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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., (© 2024. The Author(s) under exclusive licence to Japan Human Cell Society.)

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., (© 2021. The Author(s).)

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., (© 2021. The Author(s), under exclusive licence to Springer-Verlag France SAS part of Springer Nature.)

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., (© 2020. Springer-Verlag France SAS, part of Springer Nature.)

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.

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.

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.

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.

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., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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., (© 2019 Japan Pediatric Society.)

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., (© 2020 Elsevier Inc. All rights reserved.)

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., (Copyright © 2018 the American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

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.

Trisomy 13 or Patau syndrome (PS) is a well-known aneuploidy characterized by a polymalformative syndrome. We described a large series of fetuses with PS and compared them with cases described in the literature, most of which were live-born. In all, 42 fetuses, aged from 14 to 41 gestational weeks (GW), were examined. The main defects observed were similar to those described in live-born patients: congenital heart defects (76%), holoprosencephaly spectrum anomalies including arhinencephaly and hypotelorism (74%), urinary tract anomalies (71%), ear anomalies (69%), postaxial polydactyly (67%), anogenital anomalies (60%), anophthalmos, and/or microphthalmos (53%), brachycephaly (45%), and oro-facial clefts (45%). A duplication or triplication of at least one distal phalanx of the thumb or hallux was present in 38% of fetuses. This sign has only been reported previously in one patient in the literature. Fetal examination in trisomy 13, is thus, useful to complete the phenotype or to orient diagnosis toward trisomy 13 in the absence of cytogenetic analysis., (© 2018 Wiley Periodicals, Inc.)

Case: A 14-year-old girl presented with painful high-arched feet and unusual, asymptomatic, bilateral macrodactyly of the halluces. After a year of observation, a surgical reduction was performed because of the psychological effect that the abnormality had on the patient. Bilateral shortening osteotomies of the metatarsal and the proximal phalangeal bones were performed. At 2 months after surgery, complete bone healing and alignment had been achieved. At the 5-year follow-up, we noted fully functional big toes, plantigrade feet, bilateral proper toe formula, and extreme patient satisfaction with the cosmetic results., Conclusion: Dual osteotomies for toe shortening in a patient with bilateral nondysmorphic macrodactyly provided appropriate length reduction and satisfactory aesthetic and functional results.

Partite hallux sesamoids are clinically meaningful but their association with other sesamoids is not clear. The objective was to relate the prevalence of the partite hallux sesamoid bones to sesamoid bones at other metatarsophalangeal (MTP) joints. We conducted a retrospective review of plain radiographs of 7946 adult feet between November 2005 and September 2012 to identify partite hallux sesamoids and sesamoids at other MTP joints. Coexistence patterns of the partition and extra sesamoids were studied. Presence or absence of sesamoids at other MTP joints as well as sex and laterality were compared between the feet with and without partite hallux sesamoids using Pearson Chi-square test. Association between age and partition was evaluated using Spearman's correlation coefficient. Overall partite prevalence rate is 6.82%, and coexistence with extra MTP sesamoids was 0.42%. One pattern was partition in hallux sesamoid only, and 4 patterns were coexistence with extra sesamoids. The prevalence rates of partite hallux sesamoids were 7.17% (508/7081) and 3.93% (34/865) in feet without and with extra sesamoids, respectively. The relative risk of 1.889 (95% CI, 1.325-2.693) of partite hallux sesamoids was noted in feet without than with extra sesamoids (Χ 2 = 12.759, P < 0.001). A negative correlation between age and distribution of partition was identified (r = -0.061, P < 0.001). Partition of hallux sesamoid bones is a developmental variation, it can coexist with sesamoids at other MTP joints following a certain pattern; and its prevalence rate is almost twice higher in feet without than with extra MTP sesamoids. Anat Rec, 2017. © 2017 Wiley Periodicals, Inc. Anat Rec, 301:34-38, 2018. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

The two imprinting syndromes Temple syndrome (TS14) and Prader-Willi syndrome (PWS) share many features in infancy and childhood. TS14 is an important, yet often neglected, differential diagnosis to PWS. We wanted to assess the frequency of TS14 among patients tested for PWS. In all samples submitted to our lab for genetic PWS testing during 2014 and 2015, we consecutively conducted additional analyses for TS14. A total of 143 samples were included. The most frequent indications for testing were developmental delay, overweight, and hypotonia. For TS14 testing, we performed a methylation-sensitive MLPA-kit detecting deletions and methylation aberrations in chromosomal region 14q32. TS14 was confirmed in 3 out of 143 patients (2.1%). In comparison, PWS was also confirmed in three patients. Brief clinical descriptions of the TS14 patients are presented. Temple syndrome is presumably underdiagnosed, and should be considered when testing children for PWS., (© 2017 Wiley Periodicals, Inc.)

