PHF6 cooperates with SWI/SNF complexes to facilitate transcriptional progression.

Genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are mutated in nearly 25% of cancers. To gain insight into the mechanisms by which SWI/SNF mutations drive cancer, we contributed ten rhabdoid tumor (RT) cell lines mutant for SWI/SNF subunit SMARCB1 to a genome-scale CRISPR-Cas9 depletion screen performed across 896 cell lines. We identify PHF6 as specifically essential for RT cell survival and demonstrate that dependency on Phf6 extends to Smarcb1-deficient cancers in vivo. As mutations in either SWI/SNF or PHF6 can cause the neurodevelopmental disorder Coffin-Siris syndrome, our findings of a dependency suggest a previously unrecognized functional link. We demonstrate that PHF6 co-localizes with SWI/SNF complexes at promoters, where it is essential for maintenance of an active chromatin state. We show that in the absence of SMARCB1, PHF6 loss disrupts the recruitment and stability of residual SWI/SNF complex members, collectively resulting in the loss of active chromatin at promoters and stalling of RNA Polymerase II progression. Our work establishes a mechanistic basis for the shared syndromic features of SWI/SNF and PHF6 mutations in CSS and the basis for selective dependency on PHF6 in SMARCB1-mutant cancers.

Pediatric Foot: Development, Variants, and Related Pathology.

Pediatric foot development throughout childhood and adolescence can present a diagnostic dilemma for radiologists because imaging appearances may be confused with pathology. Understanding pediatric foot development and anatomical variants, such as accessory ossification centers, is essential to interpret musculoskeletal imaging in children correctly, particularly because many of these variants are incidental but others can be symptomatic. We first briefly review foot embryology. After describing common accessory ossification centers of the foot, we explain the different patterns of foot maturation with attention to irregular ossification and bone marrow development. Common pediatric foot variants and pathology are described, such as tarsal coalitions and fifth metatarsal base fractures. We also discuss pediatric foot alignment and various childhood foot alignment deformities.

Minimally Invasive Method for Treatment of Syndromic Congenital Vertical Talus Deformity in Children.

BACKGROUND: Congenital Vertical Talus (CVT) is a rare form of rigid flatfoot commonly seen in patients with underlying neurologic syndromes. This study aims to evaluate the long-term effectiveness of the minimally invasive method for correcting CVT deformity in a large cohort of syndromic patients. METHODS: A single author recorded preoperative, 2-week postoperative, 1-year postoperative, and most recent radiographic measurements and complications for 25 patients treated with the minimally invasive method from 2006 to 2021. Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaires were administered for 12 patients after January 1, 2015, when the institution began collecting PROMIS in all orthopaedic patients. Average follow-up was 55 months (13-111); 18 patients had minimum 24-month follow-up. RESULTS: Forty feet in 25 patients were analyzed. The average preoperative lateral talar axis-first metatarsal base angle (TAMBA) was 68.7 ± 21.3 vs 12.1 ± 8.9 after initial surgical intervention (P < .0001). There was a statistically significant increase in the lateral TAMBA between the initial postoperative and final follow-up visits (13.0 vs 21.6, P = .02). Radiographic recurrence of talonavicular deformity was noted in 12 feet (30.9%); 7 (15.55%) required corrective surgery. Larger preoperative lateral TAMBA was predictive of recurrence. Notably, patients with arthrogryposis experienced higher radiographic recurrence than other syndromic patients (45.0% vs 14.3%, P = .0384). PROMIS scores were within population norms. CONCLUSION: The study suggests that less than one-third of syndromic CVT patients experienced a radiographic recurrence of talonavicular deformity, with 15% requiring further surgical intervention at an average of 55 months following the initial procedure. A higher incidence of radiographic recurrence occurred in patients with distal arthrogryposis. These findings, along with the satisfactory patient-reported outcomes, suggest that the minimally invasive technique is an effective treatment method for syndromic CVT, underscoring the necessity for clinicians to provide detailed prognoses and consider more intensive follow-up for those at higher risk.

Short Report: 10-year follow-up of a boy with ARID1B-related disorder. Early intervention, longitudinal dimensional phenotype, brain imaging and outcome.

