Establishment and characterization of ZJUCHi003: an induced pluripotent stem cell line from a patient with Temple-Baraitser/Zimmermann-Laband syndrome carrying KCNH1 c.1070G > A (p.R357Q) variant.

Pathogenic variants of the KCNH1 gene can cause dominant-inherited Temple-Baraitser/Zimmermann-Laband syndrome with severe mental retardation, seizure, gingival hyperplasia and nail hypoplasia. This study established an induced pluripotent stem cell (iPSC) line using urinary cells from a girl with KCNH1 recurrent/hotspot pathogenic variant c.1070G > A (p.R357Q). The cell identity, pluripotency, karyotypic integrity, absence of reprogramming virus and mycoplasma contamination, and differential potential to three germ layers of the iPSC line, named as ZJUCHi003, were characterized and confirmed. Furthermore, ZJUCHi003-derived neurons manifested slower action potential repolarization process and wider action potential half-width than the normal neurons. This cell line will be useful for investigating the pathogenic mechanisms of KCNH1 variants-associated symptoms, as well as for evaluating novel therapeutic approaches.

Influencia del tratamiento quirúrgico para el hallux abductus valgus en la movilidad del primer radio / Influence of surgical treatment of hallux abducto-valgus on first ray mobility

Objetivo: El objetivo principal de este trabajo es determinar la variación de movilidad pre y postquirúrgica del primer radio. Pacientes y métodos: El diseño corresponde a un estudio prospectivo de series de casos en pacientes sometidos a cirugía de hallux valgus. Se valoró en 13 pies la movilidad del primer radio con el medidor del primer radio, la flexo-extensión de la primera articulación metatarsofalángica, el ángulo de Clarke y el “Arch Index” en pedigrafías, los ángulos hallux valgus e intermetatarsal I-II en radiografías dorsoplantares en carga, y la postura general del pie mediante el “Foot Posture Index” antes y después de ser sometidos a cirugía de hallux valgus. Todo ello con un periodo de seguimiento de 6 meses. Resultados: El rango total de movilidad del primer radio pasó de 11.74 ± 1.88 mm a 6.72 ± 2.20 mm; y el de la primera articulación metatarsofalángica pasó de 79.62° ± 22.33° a 48.69° ± 18.69° tras la cirugía. Los ángulos radiográficos de hallux valgus y ángulo intermetatarsal disminuyeron una media de 19.07° ± 8.20° y 7.23° ± 2.97°, respectivamente. El ángulo de Clarke cambió de 41.31° ± 10.79° a 38.31° ± 11.00°. El “Arch Index” cambió de 0.24 ± 0.06 a 0.25 ± 0.05. Y el “Foot Posture Index” pasó de 6.70 ± 3.33 de media antes de la cirugía a 5.46 ± 3.86 tras la misma. Conclusión: En los participantes incluidos en este estudio se observó una disminución generalizada de todas las variables examinadas tras la cirugía, a excepción de los parámetros valorados en las pedigrafías, que no llegaron a presentar diferencias relevantes.(AU)

Objectives: The main aim of this work is to determine the variation of first ray mobility before and after surgery. Patients and methods: The design corresponds to a prospective case series of patients operated of hallux valgus. A total of 13 feet have been included in this study. Measurements of the first ray mobility were obtained using the first ray mobility measurer. Furthermore, we assess the flexo-extension of the first metatarsophalangeal joint. The Clarke’s angle and the Arch Index were evalued on weightbearing footprints. The hallux valgus angle and intermetatarsal I-II angle were made on weightbearing dorsal-plantar projection radiographs. And finally, the general posture of the foot was quantified using the Foot Posture Index. All this with pre and post measurements of hallux valgus surgery and with a follow-up period of 6 months. Results: The total range of motion of the first ray decreased from 11.74 ± 1.88 mm to 6.72 ± 2.20 mm; and the range of motion of the first metatarsophalangeal joint underwent from 79.62° ± 22.33° to 48.69° ± 18.69° after surgery. The hallux valgus angle and intermetatarsal I-II angle decreased by a mean of 19.07° ± 8.20° and 7.23° ± 2.97°, respectively. The Clarke’s angle changed from 41.31° ± 10.79° to 38.31° ± 11.00°. The Arch Index changed from 0.24 ± 0.06 to 0.25 ± 0.05. And the Foot Posture Index went from 6.70 ± 3.33 before surgery to 5.46 ± 3.86 after it. Conclusion: In the participants included in this study, a generalized decrease was observed in all the examined variables after surgery, except for the parameters assessed in the pedigraphs, which did not present relevant differences.(AU)