Unlabelled: Closed lateral subtalar dislocation is a very rare injury. We report a case of closed lateral subtalar dislocation with entrapment of flexor hallucis longus tendon producing a checkrein deformity. The patient was managed immediately with closed reduction under regional anesthesia and fixated with percutaneous Kirschner wires. Early mobilization and weightbearing was started and there were no complications till the last follow-up visit., Levels of Evidence: Therapeutic, Level IV: Case study., (© 2016 The Author(s).)

Objective: Elimination of plantarization of the tip of the toe and torsion of digit 1 (D1) or D5 using percutaneous tenotomy of the flexor hallucis longus (FHL) - or the flexor digitorum longus (FDL) muscle., Indications: Flexible, in some cases also fixated hyperflexion misalignment and torsion misalignment of the distal phalanx of the toe with plantarization of physiologically non-loaded bearing parts of the toes in patients with diabetic foot syndrome (neuropathy)., Contraindications: Critical limb ischemia., Surgical Technique: Percutaneous tenotomy of the FHL or FDL tendons using the minimally invasive lancet technique without the use of a tourniquet while the tendon is flexed by causing hyperextension of the distal phalanx and simultaneous extension of the distal interphalangeal (DIP) or interphalangeal (IP) joints., Postoperative Management: Immediate full weight-bearing mobilization in sufficiently wide protective footwear with customized cushioning or a diabetes-adapted foot bed, follow-up in initially frequent intervals (2-4 per week) in order to track the development of the transfer lesions. In the case of existing wounds, more frequent visits and relief of the wounds using a post-operative shoe are required. No thrombosis prevention with full weight-bearing is necessary., Results: In 138 patients with diabetic foot syndrome with polyneuropathy, of which 90 were men (65.2 %) and 48 were women (34.8 %) with a median age of 65.1 years, a total of 291 toe operations with tenotomy of the FHL- or FDL-tendon were performed. Patients were either acutely affected by apical toe lesions (92.1 %) or showed an increased risk of ulcer formation (7.9 %). The median time to closing of the wound was 13 days. It was longer with higher Wagner stages. Of the surgically treated toes 3.1 % were affected by nosocomial infections. At the 1‑year follow-up 92.4 % of the patients did not show pathological results of the operated toe. Recurrence of the DFS occurred mostly during the first 6 months postoperatively. In the first year postoperatively 68.1 % of the patients remained in remission. Of the toes with Wagner grade 0, 93.7 % were free of local recurrence during the entire monitoring period and 72.2 % of the operated toes with Wagner grade 3. Within the first 1.5-8.5 months 13 % of the patients were affected by transfer lesions.