ARID1B-related disorders constitute a clinical continuum, from classic Coffin-Siris syndrome to intellectual disability (ID) with or without nonspecific dysmorphic features. Here, we describe an 11-year-old boy with an ARID1B mutation whose phenotype changed from severe developmental delay and ID to a complex neurodevelopmental disorder with multidimensional impairments, including normal intelligence despite heterogeneous IQ scores, severe motor coordination disorder, oral language disorder and attention-deficit/hyperactivity disorder. Phenotypic changes occurred after early intensive remediation and paralleled the normalization of myelination impairments, as evidenced by early brain imaging. WHAT THIS PAPER ADDS?: This report describes a 10-year multidisciplinary follow-up of a child with an ARID1B mutation who received early intensive remediation and whose phenotype changed during development. Clinical improvement paralleled the normalization of myelination impairments. This case supports a dimensional approach for complex neurodevelopmental disorders.

Caudal regression in fetus with de novo SMARCA2 pathogenic variant.

Nicolaides-Baraitser syndrome (NCBRS) is a rare autosomal dominant genetic condition that is characterized by severe intellectual disability, dysmorphic facial features, short stature, sparse hair, and early onset seizures. This diagnosis is established by suggestive clinical findings and the identification of a heterozygous SMARCA2 pathogenic variant by molecular genetic testing. There are not, however, consensus clinical diagnostic criteria for this condition as there are so few documented cases. Here, we present a case of prenatally diagnosed caudal regression with sacral agenesis and congenital vertical talus (rocker bottom feet) that was ultimately found to have a de novo SMARCA2 pathogenic variant. The patient had an amniocentesis with normal karyotype and microarray followed by failed direct rapid whole exome sequencing (WES) due to maternal cell contamination. She elected for termination of the pregnancy based on the clinical prognosis of the ultrasound findings; WES revealed a pathogenic variant after her termination. We believe this is the first case of these findings associated with NCBRS. If any future cases of either finding are found in association with a SMARCA2 genetic variant, caudal regression and rocker bottom feet should be included in the spectrum of physical traits associated with this pathogenic variant.

Childhood fever and hearing loss associated with CAPOS syndrome.

CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) syndrome is a rare genetic disorder caused by the heterozygous mutation, c.2452G > A, in the ATP1A3 gene. CAPOS syndrome involves a characteristic episode in which neuropathy develops after a fever in childhood, and here, we describe the case of a patient with CAPOS syndrome. The patient had repeated episodes of a fever around 74 months of age. Although he could speak at 23 months of age, he presented with hearing difficulty after the fever. Pure-tone audiometry revealed moderate-to-severe bilateral sensorineural hearing loss, and auditory brainstem response (ABR) showed poor response in the both ears. Auditory stead-state response (ASSR) produced relatively consistent results compared to pure-tone audiometry. A mutation in the ATP1A3 gene was detected through genetic testing. In CAPOS syndrome, a genetic mutation leads to desynchronization during neural firing. We believe that this desynchronization in neural firing is responsible for the lack of response in the ABR and the presence of a response in the ASSR. In this patient, we attribute the response detection in ASSR to its greater tolerance for errors in the timing of neural firing compared to ABR.

Review of Current Concepts in Metatarsus Adductus.

Metatarsus adductus (MA), the most common congenital foot deformity, involves adduction of the forefoot at the tarsometatarsal joint, with normal hindfoot alignment. Early diagnosis is important because treatment is more successful if initiated before age 9 months. Treatment of MA depends on deformity severity, in which mild to moderate deformity can be treated conservatively. Current standard of care for severe or rigid deformity involves referral by primary care physicians to specialists for management by casting and splinting. Recently, several orthoses have demonstrated equal effectiveness to casting and may allow for primary care physicians to treat MA without the need for referral. In this review article, we provide an overview of MA and discuss diagnosis and treatment. We also discuss novel devices and suggest how they may affect the future management of severe and rigid MA. [Pediatr Ann. 2024;53(4):e152-e156.].

Metatarsal lengthening by distraction osteogenesis for brachymetatarsia in paediatric patients: is it safe and effective?

