Measurement of compensatory wrist joint rotation using three-dimensional motion analysis in patients with unilateral proximal congenital radioulnar synostosis.

OBJECTIVE: This study aims to investigate compensatory rotational movements of the wrist joint in patients with proximal congenital radioulnar synostosis (CRUS), using a valid and reliable three-dimensional (3D) motion analysis technique. METHODS: A total of 26 patients (6 females, 14 males; mean age=15.3 years; and age range=6-32 years) who were diagnosed with unilateral proximal CRUS but were not operated were enrolled in this study. Patients were then categorized into 2 groups: Group I included 5 patients younger than 10 years, and Group II included 15 patients older than 10 years. Eighteen light-reflective skin markers were placed on the bony landmarks of both upper limbs, and both distal forearms were fixed using a U-shaped device to minimize forearm rotation. Each patient grasped the handle of an instrument that used a goniometer to measure wrist rotation; maximal passive pronation and supination angles of the wrist were measured in this manner and also using 3D motion analysis. RESULTS: There was a significant correlation between measurements by the goniometer and 3D motion analysis (r=0.985, p<0.001). The test-retest reliability of the 3D motion analysis was acceptable for both the affected side (ICC=0.992) and the contralateral normal side (ICC=0.997) with low standard measurement errors (1.3° and 0.8°, respectively). Although no significant difference was observed in the range of the wrist rotation between the affected and contralateral sides in Group I (p=0.686), there was a significant difference in the wrist rotation between the affected and contralateral sides in Group II (p=0.001). Further, the pronation angle of the wrist joint was significantly larger in the affected side than that in the contralateral normal side in Group II (p=0.001). CONCLUSION: The 3D motion analysis technique seems to be a valid and reliable method to measure the rotation of the wrist joint. Unilateral proximal CRUS patients older than 10 years of age may develop rotational hypermobility of the wrist joint compared to the contralateral normal side as a compensatory phenomenon. LEVEL OF EVIDENCE: Level III, Diagnostic Study.

Musculoskeletal abnormalities in a large international cohort of boys with 49,XXXXY.

49,XXXXY is the rarest X and Y chromosomal variation, with an incidence of 1 in 80,000-100,000 live male births and has been associated with numerous musculoskeletal abnormalities. Data was collected from an international cohort of boys with 49,XXXXY over 10 years. Children were evaluated by a multidisciplinary team consisting of a pediatric orthopedist, a neurogeneticist, a neurodevelopmentalist, and two physical therapists. Increased rates of torticollis (32.4%), hamstring tightness (42%), radioulnar synostosis (67.6%), pes planus (65.2%), and other foot abnormalities (86.9%) were observed. Several anomalies increased with age, specifically hamstring tightness, kyphosis, and scoliosis. The elucidation of the orthopedic profile of this population is necessary in order to provide healthcare providers with current medical information. This research further supports the necessity for the comprehensive multidisciplinary treatment of boys with 49,XXXXY.

A novel frameshift variant in BHLHA9 underlies mesoaxial synostotic syndactyly associated with postaxial polydactyly.

Mesoaxial synostotic syndactyly (MSSD) with phalangeal reduction is an uncommon congenital limb abnormality characterized by central osseous synostosis at a metacarpal level, mesoaxial reduction of the fingers, and preaxial cutaneous syndactyly in toes. In rare cases, the disease is also associated with fifth finger clinodactyly and postaxial polydactyly. It has autosomal recessive inheritance pattern caused by homozygous variants in the gene BHLHA9 mapped at chromosome 17p13.3. In the present study, a consanguineous family of Pakistani origin segregating MSSD in autosomal recessive form was characterized at clinical and genetic levels. Clinically, the diseased individuals have MSSD associated with clinodactyly and polydactyly. Homozygosity mapping followed by Sanger sequencing of BHLHA9 revealed a novel frameshift variant NM_001164405.1: c.409-409delC; p.(His137Thrfs*61) segregating with the disease phenotypes in the family. This is the second report providing evidence of association of polydactyly with MSSD caused by frameshift variant in the gene BHLHA9. The present molecular investigation will support genetic counselling of the local population carrying diseased variants.

Union Rates and Reported Range of Motion Are Acceptable After Open Forearm Fractures in Military Combatants.

