Case report of surgical fixation of delayed union biphalangeal toe fractures at the fusion sites.

Introduction: The prognosis for toe fractures with coalition is generally good, but in some cases, bone union may not be achieved. This is the report in which good results are obtained by surgery for a painful delayed union of biphalangeal toe fractures. Case Report: Case 1: A 64-year-old Japanese woman had left toe pain for 7 months. Plain radiography showed fourth toe fracture with coalition. Surgical fixation was performed. Case 2: A 63-year-old Japanese woman had left toe pain for a month. Plain radiography showed third toe fracture with coalition. No improvement was achieved with conservative treatment, and surgical treatment was performed. Conclusion: Surgical treatment should be performed for the nonunion of symphalangistic distal phalanx fractures with long-term pain.

Prolonged Union in Conservative Treatment of Symphalangeal Toe Fractures: Case Series.

Background: Toe symphalangism is characterized by a fusion of the interphalangeal joint between the middle and distal phalanges. While typical lesser toe fractures heal well with conservative treatment, in our clinical experience, we encountered patients with symphalangeal toe fractures who experienced long-lasting pain and delayed radiographic union. Therefore, this study aimed to report radiographic outcomes following conservative treatment of symphalangeal fractures of the lesser toes. Methods: We retrospectively reviewed 14 patients with symphalangeal lesser toe fractures who were treated conservatively. We investigated the mechanism of injury and measured the time from the initial injury date to the complete radiographic union. The fracture gap distance was measured on an initial lateral radiograph. Results: Symphalangeal fractures involved the fourth toe in 4 patients (28.5%) and the fifth toe in 10 patients (71.4%). Regarding the mechanism of injury, 6 patients (42.9%) were injured by stubbing or bumping into the door, 5 patients (35.7%) were injured by tripping, 2 patients (14.3%) were injured by heavy objects falling directly on their toes, and 1 patient (2.3%) complained of pain after wearing pointed shoes for half a day. The mean time to complete union was 9.1 months, and the median period was 5.5 months (range, 0.8-29 months). The initial gap of the fracture was 0.60 mm (range, 0.30-1.04 mm). Conclusions: The results of our case series may help counsel patients in the outpatient clinic that prolonged healing time may be required for the union of symphalangeal toe fractures.

Proximal interphalangeal-level fracture in patient with symphalangism.

Symphalangism is a rare, congenital syndrome involving ankylosis of the interphalangeal joints. We present a rare case of fracture at the level of a fused proximal interphalangeal joint in a patient with proximal symphalangism of the hand. Nonoperative management with splinting resulted in osseous healing and restored baseline function.

Esophageal atresia/tracheoesophageal fistula and proximal symphalangism in a patient with a NOG nonsense mutation.

Esophageal atresia and tracheoesophageal fistula (EA/TEF) are relatively common malformations of the human foregut. The etiology remains incompletely understood with genetic causes identified in a small minority of affected patients. We present the case of a newborn with type C EA/TEF along with proximal symphalangism found to have a de novo NOG nonsense mutation. Patients with chromosome 17q deletions including the NOG gene have previously been reported to have EA/TEF but mutations in the gene have not been identified in patients with this malformation. This case provides evidence that haploinsufficiency for NOG may be the cause for EA/TEF in the 17q deletion syndrome and suggests that the clinical spectrum of NOG-related symphalangism spectrum disorders may include EA/TEF.

Multiple synostoses syndrome: Radiological findings and orthopedic management in a single institution cohort.