PURPOSE: The primary aim is to assess the efficacy of the surgical callus distraction technique of the metatarsus in paediatric patients. Secondary objectives are to assess complications and treatment duration. We have also described the details of our surgical technique. MATERIALS AND METHODS: A case series review of paediatric patients who had metatarsal lengthening at our unit between 2014 and 2022. Patient demographics, duration of time in frame, complications and metatarsal length achieved were recorded. The AOFAS Midfoot and the MOXFQ were taken pre-operatively and at final follow-up. RESULTS: Sixteen metatarsals in 8 patients (14 feet) underwent lengthening between 2014 and 2022 using the MiniRail OrthoFix 100 (Orthofix Medical Inc, Lewisville, TX, USA). The mean age was 13.3 (12-17) years. The average duration between surgery and implant removal was 5.2 months. According to Paley's classification, there was one obstacle encountered in a patient who required a revision of their osteotomy and one problem in another patient who had an infected metatarsophalangeal joint stabilising k-wire treated with oral antibiotics. The Mean AOFAS Midfoot score improved from 53.10 to 86.40 (p < 0.0001) and the Mean MOXFQ improved from 32.5000 to 12.1250 (p < 0.05); these were statistically significant. CONCLUSION: Gradual metatarsal lengthening using the MiniRail external fixator is a safe and effective method to treat brachymetatarsia in paediatric patients. This preliminary report describes and supports metatarsal lengthening in appropriate patients. Holistic care in terms of a pre-operative assessment, psychological support and preparation for the extended rehabilitation period are vital.

[Clinical features of CAPOS syndrome caused by maternal ATP1A3 gene variation: a case report].

CAPOS syndrome is an autosomal dominant neurological disorder caused by mutations in the ATP1A3 gene. Initial symptoms, often fever-induced, include recurrent acute ataxic encephalopathy in childhood, featuring cerebellar ataxia, optic atrophy, areflflexia, sensorineural hearing loss, and in some cases, pes cavus. This report details a case of CAPOS syndrome resulting from a maternal ATP1A3 gene mutation. Both the child and her mother exhibited symptoms post-febrile induction,including severe sensorineural hearing loss in both ears, ataxia, areflexia, and decreased vision. Additionally, the patient's mother presented with pes cavus. Genetic testing revealed a c. 2452G>A（Glu818Lys） heterozygous mutation in theATP1A3 gene in the patient . This article aims to enhance clinicians' understanding of CAPOS syndrome, emphasizing the case's clinical characteristics, diagnostic process, treatment, and its correlation with genotypeic findings.

Split-hand/foot malformation 3 resulting from microduplications in 10q24 region in five patients from India.

Split-hand/foot malformation (SHFM) is a genetically heterogeneous congenital limb reduction defect characterized by the deficiencies of central rays of the autopod. Tandem duplications at 10q24 locus account for approximately 20% of all SHFM cases. Here, we report five affected individuals from four unrelated Indian families with SHFM3 caused by microduplication of 10q24 locus showing varied clinical presentations. This report substantiates and extends the current understanding of this rare, multifaceted, and complex condition.

A spectrum of TP63-related disorders with eight affected individuals in five unrelated families.

TP63-related disdorders broadly involve varying combinations of ectodermal dysplasia (sparse hair, hypohydrosis, tooth abnormalities, nail dysplasia), cleft lip/palate, acromelic malformation, split-hand/foot malformation/syndactyly, ankyloblepharon filiforme adnatum, lacrimal duct obstruction, hypopigmentation, and hypoplastic breasts and/or nipples. TP63-related disorders are associated with heterozygous pathogenic variants in TP63 and include seven overlapping phenotypes; Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC), Ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome 3 (EEC3), Limb-mammary syndrome (LMS), Acro-dermo-ungual-lacrimal-tooth syndrome (ADULT), Rapp-Hodgkin syndrome (RHS), Split-hand/foot malformation 4 (SHFM4), and Orofacial cleft 8. We report on five unrelated families with 8 affected individuals in which the probands presented with varying combinations of ectodermal dysplasia, cleft lip/palate, split-hand/foot malformation, lacrimal duct obstruction, and ankyloblepharon filiforme adnatum. The clinical diagnosis involved AEC syndrome (2 patients), EEC3 syndrome (2 patients), and a yet hitherto unclassified TP63-related disorder. Sanger sequence analysis of the TP63 gene was performed revealing five different variants among which four were novel and three were de novo. The identificated TP63 variants co-segregated with the other affected individuals in the families. The abnormalities of ectoderm derived structures including hair, nails, sweat glands, and teeth should alert the physician to the possibility of TP63-related disorders particularly in the presence of orofacial clefting.