Potassium Channel KCNH1 Activating Variants Cause Altered Functional and Morphological Ciliogenesis.

The primary cilium is a non-motile sensory organelle that extends from the surface of most vertebrate cells and transduces signals regulating proliferation, differentiation, and migration. Primary cilia dysfunctions have been observed in cancer and in a group of heterogeneous disorders called ciliopathies, characterized by renal and liver cysts, skeleton and limb abnormalities, retinal degeneration, intellectual disability, ataxia, and heart disease and, recently, in autism spectrum disorder, schizophrenia, and epilepsy. The potassium voltage-gated channel subfamily H member 1 (KCNH1) gene encodes a member of the EAG (ether-à-go-go) family, which controls potassium flux regulating resting membrane potential in both excitable and non-excitable cells and is involved in intracellular signaling, cell proliferation, and tumorigenesis. KCNH1 missense variants have been associated with syndromic neurodevelopmental disorders, including Zimmermann-Laband syndrome 1 (ZLS1, MIM #135500), Temple-Baraitser syndrome (TMBTS, MIM #611816), and, recently, with milder phenotypes as epilepsy. In this work, we provide evidence that KCNH1 localizes at the base of the cilium in pre-ciliary vesicles and ciliary pocket of human dermal fibroblasts and retinal pigment epithelial (hTERT RPE1) cells and that the pathogenic missense variants (L352V and R330Q; NP_002229.1) perturb cilia morphology, assembly/disassembly, and Sonic Hedgehog signaling, disclosing a multifaceted role of the protein. The study of KCNH1 localization, its functions related to primary cilia, and the alterations introduced by mutations in ciliogenesis, cell cycle coordination, cilium morphology, and cilia signaling pathways could help elucidate the molecular mechanisms underlying neurological phenotypes and neurodevelopmental disorders not considered as classical ciliopathies but for which a significant role of primary cilia is emerging.

Patients with KCNH1-related intellectual disability without distinctive features of Zimmermann-Laband/Temple-Baraitser syndrome.

De novo missense variants in KCNH1 encoding Kv10.1 are responsible for two clinically recognisable phenotypes: Temple-Baraitser syndrome (TBS) and Zimmermann-Laband syndrome (ZLS). The clinical overlap between these two syndromes suggests that they belong to a spectrum of KCNH1-related encephalopathies. Affected patients have severe intellectual disability (ID) with or without epilepsy, hypertrichosis and distinctive features such as gingival hyperplasia and nail hypoplasia/aplasia (present in 20/23 reported cases).We report a series of seven patients with ID and de novo pathogenic KCNH1 variants identified by whole-exome sequencing or an epilepsy gene panel in whom the diagnosis of TBS/ZLS had not been first considered. Four of these variants, p.(Thr294Met), p.(Ala492Asp), p.(Thr493Asn) and p.(Gly496Arg), were located in the transmembrane domains S3 and S6 of Kv10.1 and one, p.(Arg693Gln), in its C-terminal cyclic nucleotide-binding homology domain (CNBHD). Clinical reappraisal by the referring clinical geneticists confirmed the absence of the distinctive gingival and nail features of TBS/ZLS.Our study expands the phenotypical spectrum of KCNH1-related encephalopathies to individuals with an attenuated extraneurological phenotype preventing a clinical diagnosis of TBS or ZLS. This subtype may be related to recurrent substitutions of the Gly496, suggesting a genotype-phenotype correlation and, possibly, to variants in the CNBHD domain.

Monitoring of compound resting membrane potentials of cell cultures with ratiometric genetically encoded voltage indicators.

