Preaxial polydactyly of the foot: Clinical and genetic implications for the orthopedic practice based on a literature review and 76 patients

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 a

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

The Observed Effect of Gastric Bypass Surgery on Direct-acting Antiviral Treatment: a Case Report.

Chronic hepatitis C virus (HCV) infection can be cured with treatment using direct-acting antivirals (DAAs). Although these drugs have been widely studied, information about certain special populations is missing. In this case report we describe a treatment-experienced patient with chronic HCV infection genotype 1b, treated with 150 mg/day simeprevir, 400 mg/day sofosbuvir, and 1,000 mg/ day ribavirin for 24 weeks, after a Roux-and-Y gastric bypass. At steady-state a pharmacokinetic curve was recorded of sofosbuvir, GS-331007, and simeprevir. Ribavirin trough plasma concentration (Ctrough) was determined. The simeprevir area under the-concentration time curve (AUClast) and Ctrough were 9.42 h.mg/L and 0.046 mg/L, respectively. Compared to what was described in the literature, simeprevir exposure was low and therefore the simeprevir dose was increased to 300 mg/day. The increased dose of simeprevir was well tolerated and Ctrough was 0.532 mg/L. Sofosbuvir AUClast and Ctrough were 0.63 h.mg/L and 0.0013 mg/L. GS-331007 AUClast and Ctrough were 21.02 h.mg/L and 0.35 mg/L. Ribavirin Ctrough was 2.5 mg/L. Sofosbuvir, GS-331007, and ribavirin exposure were comparable with levels described in literature. The patient achieved a sustained virological response twelve weeks after the completion of treatment

Foot Function in Patients With Surgically Treated Preaxial Polydactyly of the Foot Compared With Age- and Sex-Matched Healthy Controls

Background: Treatment of preaxial foot polydactyly, a duplication of the first ray, consists of excision of an extra ray, aiming to improve shoe fitting and aesthetic appearance, while maintaining foot function. Currently, the effect of excision on foot function and foot-related patient experiences is unclear. Methods: A cross-sectional comparison between 37 children treated for preaxial foot polydactyly and 37 age- and sex-matched healthy controls was performed. Dynamic foot function was assessed using plantar pressure measurements and static foot characteristics by physical examination. Patient-reported outcomes for foot function and footwear were evaluated, using the Oxford Ankle Foot Questionnaire for Children (score, 0-100). Results: Compared with controls, patients had significantly lower median peak pressures at the hallux (148 kPa [IQR, 98-245] vs 272 kPa [IQR, 205-381], P <.001) and significantly higher peak pressures at the second metatarsal (217 kPa [IQR, 147-338] vs 166 kPa [IQR, 141-235], P =.002) and third to fifth metatarsals (214 kPa [IQR, 147-290] vs 161 kPa [IQR, 135-235], P <.001). Additionally, patients had a more medially deviated hallux, both while seated (15 degrees (IQR, 11-20) vs 12 degrees [IQR, 10-15], P =.001) and standing (20 degrees [IQR, 15-26] vs 18 degrees [IQR, 15-20], P =.001). No significant correlation between peak pressure distribution and hallux deviation was found. Patients reported minimal problems with foot function (87.5 [IQR, 64.6-100]), but distinct problems with footwear use (50.0 [IQR, 25.0-100]). Conclusion: Patients with surgically treated preaxial foot polydactyly had a substantially altered plantar pressure distribution with more lateral foot progression than healthy controls. Although an increased hallux deviation was not related to altered foot function, it seemed to be the reason for the patient-perceived problems with footwear. Level of Evidence: Level III, comparative series

Preaxial polydactyly of the foot: Clinical and genetic implications for the orthopedic practice based on a literature review and 76 patients

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

CD47 Agonist Peptides Induce Programmed Cell Death in Refractory Chronic Lymphocytic Leukemia B Cells via PLCγ1 Activation: Evidence from Mice and Humans

International audienceBackgroundChronic lymphocytic leukemia (CLL), the most common adulthood leukemia, is characterized by the accumulation of abnormal CD5+ B lymphocytes, which results in a progressive failure of the immune system. Despite intense research efforts, drug resistance remains a major cause of treatment failure in CLL, particularly in patients with dysfunctional TP53. The objective of our work was to identify potential approaches that might overcome CLL drug refractoriness by examining the pro-apoptotic potential of targeting the cell surface receptor CD47 with serum-stable agonist peptides.Methods and FindingsIn peripheral blood samples collected from 80 patients with CLL with positive and adverse prognostic features, we performed in vitro genetic and molecular analyses that demonstrate that the targeting of CD47 with peptides derived from the C-terminal domain of thrombospondin-1 efficiently kills the malignant CLL B cells, including those from high-risk individuals with a dysfunctional TP53 gene, while sparing the normal T and B lymphocytes from the CLL patients. Further studies reveal that the differential response of normal B lymphocytes, collected from 20 healthy donors, and leukemic B cells to CD47 peptide targeting results from the sustained activation in CLL B cells of phospholipase C gamma-1 (PLCγ1), a protein that is significantly over-expressed in CLL. Once phosphorylated at tyrosine 783, PLCγ1 enables a Ca2+-mediated, caspase-independent programmed cell death (PCD) pathway that is not down-modulated by the lymphocyte microenvironment. Accordingly, down-regulation of PLCγ1 or pharmacological inhibition of PLCγ1 phosphorylation abolishes CD47-mediated killing. Additionally, in a CLL-xenograft model developed in NOD/scid gamma mice, we demonstrate that the injection of CD47 agonist peptides reduces tumor burden without inducing anemia or toxicity in blood, liver, or kidney. The limitations of our study are mainly linked to the affinity of the peptides targeting CD47, which might be improved to reach the standard requirements in drug development, and the lack of a CLL animal model that fully mimics the human disease.ConclusionsOur work provides substantial progress in (i) the development of serum-stable CD47 agonist peptides that are highly effective at inducing PCD in CLL, (ii) the understanding of the molecular events regulating a novel PCD pathway that overcomes CLL apoptotic avoidance, (iii) the identification of PLCγ1 as an over-expressed protein in CLL B cells, and (iv) the description of a novel peptide-based strategy against CLL