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.

Early Results of Surgical Management of Camptodactyly.

BACKGROUND: We hypothesize that surgery for moderate-to-severe camptodactyly (>50 degrees) results in modest gains in range of motion and improved digital position. METHODS: A retrospective analysis of patients undergoing surgery for camptodactyly at a tertiary children's hospital between 2000 and 2014 was performed. Surgery was indicated for patients with persistent, functionally limiting flexion contractures despite observation, therapy, and splinting. Data were collected on demographics, clinical history and presentation, nonoperative management, surgery, and clinical follow-up, focusing on range of motion at the involved joint. Total passive motion (TPM) and total active motion (TAM) at the proximal interphalangeal (PIP) joint was calculated at presentation, preoperative visit, first postoperative visit out of the cast, and last follow-up visit. Average postoperative follow-up was 1.4 years. RESULTS: In total, 31 digits in 22 patients were reviewed. There were 13 males; average age at surgery was 9.6 years. There were 7 type I (infantile), 8 type II (adolescent), and 7 type III (syndromic) patients. All cases involved the PIP joint; 55% involved the small finger. All patients underwent sequential release of contracted structures until maximal extension without compromising vascularity or joint stability was obtained. Z-plasty of the volar skin was performed in 68% of digits, flexor digitorum superficialis tenotomy in 77%, volar plate release in 58%, and collateral ligament release in 48%. All patients were casted postoperatively for an average of 31 days, and 71% of digits had temporary transarticular pin fixation. At initial presentation, mean TPM and TAM were 34 and 24 degrees, respectively. TPM and TAM were 32 and 19 degrees immediately preoperatively, 30 and 13 at the first postoperative visit, and 35 and 25 at the final follow-up. Furthermore, the position of PIP arc of motion was in a more extended position postoperatively. Average TPM arc of motion was from 50 to 82 degrees preoperatively and 28 to 63 degrees at final follow-up; average TAM arc of motion was 62 to 81 degrees preoperatively and 30 to 55 degrees at final follow-up. There were no clinically meaningful differences in results based on camptodactyly type, preoperative motion, or age at surgery. There were no cases of wound infection or dehiscence. Two patients with recurrent contractures opted for subsequent PIP arthrodesis. CONCLUSIONS: Total motion of the PIP joint was similar both preoperatively and postoperatively following surgical release of camptodactyly. However postoperatively, the digit was in a more extended position over this arc of motion. For patients with functionally limiting flexion contractures, surgical release may be beneficial by providing a more extended position, for improved digital release, hygiene, and esthetics. LEVEL OF EVIDENCE: Level IV.

Absent Ring Finger Flexor Digitorum Profundus Presenting as a Jersey Finger.

We report the case of a patient who presented with an apparent acute avulsion of the ring finger flexor digitorum profundus (FDP), or jersey finger. At surgery, the FDP to the ring finger was found to be absent; also absent were the lumbrical to the ring finger and the A5 pulley. Absence of the FDP was confirmed with postoperative imaging. Although absent profundus tendons have been previously reported, none have involved the FDP to the ring finger. However, various reports have described abnormal connections between the ring and little finger flexor tendons.

Pachydermodactyly: An Unknown Entity.

Pachydermodactyly is a rare benign disease that usually affects the dorsal skin and subcutaneous tissue of the proximal interphalangeal joints of the index, middle, ring, and little fingers; the thumb is usually spared. Hyperkeratosis on the dorsal side of the affected areas is common. We present a case of a 19-year-old man who was diagnosed with pachydermodactyly after evaluation of a painless, progressive swelling and hyperkeratosis at the proximal interphalangeal and distal interphalangeal joints of all fingers, bilaterally, for 6 years before presentation. Conservative treatment was prescribed and the patient remains asymptomatic. Given the benign and nonprogressive course of the disease, symptomatic treatment alone is all that is usually required.

The prevalence of the extensor indicis tendon and its variants: a systematic review and meta-analysis.

The tendon of the extensor indicis (EI) is frequently used to restore the loss of function in other digits. However, it shows many variations which include splitting of the extensor indicis proprius (EIP) into two or three distal slips, attachment to fingers other than the index such as the extensor medii proprius (EMP), attachment onto the index and the third finger such as the extensor indicis et medii communis, or attachment to both the index and the thumb such as the extensor pollicis et indicis (EPI). This systematic review gathers the available data on the prevalence of EI tendon and its variation in the hand. Twenty-nine cadaveric studies met the inclusion criteria with a total of 3858 hands. Meta-analysis results yielded an overall pooled prevalence estimate (PPE) of EI of 96.5% and PPEs of 92.6, 7.2 and 0.3% for the single-, double- and triple-slip EIP, respectively. The single-slip EIP is frequently inserted on the ulnar side of the extensor digitorum communis of the index (EDC-index) in 98.3%. The double-slip EIP is located on the ulnar side of the EDC-index in 53.5%, on its radial side in 17% and on both sides in 28.7%. Indian populations showed the highest rate of single-slip EIP and the lowest rate of double-slip EIP when compared to Japanese, Europeans and North Americans. The pooled prevalence of EMP, EMIC and EPI were 3.7, 1.6 and 0.75%, respectively. Knowledge of the variants of the EI tendon and their prevalence should help surgeons in correctly choosing the tendon to transfer in hand surgery.