The cellular resting membrane potential (Vm) not only determines electrical responsiveness of excitable cells but also plays pivotal roles in non-excitable cells, mediating membrane transport, cell-cycle progression, and tumorigenesis. Studying these processes requires estimation of Vm, ideally over long periods of time. Here, we introduce two ratiometric genetically encoded Vm indicators, rArc and rASAP, and imaging and analysis procedures for measuring differences in average resting Vm between cell groups. We investigated the influence of ectopic expression of K+ channels and their disease-causing mutations involved in Andersen-Tawil (Kir2.1) and Temple-Baraitser (KV10.1) syndrome on median resting Vm of HEK293T cells. Real-time long-term monitoring of Vm changes allowed to estimate a 40-50 min latency from induction of transcription to functional Kir2.1 channels in HEK293T cells. The presented methodology is readily implemented with standard fluorescence microscopes and offers deeper insights into the role of the resting Vm in health and disease.

ZNF445: a homozygous truncating variant in a patient with Temple syndrome and multilocus imprinting disturbance.

BACKGROUND: ZNF445, as well as ZFP57, is involved in the postfertilization methylation maintenance of multiple imprinting-associated differentially methylated regions (iDMRs). Thus, ZNF445 pathogenic variants are predicted to cause multilocus imprinting disturbances (MLIDs), as do ZFP57 pathogenic variants. In particular, the MEG3/DLK1:IG-DMR would be affected, because the postzygotic methylation imprint of the MEG3/DLK1:IG-DMR is maintained primarily by ZNF445, whereas that of most iDMRs is preserved by both ZFP57 and ZNF445 or primarily by ZFP57. RESULTS: We searched for a ZNF445 variant(s) in six patients with various imprinting disorders (IDs) caused by epimutations and MLIDs revealed by pyrosequencing for nine iDMRs, without a selection for the original IDs. Re-analysis of the previously obtained whole exome sequencing data identified a homozygous ZNF445 variant (NM_181489.6:c.2803C>T:p.(Gln935*)) producing a truncated protein missing two of 14 zinc finger domains in a patient with Temple syndrome and MLID. In this patient, array-based genomewide methylation analysis revealed severe hypomethylation of most CpGs at the MEG3:TSS-DMR, moderate hypomethylation of roughly two-thirds of CpGs at the H19/IGF2:IG-DMR, and mild-to-moderate hypomethylation of a few CpGs at the DIRAS3:TSS-DMR, MEST:alt-TSS-DMR, IGF2:Ex9-DMR, IGF2:alt-TSS, and GNAS-AS1:TSS-DMR. Furthermore, bisulfite sequencing analysis for the MEG3/DLK1:IG-DMR delineated a markedly hypomethylated segment (CG-A). The heterozygous parents were clinically normal and had virtually no aberrant methylation pattern. CONCLUSIONS: We identified a ZNF445 pathogenic variant for the first time. Since ZNF445 binds to the MEG3/DLK1:IG-DMR and other iDMRs affected in this patient, the development of Temple syndrome and MLID would primarily be explained by the ZNF445 variant. Furthermore, CG-A may be the target site for ZNF445 within the MEG3/DLK1:IG-DMR.

Fibrodysplasia ossificans progressiva in a young adult with genetic mutation: Case report.

RATIONALE: Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by congenital skeletal deformities and soft tissue masses that progress into heterotopic ossification. Deformities of the great toes are distinctive and heterotrophic ossification usually begins in the first decade of the patient's life. Any invasive procedure could potentially trigger a flare and heterotopic calcification. The diagnosis is difficult and there is no effective treatment for FOP and the approximate life expectancy is 4 decades. PATIENT CONCERNS: A 22-year-old male patient who had suffered from pain and movement limitations for 14 years. At the early stage of disease, the child underwent an operation on both thighs with a diagnosis of myophagism. He had serious stiffness and multiple bony masses with the characteristic bilateral hallux valgus deformity and microdactyly. DIAGNOSES: The patient was diagnosed with FOP by the help of characteristic great toe malformations and widespread heterotopic ossification throughout the body. Deoxyribonucleic acid sequencing demonstrated that the patient had a de novo heterozygous mutation (c.617G>A; p.R206H) in activin A receptor/activin-like kinase 2. INTERVENTIONS: We administered a co-therapy of glucocorticoids, NSAIDs to relieve pain, and montelukast for 2 months. Bisphosphonate (5 mg, intravenous) was used once. OUTCOMES: At the follow-up 12 months later, the patient still felt low back pain sometimes and need take NSAIDs three times a week. LESSONS: Clinicians and radiologists should realize the characteristic features of FOP and early diagnosis can prevent additional invasive harm to the patient.