Hallux deformities other than hallux valgus, especially those in the sagittal plane, have not yet been elucidated in the feet of patients with rheumatoid arthritis. The objectives of the present study were to classify rheumatoid arthritis hallux deformity in both the horizontal and the sagittal planes and investigate its relationship with flatfoot. Using a cross-sectional study design, we assessed patients with rheumatoid arthritis (527 feet in 274 patients) using radiographs and classified the deformity patterns of the great toes using cluster analysis. Of the 274 patients, the range of motion in the metatarsophalangeal joint was clinically investigated in 44 (16.1%) patients. The great toes could be divided into 5 clusters according to the characteristic configuration as follows: cluster I (normal type), cluster II (hallux valgus type), cluster III (boutonniere type), cluster IV (boutonniere with hallux valgus type), and cluster V (swan-neck type). Radiographic measurements revealed the characteristic deformities of each cluster, including splayed foot for cluster II; flat foot, metatarsal primus elevatus, and plantar displacement of the proximal phalanx for cluster III; and a mixture of these characteristics for cluster IV. Plantar displacement of the proximal phalanx, which was a specific characteristic of the boutonniere deformity, correlated significantly with the decreased dorsiflexion in the metatarsophalangeal joint. Our classification method revealed the relationship of hallux deformity in the sagittal plane to flatfoot and also demonstrated the usefulness of measuring basal phalanx displacement in predicting the range of motion of the metatarsophalangeal joint., (Copyright © 2016 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: KCNH1 encodes a voltage-gated potassium channel that is predominantly expressed in the central nervous system. Mutations in this gene were recently found to be responsible for Temple-Baraitser Syndrome (TMBTS) and Zimmermann-Laband syndrome (ZLS)., Methods: Here, we report a new case of TMBTS diagnosed in a Lebanese child. Whole genome sequencing was carried out on DNA samples of the proband and his parents to identify mutations associated with this disease. Sanger sequencing was performed to confirm the presence of detected variants., Results: Whole genome sequencing revealed three missense mutations in TMBTS patient: c.1042G > A in KCNH1, c.2131 T > C in STK36, and c.726C > A in ZNF517. According to all predictors, mutation in KCNH1 is damaging de novo mutation that results in substitution of Glycine by Arginine, i.e., p.(Gly348Arg). This mutation was already reported in a patient with ZLS that could affect the connecting loop between helices S4-S5 of KCNH1 with a gain of function effect., Conclusions: Our findings demonstrate that KCNH1 mutations cause TMBTS and expand the mutational spectrum of KCNH1 in TMBTS. In addition, all cases of TMBTS were reviewed and compared to ZLS. We suggest that the two syndromes are a continuum and that the variability in the phenotypes is the result of the involvement of genetic modifiers.

KCNH1 mutations have been identified in patients with Zimmermann-Laband syndrome and Temple-Baraitser syndrome, as well as patients with uncharacterized syndromes with intellectual disability and overlapping features. These syndromes include dysmorphic facial features, nail hypo/aplasia, thumb and skeletal anomalies, intellectual disability, and seizures. We report the epilepsy phenotype in patients with KCNH1 mutations. Demographic data, electroclinical features, response to antiepileptic drugs, and results of significant diagnostic investigations of nine patients carrying mutations in KCNH1 were obtained from referring centres. Epilepsy was present in 7/9 patients. Both generalized and focal tonic-clonic seizures were observed. Complete seizure control was achieved with pharmacological treatment in 2/7 patients; polytherapy was required in 4/7 patients. Status epilepticus occurred in 4/7 patients. EEG showed a diffusely slow background in 7/7 patients with epilepsy, with variable epileptiform abnormalities. Cerebral folate deficiency and an increase in urinary hypoxanthine and uridine were observed in one patient. Epilepsy is a key phenotypic feature in most individuals with KCNH1-related syndromes, suggesting a direct role of KCNH1 in epileptogenesis, although the underlying mechanism is not understood.

Temple syndrome (TS) is caused by abnormal expression of genes at the imprinted locus 14q32. A subset of TS patients carry 14q32 deletions of paternal origin. We aimed to define possible genotype-phenotype correlations and to highlight the prevalence of thyroid dysfunction, which is a previously unreported feature of TS. We described four new patients who carry deletions of paternal origin at 14q32 detected by array-CGH and reviewed nine patients reported in the medical literature. We compared clinical features with respect to deletion size and position. Expression of DLK1 is altered in all the patients with TS, but intellectual disability (ID) is present only in patients with larger deletions extending proximally to the imprinted locus. This study led to the identification of an ID "critical region" containing four annotated genes including YY1 as the strongest candidate. Furthermore, we described three patients with thyroid dysfunction, which progressed to papillary carcinoma at a very young age in two of them. We conclude that DLK1 loss of function is likely to be responsible for the core features of TS, while haploinsufficiency of a gene outside the imprinted region causes ID. Thyroid cancer may be an unrecognized feature and monitoring for thyroid dysfunction should thus be considered in TS patients., (© 2015 Wiley Periodicals, Inc.)