PURPOSE: Multiple synostoses syndrome (MSS) is a rare genetic condition. Classical features consist of joint fusions which notably start at the distal phalanx of the hands and feet with symphalangism progressing proximally to carpal, tarsal, radio-ulnar, and radio-humeral joints, as well as the spine. Usually, genetic testing reveals a mutation of the NOG gene with variable expressivity. The goal was to present the anatomical, functional, and radiological presentations of MSS in a series of patients followed since childhood. METHODS: Patients with more than 3 synostoses affecting at least one hand joint were included. When possible, genetic screening was offered. RESULTS: A retrospective study was performed from 1972 to 2017 and included 14 patients with a mean follow-up of 18.6 years. Mutation of the NOG protein coding gene was seen in 3 patients. All presented with tarsal synostoses including 9 carpal, 7 elbow, and 2 vertebral fusions. Facial dysmorphia was seen in 6 patients and 3 were hearing-impaired. Surgical treatment of tarsal synostosis was performed in 4 patients. Progressing joint fusions were invariably seen on x-rays amongst adults. CONCLUSION: Long radiological follow-up allowed the assessment of MSS progression. Feet deformities resulted in a severe impact on quality of life, and neurological complications secondary to spine fusions warranted performing at least one imaging study in childhood. As there is no treatment of ankylosis, physiotherapy is not recommended. However, surgical arthrodesis for the treatment of pain may have reasonable outcomes.

Is the Conductive Hearing Loss in NOG-Related Symphalangism Spectrum Disorder Congenital?

We describe a dominant Japanese patient with progressive conductive hearing loss who was diagnosed with NOG-related symphalangism spectrum disorder (NOG-SSD), a spectrum of congenital stapes fixation syndromes caused by NOG mutations. Based on the clinical features, including proximal symphalangism, conductive hearing loss, hyper-opia, and short, broad middle, and distal phalanges of the thumbs, his family was diagnosed with stapes ankylosis with broad thumbs and toes syndrome (SABTT). Genetic analysis revealed a heterozygous substitution in the NOG gene, c.645C>A, p.C215* in affected family individuals. He had normal hearing on auditory brainstem response (ABR) testing at ages 9 months and 1 and 2 years. He was followed up to evaluate the hearing level because of his family history of hearing loss caused by SABTT. Follow-up pure tone average testing revealed the development of progressive conductive hearing loss. Stapes surgery was performed, and his post-operative hearing threshold improved to normal in both ears. According to hearing test results, the stapes ankylosis in our SABTT patient seemed to be incomplete at birth and progressive in early childhood. The ABR results in our patient indicated the possibility that newborn hearing screening may not detect conductive hearing loss in patients with NOG-SSD. Hence, children with a family history and/or known congenital joint abnormality should undergo periodic hearing tests due to possible progressive hearing loss. Because of high success rates of stapes surgeries in cases of SABTT, early surgical interventions would help minimise the negative effect of hearing loss during school age. Identification of the nature of conductive hearing loss due to progressive stapes ankylosis allows for better genetic counselling and proper intervention in NOG-SSD patients.

Juberg-Hayward syndrome and Roberts syndrome are allelic, caused by mutations in ESCO2.

OBJECTIVE: Juberg-Hayward syndrome (JHS; MIM 216100) is a rare autosomal recessive malformation syndrome, characterized by cleft lip/palate, microcephaly, ptosis, hypoplasia or aplasia of thumbs, short stature, dislocation of radial head, and fusion of humerus and radius leading to elbow restriction. A homozygous mutation in ESCO2 has recently been reported to cause Juberg-Hayward syndrome. Our objective was to investigate the molecular etiology of Juberg-Hayward syndrome in two affected Lisu tribe brothers. MATERIALS AND METHODS: Two patients, the unaffected parents, and two unaffected siblings were studied. Clinical and radiographic examination, whole exome sequencing, Sanger sequencing, Western blot analysis, and chromosome testing were performed. RESULTS: Two affected brothers had characteristic features of Juberg-Hayward syndrome, except for the absence of microcephaly. The elder brother had bilateral cleft lip and palate, short stature, humeroradial synostosis, and simple partial seizure with secondary generalization. The younger brother had unilateral cleft lip and palate, short stature, and dislocation of radial heads. The homozygous (c.1654C > T; p.Arg552Ter) mutation in ESCO2 was identified in both patients. The other unaffected members of the family were heterozygous for the mutation. The presence of humeroradial synostosis and radial head dislocation in the same family is consistent with both being in the same spectrum of forearm malformations. Chromosome testing of the affected patients showed premature centromere separation. Western blot analysis showed reduced amount of truncated protein. CONCLUSION: Our findings confirm that a homozygous mutation in ESCO2 is the underlying cause of Juberg-Hayward syndrome. Microcephaly does not appear to be a consistent feature of the syndrome.