Syndromic disorders caused by gain-of-function variants in KCNH1, KCNK4, and KCNN3-a subgroup of K+ channelopathies.

Decreased or increased activity of potassium channels caused by loss-of-function and gain-of-function (GOF) variants in the corresponding genes, respectively, underlies a broad spectrum of human disorders affecting the central nervous system, heart, kidney, and other organs. While the association of epilepsy and intellectual disability (ID) with variants affecting function in genes encoding potassium channels is well known, GOF missense variants in K+ channel encoding genes in individuals with syndromic developmental disorders have only recently been recognized. These syndromic phenotypes include Zimmermann-Laband and Temple-Baraitser syndromes, caused by dominant variants in KCNH1, FHEIG syndrome due to dominant variants in KCNK4, and the clinical picture associated with dominant variants in KCNN3. Here we review the presentation of these individuals, including five newly reported with variants in KCNH1 and three additional individuals with KCNN3 variants, all variants likely affecting function. There is notable overlap in the phenotypic findings of these syndromes associated with dominant KCNN3, KCNH1, and KCNK4 variants, sharing developmental delay and/or ID, coarse facial features, gingival enlargement, distal digital hypoplasia, and hypertrichosis. We suggest to combine the phenotypes and define a new subgroup of potassium channelopathies caused by increased K+ conductance, referred to as syndromic neurodevelopmental K+ channelopathies due to dominant variants in KCNH1, KCNK4, or KCNN3.

Characteristics of the accessory tendon of the extensor hallucis longus muscle: a Taiwanese study.

PURPOSE: The main tendon of the extensor hallucis longus (EHL) muscle attaches to the dorsal aspect of the distal phalanx of the great toe. One or multiple accessory tendons of the EHL have been reported in several ethnic/regional groups, except Taiwan. This study aimed to investigate the incidence, length, and insertion of the accessory tendon of the EHL in Taiwanese people. METHODS: Anatomical dissection was performed on 48 feet of 24 formalin-embalmed cadavers. The occurrence and morphological characteristics of the accessory tendon of the EHL were recorded and analyzed. RESULTS: The accessory tendon of the EHL was found in 97.92% (47/48) of the legs that were dissected. In one male cadaver, an independent muscle belly was identified in each leg, whereas all the other accessory tendons originated from the main tendon of the EHL. In this study, the insertion of the accessory tendon were classified into four patterns. The most common insertion sites were the first metatarsophalangeal (MTP) joint capsule and proximal phalanx of the great toe. The length of the accessory tendons did not correlate with age or with sex when the two tendons with independent muscle belly were excluded. CONCLUSIONS: The accessory tendon of the EHL appears to be a regular feature in Taiwanese people. Most accessory tendons of the EHL (85.7%) attached on the first MTP joint capsule may play a role in the prevention of capsular impingement during great toe extension.

Independent muscle of extensor hallucis capsularis: a cadaveric case report.