Anatomic variations of the long flexor tendons of the foot are not common. Tendinous bands connecting the flexor hallucis longus and the flexor digitorum longus are well known and have even been classified. Although the congenital absence of the flexor pollicis longus in the hand is well known, we found no reports of the absence of the flexor hallucis longus in the foot. We describe the case of a 32-year-old female who stepped on a crystal ashtray and transected the flexor hallucis tendon arising from the flexor digitorum longus. During surgery, the absence of the proper flexor hallucis longus muscle and tendon became apparent. This anomaly appears to be extremely rare, and its clinical importance is unknown, although our patient reported no functional problems before the accident., (Copyright © 2016 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Fibrodysplasia ossificans progressiva is a rare autosomal dominantly inherited disorder of connective tissue caused by mutations in the gene encoding for ACVR1/ALK2, a bone morphogenetic protein type I receptor. It is mainly characterized by congenital malformations of the great toes and the formation of qualitatively normal bone in extra-skeletal sites leading to severe disability and eventually death. We present a sporadic case from Northern Tanzania with a minor unilateral hallux anomaly and the common ACVR1 c.617G>A mutation.

Longitudinal epiphyseal bracket is a rare ossification anomaly involving the tubular bones of the hand or foot that have a proximal epiphysis, which becomes deformed as a result of the bracket. Untreated, the deformity becomes worse with age, because longitudinal growth cannot occur. The present report discusses the use of polymethylmethacrylate at the preossified disease stage in 2 patients with first metatarsal involvement. A medical record and radiographic review was performed for 2 children (3 feet), aged 1 year and 2 years and 5 months, who were treated with insertion of polymethylmethacrylate after excision of the aberrant epiphyseal bracket. Two different radiographic parameters (i.e., the intraosseous angulation and the metadiaphyseal length index) were used to measure the effect of treatment on the subsequent longitudinal growth of the metatarsals. An excellent clinical result after a long follow-up period was observed in 2 feet, and a good result was documented in 1 foot, which developed hallux valgus angulation. The use of polymethylmethacrylate as an interposition material after excision of the aberrant metatarsal epiphyseal bracket appeared to be an effective method of treatment during the preossified first stage of the disease, despite the general recommendation to use a cement spacer during the third ossified stage. Normal longitudinal growth of the metatarsals was noted without complications or risk of deformity recurrence., (Copyright © 2015 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

KCNH1 mutations have recently been described in six individuals with Temple-Baraitser syndrome (TMBTS) and six individuals with Zimmermann-Laband syndrome (ZLS). TMBTS is characterized by intellectual disability (ID), epilepsy, dysmorphic facial features, broad thumbs and great toes with absent/hypoplastic nails. ZLS is characterized by facial dysmorphism including coarsening of the face and a large nose, gingival enlargement, ID, hypoplasia of terminal phalanges and nails and hypertrichosis. In this study, we present four additional unrelated individuals with de novo KCNH1 mutations from ID cohorts. We report on a novel recurrent pathogenic KCNH1 variant in three individuals and add a fourth individual with a previously TMBTS-associated KCNH1 variant. Neither TMBTS nor ZLS was suspected clinically. KCNH1 encodes a voltage-gated potassium channel, which is not only highly expressed in the central nervous system, but also seems to play an important role during development. Clinical evaluation of our mutation-positive individuals revealed that one of the main characteristics of TMBTS/ZLS, namely the pronounced nail hypoplasia of the great toes and thumbs, can be mild and develop over time. Clinical comparison of all published KCNH1 mutation-positive individuals revealed a similar facial but variable limb phenotype. KCNH1 mutation-positive individuals present with severe ID, neonatal hypotonia, hypertelorism, broad nasal tip, wide mouth, nail a/hypoplasia, a proximal implanted and long thumb and long great toes. In summary, we show that the phenotypic variability of individuals with KCNH1 mutations is more pronounced than previously expected, and we discuss whether KCNH1 mutations allow for "lumping" or for "splitting" of TMBTS and ZLS.

This study reports on two individuals with Temple-Baraitser syndrome, manifesting typical hallux and pollex findings, global developmental delay, and seizures. In the five previous cases identified to date, consistent craniofacial and osseous characteristics have been observed. The children described herein exhibit minor differences within this phenotype and are older, highlighting the phenotypic variability and natural history of the clinical and radiographic findings.

Temple-Baraitser syndrome (TBS) is a multisystem developmental disorder characterized by intellectual disability, epilepsy, and hypoplasia or aplasia of the nails of the thumb and great toe. Here we report damaging de novo mutations in KCNH1 (encoding a protein called ether à go-go, EAG1 or KV10.1), a voltage-gated potassium channel that is predominantly expressed in the central nervous system (CNS), in six individuals with TBS. Characterization of the mutant channels in both Xenopus laevis oocytes and human HEK293T cells showed a decreased threshold of activation and delayed deactivation, demonstrating that TBS-associated KCNH1 mutations lead to deleterious gain of function. Consistent with this result, we find that two mothers of children with TBS, who have epilepsy but are otherwise healthy, are low-level (10% and 27%) mosaic carriers of pathogenic KCNH1 mutations. Consistent with recent reports, this finding demonstrates that the etiology of many unresolved CNS disorders, including epilepsies, might be explained by pathogenic mosaic mutations.