Comparing Outcomes of Acute Versus Gradual Surgical Correction in Brachymetatarsia.

Brachymetatarsia consists of a shortened metatarsal resulting in a shorter toe. Pain with shoe wear and cosmetic concerns are the main reasons for surgical intervention. Surgical techniques to increase metatarsal length include acute lengthening with interpositional bone grafting or gradual lengthening with callus distraction. We performed a retrospective cohort study for 1 surgeon's patients at 1 institution over 10 years. Twenty-nine feet in 22 patients met inclusion criteria for acute correction; 16 feet in 11 patients were included for gradual correction. Mean ages were 26.3 ± 12.1 and 27 ± 10.8 in the acute and gradual groups, respectively (p = .79). Most patients were female: 95.4% of acute cases and 90.1% of gradual cases. Most involved lengthening the fourth metatarsal: 86.7% and 100% of acute and gradual groups, respectively (p = .54). Correction obtained amounted to 14.4 ± 2.97 mm (range, 10-22 mm) in acute cases and 14.8 ± 2.39 mm (range, 10-20 mm) in gradual cases (p = .81). The mean percent increase in metatarsal length was 21.1 ± 14% for acute and 22.6 ± 12.4% for gradual (p = .72). Mean consolidation was 8.9 ± 2.51 weeks for acute and 21.4 ± 10.8 weeks for gradual (p = <.001). Nonunions were most common in the gradual group (37.5%) with need for more revisional surgery (43.5%) compared with the acute group; both were statistically significant. We conclude that acute brachymetatarsia correction can obtain correction similar to the gradual technique with fewer postoperative complications and less osseous consolidation time.

Neonatal Assessment: Put Your Best Foot Forward.

BACKGROUND: Assessment of the foot is an essential part of the newborn examination. Foot abnormalities range from an isolated deformity due to intrauterine positioning to a functional impairment due to a structural malformation. The purpose of this article is to review assessment, abnormal findings, and current treatment options of common foot deformities. EVIDENCE ACQUISITION: A review of literature was conducted using keywords in PubMed, Google Scholar, and CINAHL databases from 2018 to 2023. RESULTS: Although assessment techniques for the neonatal foot remain the same, recent nonsurgical treatment options are available for a variety of neonatal foot deformities. Early recognition allows for proper evaluation of foot deformities and corrective measures. IMPLICATIONS FOR PRACTICE AND RESEARCH: Neonatal providers equipped with knowledge of common foot problems can provide support and anticipatory guidance to families.

Symptomatic Bilateral Talonavicular Coalition in a Seven-Year-Old Boy.

Congenital talonavicular coalition is less frequent than the talocalcaneal or the calcaneonavicular and accounts for around 1% of all tarsal coalitions. Commonly, patients are asymptomatic and rarely need surgical treatment. Herein, we present a case of bilateral symptomatic talonavicular coalition in a seven-year-old boy who underwent surgery with full relief of symptoms. We also review the literature and discuss this pathological condition in detail.

Ankle and Foot Deformities in Children.

Ankle and foot deformity is one of the most common musculoskeletal disorders in children and a leading cause of functional impairment and diminished quality of life when not treated. A spectrum of conditions may produce foot and ankle deformities, with congenital disorders the most frequent cause, followed by acquired conditions. Congenital disorders include congenital talipes equinovarus or congenital clubfoot, metatarsus adductus, skewfoot, congenital vertical talus, and tarsal coalition.Some of these deformities are frequent and easily diagnosed based on clinical features, but clinical overlap between pathologies can be challenging. Thus imaging plays a paramount role in evaluating these patients. Radiographs are the first imaging modality of choice, but they may not be sufficient in infants due to the lack of ossification of the tarsal bones. Ultrasonography allows not only a detailed visualization of the cartilaginous structures but also permits a dynamic study of the foot and ankle. Computed tomography may be necessary in certain conditions such as tarsal coalitions.