BACKGROUND: High-energy open forearm fractures are unique injuries frequently complicated by neurovascular and soft tissue injuries. Few studies have evaluated the factors associated with nonunion and loss of motion after these injuries, particularly in the setting of blast injuries. QUESTIONS/PURPOSES: (1) In military service members with high-energy open forearm fractures, what proportion achieved primary or secondary union? (2) What is the pronation-supination arc of motion as stratified by the presence or absence of heterotopic ossification (HO) and synostosis? (3) What are the risks of heterotopic ossification and synostosis? (4) What factors may be associated with forearm fracture nonunion? METHODS: A retrospective study of all open forearm fractures treated at a tertiary military referral center from January 2004 to December 2014 was performed. In all, 76 patients were identified and three were excluded, leaving 73 patients for inclusion. All 73 patients had serial radiographs to assess for HO and union. Only 64 patients had rotational range of motion (ROM) data. All patients returned to the operating room at least once after initial irrigation and débridement to ensure the soft tissue envelope was stable before definitive fixation. The indication for repeat irrigation and débridement was determined by clinical appearance. Patient demographics, fracture and soft tissue injury patterns, surgical treatments, neurovascular status at the time of injury, incidence of infection, heterotopic ossification (defined as the presence of heterotopic bone visible on serial radiographs), radioulnar synostosis, bony status after initial definitive treatment (union, nonunion, or amputation), and forearm rotation at final followup were retrospectively obtained from chart review by someone other than the operating surgeon. Seventy-six open forearm fractures in 76 patients were reviewed; 73 patients were examined for osseous union as three went on to early amputation, and 64 patients had forearm ROM data available for analysis. Union was determined by earliest radiology or orthopaedic staff official dictation stating the fracture was healed. Nonunion was defined as the clinical determination by the orthopaedist for a repeat procedure to achieve bony union. Secondary union was defined as union after reoperation to achieve bony union, and final union was defined as overall percentage of patients who were healed at final followup. Of the patients analyzed for union, 20 had less than 1 year of followup, and of these, none had nonunion. Of the patients analyzed for ROM, eight patients had less than 6 months of followup (range, 84-176 days). Of these, one patient had decreased ROM, none had a synostosis, and the remaining had > 140° of motion. RESULTS: Initial treatment resulted in primary union in 62 of 73 patients (85%); secondary union was achieved in eight of 11 patients (73%); and final union was achieved in 70 of 73 patients (96%). Although pronation-supination arc in patients without HO was 140° ± 35°, a limited pronation-supination arc was primarily associated with synostosis (arc: 40° ± 40°; mean difference from patients without HO: 103° [95% confidence interval {CI}, 77°-129°], p < 0.001); patients with HO but without synostosis had fewer limitations to ROM than those with synostosis (arc: 110° ± 80°, mean difference: 77° [35°-119°], p < 0.001). Heterotopic ossification developed in 40 of 73 patients (55%), including a radioulnar synostosis in 14 patients (19%). Bone loss at the fracture site (relative risk (RR) 6.2; 95% CI, 1.8-21) and healing complicated by infection (RR, 9.9; 95% CI, 4.9-20) were associated with the development of nonunion after initial treatment. Other potential factors such as smoking status, vascular injury, both-bone involvement, need for free flap coverage and blast mechanism were not associated. CONCLUSIONS: Despite a high-energy mechanism of injury and high rate of soft tissue defects, the ultimate probability of fracture union in our series was high with a low infection risk. Nonunions were associated with bone loss and deep infection. Functional motion was achieved in most patients despite increased burden of HO and synostosis compared with civilian populations. However, if synostosis did not develop, HO itself did not appear to interfere with functional ROM. Future investigations may provide improved decision-making tools for timing of fixation and prophylactic means against HO synostosis. LEVEL OF EVIDENCE: Level III, therapeutic study.

Long-term results after simple rotational osteotomy of the radius shaft for congenital radioulnar synostosis.