Longitudinal bracketed epiphysis (delta phalanx) is a rare congenital anomaly that affects phalanges in the hand more commonly than toes. We present a rare case of congenital hallux varus with longitudinal bracketed epiphysis of proximal phalanx with bifid distal phalanx of the great toe, which was managed with monorail type of external fixator. To the best of our knowledge, this is the first report of its successful implementation in simultaneous treatment of longitudinal bracketed epiphysis of the proximal phalanx of the great toe and hallux varus. Apart from adding to the literature a case of rare subtype of delta phalanx with hallux varus, the present study highlights the role of a reliable alternative in its management.

This article reports on two children with congenital unilateral tibial dysplasia with lateral bowing with no associated sagittal plane deformity. In both cases, it is associated with ipsilateral duplication of the hallux. Long-term follow-up of the patients showed spontaneous, almost complete resolution of the bowing without progressing into fracture or pseudoarthrosis. Leg length discrepancy appeared to be the only orthopedic sequela related to this phenomenon.

Congenital anterolateral bowing of the tibia is generally considered a precursor of congenital pseudarthrosis of the tibia (CPT), which is usually associated with neurofibromatosis type 1 (NF1), a common autosomal dominant genetic disorder. In many cases, NF1 is initially suspected following the presentation of a child with anterolateral tibial bowing. The prognosis of CPT is poor, and amputation may be required. Congenital anterolateral bowing of the tibia combined with ipsilateral polydactyly of the hallux (CABTP) is a rare entity that resembles the anterolateral tibial bowing that occurs in association with CPT, and may be misdiagnosed as NF1. However, spontaneous correction of the tibial bowing with an almost normal fibula has been described in all previously reported cases. Here, we report three patients with CABTP and discuss the physical and imaging characteristics and follow-up results. We suggest that given the spontaneous resolution of bowing, the absence of neurocutaneous signs and the relatively favorable prognosis, CABTP is a distinct entity that merits its own place within the field of anterolateral bowing of the tibia and has no association with CPT or NF1. This should help avoid unnecessary investigations and interventions for NF1. This article shows for the first time tibial duplication in the area of bowing, with two medullary canals surrounded by well-defined cortex on CT., (Copyright © 2012 Wiley Periodicals, Inc.)

Juvenile hallux valgus (JHV) is a relatively common condition in the female adolescent. The etiology of the condition has been attributed to various deformities in the forefoot, ranging from the first metatarsophalangeal joint, the morphology of the distal metatarsal, and the intermetatarsal angle (IMA). There have been very few studies evaluating the first metarsocuneiform (MTC) joint, and the results available vary. The purpose of this study is to more critically evaluate the MTC joint with novel angular measurements as a contributor to JHV. A cohort of 46 feet from 29 patients (average age 14.2 years) with hallux valgus as defined as IMA of greater than 10 degrees were evaluated. The hallux valgus angle, IMA, base of first metatarsal to articular surface of medial cuneiform angle, first metatarsal to cuneiform (1MCA), second metatarsal to cuneiform (2MCA), intrinsic medial cuneiform obliquity angle (COA), distal metatarsal articular angle, and ratio of first cuneiform to second cuneiform length were measured. The same was done for an age-matched control group of 36 normal feet from 25 patients (average age 13.2 years). The two groups were statistically compared. There were several statistically significant differences between the study and control groups. Naturally, the hallux valgus angle and IMA were statistically greater by definition. In addition, the distal metatarsal articular angle and 1MCA were significantly larger in the study group. The magnitude of the 2MCA was found to positively correlate with the magnitude of the IMA. The COA angle was not found to be statistically different. In conclusion, the role of the MTC joint in JHV has been evaluated earlier with varying results. The objective of this study is to critically evaluate the MTC joint with novel angular measurements to delineate its contribution to JHV. One such novel measurement is the 1MCA. The statistically significant increase in 1MCA suggests that a property intrinsic to the articulation between the medial cuneiform and the first metatarsal may be involved in JHV. Another angle, the 2MCA was found to positively correlated with increased IMA, further implicating the MTC joint as a contributor to increased IMA and thus, JHV. Third, the COA was used to define the intrinsic obliquity of the medial cuneiform articular angle. This angle was not found to be statistically different between the study and control groups, suggesting that the morphology of the cuneiform is not involved in JHV.