Results of treatment of congenital vertical talus by the Dobbs method.

Congenital vertical talus is a rare foot deformity. The hindfoot is valgus and equinus, the midfoot is dorsiflexed and forefoot is abducted due to a fixed dorsal dislocation of the navicular on the head of the talus and the cuboid on the anterior part of the calcaneus. The epidemiology and etiology of vertical talus is unknown. Dobbs et al. (J Bone Joint Surg Am 88(6):1192-200, 2006) described a minimally invasive alternative which allowed to avoid the need for extensive soft tissue release procedures in treatment of congenital vertical talus. Eleven congenital vertical talus feet (group 5 according to Hamanishi) in eight children (four boys and four girls) constituted the study material. Upon the diagnosis, the patients' age ranged from 5 to 26 months old (the mean - 14.6). The treatment involved serial manipulation and casting according to the reverse Ponseti method (from 4 to 7 casts) followed by a minimally invasive approach consisting in temporary stabilization of the talonavicular joint with the use of K-wire and Achilles tenotomy according to the Dobbs technique. Then patients continued the shoe and bar program for 2 years. The X-ray measurements on lateral radiographic included the talocalcaneal angle, tibiotalar angle and talar axis-first metatarsal base angle whereas AP radiographic images-the talocalcaneal angle and talar axis-first metatarsal angle. The Wilcoxon test was used to compare dependent variables. The final clinical assessment made during the last follow-up (the mean: 35.8 months, the range: 25-52) revealed that neutral position of the foot and normal range of motion were observed in ten cases and recurrence of foot deformity in one case. The last X-ray examination showed normalization all of radiological parameters, except for one case, and examined parameters were statistically significant. The minimally invasive technique described by Dobbs should be the first option in treatment of congenital vertical talus. It allows to reduce the talonavicular joint, brings good results and preserves foot mobility. The attention should be put on early diagnosis.

Comparison of Different Surgical Techniques in Correction of Congenital Vertical Talus Deformity: A Systematic Review and Meta-Analysis of the Literature.

BACKGROUND: Congenital Vertical Talus (CVT) is a rare form of congenital rigid flatfoot. Numerous surgical techniques have been developed over the years in an attempt to definitively correct this deformity. We performed a systematic review and meta-analysis of the existing literature to compare the outcomes of children with CVT treated with different methods. METHODS: A detailed systematic search was conducted in accordance with PRISMA guidelines. Radiographic recurrence of the deformity, reoperation rate, ankle arc of motion, and clinical scoring was compared between the following 5 methods: Two-Stage Coleman-Stelling Technique, Direct Medial Approach, Single-Stage Dorsal (Seimon) Approach, Cincinnati Incision, and Dobbs Method. Meta-analyses of proportions were performed, and data were pooled through a random effects model using the DerSimonian and Laird approach. Heterogeneity was assessed using I^2 statistics. The authors used a modified version of the Adelaar scoring system to assess clinical outcomes. An alpha of 0.05 was used for all statistical analysis. RESULTS: Thirty-one studies (580 feet) met the inclusion criteria. The reported incidence of radiographic recurrence of talonavicular subluxation was 19.3%, with 7.8% requiring reoperation. Radiographic recurrence of the deformity was highest in the children treated with the direct medial approach (29.3%) and lowest in the Single-Stage Dorsal Approach cohort (11%) ( P <0.05). The reoperation rate was significantly lower in the Single-Stage Dorsal Approach cohort (2%) compared with all other methods ( P <0.05). There was no significant difference in the reoperation rates between the other methods. The highest clinical score was seen in the Dobbs Method cohort (8.36), followed by the group treated with the Single-Stage Dorsal Approach (7.81). The Dobbs Method resulted in the largest ankle arc of motion. CONCLUSION: We found the lowest radiographic recurrence and reoperation rates in the Single-Stage Dorsal Approach cohort, while the highest rate of radiographic recurrence was seen in those treated with the Direct Medial Approach. The Dobbs Method results in higher clinical scores and ankle arc of motion. Future long-term studies focusing on patient-reported outcomes are needed. LEVEL OF EVIDENCE: Level III.