and IV. METHODS: Patients treated with the Bilhaut procedure were radiologically matched with patients treated with reconstruction. Evaluated outcomes included the Rotterdam assessment system, pinch strength, and thumb size measurements. To determine objectively which aesthetic outcome scores truly depended on surgical technique rather than observer opinion, we analyzed evaluations by a panel of 22 individuals with varying clinical experience who were blinded to the study protocol, using a linear mixed regression model. RESULTS: The Bilhaut procedure reduced the risk of suboptimal outcome for metacarpophalangeal joint instability in type IV radial polydactyly. Conversely, the Bilhaut procedure increased the risk of suboptimal scar appearance, residual prominence at amputation site, thumb size, and nail appearance. Tip pinch strength was more significantly reduced after the Bilhaut compared with reconstruction, whereas pulp circumference and nail width exceeded 100% of the unaffected contralateral hand after the Bilhaut reconstruction. There was no significant difference in active range of motion between procedures. Nail appearance proved the only aesthetic drawback of the Bilhaut procedure after adjustment for clinical experience. CONCLUSIONS: There was superior metacarpophalangeal joint stability after the Bilhaut procedure for radial polydactyly type IV, but this did not result in the presumed benefit to thumb strength. For experienced surgeons, both procedures resulted in comparable thumb active range of motion. However, aesthetic results were more likely perceived as pleasing after conventional reconstruction, even after adjusting for observer experience with regard to nail appearance. Despite possible benefits of modified Bilhaut procedures that preserve the nail, conventional reconstruction is the preferred procedure until otherwise proven. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III.