Quality of life in children with preaxial polydactyly of the foot in comparison to adults, postaxial polydactyly and healthy controls.

The effect of preaxial polydactyly of the foot on health-related quality of life (HR-QoL) has not been investigated in current literature. To improve counseling, we investigated HR-QoL in this patient group. A patient-control study was performed with children with preaxial polydactyly ( n = 20), adults with preaxial polydactyly ( n = 15), children with postaxial polydactyly ( n = 15) and healthy controls ( n = 62). The primary outcome was the difference in the foot-specific quality of life (FS-QoL) between children with preaxial polydactyly and adults with preaxial polydactyly, children with postaxial polydactyly and controls, using the Oxford Ankle and Foot Questionnaire (OxAFQ-c) and five foot-specific visual analogue scales (VAS). The secondary outcome was the difference in general HR-QoL, using the Pediatric Quality of Life Inventory (PedsQL). Outcomes were compared with the Mann-Whitney-U test. Comparison between children with preaxial polydactyly and healthy controls and postaxial polydactyly showed worse outcomes in all OxAFQ-c domains. The foot-specific VAS score was significantly worse in children with preaxial polydactyly compared to postaxial polydactyly and controls. Only the PedsQL physical domain showed a lower outcome in children with preaxial polydactyly than in postaxial polydactyly and controls. Children and adults with preaxial polydactyly scored the same in all domains. The OxAFQ-c and the PedsQL physical domain showed significantly worse outcomes in children with preaxial polydactyly compared with healthy controls and postaxial polydactyly. However, large variation was observed, suggesting large differences between patients. In children and adults, the foot and scar appearance seems to be the biggest problem, while diminished foot function seems less of an issue.

IFN-γ mediates Paneth cell death via suppression of mTOR.

Paneth cells constitutively produce antimicrobial peptides and growth factors that allow for intestinal homeostasis, host protection, and intestinal stem cell replication. Paneth cells rely heavily on the glycolytic metabolic program, which is in part controlled by the kinase complex Mechanistic target of rapamycin (mTORC1). Yet, little is known about mTOR importance in Paneth cell integrity under steady-state and inflammatory conditions. Our results demonstrate that IFN-γ, a crucial mediator of the intestinal inflammation, acts directly on murine Paneth cells to alter their mitochondrial integrity and membrane potential, resulting in an TORC1-dependent cell death mechanism distinct from canonical cell death pathways including apoptosis, necroptosis, and pyroptosis. These results were established with the purified cytokine and a physiologically relevant common Th1-inducing human parasite Toxoplasma gondii. Given the crucial role for IFN-γ, which is a cytokine frequently associated with the development of inflammatory bowel disease and compromised Paneth cell functions, the identified mechanisms underlying mTORC1-dependent Paneth cell death downstream of IFN-γ may provide promising novel approaches for treating intestinal inflammation.

T-bet-dependent ILC1- and NK cell-derived IFN-γ mediates cDC1-dependent host resistance against Toxoplasma gondii.

Host resistance against intracellular pathogens requires a rapid IFN-γ mediated immune response. We reveal that T-bet-dependent production of IFN-γ is essential for the maintenance of inflammatory DCs at the site of infection with a common protozoan parasite, Toxoplasma gondii. A detailed analysis of the cellular sources for T-bet-dependent IFN-γ identified that ILC1s and to a lesser degree NK, but not TH1 cells, were involved in the regulation of inflammatory DCs via IFN-γ. Mechanistically, we established that T-bet dependent innate IFN-γ is critical for the induction of IRF8, an essential transcription factor for cDC1s. Failure to upregulate IRF8 in DCs resulted in acute susceptibility to T. gondii infection. Our data identifies that T-bet dependent production of IFN-γ by ILC1 and NK cells is indispensable for host resistance against intracellular infection via maintaining IRF8+ inflammatory DCs at the site of infection.

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.

The Dutch version of the Oxford Ankle and Foot Questionnaire for Children: Useful for evaluation of pediatric foot problems in groups.

BACKGROUND: The purpose of this study is to develop a Dutch version of the Oxford Ankle and Foot Questionnaire for Children (OxAFQ-c) to allow evaluation of pediatric foot care. METHODS: The OxAFQ-c was translated into Dutch, according to the ISPOR-guidelines. Children with different foot and ankle complaints completed the OxAFQ-c at baseline, after two weeks, and after 4-6 months. Measurement properties were assessed in terms of reliability, responsiveness, and construct validity. RESULTS: Test-retest reliability showed moderate intraclass correlation coefficients. Bland-Altman plots showed wide limits of agreement. After 4-6 months, the group that experienced improvement also showed improved questionnaire outcomes, indicating responsiveness. Moderate correlation between the OxAFQ-c and the Kidscreen and foot-specific VAS-scores were observed, indicating moderate construct validity. CONCLUSIONS: The Dutch OxAFQ-c showed moderate to good measurement properties. However, because we observed limited sensitivity to changes and wide limits of agreement in individual patients, we think the questionnaire should only be used in groups.

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.

Loss of Paneth Cell Autophagy Causes Acute Susceptibility to Toxoplasma gondii-Mediated Inflammation.