A mutation in the heparin-binding site of noggin as a novel mechanism of proximal symphalangism and conductive hearing loss.

The access of bone morphogenetic protein (BMP) to the BMP receptors on the cell surface is regulated by its antagonist noggin, which binds to heparan-sulfate proteoglycans on the cell surface. Noggin is encoded by NOG and mutations in the gene are associated with aberrant skeletal formation, such as in the autosomal dominant disorders proximal symphalangism (SYM1), multiple synostoses syndrome, Teunissen-Cremers syndrome, and tarsal-carpal coalition syndrome. NOG mutations affecting a specific function may produce a distinct phenotype. In this study, we investigated a Japanese pedigree with SYM1 and conductive hearing loss and found that it carried a novel heterozygous missense mutation of NOG (c.406C>T; p.R136C) affecting the heparin-binding site of noggin. As no mutations of the heparin-binding site of noggin have previously been reported, we investigated the crystal structure of wild-type noggin to investigate molecular mechanism of the p.R136C mutation. We found that the positively charged arginine at position 136 was predicted to be important for binding to the negatively charged heparan-sulfate proteoglycan (HSPG). An in silico docking analysis showed that one of the salt bridges between noggin and heparin disappeared following the replacement of the arginine with a non-charged cysteine. We propose that the decreased binding affinity of NOG with the p.R136C mutation to HSPG leads to an excess of BMP signaling and underlies the SYM1 and conductive hearing loss phenotype of carriers.

Restoration of the central slip in congenital form of boutonniere deformity: case report.

We present a case of a congenital form of a boutonniere deformity involving both little fingers with a poorly differentiated extensor mechanism and the absence of the tendinous attachment on the dorsal aspect of the middle phalanx. This complex deformity was evaluated histologically followed by successful reconstruction of the central slip.

Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis.

The secreted polypeptide noggin (encoded by the Nog gene) binds and inactivates members of the transforming growth factor beta superfamily of signalling proteins (TGFbeta-FMs), such as BMP4 (ref. 1). By diffusing through extracellular matrices more efficiently than TGFbeta-FMs, noggin may have a principal role in creating morphogenic gradients. During mouse embryogenesis, Nog is expressed at multiple sites, including developing bones. Nog-/- mice die at birth from multiple defects that include bony fusion of the appendicular skeleton. We have identified five dominant human NOG mutations in unrelated families segregating proximal symphalangism (SYM1; OMIM 185800) and a de novo mutation in a patient with unaffected parents. We also found a dominant NOG mutation in a family segregating multiple synostoses syndrome (SYNS1; OMIM 186500); both SYM1 and SYNS1 have multiple joint fusion as their principal feature. All seven NOG mutations alter evolutionarily conserved amino acid residues. The findings reported here confirm that NOG is essential for joint formation and suggest that NOG requirements during skeletogenesis differ between species and between specific skeletal elements within species.

Mutations in the NOG gene are commonly found in congenital stapes ankylosis with symphalangism, but not in otosclerosis.

Human noggin (NOG) is a responsible gene for multiple synostosis syndrome (SYNS1) and proximal symphalangism (SYM1), two conditions that are recently known to be within a wider range of clinical manifestations of stapes ankylosis with symphalangism. This study was performed to determine the range of phenotype caused by NOG mutations, using Japanese patients with various phenotypes including sporadic inherited SYM1, dominantly inherited SYM1, stapes ankylosis with broad thumb and toes (Teunissen and Cremer syndrome). In addition, 33 patients with typical otosclerosis (without symphalangism) were studied. Direct sequencing analysis disclosed three novel mutations of the NOG gene in three SYM1 families. None of the otosclerosis patients without symphalangism had NOG mutations, indicating that NOG mutations may be restrictively found within patients with various skeletal abnormalities. These results together with the literature review indicated that there are no clear genotype-phenotype correlations for NOG mutations. With regard to surgical outcome, most of the patients in these three families with NOG mutations showed remarkable air-bone gap recovery after stapes surgery. Molecular genetic testing is useful to differentiate syndromic stapes ankylosis from otosclerosis, and even mild skeletal anomalies can be a diagnostic indicator of NOG-associated disease.