Identification of an unknown frameshift variant of NOG in a Han Chinese family with proximal symphalangism.

Proximal symphalangism (SYM1) is an autosomal dominant disorder manifested by ankylosis of the proximal interphalangeal joints of fingers, carpal and tarsal bone fusion, and conductive hearing loss in some cases. Herein, we clinically diagnosed a Chinese patient with fusions of the bilateral proximal interphalangeal joints in the 2-5 digits without conductive hearing loss. Family history investigation revealed that his mother and grandfather also suffered from SYM1. Whole exome sequencing was performed to detect the genetic lesion of the family. The candidate gene variants were validated by Sanger sequencing. By data filtering, co-segregation analysis and bioinformatics analysis, we highly suspected that an unknown heterozygous frameshift variant (c.635_636insG, p.Q213Pfs*57) in NOG was responsible for the SYM1 in the family. This variant was predicted to be deleterious and resulted in a prolonged protein. This finding broadened the spectrum of NOG mutations associated with SYM1 and contributed to genetic diagnosis and counseling of families with SYM1.

Multiple synostoses syndrome: Clinical report and retrospective analysis.

Multiple synostoses syndrome (SYNS1; OMIM# 186500) is a rare autosomal dominant disorder reported in a few cases worldwide. We report a Chinese pedigree characterized by proximal symphalangism, conductive hearing loss, and distinctive facies. We examined the genetic cause and reviewed the literature to discuss the pathogeny, treatment, and prevention of SYNS1. Audiological, ophthalmological, and radiological examinations were evaluated. Whole-exome sequencing (WES) was performed to identify mutations in the proband and her parents. Sanger sequencing was used to verify the results for the proband, parents, and grandmother. The literature on the genotype-phenotype correlation was reviewed. The patient was diagnosed with multiple synostoses syndrome clinically. WES and bioinformatic analysis revealed a novel missense mutation in the NOG gene, c.554C>G (p.Ser185Cys), cosegregated in this family. The literature review showed that the phenotype varies widely, but the typical facies, conductive hearing loss, and proximal symphalangism occurred frequently. All reported mutations are highly conserved in mammals based on conservation analysis, and there are regional hot spots for these mutations. However, no distinct genotype-phenotype correlations have been identified for mutations in NOG in different races. Regular systematic examinations and hearing aids are beneficial for this syndrome. However, the outcomes of otomicrosurgery are not encouraging owing to the regrowth of bone. This study expanded the mutation spectrum of NOG and is the first report of SYNS1 in a Chinese family. Genetic testing is recommended as part of the diagnosis of syndromic deafness. A clinical genetic evaluation is essential to guide prevention, such as preimplantation genetic diagnosis.

Identification of a novel mutation of NOG in family with proximal symphalangism and early genetic counseling.

BACKGROUND: Proximal symphalangism is a rare disease with multiple phenotypes including reduced proximal interphalangeal joint space, symphalangism of the 4th and/or 5th finger, as well as hearing loss. At present, at least two types of proximal symphalangism have been identified in the clinic. One is proximal symphalangism-1A (SYM1A), which is caused by genetic variants in Noggin (NOG), another is proximal symphalangism-1B (SYM1B), which is resulted from Growth Differentiation Factor 5 (GDF5) mutations. CASE PRESENTATION: Here, we reported a Chinese family with symphalangism of the 4th and/or 5th finger and moderate deafness. The proband was a 13-year-old girl with normal intelligence but symphalangism of the 4th finger in the left hand and moderate deafness. Hearing testing and inner ear CT scan suggested that the proband suffered from structural deafness. Family history investigation found that her father (II-3) and grandmother (I-2) also suffered from hearing loss and symphalangism. Target sequencing identified a novel heterozygous NOG mutation, c.690C > G/p.C230W, which was the genetic lesion of the affected family. Bioinformatics analysis and public databases filtering further confirmed the pathogenicity of the novel mutation. Furthermore, we assisted the family to deliver a baby girl who did not carry the mutation by genetic counseling and prenatal diagnosis using amniotic fluid DNA sequencing. CONCLUSION: In this study, we identified a novel NOG mutation (c.690C > G/p.C230W) by target sequencing and helped the family to deliver a baby who did not carry the mutation. Our study expanded the spectrum of NOG mutations and contributed to genetic diagnosis and counseling of families with SYM1A.