BACKGROUND: The present study was conducted to clarify the long-term (≥10 years) results of simple rotational osteotomy for congenital radioulnar synostosis (CRUS). METHODS: Twelve forearms in 9 Asian patients with CRUS who underwent simple rotational osteotomy of the radius shaft were monitored for an average of 13.6 years (range, 10-19 years) postoperatively. Before surgery, the forearm fixation averaged 51.3° of pronation (range, 30°-90°). The true position of the forearm in ankylosis was measured by a line through the styloid processes of the radius and the ulna. Palm pronation and supination angles were also measured. The osteotomy was performed at the insertion of the pronator teres to the shaft of the radius. The pronation position was then corrected manually to allow 90° of palm supination with compensatory rotation around the wrist, and a cast was applied. We evaluated activities of daily living items at a mean of 5.2 years after surgery. At the final follow-up, the 11-item version of the Disability of the Arm, Shoulder and Hand score was recorded. RESULTS: After surgery, the forearm was fixed at an average of 4.2° of supination. At the final follow-up, the palm was able to achieve an average motion arc ranging from 26° of pronation to 62° of supination. There were no neurologic or circulatory complications after surgery. Ability to perform daily activities was markedly improved, and all patients were satisfied with the results of surgery. The average score on the 11-item version of the Disability of the Arm, Shoulder, and Hand was 3.79 points at the final follow-up. CONCLUSION: Our procedure for forearm rotation in patients with CRUS is simple, reliable, satisfactory, and safe.

Linked homozygous BMPR1B and PDHA2 variants in a consanguineous family with complex digit malformation and male infertility.

In affected members of a consanguineous family, a syndrome, which is concurrence of set of medical signs, is often observed and commonly assumed to have arisen from pleiotropy, i.e., the phenomenon of a single gene variant affecting multiple traits. We detected six sibs afflicted with a unique combination of digit malformation that includes brachydactyly, symphalangism and zygodactyly plus infertility in males owing to azoospermia, sperm immotility or necrospermia, which we hypothesised to have arisen from a defect in a single gene. We mapped the disease locus and by exome sequencing identified in patients homozygous missense variants bone morphogenetic protein receptor type IB (BMPR1B) c.640C>T (p.(Arg214Cys)) and alpha-2 pyruvate dehydrogenase (PDHA2) c.679A>G (p.(Met227Val)). Structural protein modelling, protein sequence conservation and in silico analysis indicate that both variants affect protein function. BMPR1B is known to be responsible for autosomal dominant brachydactyly and autosomal recessive acromesomelic chondrodysplasia. Our findings show that also recessive complex digit malformation can be caused by BMPR1B variant and not all biallelic BMPR1B variants cause acromesomelic dysplasia. PDHA2 is a novel candidate gene for male infertility; the protein product is a mitochondrial enzyme with highest expression in ejaculated sperm. Our findings are a unique example of two linked variants, ~ 711 Kb apart, in different genes that together manifest as a novel syndrome. They demonstrate that exome sequencing and not candidate gene approach should be employed in disease gene hunt, defining new diseases and genetic testing, to rule out the coincidental presence of two variants contributing together to the phenotype, which may be discerned as a novel disease.

Three-dimensional analysis of deformities of the radius and ulna in congenital proximal radioulnar synostosis.

We reconstructed three-dimensional images of radius and ulna in 38 forearms of 25 patients with congenital proximal radioulnar synostosis from their computed tomographic studies. We also analysed correlations between the deformities of radius and ulna and degrees of fixed pronation of these forearms. The average ulnar deviation, flexion and internal rotation deformities of the radius were 6°, 3° and 18°, respectively. The average radial deviation, extension and internal rotation deformities of the ulna were 3°, 4° and 30°, respectively. The flexion deformity of the radius and the internal rotation deformity of the radius and ulna were correlated significantly with degree of fixed pronation. We conclude that the patients with congenital proximal radioulnar synostosis have remarkable flexion deformity of the radius and internal rotation deformity of the radius and ulna, which might impede forearm rotation after corrective surgery in the proximal part of the forearm.

A point mutation in Fgf9 impedes joint interzone formation leading to multiple synostoses syndrome.

Human multiple synostoses syndrome (SYNS) is an autosomal dominant disorder characterized by multiple joint fusions. We previously identified a point mutation (S99N) in FGF9 that causes human SYNS3. However, the physiological function of FGF9 during joint development and comprehensive molecular portraits of SYNS3 remain elusive. Here, we report that mice harboring the S99N mutation in Fgf9 develop the curly tail phenotype and partially or fully fused caudal vertebrae and limb joints, which mimic the major phenotypes of SYNS3 patients. Further study reveals that the S99N mutation in Fgf9 disrupts joint interzone formation by affecting the chondrogenic differentiation of mesenchymal cells at the early stage of joint development. Consistently, the limb bud micromass culture (LBMMC) assay shows that Fgf9 inhibits mesenchymal cell differentiation into chondrocytes by downregulating the expression of Sox6 and Sox9. However, the mutant protein does not exhibit the same inhibitory effect. We also show that Fgf9 is required for normal expression of Gdf5 in the prospective elbow and knee joints through its activation of Gdf5 promoter activity. Signal transduction assays indicate that the S99N mutation diminishes FGF signaling in developmental limb joints. Finally, we demonstrate that the conformational change in FGF9 resulting from the S99N mutation disrupts FGF9/FGFR/heparin interaction, which impedes FGF signaling in developmental joints. Taken together, we conclude that the S99N mutation in Fgf9 causes SYNS3 via the disturbance of joint interzone formation. These results further implicate the crucial role of Fgf9 during embryonic joint development.