Extensor hallucis capsularis (EHC) is an accessory tendon located medially to extensor halluces longus (EHL) tendon. Most EHC is known to originate as a tendinous slip of the EHL tendon, although it may be splitted from the tibialis anterior (TA) tendon or the extensor halluces brevis (EHB) tendon. During routine dissection of a 49-year-old male cadaver, independent muscle bellies of EHC were discovered bilaterally. The EHL muscle arose from the middle anteromedial aspect of fibula, lateral to the origin of TA muscle and medial to extensor digitorum longus (EDL) muscle. An additional muscle bellies were separated from EHL muscle at the point of 6 cm away from EHL origin in the right leg, and 3 cm away in the left. They coursed downward as EHC to reach the first metatarsophalangeal joint capsule. This muscle, unlike the variations identified to date, is considered to extend to EHC, and the name "extensor hallucis capsularis muscle" is offered. This kind of variation may be important for investigating the development of deformity at the first metatarsophalangeal joint, such as hallux valgus.

Temple-Baraitser syndrome with KCNH1 Asn510Thr: a new case report.

Temple-Baraitser syndrome (TMBTS; OMIM: 611816) is a rare developmental disorder characterized by severe mental retardation and anomalies of thumb and great toe with absence/hypoplasia of the nails. Here, we report an additional patient with TMBTS, review clinical and radiological features of previously reported cases and discuss mode of inheritance. The patient exhibited a pattern of anomalies: mild dysmorphic facial features with a wide open mouth, a thick vermilion border of the upper lip and downturned corners of the mouth; nails were absent on both great toes and thumb. Electroencephalogram showed a diffusely slow background. Whole genome sequencing identified one pathogenic missense mutation in KCNH1 (c. 1529 A > C; Asn510Thr) in this TMBTS patient. The mutation was also validated by Sanger sequencing.

Genome-wide methylation analysis in Silver-Russell syndrome, Temple syndrome, and Prader-Willi syndrome.

BACKGROUND: Imprinting disorders (IDs) show overlapping phenotypes, particularly in Silver-Russell syndrome (SRS), Temple syndrome (TS14), and Prader-Willi syndrome (PWS). These three IDs include fetal and postnatal growth failure, feeding difficulty, and muscular hypotonia as major clinical features. However, the mechanism that causes overlapping phenotypes has not been clarified. To investigate the presence or absence of methylation signatures associated with overlapping phenotypes, we performed genome-wide methylation analysis (GWMA). RESULTS: GWMA was carried out on 36 patients with three IDs (SRS [n = 16], TS14 [n = 7], PWS [n = 13]) and 11 child controls using HumanMethylation450 BeadChip including 475,000 CpG sites across the human genome. To reveal an aberrantly methylated region shared by SRS, TS14, and PWS groups, we compared genome-wide methylation data of the three groups with those of control subjects. All the identified regions were known as SRS-, TS14-, and PWS-related imprinting-associated differentially methylated regions (iDMRs), and there was no hypermethylated or hypomethylated region shared by different ID groups. To examine the methylation pattern shared by SRS, TS14, and PWS groups, we performed clustering analysis based on GWMA data. The result focusing on 620 probes at the 62 known iDMRs (except for SRS-, TS14-, and PWS-related iDMRs) classified patients into two categories: (1) category A, grossly normal methylation patterns mainly consisting of SRS group patients; and (2) category B, broad and mild hypermethylation patterns mainly consisting of TS14 and PWS group patients. However, we found no obvious relationship between these methylation patterns and phenotypes of patients. CONCLUSIONS: GWMA in three IDs found no methylation signatures shared by SRS, TS14, and PWS groups. Although clustering analysis showed similar mild hypermethylation patterns in TS14 and PWS groups, further study is needed to clarify the effect of methylation patterns on the overlapping phenotypes.

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.

Temple syndrome and Kagami-Ogata syndrome: clinical presentations, genotypes, models and mechanisms.

Temple syndrome (TS) and Kagami-Ogata syndrome (KOS) are imprinting disorders caused by absence or overexpression of genes within a single imprinted cluster on human chromosome 14q32. TS most frequently arises from maternal UPD14 or epimutations/deletions on the paternal chromosome, whereas KOS most frequently arises from paternal UPD14 or epimutations/deletions on the maternal chromosome. In this review, we describe the clinical symptoms and genetic/epigenetic features of this imprinted region. The locus encompasses paternally expressed protein-coding genes (DLK1, RTL1 and DIO3) and maternally expressed lncRNAs (MEG3/GTL2, RTL1as and MEG8), as well as numerous miRNAs and snoRNAs. Control of expression is complex, with three differentially methylated regions regulating germline, placental and tissue-specific transcription. The strong conserved synteny between mouse chromosome 12aF1 and human chromosome 14q32 has enabled the use of mouse models to elucidate imprinting mechanisms and decipher the contribution of genes to the symptoms of TS and KOS. In this review, we describe relevant mouse models and highlight their value to better inform treatment options for long-term management of TS and KOS patients.