The protozoan parasite Toxoplasma gondii triggers severe small intestinal immunopathology characterized by IFN-γ- and intestinal microbiota-mediated inflammation, Paneth cell loss, and bacterial dysbiosis. Paneth cells are a prominent secretory epithelial cell type that resides at the base of intestinal crypts and releases antimicrobial peptides. We demonstrate that the microbiota triggers basal Paneth cell-specific autophagy via induction of IFN-γ, a known trigger of autophagy, to maintain intestinal homeostasis. Deletion of the autophagy protein Atg5 specifically in Paneth cells results in exaggerated intestinal inflammation characterized by complete destruction of the intestinal crypts resembling that seen in pan-epithelial Atg5-deficient mice. Additionally, lack of functional autophagy in Paneth cells within intestinal organoids and T. gondii-infected mice causes increased sensitivity to the proinflammatory cytokine TNF along with increased intestinal permeability, leading to exaggerated microbiota- and IFN-γ-dependent intestinal immunopathology. Thus, Atg5 expression in Paneth cells is essential for tissue protection against cytokine-mediated immunopathology during acute gastrointestinal infection.

T-bet-independent Th1 response induces intestinal immunopathology during Toxoplasma gondii infection.

Coordinated production of IFN-γ by innate and adaptive immune cells is central for host defense, but can also trigger immunopathology. The investigation of the lymphoid cell-specific contribution to the IFN-γ-mediated intestinal pathology during Toxoplasma gondii infection identified CD4+ T cells as a key cell population responsible for IFN-γ-dependent intestinal inflammation and Paneth cell loss, where T-bet-dependent group 1 innate lymphoid cells have a minor role in driving the parasite-induced immunopathology. This was evident from the analysis of T-bet deficiency that did not prevent the intestinal inflammation and instead revealed that T-bet-deficient CD4+ Th1 cells are sufficient for T. gondii-triggered acute ileitis and Paneth cell loss. These results revealed that T-bet-independent Th1 effector cells are major functional mediators of the type I immunopathological response during acute gastrointestinal infection.

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.

The Rotterdam Foot Classification: A Classification System for Medial Polydactyly of the Foot.

BACKGROUND: Polydactyly at the medial side of the foot ("medial polydactyly" of the foot) is a rare and diverse congenital anomaly. In order to plan and evaluate surgical treatment, the classification of medial polydactyly is useful. The aim of our study was to develop a reliable and valid classification system for medial polydactyly of the foot that is more useful than previous systems for preoperative evaluation and surgical planning. METHODS: A review of the literature and the clinical experience of a single experienced surgeon were used to determine classification categories. We identified all patients with medial polydactyly who had preoperative radiographs and clinical photographs and were treated at our hospital between 1993 and 2014. All affected feet were assessed according to our proposed classification system, the Rotterdam foot classification. The intrarater and interrater reliability among 5 observers who evaluated 30 feet were assessed with use of the Cohen kappa (κ) statistic. RESULTS: We developed a classification system that describes duplication type, syndactyly, the presence of a hypoplastic ray, and deviation of the hallux. Seventy-three feet were classified according to the system. Seven duplication types were distinguished. Complete metatarsal duplication was most frequently seen (in 29%). Twelve feet showed a broad hallux without external expression of duplication. Syndactyly between medial and lateral (duplicate) halluces was present in 30 feet; between the lateral hallux and second toe, in 13 feet; and between both duplicated halluces and the lateral hallux and second toe, in 21 feet. A hypoplastic ray was seen in 75% of the feet. Intrarater agreement for duplication, hypoplastic rays, syndactyly, and deviation were, respectively, κ = 0.79, 0.75, 0.59, and 0.78. Interrater agreement for duplication, hypoplastic rays, syndactyly, and deviation were, respectively, κ = 0.72, 0.54, 0.48, and 0.64. CONCLUSIONS: The proposed classification system contains 4 categories of anatomic features of the foot. Classification of all categories shows moderate to good reliability. Use of the Rotterdam classification in evaluating medial polydactyly improves type-specific description, which may, in the future, enhance the evaluation of surgical treatment. CLINICAL RELEVANCE: The Rotterdam foot classification system is a reliable and easy-to-use system that we believe will improve communication between clinicians and researchers and facilitate the evaluation of treatment results in medial polydactyly of the foot.

Cutting Edge: Developmental Regulation of IFN-γ Production by Mouse Neutrophil Precursor Cells.

Neutrophils are an emerging cellular source of IFN-γ, a key cytokine that mediates host defense to intracellular pathogens. Production of IFN-γ by neutrophils, in contrast to lymphoid cells, is TLR- and IL-12-independent and the events associated with IFN-γ production by neutrophils are not understood. In this study, we show that mouse neutrophils express IFN-γ during their lineage development in the bone marrow niche at the promyelocyte stage independently of microbes. IFN-γ accumulates in primary neutrophilic granules and is released upon induction of degranulation. The developmental mechanism of IFN-γ production in neutrophils arms the innate immune cells prior to infection and assures the potential for rapid release of IFN-γ upon neutrophil activation, the first step during responses to many microbial infections.