Analysis of complications after a floating elbow injury.

BACKGROUND: The aim of the present study is to analyse complications after a floating elbow injury, attempting to establish which of them act as a poor prognosis factor regarding clinical and functional results. MATERIALS AND METHODS: Twenty-three patients who suffered a floating elbow injury, treated at our institution from 2004 to 2013, were retrospectively reviewed. Patients were divided into four groups depending on the type of injury. An analysis of demographic data, associated injuries, treatment options and complications was carried out. Clinical evaluation was made by a conventional goniometer, testing flexo-extension and prono-supination ranges. For functional evaluation, the Mayo Elbow Performance Score was employed. Association between radioulnar synostosis, articular surface disruption, nerve injury and clinical and functional results was analysed. RESULTS: Patients with radioulnar synostosis had worse results in functional evaluation than patients without it (56.6 vs. 75); this difference was statistically significant (p = 0.05). Regarding intra-articular extension, we found statistical association with worse results in functional evaluation (p = 0.018); however, nerve palsy does not seem to influence functional results. CONCLUSIONS: Radioulnar synostosis and intra-articular extension of the injury are poor prognosis factor in floating elbow.

A novel missense mutation, p.(R102W) in WNT7A causes Al-Awadi Raas-Rothschild syndrome in a fetus.

Al-Awadi-Raas-Rothschild syndrome (AARRS) is a rare autosomal recessive disorder which consists of severe malformations of the upper and lower limbs, abnormal genitalia and underdeveloped pelvis. Here, we present a fetus with severe limbs defects, including bilateral humeroradial synostosis, bilateral oligodactyly in hands, underdeveloped pelvis, short femora and tibiae, absence of fibulae, severely small feet, and absence of uterus. An autosomal recessively inherited novel mutation in WNT7A found in the fetus, c.304C > T, affects an evolutionarily well-conserved amino acid, causing the p.(R102W) missense change at protein level. The findings presented in this fetus are compatible with diagnosis of AARRS, expanding the mutational spectrum of limb malformations arising from defects in WNT7A.

Long-term results after a free vascularized adipofascial graft for congenital proximal radioulnar synostosis with an average follow-up of 10 years: a series of four cases.

BACKGROUND: The aim of this study was to observe the long-term and chronologic changes in clinical and radiologic findings after a free vascularized adipofascial graft interposition with radial osteotomy for congenital proximal radioulnar synostosis (PRUS). METHODS: Six forearms in 4 patients with congenital PRUS who underwent a free vascularized adipofascial graft interposition combined with radial osteotomy were followed up for an average of 10 years (8-12 years) postoperatively. Extension and flexion angles of the elbow and pronation and supination angles of the forearm as well as radiographs were evaluated preoperatively and throughout the postoperative follow-up period. RESULTS: The average extension/flexion angles of the elbow and the average pronation/supination angles of the forearm were 3°/130° and 14°/- before surgery, -4°/135° and 39°/23° at 1 year after surgery, 6°/138° and 44°/30° at 3 years after surgery, and -2°/139° and 35°/7° at the time of the final follow-up, respectively. Final radiographs showed hypertrophy of the radial head in 4 patients, dislocation of the radial head in 2 patients, and deformity of the radial head in 1 patient. CONCLUSIONS: Extension and flexion angles of the elbow in patients with congenital PRUS were constant and the average range of pronation was relatively well maintained throughout the postoperative period, but the average range of supination decreased by 16° from 1 year postoperatively to the time of the final follow-up.

Calcaneonavicular Coalition with Naviculocuneiform and Cuneiform-First Metatarsal Coalitions A Case Report.