Novel NOG (p.P42S) mutation causes proximal symphalangism in a four-generation Chinese family.

BACKGROUND: Proximal symphalangism (SYM1; OMIM 185800), also called Cushing's symphalangism, is an infrequent autosomal dominant disease. An SYM1 patient typically features variable fusion of proximal interphalangeal joints in the hands and feet. METHODS: We recruited a four-generation Chinese non-consanguineous family with SYM1. We examined their hands and feet using X-rays to confirm fusion of proximal interphalangeal joints. We evaluated their audiology using standard audiometric procedures and equipment. Then, we identified genetic variants using whole exome sequencing and validated mutations using Sanger sequencing. Mutation pathogenicity was analyzed with bioinformatics. RESULTS: Radiographs revealed proximal-joint fusion of fingers and toes in the patients. Two elderly individuals (II:1 and II:4) exhibited slight hearing loss. Additionally, we detected a novel heterozygous missense mutation in exon 1 of NOG (NM_005450) c.124C > T, p.(Pro42Ser) in all patients. This c.124C > T mutation is highly conserved across multiple species and the p.(Pro42Ser) variation is potentially highly pathogenic. CONCLUSION: Our results suggest that heterozygous c.124C > T, p.(Pro42Ser) in NOG is a novel mutation that causes human SYM1 phenotype.

Identification of a Novel NOG Missense Mutation in a Chinese Family With Symphalangism and Tarsal Coalitions.

BACKGROUND: Proximal symphalangism (SYM1) is a rare genetic bone disorder characterized by the fusion of proximal interphalangeal joints in the hands and feet. Genetic studies have identified two genes underlying SYM1 as the noggin (NOG) and the growth differentiation factor 5 (GDF5). CASE REPORT: In the present report, a 43-year-old gravida at 11 weeks of gestation was referred for evaluation of abnormal fusions of the joints. In the initial diagnosis, physical examination was undertaken. However, traditional radiological examination was not applied due to the need to protect the fetus, making diagnosis results inefficient to determine the exact disease affecting the proband. To acquire alternative clinical evidences, we conducted radiological examinations on two other affected family members. The radiological examination revealed that they carried the symphalangism accompanied with tarsal coalition, a very rare manifestation of SYM1. A combination of whole exome sequencing (WES) and Sanger sequencing revealed a novel heterozygous missense mutation (c.163G > T; p.Asp55Tyr) in the NOG gene, which could be associated with the observed pathogenic SYM1 in the studied family. The p.Asp55Tyr mutation co-segregated with SYM1 through the affected and unaffected family members. In silico structural modeling of the p.Asp55Tyr mutation showed that it abolishes the interaction with the Arg167 residue and causes a change in the electrostatic potential profile of the type II binding site of the noggin protein. CONCLUSION: Our findings indicate that the genetic test based on WES can be useful in diagnosing SYM1 patients, with particular advantages in preventing the fetus from contacting harmful X-ray through the traditional radiography. The novel pathogenic mutation identified would further expand our understanding of the mutation spectrum of NOG in association with SYM1 disease and provide a guidance on how to determine whether the fetus is affected by SYM1 through the prenatal diagnosis.

The incidence of biphalangeal fifth toe: Comparison of normal population and patients with foot deformity.