Who was Pontormo's Halberdier? The evidence from pathology.

The identity of the young man in Jacopo Pontormo's Portrait of a Halberdier has long been disputed by art historians. Two probable candidates have been identified: Francesco Guardi, a Florentine nobleman, and Cosimo I de' Medici, Duke of Florence from 1537 and Grand Duke of Tuscany from 1569. The present study is intended to help resolve this controversy by providing evidence, based on pathological criteria, for the identification of Pontormo's Halberdier. Pathological anomalies of the finger joints in the left hand of the Halberdier are compared with those in three acknowledged portraits of Cosimo I de' Medici. These three portraits show the hands of Cosimo in approximately the same position as the Halberdier's hand, thus allowing a meaningful comparison. Detailed observation indicates that there is a close correspondence between the Halberdier's hand deformity and that of Cosimo I in the comparison portraits. This deformity is also consistent with what is known about the medical history of Cosimo I and with the skeletal remains of his left hand. The pathological evidence supports the conclusion that Pontormo's Halberdier is Cosimo I as a young man and that the painting was done around 1537 when Cosimo first became Duke.

Foot anomalies and proximal symphalangism.

We report the case of a 2-week-old girl born at term (by vaginal delivery and without antenatal or perinatal events) who was referred as having "bilateral talipes and bilateral proximal symphalangism of little and ring fingers." The "talipes" was atypical with marked equinus and varus, but no cavus or adductus of the midfoot. Her mother had both symphalangism (absence of proximal interphalangeal joints) of middle, ring, and little fingers bilaterally and fixed pes planus with a rigid fixed hindfoot-and these deformities had also been present from birth. The maternal grandmother was similarly affected. However, the neonatal subject has an unaffected older sibling; maternal siblings are also unaffected. The three affected people did not have other obvious musculoskeletal abnormalities. Because of the coalitions, the child's atypical talipes was managed by a modified Kite's procedure. Symphalangism-coalition syndromes may be associated with conductive deafness because of fusion of the auditory ossicles.

Surgical Treatment of Camptodactyly with Malek Cutaneous Approach and Stepwise Release: A Retrospective Multi-centre Study.

Background: Clinical manifestations of camptodactyly are varied and no official consensus on the etiopathogenesis or best treatment is available. Conservative treatment is generally preferred and, in refractory patients, surgery might be considered. However, reported results of surgery are often unsatisfactory and it is difficult to compare outcomes as different classification systems are adopted. We reported the outcomes of surgical treatment of camptodactyly with the Malek cutaneous approach and stepwise release, assessed using the Siegert classification. Methods: A retrospective analysis of paediatric patients (≥1 and ≤18 years) with congenital camptodactyly refractory to conservative management (flexion contracture >30°), treated with Malek cutaneous approach and stepwise release surgery between June 2009 and June 2019 with at least 1 year of follow-up was performed. Pre- and post-operative clinical and radiographic assessments were evaluated for degrees of flexion contractures and early (<30 days) or late (>30 days) complications were recorded. Results: A total of 59 patients underwent surgery, of whom 38 (64%), including 42 fingers, were enrolled; mean patient age was 8 years (range 1-18). Post-operative mean flexion contracture was significantly improved (p > 0.001) and no infections were recorded. Mean follow-up was 6 years (range 1-10) and proximal interphalangeal joint extension deficits were rated according to Siegert classification as excellent (69%), good (12%), or fair (9.5%) and poor (9.5%). Conclusions: The Malek cutaneous approach and stepwise release of the retracting soft tissues allow prompt evaluation of the anatomical structures involved in the deformity and seem to be an effective surgical correction in the long term. Level of Evidence: Level IV (Therapeutic).

Camptodactyly: a 10-year series.

Camptodactyly is a non-traumatic, painless, non-neurogenic flexion deformity at the proximal interphalangeal joint of the little finger, which may occur in isolation or in various developmental dysmorphology syndromes. In a ten-year survey of almost 10,000 consecutive neurology outpatient referrals, using a passive case finding strategy, camptodactyly was observed with a frequency of 0.43%. All were cases of isolated camptodactyly, and all but one were asymptomatic. Camptodactyly was more often bilateral, often asymmetric, than unilateral. A family history was common, sometimes with intrafamilial heterogeneity (symmetry, degree of angulation). The pattern of inheritance was not certain, but the predominance of female cases (both directly observed and reported in families) and a paucity of father-to-daughter cases suggested the possibility of either sex-linked dominant transmission or mitochondrial DNA point mutation. There was no evidence for aminoaciduria or taurinuria, as previously reported in some cases. Hence, camptodactyly is relatively common as an incidental finding in patients referred to general neurological outpatient clinics, and thus possibly also in the general population. It is possible that camptodactyly is a heterogeneous disorder. Further studies are required to ascertain whether this is the case, and to probe further the inheritance and pathogenesis of the disorder.