Coalitions involving three joints of the midfoot are rare. To our knowledge, this is the first report of a patient having fibrocartilaginous coalition of the calcaneonavicular joint along with partial osseous fusion of the naviculocuneiform (Chopart's joint) and medial cuneiform-first metatarsal joints. These multi-coalition pathologies are challenging to address operatively as pain can persist even after recognizing and surgically addressing each coalition in a patient.

Safety and Efficacy of Derotational Osteotomy for Congenital Radioulnar Synostosis.

BACKGROUND: Congenital radioulnar synostosis (CRUS) refers to an abnormal connection between the radius and ulna due to embryological failure of separation. Derotational osteotomy has been advocated for children with functional limitations, although historically this procedure has been associated with a 36% complication rate including compartment syndrome and loss of correction. METHODS: A retrospective evaluation of consecutive patients who underwent derotational osteotomy for CRUS at a single institution was performed. Children with functional limitations secondary to excessive pronation were indicated for surgery with a goal of correction to 10 to 20 degrees of pronation. All patients were treated with a standardized surgical technique including careful subperiosteal elevation, rotational osteotomy at the level of the synostosis, control of the osteotomy fragments, appropriate pinning techniques, and prophylactic forearm fasciotomies. Electronic medical records, preoperative radiographs, and postoperative radiographs were reviewed. RESULTS: Derotational osteotomy was performed in 31 forearms in 26 children (13 bilateral, 13 unilateral) with a mean age of 6.8 years (range, 3.0 to 18.8 y). The mean clinical follow-up was 46 months (range, 6 to 148 mo). The mean preoperative pronation deformity was 85 degrees (range, 60 to 100 degrees). The mean correction achieved was 77 degrees (range, 40 to 95 degrees), resulting in a mean final position of 8 degrees of pronation (range, 0 to 30 degrees). All patients successfully achieved union by 8 weeks postoperatively. There were no cases of compartment syndrome, vascular compromise, or loss of fixation. The overall complication rate was 12% (2 transient anterior interosseous nerve palsies, 1 transient radial nerve palsy, 1 symptomatic muscle herniation). Both transient anterior interosseous nerve palsies occurred in patients with rotational corrections exceeding 80 degrees. CONCLUSIONS: Derotational osteotomy can be safely and effectively performed in children with CRUS. Meticulous surgical technique, including control of the osteotomy, judicious pin fixation, and prophylactic fasiotomies, may diminish the risk of neurovascular compromise and loss of correction. Transient anterior interosseous nerve palsies occurred, and may be related to large rotational corrections.

A family of distal arthrogryposis type 5 due to a novel PIEZO2 mutation.

Distal arthrogryposis (DA) encompasses a heterogeneous group of hereditary disorders with multiple congenital contractures predominant in the distal extremities. A total of 10 subtypes are proposed based on the pattern of contractures and association with extraarticular symptoms. DA5 is defined as a subtype with ptosis/oculomotor limitation. However, affected individuals have a variety of non-ocular features as well. We report on a two-generation family, including four affected individuals who all had congenital contractures of the distal joints, ptosis, restricted ocular movements, distinct facial appearance with deep-set eyes, and shortening of the 1st and 5th toes. The proband and her affected mother had restrictive lung disease, a recently recognized syndromic component of DA5, while younger patients did not. The proband had metacarpal and metatarsal synostosis, and the mother showed excavation of the optic disk. Whole-exome sequencing revealed a novel heterozygous mutation c.4456G>C (p.A1486P) of PIEZO2. PIEZO2 encodes a mechanosensitive ion channel, malfunction of which provides pleiotropic effects on joints, ocular muscles, lung function, and bone development.

Improved bone defect healing by a superagonistic GDF5 variant derived from a patient with multiple synostoses syndrome.

Multiple synostoses syndrome 2 (SYNS2) is a rare genetic disease characterized by multiple fusions of the joints of the extremities, like phalangeal joints, carpal and tarsal joints or the knee and elbows. SYNS2 is caused by point mutations in the Growth and Differentiation Factor 5 (GDF5), which plays an essential role during skeletal development and regeneration. We selected one of the SYNS2-causing GDF5 mutations, p.N445T, which is known to destabilize the interaction with the Bone Morphogenetic Protein (BMP) antagonist NOGGIN (NOG), in order to generate the superagonistic GDF5 variant GDF5(N445T). In this study, we tested its capacity to support regeneration in a rat critical-sized defect model in vivo. MicroCT and histological analyses indicate that GDF5(N445T)-treated defects show faster and more efficient healing compared to GDF5 wild type (GDF5(wt))-treated defects. Microarray-based gene expression and quantitative PCR analyses from callus tissue point to a specific acceleration of the early phases of bone healing, comprising the inflammation and chondrogenesis phase. These results support the concept that disease-deduced growth factor variants are promising lead structures for novel therapeutics with improved clinical activities.