Between March and October 2008, the nails of 541 (252 females, 289 males) consecutively born neonates with an average age of 3.2 days were examined in the Neonatology Unit. Of these newborns with nail disorders, 36 were re-examined after a period that ranged from seven days to six months. The most frequent nail alteration was the incomplete development of the hallux nail, which was triangular - sometimes trapezoidal - shaped. This alteration, which had been previously reported in the literature as congenital hypertrophy of the lateral folds of the hallux, spontaneously regressed within one to three months in the infants re-examined. There was no associated inflammation or onychocryptosis at any time. The apparent hypertrophy of the nail folds seemed to be secondary to the lack of pressure of the nail lamina.

Congenital aplasia of the hallux (big toe) was observed in seven adult and infant members of a free-ranging group of silvery marmosets (Mico argentatus) in the Alter do Chão savannah of central Amazonia. Apparently heritable, the condition was more common in males (80%) than females (50%) but was found in no other members of the population. Animals with the condition presented normal behaviour.

Background: To evaluate the prevalence and localization of abnormalities in the hallucal sesamoids detectable by magnetic resonance (MR) imaging in patients with forefoot pain and to determine which pathologies of tarsus, metatarsus and phalanges are associated with these abnormalities., Materials and Methods: The forefoot MRI examinations of 50 consecutive patients (32 females, 18 males; mean age 51 years, age range 20-86 years) were retrospectively analyzed by two musculoskeletal radiologists. A minimum of coronal and sagittal T1-weighted images and STIR images or T2-weighted images with fat saturation were performed on a 1.5-T scanner. Abnormal findings in the sesamoids were correlated with pathology in the I.MTP (metatarsal-phalangeal) joint, pathology in other parts of the forefoot and clinical information., Results: Signal abnormalities of the sesamoids were found in 7 patients out of 50 (14%). Two patients presented a bone marrow edema (BME) in both sesamoids, in 1 patient only the lateral one was affected; all three associated with pathology and pain in the I.MTP joint. In four patients only the medial sesamoid was affected, not associated with pathology in the I.MTP joint but with pathology in other parts of the forefoot., Conclusion: The prevalence of signal abnormalities in hallucal sesamoids was 14%. BME of the lateral sesamoid or of both were predominantly associated with pathology in the I.MTP joint. In contrast, signal abnormalities of the medial sesamoid, without affection of the lateral one, were associated with pathology in other parts of the forefoot suggesting an overuse injury as a result of compensating posture., (Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.)

The first ray is the most important structure of the forefoot in its contribution to normal locomotion. Because first ray dysfunction is encountered in clinical practice with the development of hallux valgus, metatarsus primus varus, and hallux rigidus, there has been a belief that there is a mechanical basis for these conditions. Since publications in the 1930s, there has been significant research focused on the first ray. This article discusses the subtleties of normal and abnormal mechanics of the first ray to promote a better understanding for foot and ankle practitioners when treating these various disorders.

Background: Diabetes is the most common endocrinologic complication during pregnancy, and poor control can lead to a variety of congenital anomalies in the fetus. However, it is often difficult to differentiate between diabetes-related anomalies and an underlying genetic syndrome. In the 1990s it was proposed that preaxial hallucal polydactyly, particularly when proximally placed, was a distinguishing feature of diabetic embryopathy., Methods: We summarize the clinical findings in 18 patients (five previously reported in abstract form) with diabetic embryopathy and preaxial hallucal polydactyly to determine which features are most suggestive of diabetic embryopathy., Results: All 18 patients had preaxial hallucal polydactyly (seven bilateral, 11 unilateral), of which 15 patients had proximal implantation of the extra hallux. Further skeletal findings included the following: segmentation anomalies of the spine, equinovarus deformity of the feet, tibial hemimelia, hip dysplasia, and femoral hypoplasia. Upper limb malformations were rare. Eleven of the 18 mothers had prepregnancy insulin-dependent diabetes, while one mother had prepregnancy type 2 diabetes that required insulin therapy in the 3(rd) trimester. Five mothers had gestational diabetes that required insulin and one mother had gestational diabetes that was controlled by diet. The majority of mothers had poorly controlled diabetes during the pregnancy., Conclusions: Proximally placed preaxial hallucal polydactyly, particularly when coupled with segmentation anomalies of the spine and tibial hemimelia, is highly suggestive of diabetic embryopathy. Varying degrees of diabetes in the mothers point to a possible genetic predisposition interacting with the teratogenic effects of poor glycemic control leading to specific limb anomalies.