Delayed-Onset NOG Gene-Related Syndromic Conductive Deafness: A Case Report.

We report a 6-year-old girl with progressive bilateral conductive hearing loss for 2 years. She passed the newborn hearing screening conducted with otoacoustic emissions testing and had a normal development of speech and language, which indicated that her deafness was delayed-onset. She also had congenital proximal interphalangeal joints. Proximal symphalangism was confirmed by genetic testing (NOG gene: c.406C > T, p.R136C). Bilateral stapes ankyloses were proved by surgery and her hearing was improved after stapedotomy by over 30 dB. Besides, this case should remind clinicians to carefully distinguish NOG gene-related deafness from congenital ossicular malformation and pediatric otosclerosis.

Design of splints based on the NiTi alloy for the correction of joint deformities in the fingers.

BACKGROUND: The proximal interphalange joint (PIP) is fundamental for the functional nature of the hand. The contracture in flexion of the PIP, secondary to traumatisms or illnesses leads to an important functional loss. The use of correcting splints is the common procedure for treating this problem. Its functioning is based on the application of a small load and a prolonged stress which can be dynamic, static progressive or static serial.It is important that the therapist has a splint available which can release a constant and sufficient force to correct the contracture in flexion. Nowadays NiTi is commonly used in bio-engineering, due to its superelastical characteristics. The experience of the authors in the design of other devices based on the NiTi alloy, makes it possible to carry out a new design in this work--the production of a finger splint for the treatment of the contracture in flexion of the PIP joint. METHODS: Commercial orthosis have been characterized using a universal INSTRON 5565 machine. A computational simulation of the proposed design has been conducted, reproducing its performance and using a model "ad hoc" for the NiTi material. Once the parameters have been adjusted, the design is validated using the same type of test as those carried out on commercial orthosis. RESULTS AND DISCUSSION: For commercial splint the recovering force falls to excessively low values as the angle increases. Angle curves for different lengths and thicknesses of the proposed design have been obtained, with a practically constant recovering force value over a wide range of angles that vary between 30° and 150° in every case. Then the whole treatment is possible with only one splint, and without the need of progressive replacements as the joint recovers. CONCLUSIONS: A new model of splint based on NiTi alloy has been designed, simulated and tested comparing its behaviour with two of the most regularly used splints. Its uses is recommended instead of other dynamic orthosis used in orthopaedics for the PIP joint. Besides, its extremely simple design, makes its manufacture and use on the part of the specialist easier.

Effect of passive stretching on simple camptodactyly in children younger than three years of age.

PURPOSE: To present the effectiveness of passive stretching as a treatment for camptodactyly, without any other form of physiotherapy or splinting. METHODS: From May 2003 to August 2008, 61 digits of 22 patients were treated conservatively using passive stretching exercises. All children were less than 3 years old and had no other anomalies. Flexion contractures before and after treatment in mild, moderate, and severe groups were measured and changes were analyzed statistically. The correlations between various clinical factors and treatment outcome were also analyzed statistically. The average follow-up period was 26 months (range, 12-47 mo). RESULTS: Mean flexion contracture improved from 20° to 1° in the mild group (p < .001), from 39° to 12° in the moderate group (p < .001), and from 75° to 28° in the severe group (p < .001). Of the clinical factors examined, only initial flexion contracture was found to be significantly correlated with treatment outcome (r = -0.287, p = .0025). CONCLUSIONS: Passive stretching can effectively improve flexion deformity in camptodactyly in infants and young children. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

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 digit camptodactyly caused by anomalous ulnar sided flexor digitorum superficialis insertions.

We report an anomalous insertion of the flexor digitorum superficialis (FDS) tendon causing multiple digit camptodactyly. The abnormal tendon was present in the ring and middle fingers, passing from the FDS tendon (proximal to the proximal interphalangeal-PIP-joint) to the extensor expansion (distal to the PIP joint). It was present on the ulnar aspect only, with no corresponding structure on the radial side. Division of the anomalous insertion corrected the fixed flexion deformity at the PIP joint. This anomaly has not been reported in clinical or cadaveric studies and could have been overlooked if a volar approach had been used.

Pachydermatodactyly mimics polyarticular juvenile idiopathic arthritis.

Pachydermatodactyly is an infrequently recognized disorder characterized by painless swelling of the soft tissues around the proximal interphalangeal joints. We report 2 cases erroneously diagnosed as polyarticular juvenile idiopathic arthritis, then referred to pediatric rheumatology for further assessment because of lack of improvement after initial treatment.