BACKGROUND: Pedal biphalangism, which was also defined as symphalangism, is seen at a frequency that cannot be ignored; however, no study can be found in the literature evaluating biphalangism in normal population in comparison to those who have foot disorders. The aim of this study was to evaluate the incidence of the pedal fifth toe symphalangism in normal population and in patients with foot deformity including hallux valgus, pes planus, pes cavus, and pes equinovarus. We hypothesized that pedal fifth toe symphalangism may be a predisposing factor or an accompanying structural variation for foot deformity. MATERIALS: Patients admitted to the emergency department of our center in October and November 2016 were defined as the control group, and patients with the diagnosis of hallux valgus, pes planus, pes cavus, and pes equinovarus treated between 2011 and 2016 in our department were defined as the foot deformity group. Individuals who had anteroposterior, oblique, and lateral radiographs of foot were included in the study. RESULTS: One thousand and four patients participated in the cross-sectional observational study. Biphalangeal fifth toe was found in 328 of 1004 (32.7%) patients. In foot deformity group ( n = 672), 222 patients (33%) had biphalangeal fifth toe. In the control group, 106 (31.9%) of the 332 patients had biphalangeal fifth toe. There was no statistically significant difference in the incidence of biphalangeal fifth toe between the two groups ( p = 0.72). CONCLUSIONS: According to the results of this study, biphalangeal fifth toe is a common pedal anatomical variant seen approximately in one-third of the population who have either foot deformity or not. This information may be valuable for podiatrist undertaking the conservative or surgical treatment of fifth toe-related disorders.

A rare case of thumb polydactyly with metacarpophalangeal joint synostosis.

We report on a rare case of thumb polydactyly with metacarpophalangeal joint synostosis in a 14-year old otherwise healthy boy. Our case can only be classified in the Rotterdam classification, was treated with resection of the hypoplastic radial component and yielded a very satisfactory outcome with a stable thumb.

[Diagnosis and treatment of thumb polydactyly with symphalangism in children].

Objective: To investigate the diagnosis and treatment of thumb polydactyly with symphalangism in children. Methods: Seven cases of thumb polydactyly with symphalangism were treated between January 2013 and May 2017. There were 5 males and 2 females, aged from 10 months to 11 years, with an average age of 3.1 years. The thumb-polydactyly was diagnosed with MRI and it was seen that the base of radial multi-finger and the proximal phalangeal joint were connected by cartilage. All patients were treated with resection, lateral collateral ligament reconstruction, bone osteotomy and internal fixation. Results: The operation was successfully completed, and there was no early complications such as infection and flap necrosis. All patients were followed up 6-23 months (mean, 14.1 months). At last follow-up, there was no deformity finger, scar contracture, and other complications. The extension of the interphalangeal joint was no limited, and the flexion range of the interphalangeal joint was 20-75° (mean, 56.7°). The appearance and function of the thumb was rated as excellent in 3 cases and good in 4 cases by Japanese Society for Surgery of the Hand (JSSH) scoring, with the excellent and good rate of 100%. Conclusion: The thumb polydactyly with symphalangism in children can be combined with clinical manifestations, X-ray film, and MRI examination to diagnose, and can obtain satisfactory results through the reconstruction of lateral collateral ligament, bone osteotomy, and internal fixation.

Autosomal dominant stapes fixation, syndactyly, and symphalangism in a family with NOG mutation: Long term follow-up on surgical treatment.

OBJECTIVE: Evaluation of clinical findings and audiological outcome after surgery in a Danish family with autosomal dominant facio-audio-symphalangism syndrome with stapes fixation, syndactyly and symphalangism. METHODS: Retrospective report on eight affected family members in a Danish family. Clinical investigation included X-ray, audiology and in one case video-recorded surgery. Main outcome measure was audiologic results after stapedectomy. Sanger DNA sequencing of NOG was performed on peripheral blood. RESULTS: Audiologic analysis showed that seven of eight affected family members had bilateral conductive hearing loss. Three patients were treated with stapedectomy, on one or both ears, due to fixation of stapes. All the affected members had syndactyly and symphalangism. A not previously reported mutation in the NOG gene (c.688_699del, p.Cys230_Cys232delins11) was found to segregate with the stapes fixation, syndactyly, and symphalangism. p.Cys230_Cysdelins11 was classified as likely pathogenic according to guidelines from the American College of Medical Genetics and Genomics. CONCLUSION: The clinical presentation of the reported mutation corresponds with previous case reports of families with NOG mutation. In this family, surgery with stapedectomy had lasting effect without renewed fixation of the stapes in a follow up period of 18 months-38 years.