Only a few nail dystrophies may be improved by surgery: malalignment of the big toenail, racquet thumbs, trapezoidal nails, and vertical implantation of the nail on the fifth toe. Knowledge of the surgical management of these deformities may allow a nice cosmetic outcome if performed by skilled surgeons.

We present a case of a male with severe mental retardation, seizure disorder, and absence/hypoplasia of the thumb and great toe nails. This combination of clinical findings has been reported only once previously. We suggest it represents a distinct syndrome. Our case has the additional finding of broad thumbs.

Background: A clawed hallux is defined as extension of the first metatarsophalangeal (MTP) joint combined with flexion of the interphalangeal (IP) joint. Two operative procedures, the modified Jones procedure and flexor hallucis longus (FHL) transfer, are indicated for correction. The purpose of this study were to evaluate the overall effectiveness of these two procedures in correcting both the clawed hallux deformity and its mechanical consequences and to compare their effect on postoperative plantar pressures., Methods: The modified Jones procedure and FHL transfer were done on cadaver specimens that were tested before and after surgery in a specialized foot-loading frame. We quantified the angular correction of the MTP and the IP joints, as well as the plantar pressures under the head of the first metatarsal and the hallux., Results: Both surgeries were equally effective in correcting the angular deformity at the MTP and IP joints (p = 0.037 and 0.0020, respectively). A significant reduction in the plantar pressure (p = 0.015) beneath the first metatarsal was observed with both the modified Jones procedure and the FHL transfer. Overall, there was no significant difference between preoperative and postoperative pressures beneath the hallux (p = 0.5); however, for the FHL overpull group there was significantly less pressure beneath the hallux after surgery (p = 0.014)., Conclusions: The two surgeries produced similar results, but the FHL transfer does not require fusion of the hallux, which is considered an undesirable co-morbidity of the modified Jones procedure.

Congenital unilateral anterolateral tibial bowing in combination with a bifid ipsilateral great toe is a very rare deformity which resembles the anterolateral tibial bowing that occurs in association with congenital pseudarthrosis of the tibia. However, spontaneous resolution of the deformity without operative treatment and with a continuously straight fibula has been described in all previously reported cases. We report three additional cases and discuss the options for treatment. We suggest that this is a specific entity within the field of anterolateral bowing of the tibia and conclude that it has a much better prognosis than congenital pseudarthrosis of the tibia, although conservative treatment alone may not be sufficient.

Macrodactyly involving the great toe is difficult to treat when both the functional and cosmetic problems are addressed simultaneously. Partial resection of the distal phalanx is an easy way to reduce the length of the involved toe. However, there are cosmetic concerns with loss of the toenail. The authors report on a clinical case in which shortening and debulking of the toe was performed while preserving the hallux nail. The nail complex was transferred as an island flap to the dorsal aspect of the proximal phalanx. At the 1-year follow-up, the length of the reconstructed toe was significantly decreased, with a normal-looking nail.

Multiple toes may develop on the medial or lateral side of the forefoot or in its middle. This may involve duplication of only the distal phalanx or the whole hallux including the metatarsal. In a duplicated big toe, the phalanx to be maintained, because short muscles of the leg are attached to it, is usually localized medially. A rare case of dysplasia of the first metatarsus, following a resection indicated in childhood for a hallux triples, is described in a 20-year-old girl. In order to remove hallux insufficiency and an overloading of the middle metatarsals, the authors decided to carry out a one-stage prolongation of the first metatarsal, using an autologous tricorticcal graft collected from the pelvis and a dynamic compression plate. No surgical treatment of the middle metatarsals was indicated because a disproportionate, short foot would result. Both the subjective and objective status of the patient at 6 months after the operation showed that the non-standard prolongation procedure was correctly indicated and allowed for physiological loading of the foot and restoration of normal walking.