Proximal radial diaphyseal segment resection for posttraumatic proximal radioulnar synostosis: a prospective study of 15 cases.

BACKGROUND: Proximal radioulnar synostosis is a complication after elbow injuries. Various treatment methods have been reported and are associated with unpredictable outcomes. In a prospective study, we evaluated the medium-term effects of proximal radial resection on wrist and elbow function and forearm rotation in 15 cases. METHODS: We treated 15 patients with posttraumatic proximal radioulnar synostosis by resection of 1 cm of the proximal radial diaphysis. On the preoperative examination and last follow-up, the Mayo Elbow Performance Score, grip force, visual analog scale for elbow and wrist score, radiographic ulnar variance changes, and elbow range of motion were measured. The Disabilities of the Arm, Shoulder, and Hand (QuickDASH) score and the general satisfaction of the patients were assessed at the final follow-up. RESULTS: The mean duration of follow-up was 31 ± 13 months. The mean active postoperative supination/pronation arc was 101° ± 45°. The mean increase measured in the ulnar variance at the final follow-up was 3.3 ± 1.5 mm (P = .02). The mean final QuickDASH score was 13.3 ± 12.1. The preoperative and final Mayo scores were 57 ± 10 and 91 ± 7, respectively (P = .01). The general satisfaction with the results of the operation was 86.6%. CONCLUSIONS: We suggest that proximal radial resection for the treatment of posttraumatic proximal radioulnar synostosis shows acceptable results in adults regarding the recovery of range of motion and patient satisfaction. This technique might be considered as a salvage procedure, particularly in cases with previous failed heterotopic resection at the proximal radioulnar joint, resulting in disturbed anatomy. LEVEL OF EVIDENCE: Level IV, case series, treatment study.

A GDF5 point mutation strikes twice--causing BDA1 and SYNS2.

Growth and Differentiation Factor 5 (GDF5) is a secreted growth factor that belongs to the Bone Morphogenetic Protein (BMP) family and plays a pivotal role during limb development. GDF5 is a susceptibility gene for osteoarthritis (OA) and mutations in GDF5 are associated with a wide variety of skeletal malformations ranging from complex syndromes such as acromesomelic chondrodysplasias to isolated forms of brachydactylies or multiple synostoses syndrome 2 (SYNS2). Here, we report on a family with an autosomal dominant inherited combination of SYNS2 and additional brachydactyly type A1 (BDA1) caused by a single point mutation in GDF5 (p.W414R). Functional studies, including chondrogenesis assays with primary mesenchymal cells, luciferase reporter gene assays and Surface Plasmon Resonance analysis, of the GDF5(W414R) variant in comparison to other GDF5 mutations associated with isolated BDA1 (p.R399C) or SYNS2 (p.E491K) revealed a dual pathomechanism characterized by a gain- and loss-of-function at the same time. On the one hand insensitivity to the main GDF5 antagonist NOGGIN (NOG) leads to a GDF5 gain of function and subsequent SYNS2 phenotype. Whereas on the other hand, a reduced signaling activity, specifically via the BMP receptor type IA (BMPR1A), is likely responsible for the BDA1 phenotype. These results demonstrate that one mutation in the overlapping interface of antagonist and receptor binding site in GDF5 can lead to a GDF5 variant with pathophysiological relevance for both, BDA1 and SYNS2 development. Consequently, our study assembles another part of the molecular puzzle of how loss and gain of function mutations in GDF5 affect bone development in hands and feet resulting in specific types of brachydactyly and SYNS2. These novel insights into the biology of GDF5 might also provide further clues on the pathophysiology of OA.

Inherited thrombocytopenias: an approach to diagnosis and management.

Inherited thrombocytopenias vary in their presentation, associated features, and molecular etiologies. An accurate diagnosis is important to provide appropriate therapy as well as counseling for the individual and their family members. As the genetic basis of more disorders is understood, it will be possible to diagnose a greater fraction of patients as well as learn more about the process of megakaryopoiesis and platelet production.