"Electrifying dysmorphology": Potassium channelopathies causing dysmorphic syndromes.

Potassium channels are a heterogeneous group of membrane-bound proteins, whose functions support a diverse range of biological processes. Genetic disorders arising from mutations in potassium channels are classically recognized by symptoms arising from acute channel dysfunction, such as periodic paralysis, ataxia, seizures, or cardiac conduction abnormalities, often in a patient with otherwise normal examination findings. In this chapter, we review a distinct subgroup of rare potassium channelopathies whose presentations are instead suggestive of a developmental disorder, with features including intellectual disability, craniofacial dysmorphism or other physical anomalies. Known conditions within this subgroup are: Andersen-Tawil syndrome, Birk-Barel syndrome, Cantú syndrome, Keppen-Lubinsky syndrome, Temple-Baraitser syndrome, Zimmerman-Laband syndrome and a very similar disorder called Bauer-Tartaglia or FHEIG syndrome. Ion channelopathies are unlikely to be routinely considered in the differential diagnosis of children presenting with developmental concerns, and so detailed description and photographs of the clinical phenotype are provided to aid recognition. For several of these disorders, functional characterization of the genetic mutations responsible has led to identification of candidate therapies, including drugs already commonly used for other indications, which adds further impetus to their prompt recognition. Together, these cases illustrate the potential for mechanistic insights gained from genetic diagnosis to drive translational work toward targeted, disease-modifying therapies for rare disorders.

Fibrodysplasia ossificans progressiva: Review and research activities in Japan.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic skeletal disorder manifesting progressive heterotopic ossification (HO) and congenital malformation of the great toes. Since 2007, we have conducted research on FOP. Here, we review the findings on FOP published to date, including the results of our research. Epidemiological studies in Japan have indicated that FOP has nearly the same prevalence in Japan as in the rest of the world. Basic research on its pathoetiology has progressed rapidly since the identification of the causal gene in 2006. Clinical and radiological findings have been thoroughly researched, including early radiological signs, and diagnostic criteria were established, designating FOP as an intractable disease in Japan. In patients with FOP, the progression of HO is associated with numerous disabilities, often manifesting in vicious cycles that can lead to early mortality. Through cross-sectional and short-term longitudinal studies, we have explored patient education, quality of life, and activities of daily living among Japanese patients. The management of FOP requires education of patients and caregivers, the use of medications to settle inflammation and flare-ups, instructions to ensure proper oral care, and other compensatory approaches that aid in rehabilitation. An avoidance of medical intervention, which may cause HO to progress, is also important. The advent of new drugs to prevent HO could have clinical benefit.

Abnormalities of the hallux skin and nail in the course of very rare arteriovenous malformation / Anormalidades de unha e pele do hálux no decorrer de malformação arteriovenosa muito rara

Abstract Arteriovenous malformations (AVMs) are usually found in the pelvic area and the brain. These vascular anomalies are rarely reported in the toes. AVMs in the toes may be asymptomatic, but can also cause atypical symptoms. Congenital AVMs can expand as patients age and manifest in adulthood. They may be provoked by injury. Acquired AVM might be caused by iatrogenic factors, venous or arterial catheterization, percutaneous invasive vascular procedures, surgery, or degenerative vascular disorders. An AVM can damage surrounding tissues and can cause destruction of skin, nails and bones. The course of the disease is often unpredictable and diagnosis is usually delayed as a result.