Diagnosis and treatment of thumb polydactyly with symphalangism in children / 中国修复重建外科杂志

Objective: To investigate the diagnosis and treatment of thumb polydactyly with symphalangism in children. Methods: Seven cases of thumb polydactyly with symphalangism were treated between January 2013 and May 2017. There were 5 males and 2 females, aged from 10 months to 11 years, with an average age of 3.1 years. The children were diagnosed with MRI and it was seen that the base of radial multi-finger and the proximal phalangeal joint were connected by cartilage. All patients were treated with resection, lateral collateral ligament reconstruction, bone osteotomy and internal fixation. Results: The operation was successfully completed, and there was no early complications such as infection and flap necrosis. All patients were followed up 6-23 months (mean, 14.1 months). At last follow-up, there was no deformity finger, scar contracture, and other complications. The extension of the interphalangeal joint was no limited, and the range of flexion of the interphalangeal joint was 20-75°(mean, 56.7°). The appearance and function of the thumb was rated as excellent in 3 cases and good in 4 cases by Japanese Society for Surgery of the Hand Scoring (JSSH), with the excellent and good rate of 100%. Conclusion: The thumb polydactyly with symphalangism in children can be combined with clinical manifestations, X-ray film, and MRI examination to diagnose, and can obtain satisfactory results through the reconstruction of lateral collateral ligament, bone osteotomy and internal fixation.

Mobilization of Joints of the Hand with Symphalangism.

This article classifies symphalangism of the hand into three grades and suggests surgical indications. Grade I and early grade II joints can be mobilized with early surgical intervention. Surgical results may vary but even a 20° gain in motion could be helpful for children and their parents. Postoperative passive range-of-motion exercises are very important in maintaining mobility of the joints. It is important that the parents understand exercise may cause some pain and they must be motivated to help their children during the rehabilitation period.

Recurrent missense mutation of GDF5 (p.R438L) causes proximal symphalangism in a British family.

Proximal symphalangism (SYM1B) (OMIM 615298) is an autosomal dominant developmental disorder affecting joint fusion. It is characterized by variable fusions of the proximal interphalangeal joints of the hands, typically of the ring and little finger, with the thumb typically being spared. SYM1 is frequently associated with coalition of tarsal bones and conductive hearing loss. Molecular studies have identified two possible genetic aetiologies for this syndrome, NOG and GDF5. We herein present a British caucasian family with SYM1B caused by a mutation of the GDF5 gene. A mother and her three children presented to the orthopaedic outpatient department predominantly for feet related problems. All patients had multiple tarsal coalitions and hand involvement in the form of either brachydactyly or symphalangism of the proximal and middle phalanx of the little fingers. Genetic testing in the eldest child and his mother identified a heterozygous missense mutation in GDF5 c.1313G>T (p.R438L), thereby establishing SYM1B as the cause of the orthopaedic problems in this family. There were no mutations identified in the NOG gene. This report highlights the importance of thorough history taking, including a three generation family history, and detailed clinical examination of children with fixed planovalgus feet and other family members to detect rare skeletal dysplasia conditions causing pain and deformity, and provides details of the spectrum of problems associated with SYM1B.

Further delineation of facioaudiosymphalangism syndrome: Description of a family with a novel NOG mutation and without hearing loss.

Mutations in the NOG gene give rise to a wide range of clinical phenotypes. Noggin, the protein encoded by this gene is a secreted modulator of multiple pathways involved in both bone and joint development. Proximal symphalangism is commonly observed in patients bearing mutations in this gene, however secondary symptomes are often found including typical facies with hemicylindrical nose with bulbous tip, hyperopia, reduced mobility of multiple joints, hearing loss due to stapes fixation, and recurrent pain from affected joints. With large variation of the phenotype both within and between affected families careful delineation of the genotype-phenotype correlation is needed. In this work we describe a Danish family suffering from SYNS1 due to a novel NOG gene mutation (C230Y). We provide detailed clinical description of the family members presenting rare phenotype of the shoulders shared by affected individuals but no hearing loss, further adding to the phenotypic variability of the syndrome. With these findings we broaden the understanding of NOG-related-symphalangism spectrum disorder. © 2016 Wiley Periodicals, Inc.