Resumo As malformações arteriovenosas (MAVs) são geralmente encontradas na região pélvica e no cérebro.. Essas anomalias vasculares raramente são relatadas nos dedos dos pés. A MAV nesse local pode ser assintomática ou apresentar sintomas atípicos. MAVs congênitas podem evoluir com a idade e se manifestar na idade adulta. O fator provocante pode ser uma lesão traumática. Uma MAV adquirida pode ser causada por fatores iatrogênicos, cateterismo venoso e arterial, procedimentos percutâneos vasculares invasivos, cirurgias e alterações degenerativas vasculares. A MAV pode danificar tecidos adjacentes e pode causar destruição de pele, unhas e ossos. O curso da doença é muitas vezes imprevisível, e como resultado, atrasar o diagnóstico.

Surgical Reconstruction Technique of Two Patients With Tarsal Type Preaxial Polydactyly: Two True Prehalluces.

Polydactyly of the foot occurs in 1.7 cases per 1000 live births, comprising 45% of congenital abnormalities of the foot. Most reported cases of polydactyly of the foot are postaxial, and 15% are preaxial; of those, tarsal type preaxial polydactyly (a true prehallux) occurs in only 3% of cases. Because of this rarity, there is minimal literature available to guide management or surgical reconstruction. Two newborns presented with similar tarsal type preaxial polydactylies in the context of multiple congenital anomalies at a single institution. Patient 1 presented at birth with an accessory digit arising medially from the right foot at the medial malleolus. Two weeks later, genetically unrelated, patient 2 presented at birth with an accessory digit arising medially from the right foot at the talus. Both patients underwent resection of the extra digit and reconstruction including transfer of the accessory anterior tibial tendon arising from the preaxial extra digit to the remaining first ray. Two years after surgery, both patients are walking well with preserved dorsiflexion strength. Given the rarity of true prehallux cases, reported surgical treatment and outcomes are lacking. This case demonstrates the management of 2 patients to better guide future patient care. Although nonsurgical treatment with shoewear modification is an option, surgical reconstruction facilitated wearing typical shoes while preserving ambulatory ability. Both patients in this series had an accessory anterior tibial tendon. Surgical transfer of the tendon prevented loss of dorsiflexion strength and foot drop postoperatively.

Temple syndrome in a patient with variably methylated CpGs at the primary MEG3/DLK1:IG-DMR and severely hypomethylated CpGs at the secondary MEG3:TSS-DMR.

BACKGROUND: The human chromosome 14q32.2 imprinted region harbors the primary MEG3/DLK1:IG-differentially methylated region (DMR) and secondary MEG3:TSS-DMR. The MEG3:TSS-DMR can remain unmethylated only in the presence of unmethylated MEG3/DLK1:IG-DMR in somatic tissues, but not in the placenta, because of a hierarchical regulation of the methylation pattern between the two DMRs. METHODS: We performed molecular studies in a 4-year-old Japanese girl with Temple syndrome (TS14). RESULTS: Pyrosequencing analysis showed extremely low methylation levels of five CpGs at the MEG3:TSS-DMR and grossly normal methylation levels of four CpGs at the MEG3/DLK1:IG-DMR in leukocytes. HumanMethylation450 BeadChip confirmed marked hypomethylation of the MEG3:TSS-DMR and revealed multilocus imprinting disturbance (MLID) including mild hypomethylation of the H19/IGF2:IG-DMR and mild hypermethylation of the GNAS A/B:TSS-DMR in leukocytes. Bisulfite sequencing showed markedly hypomethylated CpGs at the MEG3:TSS-DMR and irregularly and non-differentially methylated CpGs at the MEG3/DLK1:IG-DMR in leukocytes and apparently normal methylation patterns of the two DMRs in the placenta. Maternal uniparental disomy 14 and a deletion involving this imprinted region were excluded. CONCLUSIONS: Such a methylation pattern of the MEG3/DLK1:IG-DMR has not been reported in patients with TS14. It may be possible that a certain degree of irregular hypomethylation at the MEG3/DLK1:IG-DMR has prevented methylation of the MEG3:TSS-DMR in somatic tissues and that a hypermethylation type MLID has occurred at the MEG3/DLK1:IG-DMR to yield the apparently normal methylation pattern in the placenta.